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1
Gignac, G. A., M. J. Morris, G. Heller, and H. I. Scher. "A model assessing how variable timing of outcome assessments impacts progression-free survival (PFS)." Journal of Clinical Oncology 25, no. 18_suppl (2007): 5130. http://dx.doi.org/10.1200/jco.2007.25.18_suppl.5130.
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5130 Background: PFS has been proposed as an endpoint in prostate cancer because tumor regression cannot be assessed easily and the significance of post-therapy changes in PSA is uncertain. There is significant variability in the frequency by which outcomes are assessed across clinical trials. We sought to create a model that would define the degree of error in estimating PFS from this variability. Methods: A simulation experiment was performed. An exponential distribution was used to generate 100 progression times for 3 hypothetical risk cohorts: rapid (median PFS of 18 wks), intermediate (36 wks) and slow progressors (72 wks). We examined how reported PFS would change depending on 3 assessment schedules: every (q) 6, 8 and 12 wks for 48 wks each, then q6 months for 2 years. The logrank statistic was used to compare PFS between schedules. If different schedules have no impact the expected type 1 error rate should be 5% (where a difference in PFS time is detected when none existed). Each simulation was repeated 1000 times. Results: Nine pairwise comparisons were performed and Kaplan-Meier PFS estimates created for the 3 assessment schedules and 3 risk cohorts (see table 1 ). In the highest risk cohort, PFS of 18 wks, 38% of the time the logrank test showed a falsely prolonged PFS for pts assessed on the q12 vs 6 wks schedule. This type 1 error rate (by simulation) was reduced to 20% and 11%, when the schedules were q8 vs 12 wks and q6 vs 8 wks, respectively, but remained above the 5% expected rate for type 1 error. For lower risk pts, PFS of 72 wks, the disparity in PFS times was diminished. Conclusions: Progression free survival is significantly skewed by the schedule of assessing treatment effects in clinical trials. This argues for uniformity in the timing of outcome assessments across trials and between arms in randomized trials. Grant support: 5T32CA09207 [Table: see text] No significant financial relationships to disclose.
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Larrañaga, A., M.C. Lucas-Estañ, S. Lagén, Z. Ali, I. Martinez, and J. Gozalvez. "An open-source implementation and validation of 5G NR configured grant for URLLC in ns-3 5G LENA: A scheduling case study in industry 4.0 scenarios." JOURNAL OF NETWORK AND COMPUTER APPLICATIONS 215 (January 1, 2023): 103638. https://doi.org/10.1016/j.jnca.2023.103638.
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Md. Baniyamuddin and Aziz Khan. "A comparative study on enrolment of scheduled caste and scheduled tribe learners in bachelor of social work programme of IGNOU in Assam before and after implementation of IGNOU fee exemption scheme under SCSP/TSP Grant." International Journal of Science and Research Archive 7, no. 2 (2022): 402–10. http://dx.doi.org/10.30574/ijsra.2022.7.2.0294.
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Education is a very important determinant of overall development of a community or a society. It is the responsibility of a state in democratic country like India to provide equal opportunity of qualitative educational development to all sections of the society. Distance education is mainly focused on democratization of higher education by providing a platform to disadvantageous section of people due to some unavoidable circumstances. It facilitated them; get the hands on training through distance mode without hampering the daily social responsibilities and activities of learners. IGNOU BSW programme is one of the important professional based programme for learners dealing with professional training/degree in Social Work. India’s Northeast region is popularly celebrated for its cultural diversity with sizable number of Schedule Tribe (ST) community as inhabitant of this region. Social Work Education in the Northeast region of India began only in the year 1992. The present study is carried out on 620 learners of BSW programme enrolled at IGNOU RC, Guwahati in last ten years from 2010 to 2019 with an intention to assess the impact of IGNOU fee exemption scheme in admission of Scheduled Caste (SC) and Scheduled Tribe (ST) learners in undergraduate programmes. This will enable us to know and assess the participation/ involvement of SC/ST learners in free admission scheme of IGNOU under SCSP/TSP Grant in Assam by examining their percent shares in annual admission. Apart from that we have also examined the overall general trends of admission on the basis of Area (Urban, Rural & Tribal), Gender, the age profile, and marital status of learners enrolled in this programme. This study is undertaken to determine and access the fulfilment of University’s motto “reaching the unreached” in weaker section and scheduled communities of our society.
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Jain, Nitin, Elias J. Jabbour, Marina Konopleva, et al. "A Phase 1 Trial of Adct-602, a CD22 Targeting Antibody Drug Conjugate Bound to PBD Toxin in Adult Patients with Relapsed or Refractory CD22+ B-Cell Acute Lymphoblastic Leukemia." Blood 138, Supplement 1 (2021): 1237. http://dx.doi.org/10.1182/blood-2021-153141.
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Abstract Introduction: Outcomes of patients (pts) with relapsed or refractory (R/R) B-cell acute lymphoblastic leukemia (B-ALL) remain dismal, with 5-year survival <20%. CD22 is expressed on lymphoblasts in >90% of pts with B-ALL and is an established therapeutic target. ADCT-602 is an antibody drug conjugate composed of a humanized monoclonal antibody directed against CD22 and conjugated to SG3199, a pyrrolobenzodiazepine (PBD) dimer cytotoxin. In preclinical studies, ADCT-602 demonstrated potent anti-tumor activity in mouse models of B-cell malignancies. We present here interim data from an ongoing Phase 1/2 trial evaluating ADCT-602 in pts with R/R B-ALL (NCT03698552). Methods: This is an investigator-initiated Phase 1/2 trial of ADCT-602 monotherapy in pts with R/R B-ALL. The primary objective of the Phase 1 part is to assess the safety and determine the maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D) of ADCT-602. The primary objective of Phase 2 is to evaluate efficacy (CR/CRi rate). Secondary objectives include duration of response (DOR), progression-free survival (PFS) and overall survival (OS), and characterize the pharmacokinetic (PK) profile of ADCT-602. Eligible pts must be ≥18 years of age with R/R B-ALL with bone marrow blasts ≥5%. CD22 must be expressed in ≥20% blasts. Pts must have adequate organ function (creatinine ≤1.5 mg/dL; ALT and AST ≤2 times upper limit of normal (ULN), ≤5 times ULN if there is liver or bone involvement; total bilirubin ≤1.5 times ULN; LVEF ≥45%). In part 1, pts were assigned to treatment according to a 3+3 dose-escalation design. ADCT-602 was initially given IV once every 3 weeks; recently, based on the PK data, the administration schedule was amended to weekly infusions. Results: From November 2018 to June 2021, 14 pts (8 male, 6 female) with B-ALL have been treated with ADCT-602. The median age was 39.5 years (range, 22-82) and pts had received a median of 5 (range, 2-7) prior therapies [inotuzumab ozogamicin 10/14 (71%); blinatumomab 13/14 (93%); venetoclax 10/14 (71%); CD19 CAR 5/14 (36%)]. Seven (7/14, 50%) pts had a prior allogeneic stem cell transplant (allo-SCT), including 3 pts with 2 prior allo-SCT. The median pretreatment bone marrow blasts were 70.5% (range, 16-95). The median CD22 expression on blasts was 90.5% (range, 33.6-99.9). A total of 11 pts were treated in the Q3week schedule [30µg/kg, n=3; 60µg/kg, n=4; 90µg/kg, n=4]. As the PK data (shown below) indicated rapid clearance of the antibody, the trial was amended to allow for weekly dosing and 3 pts have been treated at 30µg/kg weekly dose level. No pt had a DLT. Two pts (one each at 60µg/kg and 90µg/kg every 3 weeks schedule) did not complete the DLT window due to rapid disease progression and were taken off treatment prior to day 28. One pt (in the weekly schedule) had grade 4 thrombocytopenia possibly related to ADCT-602. No pt had veno-occlusive disease. Two pts achieved MRD-negative remission. One pt was 35-year-old with R/R B-ALL (complex karyotype, NRAS mutation) with several prior lines of therapy (HCVAD, pegasparaginase-based therapy, allo-SCT, inotuzumab, POMP). Baseline bone marrow blasts were 87% with 99.9% CD22 expression. Pt received ADCT-602 at 30µg/kg Q3week schedule and achieved MRD negative CRp after Cycle 1 which improved to MRD negative CR after Cycle 2. He received a total of 6 cycles of ADCT-602 before transitioning to second allo-SCT. Another pt was 22-year-old with R/R B-ALL (complex karyotype) with multiple prior therapies (including 2 prior allo-SCT, CD19 CAR-T, inotuzumab, blinatumomab, pegasparaginase, venetoclax) received ADCT-602 at 30µg/kg weekly schedule. Baseline bone marrow blasts were 24% with 97% CD22 expression. Pt achieved MRD negative CRp after Cycle 1 and is currently receiving Cycle 2. PK data, available for 9 pts treated at every 3-week schedule [30 mcg/kg, n=3; 60 mcg/kg, n=4; 90 mcg/kg, n=2] showed rapid clearance of antibody with mean apparent half-life of <1 day during Cycle 1. This supported transitioning ADCT-602 administration to the weekly dosing. Conclusions: In this Phase 1 study in pts with very heavily pretreated R/R B-ALL with a median of 5 prior lines of therapy and high baseline bone marrow tumor burden, single-agent ADCT-602 was well tolerated with no DLTs noted. Two pts achieved MRD-negative remission. Dose escalation in the weekly schedule continues and 2 additional dose levels (40µg/kg weekly and 50µg/kg weekly) are planned. Disclosures Jain: Aprea Therapeutics: Research Funding; Janssen: Honoraria; ADC Therapeutics: Honoraria, Research Funding; TG Therapeutics: Honoraria; Incyte: Research Funding; Cellectis: Honoraria, Research Funding; Beigene: Honoraria; Adaptive Biotechnologies: Honoraria, Research Funding; Servier: Honoraria, Research Funding; Pfizer: Research Funding; Bristol Myers Squibb: Honoraria, Research Funding; AstraZeneca: Honoraria, Research Funding; Genentech: Honoraria, Research Funding; Fate Therapeutics: Research Funding; Precision Biosciences: Honoraria, Research Funding; AbbVie: Honoraria, Research Funding; Pharmacyclics: Research Funding. Jabbour: Amgen, AbbVie, Spectrum, BMS, Takeda, Pfizer, Adaptive, Genentech: Research Funding. Konopleva: Sanofi: Other: grant support, Research Funding; Novartis: Other: research funding pending, Patents & Royalties: intellectual property rights; Calithera: Other: grant support, Research Funding; Ablynx: Other: grant support, Research Funding; AbbVie: Consultancy, Honoraria, Other: Grant Support, Research Funding; Cellectis: Other: grant support; Stemline Therapeutics: Research Funding; Genentech: Consultancy, Honoraria, Other: grant support, Research Funding; Forty Seven: Other: grant support, Research Funding; KisoJi: Research Funding; Reata Pharmaceuticals: Current holder of stock options in a privately-held company, Patents & Royalties: intellectual property rights; Agios: Other: grant support, Research Funding; AstraZeneca: Other: grant support, Research Funding; F. Hoffmann-La Roche: Consultancy, Honoraria, Other: grant support; Ascentage: Other: grant support, Research Funding; Eli Lilly: Patents & Royalties: intellectual property rights, Research Funding; Rafael Pharmaceuticals: Other: grant support, Research Funding. Pemmaraju: Celgene Corporation: Consultancy; LFB Biotechnologies: Consultancy; HemOnc Times/Oncology Times: Membership on an entity's Board of Directors or advisory committees; ASCO Leukemia Advisory Panel: Membership on an entity's Board of Directors or advisory committees; Samus: Other, Research Funding; Novartis Pharmaceuticals: Consultancy, Other: Research Support, Research Funding; Sager Strong Foundation: Other; Plexxicon: Other, Research Funding; Dan's House of Hope: Membership on an entity's Board of Directors or advisory committees; ASH Communications Committee: Membership on an entity's Board of Directors or advisory committees; Abbvie Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other, Research Funding; Stemline Therapeutics, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other, Research Funding; DAVA Oncology: Consultancy; Protagonist Therapeutics, Inc.: Consultancy; Cellectis S.A. ADR: Other, Research Funding; Daiichi Sankyo, Inc.: Other, Research Funding; CareDx, Inc.: Consultancy; Aptitude Health: Consultancy; Springer Science + Business Media: Other; Roche Diagnostics: Consultancy; MustangBio: Consultancy, Other; Incyte: Consultancy; Affymetrix: Consultancy, Research Funding; Clearview Healthcare Partners: Consultancy; Blueprint Medicines: Consultancy; Bristol-Myers Squibb Co.: Consultancy; ImmunoGen, Inc: Consultancy; Pacylex Pharmaceuticals: Consultancy. Thompson: Amgen: Other: Institution: Honoraria, Research Grant/Funding; Gilead: Other: Institution: Advisory/Consultancy, Honoraria; Adaptive Biotechnologies: Other: Institution: Advisory/Consultancy, Honoraria, Research Grant/Funding, Expert Testimony; Genentech: Other: Institution: Advisory/Consultancy, Honoraria, Research Grant/Funding; AbbVie: Other: Institution: Advisory/Consultancy, Honoraria, Research Grant/Funding; Pharmacyclics: Other: Institution: Advisory/Consultancy, Honoraria, Research Grant/Funding; Janssen: Consultancy, Honoraria. Short: Astellas: Research Funding; AstraZeneca: Consultancy; Jazz Pharmaceuticals: Consultancy; NGMBio: Consultancy; Novartis: Honoraria; Takeda Oncology: Consultancy, Research Funding; Amgen: Consultancy, Honoraria. Kadia: Genentech: Consultancy, Other: Grant/research support; Pfizer: Consultancy, Other; AstraZeneca: Other; Cure: Speakers Bureau; BMS: Other: Grant/research support; Jazz: Consultancy; Liberum: Consultancy; Sanofi-Aventis: Consultancy; Pulmotech: Other; Astellas: Other; Genfleet: Other; Ascentage: Other; Cellonkos: Other; Novartis: Consultancy; Dalichi Sankyo: Consultancy; Amgen: Other: Grant/research support; Aglos: Consultancy; AbbVie: Consultancy, Other: Grant/research support. Borthakur: GSK: Consultancy; Protagonist: Consultancy; Takeda: Membership on an entity's Board of Directors or advisory committees; University of Texas MD Anderson Cancer Center: Current Employment; ArgenX: Membership on an entity's Board of Directors or advisory committees; Astex: Research Funding; Ryvu: Research Funding; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees. Daver: Daiichi Sankyo: Consultancy, Research Funding; Novimmune: Research Funding; Gilead Sciences, Inc.: Consultancy, Research Funding; Astellas: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; Novartis: Consultancy; Pfizer: Consultancy, Research Funding; ImmunoGen: Consultancy, Research Funding; Bristol Myers Squibb: Consultancy, Research Funding; Sevier: Consultancy, Research Funding; Glycomimetics: Research Funding; Trillium: Consultancy, Research Funding; Abbvie: Consultancy, Research Funding; Hanmi: Research Funding; FATE Therapeutics: Research Funding; Trovagene: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; Jazz Pharmaceuticals: Consultancy, Other: Data Monitoring Committee member; Dava Oncology (Arog): Consultancy; Celgene: Consultancy; Syndax: Consultancy; Shattuck Labs: Consultancy; Agios: Consultancy; Kite Pharmaceuticals: Consultancy; SOBI: Consultancy; STAR Therapeutics: Consultancy; Karyopharm: Research Funding; Newave: Research Funding. DiNardo: Takeda: Honoraria; ImmuneOnc: Honoraria, Research Funding; GlaxoSmithKline: Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria; Notable Labs: Current holder of stock options in a privately-held company, Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy, Research Funding; Agios/Servier: Consultancy, Honoraria, Research Funding; Bristol Myers Squibb: Honoraria, Research Funding; Forma: Honoraria, Research Funding; Foghorn: Honoraria, Research Funding; Celgene, a Bristol Myers Squibb company: Honoraria, Research Funding. Ravandi: Jazz: Honoraria, Research Funding; Astex: Honoraria, Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Xencor: Honoraria, Research Funding; Agios: Honoraria, Research Funding; Taiho: Honoraria, Research Funding; Prelude: Research Funding; Syros Pharmaceuticals: Consultancy, Honoraria, Research Funding; Bristol Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Honoraria, Research Funding; Novartis: Honoraria; AstraZeneca: Honoraria; AbbVie: Honoraria, Research Funding. Kantarjian: Astellas Health: Honoraria; Daiichi-Sankyo: Research Funding; Ascentage: Research Funding; Pfizer: Honoraria, Research Funding; AbbVie: Honoraria, Research Funding; Immunogen: Research Funding; Aptitude Health: Honoraria; NOVA Research: Honoraria; Amgen: Honoraria, Research Funding; KAHR Medical Ltd: Honoraria; Astra Zeneca: Honoraria; Ipsen Pharmaceuticals: Honoraria; BMS: Research Funding; Novartis: Honoraria, Research Funding; Jazz: Research Funding; Precision Biosciences: Honoraria; Taiho Pharmaceutical Canada: Honoraria. OffLabel Disclosure: ADCT-602 is not approved for B-ALL
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Levis, Mark J., Mehdi Hamadani, Brent R. Logan, et al. "BMT CTN Protocol 1506: A Phase 3 Trial of Gilteritinib As Maintenance Therapy after Allogeneic Hematopoietic Stem Cell Transplantation in Patients with FLT3-ITD+ AML." Blood 134, Supplement_1 (2019): 4602. http://dx.doi.org/10.1182/blood-2019-124322.
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Background: Fms-like tyrosine kinase 3 internal tandem duplication (FLT3-ITD) mutations in acute myeloid leukemia (AML) are a common indication for allogeneic hematopoietic stem cell transplant (HCT) in first complete remission (CR1). Despite HCT, relapses are common and cure rates are limited thereafter. The use of FLT3 inhibitors as post-HSCT maintenance therapy has not been prospectively evaluated in the phase 3 setting. Gilteritinib is a selective, potent FLT3 inhibitor with robust activity and favorable tolerability in relapsed/refractory AML. This trial will compare the safety and efficacy of 2-year maintenance therapy with gilteritinib versus placebo in patients with FLT3-ITD+ AML in CR1 after allogeneic HSCT. The broad goal of this study is to determine if there is a benefit to FLT3 inhibition as maintenance therapy post-HCT and to identify which patients, if any, benefit. We will use a novel NGS-based assay for FLT3-ITD mutations to detect minimal residual disease (MRD) in order to stratify patients pre-HSCT and correlate with relapse post-HCT. Study Design and Methods: This Phase 3, randomized, double-blind, placebo-controlled multicenter trial (NCT02997202; Blood and Marrow Transplant Clinical Trials Network Protocol 1506), is being conducted at 149 sites worldwide. The target enrollment is 532 adult subjects (aged ≥18 years) with FLT3-ITD+ AML in CR1 who are ≥30 days and ≤90 days from scheduled allogeneic HSCT. Of these 532 subjects, 346 subjects who have achieved successful engraftment without uncontrolled graft-versus-host disease (GVHD) or other serious toxicity will be randomized (1:1; stratified by conditioning regimen intensity, time from HSCT [Day 0] to randomization [30-60 days vs 61-90 days], and presence of minimal residual disease [MRD] in the pre-transplant bone marrow sample) to receive oral gilteritinib (120 mg) or matching placebo as maintenance therapy for 2 years. The primary endpoint is relapse-free survival (RFS) in the two treatment arms; RFS will be assessed from the time of randomization to the time of death or morphologic leukemia relapse (as defined by Revised IWG criteria). MRD status will continue to be monitored over the duration of the maintenance therapy, although investigators will be blinded to the MRD assay results. Overall survival is a key secondary endpoint. Other endpoints include safety/tolerability, non-relapse mortality, event-free survival, incidences of acute/chronic GVHD, and MRD. As of July 31, 2019, 341 patients have been registered and 236 have been randomized. To achieve a target number of 346 subjects for randomization (n=173 per treatment arm), we estimated that enrollment of 532 subjects would be required given an expected dropout rate of 35% between the time of registration to the time of randomization. The RFS rate in the placebo arm (control) is assumed to be 67% at 1 year, 59% at 2 years, and 55% at 3 years (according to the Center for International Blood & Marrow Transplant Research data for FLT3-ITD+ patients transplanted in CR1 who were alive and were progression free at 60 days). A total of 122 events will provide 85% power to detect a hazard ratio (HR) of 0.57 (corresponding to a 15% difference in 2-year RFS) with two-sided significance level of 0.05. With a 2-year accrual period and a 5% annual dropout rate, enrollment of 346 subjects will ensure a high probability of obtaining 122 events. The primary efficacy analysis will be performed using the intention-to-treat (ITT) population, which is defined as all subjects who are randomized. RFS will be compared across the treatment groups using the stratified Log-rank test. A stratified Cox model with treatment as covariate will be used to determine HR and confidence intervals at 1, 2, and 3 years. Kaplan-Meier estimates of RFS will be reported at 1, 2, and 3 years. No interim efficacy or futility analyses are planned. Figure Disclosures Levis: Daiichi Sankyo Inc: Consultancy, Honoraria; Menarini: Consultancy, Honoraria; Novartis: Consultancy, Research Funding; Agios: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Astellas: Consultancy, Research Funding; FUJIFILM: Consultancy, Research Funding. Hamadani:Otsuka: Research Funding; ADC Therapeutics: Consultancy, Research Funding; Medimmune: Consultancy, Research Funding; Pharmacyclics: Consultancy; Takeda: Research Funding; Sanofi Genzyme: Research Funding, Speakers Bureau; Celgene: Consultancy; Merck: Research Funding; Janssen: Consultancy. Rosales:Astellas: Employment. Delgado:Astellas: Employment. Bahceci:Astellas: Employment, Patents & Royalties. Devine:Kiadis Pharma: Other: Protocol development (via institution); Bristol Myers: Other: Grant for monitoring support & travel support; Magenta Therapeutics: Other: Travel support for advisory board; My employer (National Marrow Donor Program) has equity interest in Magenta. Horowitz:Actinium: Other: Unrestricted educational and research grant; Gamida Cell: Other: Unrestricted educational and research grant, Research Funding; Oncoimmune: Other: Unrestricted educational and research grant; Miltenyi Biotech: Other: Unrestricted educational and research grant, Research Funding; Janssen: Other: Unrestricted educational and research grant, Research Funding; Kite Pharma/Gilead: Other: Unrestricted educational and research grant, Research Funding; Magenta: Consultancy, Other: Unrestricted educational and research grant; GlaxoSmithKline: Other: Unrestricted educational and research grant; Shire: Other: Unrestricted educational and research grant; CSL Behring: Other: Unrestricted educational and research grant, Research Funding; Seattle Genetics: Other: Unrestricted educational and research grant; Mesoblast: Other: Unrestricted educational and research grant, Research Funding; Bristol-Myers Squibb: Other: Unrestricted educational and research grant, Research Funding; Daiichi Sankyo: Other: Unrestricted educational and research grant; Sanofi: Other: Unrestricted educational and research grant, Research Funding; Pharmacyclics: Other: Unrestricted educational and research grant; Amgen: Other: Unrestricted educational and research grant; Chimerix: Other: Unrestricted educational and research grant; Regeneron: Other: Unrestricted educational and research grant. Chen:Incyte: Consultancy; Kiadis: Consultancy; Magenta: Consultancy; Abbvie: Consultancy; Takeda: Consultancy.
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Yamaguchi, Masaki, Naoki Takezako, Toru Kiguchi, et al. "Phase II Trial of a Peptide Vaccine, Ocv-501 in Elderly Patients with Acute Myeloid Leukemia." Blood 132, Supplement 1 (2018): 29. http://dx.doi.org/10.1182/blood-2018-99-110013.
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Abstract Introduction: In recent decades, a considerable number of tumor antigens have been characterized, including the leukemia-associated antigen, Wilm's tumor 1 (WT1). WT1 is found to be expressed at low levels in various normal tissues such as gonads, kidney and the hematopoietic system. However, it is highly overexpressed in various hematological malignancies and solid tumors, including in the majority of acute myeloid leukemia (AML) cases. OCV-501 is a human leukocyte antigen (HLA) class II-restricted helper peptide derived from the WT1 protein. This Phase II trial was conducted to evaluate the efficacy and safety of OCV-501 in elderly patients with AML (ClinicalTrials.gov identifier: NCT01961882). Methods: This multicenter, randomized, double-blind, placebo-controlled trial was conducted in Japan, the Republic of Korea and Taiwan between October, 2013 to November, 2017. The key eligibility criteria for this trial were patients with AML, aged 60 years or older, who achieved first complete remission within one or two courses of standard induction therapy, completed more than one course of standard consolidation therapy, and not scheduled for hematopoietic stem cell transplantation. Patients were assigned to receive either OCV-501 monotherapy or placebo. Subcutaneous administration of OCV-501 3mg or placebo was given once weekly up to the eighth administration, and once biweekly from the ninth administration onwards up to a duration of 2 years, followed by post-treatment observation period. The primary endpoint was disease-free survival (DFS) that was defined as the time from randomization to AML relapse or death from any cause, whichever came first, within the observation period. Secondary endpoints were overall survival (OS), quality of life (QOL; The European Organization for Research and Treatment of cancer [EORTC] QLQ-C30), and performance status (Eastern Cooperative Oncology Group performance status [ECOG PS]). Safety, including any occurrence of adverse events (AEs) was evaluated. Results: A total of 133 patients who had achieved first remission after prior induction and consolidation therapies were randomized to receive either OCV-501 (OCV-501 arm, N=68) or placebo (placebo arm, N=65). The median age of the patients was 67 years (range, 60 - 85) and most of them had good performance status (ECOG PS score 0 - 1). The WT1 mRNA level at Day 1 was <50 copies/μg RNA in 37 patients in the OCV-501 arm and 28 patients in the placebo arm. In the evaluation of efficacy, there was no significant difference in DFS between both arms, and the median DFS was 12.1 months and 8.4 months in the OCV-501 arm and placebo arm, respectively. The median OS was 38.5 months and 31 months in the OCV-501 arm and placebo arm, respectively. The results of patient QOL and PS were similar between both arms. Overall, there were no significant safety findings throughout the trial. A majority of the patients in both arms had at least 1 treatment-emergent AE (TEAE); however, most of the TEAEs were mild in severity (Grade 1 or 2). The most frequently reported TEAE was site injection induration. Conclusion: There was no significant difference in DFS between OCV-501- and placebo-treated patients. OCV-501 was found to be generally safe and well-tolerated in elderly AML patients. Disclosures Yamaguchi: Chugai Pharmaceutical Co., Ltd.: Honoraria; Janssen Pharmaceutical KK: Honoraria; Celgene KK: Honoraria; Ono Pharmaceutical Co., Ltd.: Honoraria. Kiguchi:Teijin Co., Ltd.: Other: Grant; Sanofi K.K., Ltd.: Other: Grant; Celltrion, Inc.: Other: Grant; Taiho Pharmaceutical Co., Ltd.: Other: Grant; SymBio Pharmaceuticals, Ltd.: Other: Grant; Takeda Pharmaceutical Co., Ltd.: Other: Personal fees; Ono Pharmaceutical Co., Ltd.: Other: Personal fees; Astellas Pharmaceutical Co., Ltd.: Other: Grant; Celgene Co., Ltd.: Other: Grant and personal fees; Janssen Pharmaceutical Co., Ltd.: Other: Grant and personal fees; Sumitomo Dainippon Pharmaceutical Co., Ltd.: Other: Grant and personal fees; Novartis Pharmaceutical Co., Ltd.: Other: Grant and personal fees; Nippon Shinyaku Co., Ltd.: Other: Grant and personal fees; Mochida Pharmaceutical Co., Ltd.: Other: Personal fees; Eisai Co., Ltd.: Other: Personal fees; MSD Co., Ltd.: Other: Grant and personal fees; Daiichi Sankyo Pharmaceutical Co., Ltd.: Other: Grant; Chugai Pharmaceutical Co., Ltd: Other: Grant; Bristol Myers Squibb Co., Ltd.: Other: Grant and personal fees; Pfizer Co., Ltd.: Other: Personal fees; Otsuka Pharmaceutical Co., Ltd.: Other: grant and personal fees; Kyowa Hakko Kirin Co., Ltd.: Other: Grant and personal fees. Miyawaki:Novartis Pharma KK: Consultancy; Otsuka Pharmaceutical Co., Ltd.: Consultancy; Astellas Pharma Inc.: Consultancy. Heike:Sumitomo Dainippon Pharma Co., Ltd.: Other: Advisor; Otsuka Pharmaceutical Co., Ltd.: Other: Advisor. Mitsuki:Otsuka Pharmaceutical Co., Ltd.: Employment. Yoshida:Otsuka Pharmaceutical Co., Ltd.: Employment. Liew:Otsuka Pharmaceutical Co., Ltd.: Employment. Naoe:Astellas Pharma Inc.: Research Funding; Otsuka Pharmaceutical Co., Ltd.: Research Funding; Pfizer Japan Inc.: Research Funding; Nippon Shinyaku Co., Ltd.: Research Funding; Fujifilm Corporation: Patents & Royalties, Research Funding; Toyama Chemical Co., Ltd.: Research Funding.
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Huang, T., Y. Tsai, C. Lin, A. Cheng, K. Yeh, and C. Hsu. "Weekly paclitaxel, cisplatin, and 24-hour infusion of high-dose 5-fluorouracil plus leucovorin (weekly TP-HDFL) in patients with metastatic or recurrent esophageal cancer." Journal of Clinical Oncology 25, no. 18_suppl (2007): 15165. http://dx.doi.org/10.1200/jco.2007.25.18_suppl.15165.
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15165 Background: Paclitaxel (T), cisplatin (P), and 5-fluorouracil (5-FU) are active chemotherapy drugs for esophageal cancer. The 3-drug combination using a conventional 3-weekly schedule was active in patients with advanced esophageal cancer with response rate of 46% (Ilson DH et al: J Clin Oncol 1998;16:1826). The toxicity was substantial, with 57% grade 3/4 hematologic toxicities and 18% grade 3/4 peripheral neuropathy. We reported a multifractionated schedule using twice-weekly TP and weekly 5-FU (Lin CC et al: Anticancer Drugs 2007;18: in press). The multifractionated schedule, while induced comparable antitumor activity, had similar hematologic toxicities, less neuropathy, but more diarrhea than conventional 3-weekly schedule. The optimal way of combining T, P, and 5-FU remains to be defined. Methods: Patients with metastatic or recurrent esophageal cancer treated with weekly T, P, high-dose 5-FU plus leucovorin (weekly TP- HDFL) were retrospectively analyzed. The regimen consisted of T 70–80 mg/m2 IV 1h D1, P 35 mg/m2 IV 3h D2, 5-FU 2000 mg/m2 plus leucovorin 300 mg/m2 IV 24h D2, for 2 or 3 weeks followed by 1 week off. Results: Between Dec 2004 and Sep 2006, a total of 15 patients (male 14, squamous cell carcinoma 12) with a median age of 54 (range 37–76) were included. Eleven patients had de novo metastatic disease and 4 had recurrent disease. The disease extent included local esophageal tumor, lymph nodes, lung, liver, and bone in 13, 13, 5, 4, and 5 patients, respectively. The patients received an average of 3 cycles (range 1–5). Grade 3/4 neutropenia, leukopenia, thrombocytopenia, and infection occurred in 4, 3, 1, and 5 patients, respectively. No grade 3/4 vomiting, mucositis, diarrhea, and peripheral neuropathy occurred. The overall response rate was 33% (95% CI 12–87) (PR 5, SD 6, PD 4). With a median follow-up of 5 months, the median progression-free and overall survival were 3 (range 2–7) and 12.5 months (range 3+-12.5), respectively. Conclusions: Weekly TP-HDFL has a comparable activity and a better toxicity profile in patients with advanced esophageal cancer compared to previously reported 3-weekly or multifractionated schedule. (The study was supported by the grant of DOH95-TD-B-111- 001) No significant financial relationships to disclose.
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Stefansdottir, Runa, Robert Brychta, Vaka Rognvaldsdottir, Erlingur Johannsson, and Chen Kong. "0105 Sleep timing and consistency are associated with the standardised test performance of Icelandic adolescents." Sleep 45, Supplement_1 (2022): A48. http://dx.doi.org/10.1093/sleep/zsac079.103.
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Abstract Introduction Sleep has been shown to affect cognitive function in laboratory studies; however, its association to the academic performance of adolescents has largely been demonstrated using self-reported measures. Studies with objective measures of both sleep and academic performance are limited. The aim of the present study was to determine whether the free-living sleep quantity, quality, and timing of 15-year-old adolescents measured with wrist actiography are associated with their scores on national standardised examinations as an objective measure of academic achievement. Methods We measured sleep with wrist actiography for 1 week in 253 (150 girls) Icelandic adolescents with a mean (SD) age of 15.9 (0.3) years. Multiple linear regression was used to assess associations between sleep parameters and combined standardised examination scores in mathematics, English, and Icelandic obtained from the Icelandic Directorate of Education. Results We found that students went to bed at 00:49 hours (± 51.8 min) and slept for a mean (SD) of 6.6 (0.7) hr/night, with a median (interquartile range) night-to-night variation in sleep duration of 1.2 (0.7) hr and an efficiency of 88.1 (5.3)%. Combined analyses adjusted for sex, demonstrated that both bedtime and night-tonight variability in total sleep time were negatively associated with the average score across all topics. Sex-specific associations did not indicate clear differences between boys and girls. Conclusion These findings suggest that, in addition to appropriate sleep duration, public health guidance should also highlight the importance of early and consistent sleep schedules to academic achievement for both boys and girls. Support (If Any) National Institute of Diabetes and Digestive and Kidney Diseases intramural research program, Grant/Award Number: Z01 DK071013 and Z01 DK071014; Icelandic Centre for Research, Grant/ Award Number: 152509-051
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Bug, Gesine, Andreas Burchert, Eva-Maria Wagner, et al. "Phase I/II Study of the Deacetylase Inhibitor Panobinostat As Maintenance Therapy after an Allogeneic Stem Cell Transplantation in Patients with High-Risk MDS or AML: The Panobest-Trial." Blood 126, no. 23 (2015): 4344. http://dx.doi.org/10.1182/blood.v126.23.4344.4344.
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Abstract Background: Leukemic relapse and graft-versus-host disease (GvHD) remain major obstacles after an allogeneic stem cell transplantation (HSCT). Panobinostat is a potent inhibitor of class I, II and IV deacetylases and has shown antileukemic as well as immunomodulatory activity. The hypothesis of our phase I/II PANOBEST trial was that panobinostat can effectively prevent relapse in patients (pts) with high-risk (HR) myeloid diseases while simultaneously reducing GvHD. We aimed to determine dose-limiting toxicity (DLT), maximum tolerated dose (MTD) and/or recommended phase 2 dose (RP2D) of panobinostat in adult pts with HR acute myeloid leukemia (AML) or myelodysplastic syndromes (MDS) in complete hematologic remission (CR) after a reduced-intensity HSCT. Secondary objectives were evaluation of safety and tolerability of panobinostat, and overall (OS) and disease-free survival (DFS) at 1 and 2 years after HSCT. Methods: In two sequential schedules, panobinostat was administered orally thrice weekly, (TIW), either every week (A) or every other week (B). In schedule A, panobinostat was started at a dose of 10 mg TIW and escalated to 30 mg TIW using a 3+3 design; in schedule B, panobinostat was given at doses of 20-40 mg TIW. Panobinostat was initiated between day +60 and +150 after HSCT and given for up to 1 year. Eligibility criteria included: ANC ≥ 1,000/μL, platelets ≥ 75,000/μL, adequate organ function and no severe GvHD. DLT was defined as prolonged G4 hematologic toxicity or any non-hematologic toxicity ≥ G3 unrelated to disease progression or intercurrent illness within 28 days of the first panobinostat dose. Results: 42 pts (37 AML, 5 MDS) were enrolled, with a median age of 52 years (range, 21-71). Cytogenetics were classified as low (n=6), intermediate-1/2 (n=20) or adverse risk (n=16) according to ELN criteria. Panobinostat was started a median of 98 days (range, 60-147) after HSCT from a matched related (n=9), matched unrelated (n=24), mismatched unrelated (n=6) or haploidentical donor (n=3). The majority of patients (n=28, 67%) were transplanted with active disease (bone marrow blasts 0-80%, median 21%, 1 pt. with extramedullary AML), 9 in CR1 (21%) and 5 in CR2 (12%). Patient and transplant characteristics were equally distributed between schedules A and B. Of 42 pts, 22 (54%) have completed one year of panobinostat, 1 remains on treatment and 19 (46%) discontinued prematurely after a median of 70 days (range, 12-342) due to adverse events (AEs) (n=10), relapse (n=6), patient decision (n=2) or prohibited comedication (n=1). To date, 24 out of 42 patients experienced panobinostat-related grade 3/4 AEs (schedule A: n=14, 67%; schedule B: n=10, 48%). The most common AEs were hematologic toxicity (G3: 14 pts, 33%; G4: 2 pts, 5%), constitutional (G3: 7 pts, 17%) and gastrointestinal symptoms (G3: 5 pts, 12%). Neurological AE and pain (G3, 2 pts each, 5%) as well as metabolic/laboratory alterations (G3: 3 pts., 7%) and renal toxicity (G3, 1 pt, 5%) were also reported. AEs were fully and rapidly reversible after interrupting panobinostat (n=24); 14 patients needed dose adjustment and no study-related deaths occurred. The RP2D was 20 mg TIW in arm A and 30 mg TIW every other week in arm B based on 5 DLTs: fatigue G3 at 20 mg, colitis and nausea/emesis G3 each at 30 mg (arm A), diarrhea and headache G3 at 40 mg each (arm B). Prophylactic or preemptive donor lymphocyte infusions (median 2, range, 1-6) were administered to 10 pts (42%, median 1.5x106 CD3+ cells/kg) in arm A and 8 pts (33%, median 0.5x106 CD3+ cells/kg) in arm B. Cumulative incidence (CI) of moderate (n=8) or severe (n=2) chronic GvHD was 24±0.4% at one year after HSCT and did not differ between both arms. There was no evidence of impaired immune reconstitution. To date, median OS and DFS have not been reached after a median follow up of 22 months (range, 6-57). At two years after HSCT, 5 patients have died from relapse (n=3), sepsis (n=1) or sudden death (n=1 at 3.5 months after study discontinuation) and CI of relapse was 21±0.5%, resulting in probabilities for 2-year OS and DFS of 88±5% and 74±7%, resp. Discussion: Panobinostat maintenance following HSCT for high-risk AML or MDS is feasible with a RP2D dose of 20 mg TIW weekly or 30 mg TIW every other week and associated with a low relapse rate. This provides a rationale for a prospective randomized trial of panobinostat as post-transplant intervention. Disclosures Bug: NordMedica: Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Other: Travel grants, Research Funding; Novartis Oncology: Honoraria, Other: Travel grants, Research Funding; Boehringer Ingelheim: Membership on an entity's Board of Directors or advisory committees; Astellas: Other: Travel grant; TEVA Oncology: Other: Travel grant; Gilead: Honoraria. Off Label Use: Panobinostat has not been approved for maintenance therapy after an allogeneic stem cell transplantation in ANL and MDS patients . Burchert:Bristol Myers Squibb: Honoraria. Bader:Neovii: Other: Institutional grants; Medac: Other: Institutional grants; Amgen: Consultancy; Novartis: Consultancy; Jazz Pharmaceuticals: Consultancy; Riemser: Other: Institutional grants. Ottmann:Ariad: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Astra Zeneca: Honoraria, Membership on an entity's Board of Directors or advisory committees.
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Kim, Bum-Joo. "The Estimation of Local Education Finance Burden Due to the Fiscal Requirements for AI Digital Textbook Subscription." Korean Society for the Economics and Finance of Education 33, no. 4 (2024): 1–27. https://doi.org/10.46967/jefe.2024.33.4.1.
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The purpose of this study is to estimate the fiscal requirements for AI digital textbook subscriptions, which will be introduced with a subscription-based pricing model from 2025 to 2028, and to forecast the burden on local education finance for provincial and municipal education offices. It also aims to present policy considerations regarding future funding allocation that should be taken into account in legislative decision-making. Based on the 2025-2028 schedule for AI digital textbook implementation announced by the Ministry of Education in June 2023, the number of students by grade, and the set price ranges, the results show that applying Scenario S1-1 (an average monthly subscription fee of 5,000 KRW with a 12-month subscription for semester-based textbooks) would require a total of 4.7255 trillion KRW in student subscription fees over four years. Furthermore, it is expected that the fiscal requirements will range from 1.9252 trillion KRW under the minimum scenario (S2-2) to 6.6156 trillion KRW under the maximum scenario (S1-3). Given that the introduction of AI digital textbooks will significantly increase local education finance burdens due to the substantial fiscal requirements involved, potentially causing major changes in the existing textbook system, it is deemed appropriate that this initiative be pursued based on prompt and clear legislative decisions by the National Assembly under the principle of the rule of law for education systems as stipulated in the Constitution of the Republic of Korea. When these premises are clear, the following funding options can be considered: ① extending the effective period or removing the sunset clause for special grants that increase national support for high school tuition-free policies, including textbook costs, ② abolishing the temporary special grant system for digital education innovation needs to secure additional ordinary grant funding, ③ inducing investment from the central government’s general budget to secure additional funding for AI digital textbooks, and ④ utilizing temporary national project special grants in 2025.
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Ribera, Josep-Maria, Olga García, Pau Montesinos, et al. "Ponatinib and Chemotherapy in Young Adults with De Novo Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia. Results of Ponalfil Clinical Trial after Completion of Recruitment." Blood 136, Supplement 1 (2020): 29–30. http://dx.doi.org/10.1182/blood-2020-137489.
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Background and objective. The combination of tyrosine kinase inhibitors (TKI) and chemotherapy (intensive, attenuated or minimal) has improved the prognosis of patients (pts) with Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ALL). The combination of HyperCVAD and ponatinib has improved the molecular response and survival compared with other combinations of chemotherapy with first or second generation TKI (Jabbour E, et al, Lancet Haematol. 2018; 5:e618-e627). The Spanish PETHEMA group conducted the phase 2 PONALFIL trial, which incorporates ponatinib to the same induction and consolidation schedule of the ALL Ph08 trial (Ribera JM et al. Cancer 2019;125:2810-2817) The results of this trial after completed recruitment are herein reported. Patients and method. The PONALFIL trial (NCT02776605) combined ponatinib (30 mg/d) and induction chemotherapy (vincristine, daunorubicin and prednisone) followed by consolidation (high-dose methotrexate, ARA-C, mercaptopurine, etoposide) and allogeneic HSCT. TKI use as maintenance was only scheduled for pts with persistence or reappearance of MRD. By July 2020 the 30 scheduled pts were recruited. The response to therapy (complete morphological [CR], molecular [complete, CMR or major, MMR] after induction and before allogeneic HSCT) (assessed by centralized BCR-ABL/ABL ratio),event-free survival (EFS), overall survival [OS]) and toxicity are herein analyzed. Results. Median age was 50 (20-59) years and 14/30 pts were female. One pt showed CNS involvement at diagnosis. ECOG score at diagnosis was &lt;2 in 86% of pts. Median of WBC count was 6.4 (0.6-359.3) x109/L, Hb 90 (63-145) g/L, platelets 38 (11-206) x109/L. The immunologic phenotype was common in 26 cases, with molecular isoform p190 in 20 patients (67%), p210 in 9 (30%) and p230 in 1 (3%). CR was attained 26/26 patients (100%) (4 are still on induction therapy), with CMR in 11/26 cases (42%), MMR in 6/26 (23%) and no molecular response in 9/26 (35%)).Two patients withdrew the trial (thrombosis of the central retina artery and severe intestinal infection, one case each). Consolidation was given to 24 patients, 2/24 are receiving consolidation and 22 patients received allogeneic HSCT (14 in CMR, 6 in MMR, 2 without molecular response). No relapses before HSCT were detected. No transplant-related mortality was observed to date, but 1 patient withdrew the trial by severe GVHD. Ponatinib was given after HSCT in 4 pts due to loss of molecular response. Three pts relapsed after HSCT, one of them after documented loss of molecular response. All pts are alive (median follow-up of 4.5 months, range 0.5-26.2.2). The EFS probability at 30 months was 91% (79%, 100%) (Figure 1). One hundred and two adverse events (AE) have been registered in 20 patients, 25 of whom were severe (SAE) and occurred in 14 patients, prompting to withdrawn of the trial in 3 (thrombosis of the central artery of the retina, severe bowel infection, grade IV aGVHD, one case each). The most frequent AE were hematologic (26%), gastrointestinal (15%), infections (10%), hepatic (8%) and cutaneous (5%). Cardiovascular events occurred in 2 patients (angor pectoris and thrombosis of central artery of the retina, one case each). Conclusions. The preliminary results of the PONALFIL trial after recruitment completed show a high short-term antileukemic efficacy with acceptable toxicity profile. Supported in part by grant 2017 SGR288 (GRC) Generalitat de Catalunya and "La Caixa" Foundation. Figure 1. Event free survival (EFS) of the whole series. Figure 1 Disclosures Ribera: Pfizer, Amgen, Ariad, Novartis: Consultancy, Speakers Bureau; Pfizer, Amgen: Research Funding. Martinez-Lopez:Incyte: Consultancy, Research Funding; Novartis: Consultancy; BMS: Consultancy, Research Funding; Janssen-cilag: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Honoraria. Garcia-Sanz:Amgen: Membership on an entity's Board of Directors or advisory committees; BMS: Honoraria; Gilead: Honoraria, Research Funding; Incyte: Research Funding; Janssen: Honoraria, Research Funding; Novartis: Honoraria; Pharmacyclics: Honoraria; Takeda: Consultancy, Research Funding.
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Kiltz, U., R. Kempin, A. Schlegel, et al. "AB1245 DAILY MANAGEMENT OF PATIENTS WITH AXIAL SPONDYLOARTHRITIS: SELF-MONITORING OF DISEASE ACTIVITY WITH A SMARTPHONE APP IS FEASIBLE – A PROOF OF CONCEPT STUDY." Annals of the Rheumatic Diseases 79, Suppl 1 (2020): 1914.2–1914. http://dx.doi.org/10.1136/annrheumdis-2020-eular.3529.
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Background:Assessment and monitoring of disease activity and functioning is of major importance for the course of axial spondyloarthritis (axSpA). This is equally important for patient monitoring in daily routine as also for tight control strategies. Even though there is evidence that a closer monitoring of patients is better than routine care, more intensive treatment schedules are often not realized in daily practice for several reasons including shortage of time and personal resources. Using application software devices (apps) in clinical routine for the recording of disease-specific patient reported outcomes (PRO) may facilitate monitoring and improve clinical decision processes but there is a lack of data on the use of apps.Objectives:To investigate the use of such App technology in respect to usability, feasibility and equivalence of data in daily care of patients with axSpA. In more detail, it will be first determined how many patients are capable and ready to use the technology in a routine setting. Furthermore, the usage and behavior of patients using the app will be studied, the usability of the app and the equivalence of the collected parameters as well as the adherence to the documentation of disease activity over time.Methods:Patients diagnosed with axSpA were consecutively included in this ongoing monocentric prospective cohort study. In addition to patient and disease characteristics, information on previous experience with digital health apps was collected. Patients were asked to submit BASDAI and BASFI scores regularly every 2 weeks. The free to use AxSpA Live App is available for Android and iOS as a Class I certified medical device.Results:Out of 103 axSpA patients asked, 69 patients with axSpA (mean age 41.5 ± 11.3, 58% male, 76.8% use of bDMARDs, BASDAI 4.3 ± 2.0, BASFI 3.8 ± 2.5) out of 103 patients (67%) agreed to use participate, while 5 did not have a smartphone, 1 was unable to download the app for technical reasons, 28 reported other personal reasons). Of the 69, 62 patients (89.9%) reported using electronic media frequently and had used digital health apps (mean apps used 1.0 ± 1.3) in everyday life before. There were no systematic differences between pain levels documented on paper or by app at baseline (ICC 0.9 (95%CI 0.82 – 0.93). Out of 55 patients who completed week 2, only 33 patients (60%) used the App regularly to transmit their BASDAI/BASFI responses within the first two weeks (60%). Patients who started a new drug treatment because of high disease activity, reported BASDAI values more often than patients without a treatment change within a follow-up period of 5.5± 2.4 weeks (Table).Conclusion:The majority of patients with axSpA were able to use the AxSpA Live App. Most patients report scores regularly. The current disease activity seems to influence the adherence to reporting.Patients without change in their medication (n=53)Patients with change in their medication (n=16)Age, years42.0 (11.9)39.8 (9.3)Sex, male (%)62.343.8BASDAI, baseline4.1 (2.1)4.9 (1.7)BASFI, baseline3.8 (2.6)3.8 (2.3)Time of follow-up, in weeks5.4 (2.4)5.6 (2.5)Number of transmitted BASDAI values at week 222 (41%)11 (69%)Median number of transmitted BASDAI values during follow up1.0(3.6)1.5 (1.4)This work was supported by an unrestricted Grant by Novartis Pharma GmbH, GermanyAcknowledgments:n/aDisclosure of Interests:Uta Kiltz Grant/research support from: AbbVie, Amgen, Biogen, Novartis, Pfizer, Consultant of: AbbVie, Biocad, Eli Lilly and Company, Grünenthal, Janssen, Novartis, Pfizer, UCB, Speakers bureau: AbbVie, MSD, Novartis, Pfizer, Roche, UCB, Robin Kempin: None declared, Anna Schlegel: None declared, Xenofon Baraliakos Grant/research support from: Grant/research support from: AbbVie, BMS, Celgene, Chugai, Merck, Novartis, Pfizer, UCB and Werfen, Consultant of: AbbVie, BMS, Celgene, Chugai, Merck, Novartis, Pfizer, UCB and Werfen, Speakers bureau: AbbVie, BMS, Celgene, Chugai, Merck, Novartis, Pfizer, UCB and Werfen, Styliani Tsiami: None declared, Bjoern Buehring Grant/research support from: GE/Lunar, Kinemed, Consultant of: Gilead, Abbvie, Lilly, GE/Lunar, Janssen, Amgen, Speakers bureau: UCB, David Kiefer Grant/research support from: Novartis, Juergen Braun Grant/research support from: Abbvie (Abbott), Amgen, BMS, Boehringer, Celgene, Celltrion, Centocor, Chugai, Eli Lilly and Company, Medac, MSD (Schering Plough), Mundipharma, Novartis, Pfizer (Wyeth), Roche, Sanofi- Aventis, and UCB Pharma, Consultant of: Abbvie (Abbott), Amgen, BMS, Boehringer, Celgene, Celltrion, Centocor, Chugai, EBEWE Pharma, Eli Lilly and Company, Medac, MSD (Schering-Plough), Mundipharma, Novartis, Pfizer (Wyeth), Roche, Sanofi-Aventis, and UCB Pharma, Speakers bureau: Abbvie (Abbott), Amgen, BMS, Boehringer, Celgene, Celltrion, Centocor, Chugai, EBEWE Pharma, Eli Lilly and Company, Medac, MSD (Schering-Plough), Mundipharma, Novartis, Pfizer (Wyeth), Roche, Sanofi-Aventis, and UCB Pharma
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Gooding, Sarah, I.-Jun Lau, Mimi Sheikh, et al. "Double Refractory Myeloma: Analysis Of Clinical Outcomes and Medical-Resource Utilisation In a Single Centre." Blood 122, no. 21 (2013): 1727. http://dx.doi.org/10.1182/blood.v122.21.1727.1727.
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Abstract Background Introduction of proteasome inhibitors and immunomodulatory agents over the last decade has improved survival for multiple myeloma (MM) patients. A retrospective analysis of patients who developed resistance/intolerance to these agents showed a median overall survival (OS) and progression-free survival (PFS) of 9 months and 5 months, respectively (Kumar et al. 2012). Recent clinical trials have focused on improving outcomes for these double-refractory (DR) patients. However very limited published data from real world clinical practice is available on clinical outcomes and medical-resource utilisation (MRU) costs for this cohort of patients. We have analysed clinical outcomes and patient-level MRU costs of double-refractory/intolerant patients in a single centre. Methods Data on clinical outcomes, anti-myeloma therapies prescribed and MRU were obtained from a single centre in Oxford, UK, for 36 MM patients who have received four lines of treatment between 2011 and 2013. Six patients had not received prior bortezomib due to neuropathy. For ease of comparison and uniformity, thirty patients pre-treated with lenalidomide and bortezomib who had progressed on last therapy were included in this analysis (83% of the cohort). Clinic attendances, inpatient admissions, supportive therapies, transfusions and blood tests from start of fourth-line therapy until death or last follow-up were retrieved from health care records. Survival analysis was performed; Kaplan–Meier survival plots were generated to evaluate OS and PFS following initiation of fourth-line therapy. The occurrences of MRU were extracted to estimate the use and cost of each, using the UK NHS schedule of reference costs 2011-12 and published sources. Results Patients were selected for analysis on the basis of having received/receiving four lines of anti-MM therapy. Patient characteristics are summarised in Figure 1. Median age at diagnosis was 65.3 years (48–83 years). When offered a choice of therapy 77% of patients preferred an active treatment to care with palliative intent. The mean age of those who chose palliative care was 75.8 years compared to 63.7 for active therapy (p = 0.003). Treatment regimens were typically bendamustine based (53%), retreatment with bortezomib (10%) or lenalidomide based (27%). Patients were treated for a mean of 15.3 weeks (SD: 11.3). There were 42 hospital admissions reported during fourth-line, lasting 8 days on average. Patients required 6.8 red blood cell units and 2.9 platelet units on average. At least one RBC and platelet transfusion was required by 22 and 13 patients respectively. Median PFS in this cohort was 11 weeks and median OS was 23 weeks; however, the sample size was too small to obtain definitive PFS or OS conclusions. There was steep drop in survival early on (Figure 2), with a small number of patients surviving over a longer period. The most common Grade 3-4 adverse events were anaemia (60%), thrombocytopaenia (57%) and bone pain (37%). Eighteen out of the 30 patients had died by the end of follow-up, of whom 78% died in hospital. Prolonged inpatient stays, frequent adverse events and high transfusion requirements suggest poor quality of life (QoL) among these patients. Outpatient and day therapy unit attendances occurred frequently, with 4.3 and 12.6 per patient respectively over the mean treatment duration of 15.3 weeks. Investigations including CT and MRI scans were performed in 33% of patients. Blood tests were frequent, with mean full blood count testing of 21.6 per patient. The mean drug cost of fourth-line anti-MM therapy was £5,101 per patient. The mean MRU cost during fourth-line therapy was £11,160: clinical attendances £5,015 (45%); inpatient admissions £2,999 (27%); transfusions £2,479 (22%); supportive therapy £498 (4%); blood tests £169 (2%). The mean total cost of treatment plus MRU was therefore £16,260 [£9,201–23,320]; £1,066 per week on treatment. Conclusion Over 75% of myeloma patients in the fourth-line setting want to be treated with an active intent to improve survival. PFS and OS in our cohort were similar to published estimates. These patients, due to the nature of their disease, have high MRU costs. Therapies that induce higher response rates or reduce disease progression could lower MRU costs and improve QoL. Our data will provide an optimal comparison when formal cost-effectiveness evaluation is performed with new therapies for this DR cohort. Disclosures: Gooding: Celgene: Unrestricted Educational Grant Other. Lau:Celgene: Unrestricted Educational Grant Other. Sheikh:Celgene: Unrestricted Educational Grant Other. Roberts:Celgene: Unrestricted Educational Grant Other. Wong:Celgene: Unrestricted Educational Grant Other. Dickens:Celgene: Unrestricted Educational Grant Other. Elvidge:Celgene: Consultancy. Lee:Celgene: Consultancy. Ramasamy:Celgene: Honoraria, Unrestricted Educational Grant Other.
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Lammers-van der Holst, Heidi, Yuan Zhang, Laura Barger, et al. "299 Limited Time for Sleep in Night Shift Workers is associated with Risk of Insomnia and Shift Work Disorder." Sleep 44, Supplement_2 (2021): A119—A120. http://dx.doi.org/10.1093/sleep/zsab072.298.
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Abstract Introduction Sleep deficiency is a severe problem faced by night shift workers. Approximately one-third of night workers report insomnia during daytime sleep and excessive sleepiness during nighttime work; when severe, these symptoms characterize shift work disorder (SWD). Difficulty sustaining 7 to 9 hours of sleep during the daytime is partly due to a circadian drive for wakefulness. Not much is known, however, about how non-work activities contribute to the inability to obtain recovery sleep. We sought to explore how much time night workers are able to allocate for daytime sleep, and how this relates to insomnia-like symptoms and the likelihood of developing SWD. Methods Night shift workers (n=452, 19–69 years old, 54% men) from various occupations who worked at least four night shifts per month completed an online survey. This included questions related to shift duration, hours per workday of non-optional non-work activities, self-rated sleep need, the Insomnia Severity Index (ISI) and a validated 4-item SWD screening questionnaire. For each participant, we calculated the duration of work plus non-optional activities and compared the remaining available time for sleep to their self-described sleep need. Non-parametric Chi-square analyses and Pearson correlations were conducted. Results On average, shift duration was 8.9±1.6 hours, non-optional activities were 3.6±2.9 hours, and sleep need was 7.6±1.6 hours, leaving 15% of shift workers with insufficient free time to obtain the amount of sleep they needed. The percentage of workers at high risk for SWD was significantly greater among those who did not have enough free time for sleep compared to those whose schedules allowed sufficient sleep time (72% vs. 42%; χ2=20.2, p&lt;0.0001). We also found that shift workers with insufficient free time for sleep reported higher insomnia severity (r2=-0.20, p&lt;0.0001). Conclusion About 15% of night workers have non-optional activities outside work that limit their time to obtain sufficient sleep, and this contributes to greater insomnia-like symptoms and increased risk for SWD. Future research should focus on understanding what these non-optional activities are and whether they differ between night and day workers. These insights will enable personalized countermeasures to maximize the sleep and health of shift workers. Support (if any) Supported by US NIH grant R01-AG044416.
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Clavo, B., F. Robaina, A. Ruiz, et al. "Predictive factors in advanced head and neck cancer treated by radio-chemotherapy and hypoxia modification." Journal of Clinical Oncology 25, no. 18_suppl (2007): 6085. http://dx.doi.org/10.1200/jco.2007.25.18_suppl.6085.
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6085 Background: Anemia and tumor hypoxia are known factors for resistance to radio-chemotherapy (RT-CT). In a previous report we have suggested that spinal cord stimulation (SCS) can modify tumor oxygenation and regional blood flow in head and neck cancer (HNC). The aim of the present prospective study was to test the predictive value of pO2 measurement in HNC treated by RT-CT and hypoxia modification using SCS. Methods: Twelve male patients with advanced HNC were analyzed. Stage IVb-IVa: 8–4; mean age 58 + 7.6 years (46–70). Scheduled therapy was hyperfractionated RT (120 cGy/fraction, two fractions/day, total dose 81.6 Gy) from a Co- 60 source, and tegafur 800 mg/day. SCS devices were placed before RT-CT under local anesthesia. During treatment, SCS was connected from 20–30 min before to 20–30 min after each radiotherapy session. Before treatment, they were assessed: Hemoglobin levels and tumor oxygenation pre-SCS and pos-SCS (measured by a polarographic probe system ‘pO2 Histograph‘), expressed as median-pO2, and the fraction of pO2 values less than 5 mmHg (HF5) and less than 2.5 mmHg (HF2.5). Correlations were assessed using Pearson and Spearman tests, and actuarial survival using Kaplan-Meier estimates and Log-rank test. Results: Hemoglobin levels were correlated with oxygenation pre-SCS and pos-SCS: median-pO2 (p=0.005 and p=0.011), HF5 (p=0.048 and p=0.005) respectively. Anemia was associated with more advanced stage (IVb vs IVa, p=0.022), higher HF5 pos-SCS (p=0.028) and lower disease-free survival (p=0.019). The HF2.5 pos-SCS was adversely correlated with the 2 years actuarial: disease-free survival (p=0.027), cause-specific survival (p=0.008) and overall survival (p=0.008). HF2.5 was also correlated with hematocrit (p=0.044). Conclusions: Low hemoglobin levels and anemia are associated with more hypoxic and more advanced tumors. Pre-treatment tumor hypoxia (assessed by the fraction of pO2 values less than 2.5 mmHg during-SCS) is a strong predictive factor for survival in advanced HNC. Patients with highly hypoxic tumors should be selected for more aggressive treatments. Partially supported by: Grant ‘FUNCIS: PI 31–98‘. Scientific supervision was carried out by GICOR. No significant financial relationships to disclose.
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Versluis, JM, EA Rozeman, AM Menzies, et al. "L3 Update of the OpACIN and OpACIN-neo trials: 36-months and 24-months relapse-free survival after (neo)adjuvant ipilimumab plus nivolumab in macroscopic stage III melanoma patients." Journal for ImmunoTherapy of Cancer 8, Suppl 2 (2020): A2.1—A2. http://dx.doi.org/10.1136/jitc-2020-itoc7.3.
Full textAbstract:
BackgroundBefore adjuvant checkpoint inhibition the 5-year overall survival (OS) rate was poor (<50%) in high-risk stage III melanoma patients. Adjuvant CTLA-4 (ipilimumab, IPI) and PD-1 (nivolumab, NIVO, or pembrolizumab) blockade have been shown to improve relapse-free survival (RFS) and OS (latter only for IPI so far). Due to a broader immune activation neoadjuvant therapy with checkpoint inhibitors might be more effective than adjuvant, as suggested in preclinical experiments. The OpACIN trial compared neoadjuvant versus adjuvant IPI plus NIVO, while the subsequent OpACIN-neo trial tested three different dosing schedules of neoadjuvant IPI plus NIVO without adjuvant therapy. High pathologic response rates of 74–78% were induced by neoadjuvant IPI plus NIVO. Here, we present the 36- and 24-months RFS of the OpACIN and OpACIN-neo trial, respectively.Materials and MethodsThe phase 1b OpACIN trial included 20 stage IIIB/IIIC melanoma patients, which were randomized to receive IPI 3 mg/kg plus NIVO 1 mg/kg either adjuvant 4 cycles or split 2 cycles neoadjuvant and 2 adjuvant. In the phase 2 OpACIN-neo trial, 86 patients were randomized to 2 cycles neoadjuvant treatment, either in arm A: 2x IPI 3 mg/kg plus NIVO 1 mg/kg q3w (n=30), arm B: 2x IPI 1 mg/kg plus NIVO 3 mg/kg q3w (n=30), or arm C: 2x IPI 3 mg/kg q3w followed immediately by 2x NIVO 3 mg/kg q3w (n=26). Pathologic response was defined as <50% viable tumor cells and in both trials centrally reviewed by a blinded pathologist. RFS rates were estimated using the Kaplan-Meier method.ResultsOnly 1 of 71 (1.4%) patients with a pathologic response on neoadjuvant therapy had relapsed, versus 16 of 23 patients (69.6%) without a pathologic response, after a median follow-up of 36 months for the OpACIN and 24 months for the OpACIN-neo trial. In the OpACIN trial, the estimated 3-year RFS rate for the neoadjuvant arm was 80% (95% CI: 59%-100%) versus 60% (95% CI: 36%-100%) for the adjuvant arm. Median RFS was not reached for any of the arms within the OpACIN-neo trial. Estimated 24-months RFS rate was 84% for all patients (95% CI: 76%-92%); 90% for arm A (95% CI: 80%-100%), 78% for arm B (95% CI: 63%-96%) and 83% for arm C (95% CI: 70%-100%). Baseline interferon-γ gene expression score and tumor mutational burden predict response.ConclusionsOpACIN for the first time showed a potential benefit of neoadjuvant IPI plus NIVO versus adjuvant immunotherapy, whereas the OpACIN-neo trial confirmed the high pathologic response rates that can be achieved by neoadjuvant IPI plus NIVO. Both trials show that pathologic response can function as a surrogate markers for RFS.Clinical trial informationNCT02437279, NCT02977052Disclosure InformationJ.M. Versluis: None. E.A. Rozeman: None. A.M. Menzies: F. Consultant/Advisory Board; Modest; BMS, MSD, Novartis, Roche, Pierre-Fabre. I.L.M. Reijers: None. O. Krijgsman: B. Research Grant (principal investigator, collaborator or consultant and pending grants as well as grants already received); Modest; BMS. E.P. Hoefsmit: None. B.A. van de Wiel: None. K. Sikorska: None. C. Bierman: None. P. Dimitriadis: None. M. Gonzalez: None. A. Broeks: None. R.M. Kerkhoven: None. A.J. Spillane: None. J.B.A.G. Haanen: B. Research Grant (principal investigator, collaborator or consultant and pending grants as well as grants already received); Modest; BMS, MSD, Neon Therapeutics, Novartis. F. Consultant/Advisory Board; Modest; BMS, MSD, Novartis, Pfizer, AZ/MedImmune, Rocher/Genentech, Ipsen, Bayer, Immunocore, SeattleGenetics, Neon Therapeutics, Celsius Therapeutics, Gadet, GSK. W.J. van Houdt: None. R.P.M. Saw: None. H. Eriksson: None. A.C.J. van Akkooi: B. Research Grant (principal investigator, collaborator or consultant and pending grants as well as grants already received); Modest; Amgen, BMS, Novartis. F. Consultant/Advisory Board; Modest; Amgen, BMS, Novartis, MSD Merck, Merck-Pfizer, 4SC. R.A. Scolyer: F. Consultant/Advisory Board; Modest; MSD, Neracare, Myriad, Novartis. T.N. Schumacher: B. Research Grant (principal investigator, collaborator or consultant and pending grants as well as grants already received); Modest; MSD, BMS, Merck. E. Ownership Interest (stock, stock options, patent or other intellectual property); Modest; AIMM Therapeutics, Allogene Therapeutics, Amgen, Merus, Neogene Therapeutics, Neon Therapeutics. F. Consultant/Advisory Board; Modest; Adaptive Biotechnologies, AIMM Therapeutics, Allogene Therapeutics, Amgen, Merus, Neon Therapeutics, Scenic Biotech. Other; Modest; Third Rock Ventures. G.V. Long: F. Consultant/Advisory Board; Modest; Aduro, Amgen, BMS, Mass-Array, Pierre-Fabre, Novartis, Merck MSD, Roche. C.U. Blank: B. Research Grant (principal investigator, collaborator or consultant and pending grants as well as grants already received); Modest; BMS, Novartis, NanoString. E. Ownership Interest (stock, stock options, patent or other intellectual property); Modest; Uniti Cars, Neon Therapeutics, Forty Seven. F. Consultant/Advisory Board; Modest; BMS, MSD, Roche, Novartis, GSK, AZ, Pfizer, Lilly, GenMab, Pierre-Fabre.
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Baertsch, Marc-A., Jens Hillengass, Stefan Schönland, et al. "Efficacy and Tolerability of the Histone-Deacetylase Inhibitor Panobinostat in Clinical Practice: a Single Center Experience." Blood 128, no. 22 (2016): 5686. http://dx.doi.org/10.1182/blood.v128.22.5686.5686.
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Abstract The histone-deacetylase inhibitor panobinostat (PAN) has shown efficacy in phase II and III trials for multiple myeloma (MM) and has recently been approved in combination with bortezomib (BTZ) and dexamethasone (DEX) for the treatment of MM patients with at least two prior lines of therapy including BTZ and an immunomodulatory agent (IMiD). Here we retrospectively report our single center experience with PAN/BTZ/DEX (FVD) in a heavily pretreated patient population (n=24) with a high degree of proteasome inhibitor (PI) and IMiD refractoriness. Patients were treated starting from October 2015. The median age at treatment initiation was 67 years (range 49-87) and the number of prior lines of treatment was 5 (range 2-17) with a median interval from initial diagnosis of 6.3 years (range 2.1-15.2). Fourteen patients (58%) had high risk cytogenetic aberrations (del17p, t4;14, t14;16, +1q [>3 copies]) according to fluorescence in situ hybridization diagnosed at any time before FVD initiation and 11 of 20 patients (55%) evaluable for ISS at diagnosis had stage II/III disease. PI and IMiD refractoriness was present in 13 (54%) and 21 (88%) patients, respectively. Twelve patients (50%) were refractory to BTZ and 7 (29%) to carfilzomib (CFZ); 6 patients (25%) were double refractory to BTZ and CFZ. However, only 2 (8%) and 3 (13%) had received BTZ or CFZ, respectively, as part of their last line of therapy before FVD. In 22 evaluable patients, overall response rate (≥ PR; ORR) was 32% (7 of 22) and clinical benefit rate (≥ MR; CBR) was 50% (11 of 22). The median progression free survival (PFS) in the overall population was 3.3 months with median overall survival (OS) immature for reporting. Marked differences between BTZ sensitive and BTZ refractory patients were observed. ORR was 64% (7 of 11) vs. 0% (0 of 11) and CBR was 73% (8 of 11) vs. 36% (4 of 11), respectively; 73% (8 of 11) of the BTZ refractory patients achieved at least SD. Median PFS was 6.3 vs. 1.7 months and median OS immature vs. 5.1 months in BTZ sensitive and BTZ refractory patients, respectively. Interestingly, the only patient refractory to CFZ but sensitive to BTZ (6 prior lines of therapy) achieved VGPR and PFS of 6.3 months, suggesting discrete mechanisms of resistance to different PIs. Fatigue/asthenia was reported by 82% of patients and was mainly CTCAE grade 2 (52%); however, 3 patients had grade 3 fatigue/asthenia with reduced fluid intake resulting in deterioration of renal function, reduced vigilance and inpatient admission. Thrombopenia occurred in 96% and was mainly CTCAE grade 3/4 (32% and 37%, respectively). Diarrhea was reported by 19% and was CTCAE grade 1/2 in all cases. Peripheral neuropathy newly occurred or worsened in 29% with 24% CTCAE grade 1/2. Other adverse events with CTCAE grade ≥ 3 were atrial fibrillation (2x), liver failure, gastrointestinal bleeding, gastroenteritis, hypocalcemia, syncope, hypotension and post-surgical bleeding. Dose reductions with regard to the PANORAMA trial dosing schedule (San-Miguel JF et al., Lancet Oncol, 2014) were performed either upfront in patients deemed unable to tolerate full doses or during the course of treatment due to adverse events. Nineteen patients (79%) started with full dose PAN; doses were reduced and/or discontinued either upfront or during treatment in 14 patients (58%). In conclusion, FVD showed efficacy in a heavily pretreated MM patient population with a high degree of high risk patients according to cytogenetics and patients refractory to novel agents including PI. With dose reductions in a significant proportion, treatment was tolerated by most patients. However, caution should be exercised especially in elderly patients with restricted general condition where upfront dose reduction seems an appropriate measure to reduce the risk of severe adverse events. Efficacy also in patients refractory to the second generation PI CFZ warrants further investigation of FVD in this difficult to treat patient population. Disclosures Baertsch: Amgen: Other: travel grant; Novartis: Honoraria, Other: travel grant, Research Funding; Janssen: Other: travel grant; BMS: Other: travel grant. Hillengass:Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi: Research Funding; Amgen: Consultancy, Honoraria; Novartis: Research Funding; Celgene: Honoraria; BMS: Honoraria. Schönland:Janssen, Prothena, GSK: Consultancy, Employment, Equity Ownership, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, accommations, Patents & Royalties, Research Funding, Speakers Bureau. Hegenbart:Janssen: Honoraria, Other: Travel grant; Pfizer: Other: Travel grant. Goldschmidt:Chugai: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; Millennium: Membership on an entity's Board of Directors or advisory committees, Research Funding; Onyx: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees. Raab:Celgene: Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Research Funding; BMS: Consultancy; Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Consultancy, Research Funding.
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Kroeger, Nicolaus, Katja Sockel, Christine Wolschke, et al. "Prospective Multicenter Phase 3 Study Comparing 5-Azacytidine (5-Aza) Induction Followed By Allogeneic Stem Cell Transplantation Versus Continuous 5-Aza According to Donor Availability in Elderly MDS Patients (55-70 years) (VidazaAllo Study)." Blood 132, Supplement 1 (2018): 208. http://dx.doi.org/10.1182/blood-2018-99-115932.
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Abstract Introduction: 5-azacytidine treatment prolongs survival in older patients with high-risk MDS compared to standard of care options outside allogeneic stem cell transplantation (AHSCT) wich is still the only potentially curative treatment option that is however associated with a considerable treatment-related morbidity and mortality (TRM). Reduced-intensity conditioning (RIC) prior to transplantation has broadened the application of this therapeutic approach also to elderly MDS patients. Here we present results from a prospective multicenter trial of the German MDS and Cooperative Transplant Study Group comparing 5-azacytidine (5-Aza) treatment alone with 5-Aza induction followed by AHSCT according to donor availability in elderly patients with newly-diagnosed untreated HR MDS aged 55-70 years (EudraCT Number 2010-018467-42). Primary endpoint was overall survival (OS) at three years after 5 Aza induction in both arms; major secondary endpoints were to assess the response rate, event-free survival (EFS) at three years, toxicity, treatment-related mortality (TRM) and the impact of the comorbidity-index (HCT-CI) on outcome in both treatment arms. Methods and Patients Patients with proven de novo or therapy-related MDS / CMML (WBC <13 GPT/l) according to FAB and risk profile according to IPSS: intermediate II-risk or high-risk or intermediate I with high-risk cytogenetic and patients with secondary AML (according to WHO) and blasts ≤ 30 % (= RAEB-t according to FAB) and sufficient organ function, could be included. A donor search was started at the time of inclusion and all patients were scheduled to receive 4 to 6 cycles of 5-Aza induction therapy. In case a HLA -identical sibling or a 10/10 HLA compatible unrelated donor could be identified during the first cycles of 5-Aza and patients had at least stable disease they were allocated for a busulfan-based RIC allograft. In case no suitable donor could be identified 5-Aza was continued until progression or unacceptable toxicity. This protocol-defined primary analysis uses the full 5% alpha error for the primary analysis. A final follow-up analysis will be performed once all patients have been followed-up at least for three years but no later than January 2019. Results Between June 2011 and November 2016 190 patients with a median age of 63 years from 14 German centers were included into the trial. Following 5-Aza induction, only 109 out of 190 patients (57%) were eligible for allocation to one of the treatment arms and proceeded to AHSCT (n=83) or continued 5-Aza therapy (n=26). Reasons for premature study termination of 81 patients (43%) within the first 5-Aza cycles included progressive disease (n=25; 31%), death (n=14; 17%), inclusion or exclusion criteria not fulfilled (n=18, 22%), withdrawal of informed consent (n=7; 9%), adverse events (n=7; 9%) or other reasons (n=10; 12%). Regarding the primary study endpoint and after 5 Aza induction therapy in an intention to treat analysis the OS at 3 years was 49% (95% CI: 36-61%) after AHSCT and 22% (95% CI: 6-44%) after continuous treatment with 5-Aza (p= 0.027). The time dependent Hazard ratio for AHSCT decreased over time: while at 1 year the HR was still 1.4 due to early TRM, this HR decreased to 0.35 at 2 years and 0.09 at 3 years. EFS at 3 years was 35% (95% CI: 22-48%) after AHSCT and 0% after 5-Aza continuous treatment (p< 0.001). The TRM after AHSCT at 1 and 3 years was 17% (95% CI 10-26%) and 23% (95% CI: 14-33%), respectively. Conclusions This prospective phase 3 study comparing 5-Aza followed by AHSCT with continuous 5-Aza therapy in older patients (55 to 70 years) suffering from higher-risk MDS demonstrates an improved EFS and OS in favor of AHSCT. Induction therapy with 5-Aza prior to AHSCT is associated with a considerable rate of drop outs due to progression, adverse events, and mortality prior to AHSCT. The study was registered under ClinicalTrial.gov: NCT01404741. The study was supported by a research grant from Celgene, Germany. Figure. Figure. Disclosures Kroeger: Celgene: Honoraria, Research Funding; Neovii: Honoraria, Research Funding; JAZZ: Honoraria; Riemser: Honoraria, Research Funding; Sanofi: Honoraria; Novartis: Honoraria, Research Funding. Bethge:Miltenyi Biotec GmbH: Consultancy, Honoraria, Research Funding; Neovii GmbH: Honoraria, Research Funding. Schlenk:Pfizer: Research Funding, Speakers Bureau. Kobbe:Amgen: Honoraria, Research Funding; Celgene: Honoraria, Other: Travel Support, Research Funding; Roche: Honoraria, Research Funding. Bug:Novartis Pharma: Honoraria, Research Funding; Jazz Pharmaceuticals: Other: Travel Grant; Celgene: Honoraria; Astellas Pharma: Other: Travel Grant; Janssen: Other: Travel Grant; Amgen: Honoraria; Neovii: Other: Travel Grant. Scheid:Celgene: Honoraria; Janssen: Honoraria; Novartis: Honoraria, Research Funding; Takeda: Honoraria, Research Funding; BMS: Honoraria; Amgen: Honoraria. Krönke:Celgene: Honoraria. Stelljes:Novartis: Honoraria; Amgen: Honoraria; JAZZ: Honoraria; MSD: Consultancy; Pfizer: Consultancy, Honoraria, Research Funding. Beelen:Medac: Consultancy, Other: Travel Support. Platzbecker:Celgene: Research Funding.
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Farooq, Wasfa, Natasha Baig, Bashir Ahmed Khan, and Muhammad Rafie Raza. "Virtual Teaching and Training Models in Pediatric Oncology: A Retrospective Study from an LMIC." Indian Journal of Medical and Paediatric Oncology 43, no. 03 (2022): 241–49. http://dx.doi.org/10.1055/s-0042-1750206.
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Abstract Introduction A multidisciplinary approach is essential for success in pediatric oncology treatment. Updated protocols, quality nursing care, psychosocial support, safe and standardized preparation of chemotherapy, infection control, and effective data management are key shareholders for the effective management of childhood cancer. The Department of Pediatric Oncology at Indus Hospital and Health Network (IHHN) initiated consistent teaching and trainings with the help of the My Child Matters Grant from Sanofi Espoir Foundation. These courses were conducted in person starting in 2019 and had to be postponed and restructured due to coronavirus (COVID-19) pandemic in early 2020. Objectives The aim of this study was to determine the impact of virtual teaching models for healthcare workers employed in pediatric hematology/oncology departments in low-resource settings. Materials and Methods After in-person courses in 2019, courses for all six disciplines (physicians, nursing, infection control, pharmacy, psychosocial care, and cancer registry) were conducted virtually starting December 2020, open to all and free of cost. A total of 878 registrations were obtained and 267 certifications given. Lectures with Q&A sessions were conducted via zoom and recordings shared through email. Each course was conducted by the relevant department at IHHN with pre- and postassessment conducted through Google Forms. Session feedback was taken through zoom polls and a comprehensive course feedback conducted after completion; e-certificates were awarded to successful participants according to a predetermined criterion. Results A total of 434 physicians' registrations were done from around Pakistan and countries like Saudi Arabia, Malaysia, Jordan, and Canada for the online physicians' course, of which 110 received certifications after completing post-test and attendance criteria of 55%. Pharmacy, infection control, psychosocial care, and cancer registry courses saw participation and certification of 51, 41, 24, and 14 participants, respectively. Online sessions received positive feedback in terms of instructors, course content, convenience, and access from over 90% participants. Conclusion Due to the ease in coordinating hectic schedules and cost-effectiveness of online lectures, this virtual teaching model will persist despite the trajectory of the COVID-19 pandemic. Similar ventures aimed at pediatric oncology teaching and training are needed in a widespread manner to improve outcomes of childhood cancer.
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Karrison, T., H. L. Kindler, D. R. Gandara, et al. "Final analysis of a multi-center, double-blind, placebo-controlled, randomized phase II trial of gemcitabine/cisplatin (GC) plus bevacizumab (B) or placebo (P) in patients (pts) with malignant mesothelioma (MM)." Journal of Clinical Oncology 25, no. 18_suppl (2007): 7526. http://dx.doi.org/10.1200/jco.2007.25.18_suppl.7526.
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7526 Background: In phase II trials in MM, GC on a 21-day (D) schedule has response rates of 16%–26% and median overall survival (OS) of 9.6–13 months (mo). Since VEGF has a key role in MM biology, we added anti-VEGF antibody B to GC in a multi-center, double- blind, placebo-controlled randomized phase II trial. Methods: Eligible pts had unresectable MM; no prior chemotherapy; PS 0–1; no thrombosis, bleeding, or major vessel invasion. Primary endpoint: progression-free survival (PFS). Statistics: 90% power to detect HR 0.57. Stratification: PS (0/1), histology (epithelial/other). G 1,250 mg/m2 D 1, 8 Q21D, C 75 mg/m2 D1 Q21D, and B 15 mg/kg or P D1 Q21D was given × 6 cycles, then B or P Q21D until progression. Baseline plasma VEGF was measured. 115 pts enrolled 12/01- 07/05 at 11 sites, 108 (GCB/GCP) 53/55 were evaluable. Male 74%/84%; median age 62/65 (range 44–78/20–84); PS 1 55%/47%; epithelial 74%/67%; pleural 93%/91%; thrombocytosis 40%/40%. Results: Cycles: total 458/424, median 7/6, range 1–42/2–39. Statistically significantly different (SSD) toxicity (p <0.05), any grade: alopecia 60%/38%; epistaxis 62%/24%; hypertension 45%/22%; non-neutropenic infection 15%/4%; proteinuria 62%/47%; stomatitis 23%/7%. There were no SSD toxicities = grade 3. Median PFS 6.9/6.0 mo (HR 0.93, p=0.88). Median OS 15.6/14.7 mo (p=0.91). 1-year survival 59%/57%. Partial response 25%/22%; stable disease 51%/60%. Median VEGF (N=56) 131/154 pg/ml (range 31–1760/5–1786). Higher VEGF was associated with shorter PFS (p=0.02) and OS (p=0.0066). In pts with VEGF = the median, PFS (p=0.043) and OS (p=0.028) were significantly greater for GCB than GCP; in high VEGF strata this was not SSD. Conclusion: Adding B to GC in MM pts does not yield statistically significant differences in PFS, OS, response, or grade ¾ toxicity. GCB-treated pts with low VEGF levels had longer PFS and OS. Supported by NCI grant N01-CM-17102. No significant financial relationships to disclose.
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Frerichs, Kristine A., Monique C. Minnema, Mark-David Levin, et al. "Efficacy and Safety of Daratumumab Combined with All-Trans Retinoic Acid in Relapsed/Refractory Multiple Myeloma; Results of the Phase 1/2 Dara/ATRA Study." Blood 134, Supplement_1 (2019): 1826. http://dx.doi.org/10.1182/blood-2019-123383.
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Introduction: Daratumumab (DARA) has potent single agent activity in relapsed/refractory multiple myeloma (RRMM). The effectivity of DARA is partially dependent on the expression of its target, CD38, on tumor cells. Upregulation of CD38 on MM cells by all-trans retinoic acid (ATRA) improved the ex vivo efficacy of DARA, even in DARA-resistant MM cells. We therefore evaluated the efficacy and safety of DARA combined with ATRA in RRMM patients in the DARA/ATRA study (NCT02751255). Methods: In part A of this prospective, multicenter phase 1/2 trial, DARA was administered according to the approved schedule (16 mg/kg; cycles 1-2: weekly; cycles 3-6: biweekly; cycles ≥7: monthly). In part B, ATRA was given twice daily during 3 days prior to each DARA infusion. DARA dosing was resumed according to the aforementioned schedule. Inclusion criteria were ≥2 prior lines of treatment, WHO performance score 0-2, adequate bone marrow reserve, kidney and hepatic function. Patients were enrolled in part B, after treatment in part A, if they developed disease progression (PD), or if they had insufficient response defined as < minimal response (MR) after cycle 2, or < partial response (PR) after cycle 3, and if they still fulfilled the other inclusion criteria. All patients gave written informed consent. In phase 1 of part B, we determined the maximum tolerated dose (MTD) of ATRA (dose levels: 15, 30 and 45mg/m2) and the recommended dose level (RDL) for phase 2. We here report overall response rate (ORR), progression free survival (PFS(A)), overall survival (OS) and adverse events (AEs) for all patients in part A. For patients treated at the RDL in part B, we report ORR, PFS(A), PFS for part A + B combined (PFS(A+B)) and AEs. Results: Between July 2016 and October 2017, 63 patients were enrolled in part A, baseline characteristics are described in Table 1. At data cut-off (July 1st, 2019), 6 patients were still on treatment in part A. The median duration of follow-up of surviving patients at data cut-off was 26 months (range 18.2 - 39.4 months). The ORR in part A was 41% (22% PR, 14% very good PR [VGPR] and 5% (stringent) complete remission; Figure 1). The median PFS(A) and OS from start of DARA for all enrolled patients were 7.0 months (95% CI 5.3-8.8) and 28.2 months (95% CI 20.4-36.0), respectively. Eight patients did not meet eligibility criteria for part B, and 1 patient refused further treatment in part B. In part B phase 1, 14 patients were treated with ATRA at the 3 dose levels. The MTD was not reached and the RDL for phase 2 was defined as 45mg/m2. At data cut-off, 34 patients were enrolled in part B phase 2, of whom 2 patients were still on treatment. Thirty-two patients stopped treatment due to PD (n=28) or withdrawal of consent (n=4). Next, we focused on all 42 patients who were treated at the RDL in part B (8 patients in phase 1, and 34 patients in phase 2). The ORR in part B was 5% (VGPR n=2). However, 57% achieved MR or stable disease (SD; Figure 1). During part A, median PFS(A) in these patients was 6.7 months (95% CI 2.7-10.6). When stratified by ≥PR vs SD/MR vs PD/not evaluable (NE), median PFS(A) was 9.9 months (95% CI 3.1-16.7) vs 3.2 months (95% CI 2.5-3.9) vs 1.2 months (95% CI 0.8-1.5), respectively. Addition of ATRA and re-intensification of DARA in DARA-refractory patients resulted in a median PFS(A+B) of 7.9 months (95% CI 5.6-10.1 months). When stratified by ≥PR vs SD/MR vs PD/NE in part A, median PFS(A+B) was 17.7 months (95% CI 9.6-25.7) vs 5.4 months (95% CI 3.8-7.0) vs 2.5 months (95% CI 2.1-2.9), respectively. The presence of extramedullary plasmacytomas (P=0.004 and P=0.012) and WHO ≥ 1 (P=0.002 and P=0.005) were associated with lower PFS(A) and PFS(A+B). Importantly, combination of ATRA with DARA did not increase the rate of AEs (Table 2). The incidence of any grade infusion related reactions (IRR) was 34.9%. There were no complications with red blood cell transfusions. Conclusion: Here, we report for the first time on the efficacy of DARA re-intensification, combined with ATRA in DARA-refractory patients. Overall, this approach resulted in a modest prolongation of PFS. Patients with primary DARA-refractory disease did not benefit from the addition of ATRA. However, in patients with ≥PR on DARA monotherapy prior to progression, addition of ATRA and re-intensification of DARA was of marked clinical benefit with an additional 7.8 months of disease control. The combination of DARA and ATRA was well tolerated and safe. Disclosures Minnema: Celgene Corporation: Honoraria, Research Funding; Amgen: Honoraria; Gilead: Honoraria; Servier: Honoraria; Jansen Cilag: Honoraria. Levin:Takeda: Membership on an entity's Board of Directors or advisory committees, Other: Educational grant ; Amgen: Membership on an entity's Board of Directors or advisory committees, Other: Educational grant ; Janssen: Membership on an entity's Board of Directors or advisory committees, Other: Educational Grant; Roche: Membership on an entity's Board of Directors or advisory committees, Other: Educational Grant; Abbvie: Membership on an entity's Board of Directors or advisory committees, Other: Educational Grant. Broyl:Celgene, amgen, Janssen,Takeda: Honoraria. Bos:Celgene: Research Funding; Kiadis Pharma: Other: Shareholder (of Cytosen, acquired by Kiadis). Kersten:Miltenyi: Honoraria; Mundipharma: Honoraria, Research Funding; Kite Pharma: Honoraria, Research Funding; Bristol-Myers Squibb: Honoraria, Research Funding; Gilead: Honoraria; Amgen: Honoraria, Research Funding; Takeda Oncology: Research Funding; Celgene: Honoraria, Research Funding; Roche: Honoraria, Research Funding; Novartis: Honoraria. Mutis:Janssen Research and Development: Research Funding; Celgene: Research Funding; Onkimmune: Research Funding; Genmab: Research Funding. Zweegman:Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Research Funding. Sonneveld:SkylineDx: Research Funding; Takeda: Honoraria, Research Funding; Karyopharm: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; BMS: Honoraria; Amgen: Honoraria, Research Funding. Van De Donk:Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Membership on an entity's Board of Directors or advisory committees; Janssen Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; Servier: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; Bayer: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; AMGEN: Membership on an entity's Board of Directors or advisory committees, Research Funding. OffLabel Disclosure: ATRA for treatment of MM
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Montes, Anel, Ma Andrade, Ilda Murillo, Luis Lopez-Gomez, Teresa Baringo, and Pilar Giraldo. "RIT with 90Y Ibritumomab Tiuxetan in Agressive Non-Hodgkin Lymphoma. Evaluation of Recent Outcomes in a Single Institution." Blood 120, no. 21 (2012): 4883. http://dx.doi.org/10.1182/blood.v120.21.4883.4883.
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Abstract Abstract 4883 Diffuse Large B Cell (DLBC) and Mantle Cell Lymphoma (MCL), are two subtypes of aggressive non-Hodgkin lymphoma (A-NHL),that frequently present as advanced systemic disease limiting the use of involved field radiation. They are also predominant in advanced age population non suitable for intensive therapy such as stem cell transplantation. Their aggressive systemic behavior, confer high rates of relapse and short overall survival. The development of radioimmunotherapy brings a new therapeutic approach for both types of A-NHL. We present the results derived from a single-institute use of 90Y-Ibritumomab Tiuxetan (90Y-IT) (Zevalin®) in DLBC and MCL, both as consolidation therapy in first complete response (C-1CR) after chemoimmunotherapy and as second line treatment in relapsed disease (RD). Patients and Methods: we included 19 patients with A-NHL, 10 MCL and 9 DLBCL, treated with 90Y-IT according to a multidisciplinary clinical protocol, between September 2005 and February 2012. Inclusion criteria were: histological confirmed CD20+ MCL or DLBCL, with absolute neutrophil count (ANC) ≥ 1.5 × 109/L, absolute platelet count (APC) ≥ 100 × 109/L, ≤ 25% bone marrow CD20+ lymphocytes, in Complete Remission (CR) after first line chemoimmunotherapy or with relapsed disease. All patients received two prior 250 mg/m2 Rituximab doses, followed by 0.4 mCi /kg IV 90Y-IT. Response was evaluated by PET/TC 12 weeks after treatment. Major endpoints were: objective response rate (ORR), overall survival (OS), progression free survival (PFS), and safety. Other clinical prognostic factors were taken into account upon their possible influence in treatment value. Results: 18 of 19 patients treated with 90Y-IT completed follow-up and were taken into analysis, 10 MCL (52.6%) and 9 DLBCL (47.4%); M/F distribution 10/9 (73.6/26.4%); Overall ECOG 0–1 82.35%. Mean follow-up time: 46.8 months. 8 patients were treated as C-1CR, 4 MCL and 4 DLBCL. For MCL mean age was 66.9 (53–79) years. MIPI score distribution: 0–3 (70.0%), >3 (30.0%). Status before 90Y-IT was: C-1CR 3; relapsed in CR after chemotherapy 3; relapsed/refractory with active disease after chemotherapy (PR) 4. Previous chemotherapeutic schedules: ≤2 (50 %). Overall response (80.0%) 7 CR; 1 PR. Mean estimated OS since 90Y-IT: 57.0 months (52.4–61.6), median OS: 59 months (34.8–86.1) and mean PFS: 24.9 months (95% CI: 14.3–35.6); median PFS: 22 months (95% CI: 1.9–42.0). For DLBCL: mean age 53 (35–87) years. IPI-R score distribution: 0–2 (33.3%), >2 (66.7%). Status before 90Y-IT was: C-1CR 5; relapse/refractory with active disease after chemotherapy (PR) 4; Previous chemotherapeutic schedules ≤2 (77.8%). Overall responses (88.8%) 5 CR; 3 PR. Mean OS since 90Y-IT: 49.2 months (42.8–55.6); median OS: NR and mean PFS: 39 months (95% CI: 22.6–55.4). Until analysis 11 patients have relapsed (57.8%), 8 MCL (80%) and 3 DLBCL (37.5%). Four patients had died, 3 because of disease progression even after several chemotherapeutic treatments. In respect to safety: thrombocytopenia was the most frequent hematologic toxicity presented in 63.1%, grade 3–4 in 21%, with median time to presentation of 2.8 weeks and median time for recovery of 3 weeks. Neutropenia occurred in 52.6%, grade 3–4 in 21%, with median time for recovery of 2 weeks. 1 patient (5.2%) required red cell transfusion and 4 (21.5%) needed platelet transfusion. The most frequent non hematologic toxicity was asthenia. One MCL patient who relapsed 28 months and received 2 more chemotherapy schedules has been diagnosed, four years after 90Y-IT as lung carcinoma. Conclusions: 90Y-IT is a safe and effective consolidation therapy in A-NHL, that allows sustained CR and extends PFS with a low toxicity profile. There are needed further studies to evaluate the impact of radioimmunotherapy in A-NHL. This worh has bee partially sponsored by a grant from FEHHA Disclosures: No relevant conflicts of interest to declare.
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Short, Nicholas J., Guillermo Montalban-Bravo, Yesid Alvarado, et al. "Azacitidine, Venetoclax and Pevonedistat As Frontline Therapy for Patients with Secondary Acute Myeloid Leukemia Who Are Unfit for Intensive Chemotherapy: Results from a Phase I/II Study." Blood 138, Supplement 1 (2021): 2349. http://dx.doi.org/10.1182/blood-2021-153682.
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Abstract Background: Pevonedistat is a first-in-class inhibitor of NEDD8-activating enzyme that catalyzes the rate-limiting step of protein neddylation, a critical step in the degradation of cellular proteins that occurs upstream of the proteasome. The combination of azacitidine plus pevonedistat has resulted in high response rates and durable remissions in both myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML), particularly in secondary AML (s-AML). Preclinical studies suggest that pevonedistat synergizes with venetoclax through neutralization of Mcl-1, providing rationale for the triplet combination of azacitidine, venetoclax and pevonedistat. Methods: In this phase I/II study, adult patients (pts) with newly diagnosed s-AML, including pts with therapy-related AML (t-AML) or AML with MDS-related changes, who were unsuitable for intensive chemotherapy were eligible. Pts were required to have a performance status ≤2, total bilirubin ≤ upper limit of normal (ULN), ALT/AST ≤2.5 x ULN, and creatinine clearance ≥30 mL/min. In cycle 1, pts received azacitidine 75 mg/m 2 SC/IV on days 1-7, venetoclax on days 1-28, and pevonedistat 20 mg/m 2 IV on days 1, 3 and 5 on a 28-day schedule. Venetoclax dose ranged from 200mg to 400mg daily during the phase I dose escalation. For cycles 2 and beyond, venetoclax was given on days 1-21. Results: Between 3/2019 and 5/2021, 28 pts were treated (3 pts at venetoclax 200mg daily and 25 pts at 400mg daily). Baseline characteristics are shown in Table 1. The median age was 74 years (range, 61-80), and 12 pts (43%) were ≥75 years of age. The study population was enriched with pts with poor-risk features, including 19 pts (68%) with adverse-risk cytogenetics, 14 (50%) with prior hypomethylating (HMA) or chemotherapy exposure for preceding hematologic malignancy, and 8 (29%) with TP53 mutation. The overall response rate (CR+CRi+MLFS) was 71%, and the CR+CRi rate was 64%. Thirteen pts (46%) achieved CR as best response, 5 (18%) achieved CRi, and 2 (7%) achieved MLFS. Among the 18 pts who achieved CR/CRi, 8 (44%) achieved MRD negativity by multiparameter flow cytometry. Responses were observed across subgroups, including in 8/14 pts (57%) with prior HMA/chemotherapy exposure, 6/8 pts (75%) with TP53 mutation, 12/19 pts (63%) with poor-risk cytogenetics, and 8/9 pts (89%) without non-poor-risk cytogenetics. With a median follow-up of 13.4 months (range 0.4 to 26.3+ months), the median overall survival (OS) was 8.2 months, and the median relapse-free survival was 7.5 months (Figure 1). The median OS for pts with poor-risk and non-poor cytogenetics was 7.9 and 18.0 months, respectively; for pts with and without prior HMA/chemotherapy exposure was 6.2 and 8.9 months, respectively; and for pts with inv(3) AML, TP53-mutated AML, and non-inv(3)/non-TP53-mutated AML was 3.8, 8.9, and 18.0 months, respectively. Four pts (14% of the entire cohort, 20% of responding pts) proceed to hematopoietic stem cell transplantation (HSCT), 3 of whom are still alive and 1 with inv(3) who relapsed post-HSCT and died from progressive AML. The combination was overall well-tolerated with myelosuppression as expected with the combination of HMA plus venetoclax in AML. The median number of cycles received was 2 (range, 1-13 cycles). Non-hematologic grade ≥3 adverse events occurring in ≥2 pts included infection or neutropenic fever in 18 pts (61%), hypophosphatemia in 8 pts (29%), hyperglycemia, hyperbilirubinemia and ALT/AST elevation in 3 pts each (11%), and pneumonitis, acute kidney injury, hypokalemia and vomiting in 2 pts each (7%). One pt developed multiorgan failure on cycle 1, day 1 of therapy, with transaminase elevation, hyperbilirubinemia, renal failure and hyperferritinemia; this pt recovered with holding therapy and supportive care. Hypophosphatemia, which has previously been reported with pevonedistat, was easily managed with oral or intravenous phosphorus supplementation. The 4-week and 8-week mortality rates were 7% and 14%, respectively. Conclusions: The combination of azacitidine, venetoclax and pevonedistat was safe and effective in a very poor-risk population of pts with s-AML, half of whom had prior HMA or chemotherapy exposure for antecedent hematologic malignancy. A randomized study evaluating azacitidine and venetoclax ± pevonedistat (NCT04266795) is ongoing and will help to clarify the potential role of pevonedistat in the frontline treatment of AML. Figure 1 Figure 1. Disclosures Short: AstraZeneca: Consultancy; Jazz Pharmaceuticals: Consultancy; NGMBio: Consultancy; Astellas: Research Funding; Novartis: Honoraria; Takeda Oncology: Consultancy, Research Funding; Amgen: Consultancy, Honoraria. Alvarado: Daiichi-Sankyo: Research Funding; Jazz Pharmaceuticals: Research Funding; FibroGen: Research Funding; BerGenBio: Research Funding; MEI Pharma: Research Funding; Sun Pharma: Consultancy, Research Funding; CytomX Therapeutics: Consultancy; Astex Pharmaceuticals: Research Funding. Konopleva: KisoJi: Research Funding; Ascentage: Other: grant support, Research Funding; AstraZeneca: Other: grant support, Research Funding; Agios: Other: grant support, Research Funding; Ablynx: Other: grant support, Research Funding; Cellectis: Other: grant support; Forty Seven: Other: grant support, Research Funding; AbbVie: Consultancy, Honoraria, Other: Grant Support, Research Funding; Rafael Pharmaceuticals: Other: grant support, Research Funding; Eli Lilly: Patents & Royalties: intellectual property rights, Research Funding; Calithera: Other: grant support, Research Funding; Sanofi: Other: grant support, Research Funding; Stemline Therapeutics: Research Funding; F. Hoffmann-La Roche: Consultancy, Honoraria, Other: grant support; Reata Pharmaceuticals: Current holder of stock options in a privately-held company, Patents & Royalties: intellectual property rights; Genentech: Consultancy, Honoraria, Other: grant support, Research Funding; Novartis: Other: research funding pending, Patents & Royalties: intellectual property rights. Jabbour: Amgen, AbbVie, Spectrum, BMS, Takeda, Pfizer, Adaptive, Genentech: Research Funding. Yilmaz: Pfizer: Research Funding; Daiichi-Sankyo: Research Funding. Jain: Genentech: Honoraria, Research Funding; Cellectis: Honoraria, Research Funding; Precision Biosciences: Honoraria, Research Funding; ADC Therapeutics: Honoraria, Research Funding; Pfizer: Research Funding; Adaptive Biotechnologies: Honoraria, Research Funding; Bristol Myers Squibb: Honoraria, Research Funding; Aprea Therapeutics: Research Funding; Janssen: Honoraria; Incyte: Research Funding; Servier: Honoraria, Research Funding; AstraZeneca: Honoraria, Research Funding; Fate Therapeutics: Research Funding; Beigene: Honoraria; TG Therapeutics: Honoraria; Pharmacyclics: Research Funding; AbbVie: Honoraria, Research Funding. Borthakur: Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Ryvu: Research Funding; ArgenX: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; Astex: Research Funding; University of Texas MD Anderson Cancer Center: Current Employment; GSK: Consultancy; Protagonist: Consultancy. DiNardo: ImmuneOnc: Honoraria, Research Funding; Notable Labs: Current holder of stock options in a privately-held company, Membership on an entity's Board of Directors or advisory committees; Foghorn: Honoraria, Research Funding; Forma: Honoraria, Research Funding; Bristol Myers Squibb: Honoraria, Research Funding; GlaxoSmithKline: Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria; Novartis: Honoraria; Agios/Servier: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Research Funding; Celgene, a Bristol Myers Squibb company: Honoraria, Research Funding. Daver: Astellas: Consultancy, Research Funding; Bristol Myers Squibb: Consultancy, Research Funding; Sevier: Consultancy, Research Funding; Glycomimetics: Research Funding; Gilead Sciences, Inc.: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; FATE Therapeutics: Research Funding; Amgen: Consultancy, Research Funding; Abbvie: Consultancy, Research Funding; Trovagene: Consultancy, Research Funding; Hanmi: Research Funding; Novimmune: Research Funding; Daiichi Sankyo: Consultancy, Research Funding; Trillium: Consultancy, Research Funding; ImmunoGen: Consultancy, Research Funding; Novartis: Consultancy; Jazz Pharmaceuticals: Consultancy, Other: Data Monitoring Committee member; Dava Oncology (Arog): Consultancy; Celgene: Consultancy; Syndax: Consultancy; Shattuck Labs: Consultancy; Agios: Consultancy; Kite Pharmaceuticals: Consultancy; SOBI: Consultancy; STAR Therapeutics: Consultancy; Karyopharm: Research Funding; Newave: Research Funding. Issa: Syndax Pharmaceuticals: Research Funding; Novartis: Consultancy, Research Funding; Kura Oncology: Consultancy, Research Funding. Pemmaraju: MustangBio: Consultancy, Other; ASH Communications Committee: Membership on an entity's Board of Directors or advisory committees; Aptitude Health: Consultancy; Samus: Other, Research Funding; Plexxicon: Other, Research Funding; Sager Strong Foundation: Other; CareDx, Inc.: Consultancy; Cellectis S.A. ADR: Other, Research Funding; Daiichi Sankyo, Inc.: Other, Research Funding; Dan's House of Hope: Membership on an entity's Board of Directors or advisory committees; HemOnc Times/Oncology Times: Membership on an entity's Board of Directors or advisory committees; ASCO Leukemia Advisory Panel: Membership on an entity's Board of Directors or advisory committees; Abbvie Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other, Research Funding; Springer Science + Business Media: Other; Pacylex Pharmaceuticals: Consultancy; Celgene Corporation: Consultancy; Roche Diagnostics: Consultancy; DAVA Oncology: Consultancy; Stemline Therapeutics, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other, Research Funding; LFB Biotechnologies: Consultancy; Novartis Pharmaceuticals: Consultancy, Other: Research Support, Research Funding; Incyte: Consultancy; Affymetrix: Consultancy, Research Funding; Protagonist Therapeutics, Inc.: Consultancy; Clearview Healthcare Partners: Consultancy; Blueprint Medicines: Consultancy; Bristol-Myers Squibb Co.: Consultancy; ImmunoGen, Inc: Consultancy. Sasaki: Daiichi-Sankyo: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Research Funding. Ravandi: AstraZeneca: Honoraria; Jazz: Honoraria, Research Funding; Taiho: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Agios: Honoraria, Research Funding; Bristol Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Honoraria, Research Funding; Astex: Honoraria, Research Funding; Syros Pharmaceuticals: Consultancy, Honoraria, Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Xencor: Honoraria, Research Funding; Novartis: Honoraria; Prelude: Research Funding. Kadia: Genfleet: Other; Cure: Speakers Bureau; Genentech: Consultancy, Other: Grant/research support; Amgen: Other: Grant/research support; Dalichi Sankyo: Consultancy; Jazz: Consultancy; Novartis: Consultancy; Liberum: Consultancy; Aglos: Consultancy; Pfizer: Consultancy, Other; AbbVie: Consultancy, Other: Grant/research support; Pulmotech: Other; BMS: Other: Grant/research support; Astellas: Other; Sanofi-Aventis: Consultancy; AstraZeneca: Other; Cellonkos: Other; Ascentage: Other. Andreeff: Breast Cancer Research Foundation: Research Funding; Aptose: Consultancy; Daiichi-Sankyo: Consultancy, Research Funding; Karyopharm: Research Funding; Novartis, Cancer UK; Leukemia & Lymphoma Society (LLS), German Research Council; NCI-RDCRN (Rare Disease Clin Network), CLL Foundation; Novartis: Membership on an entity's Board of Directors or advisory committees; Glycomimetics: Consultancy; Senti-Bio: Consultancy; Oxford Biomedica UK: Research Funding; Syndax: Consultancy; AstraZeneca: Research Funding; ONO Pharmaceuticals: Research Funding; Amgen: Research Funding; Reata, Aptose, Eutropics, SentiBio; Chimerix, Oncolyze: Current holder of individual stocks in a privately-held company; Medicxi: Consultancy. Bose: Pfizer: Research Funding; Constellation Pharmaceuticals: Research Funding; Novartis: Honoraria; Sierra Oncology: Honoraria; Kartos Therapeutics: Honoraria, Research Funding; Blueprint Medicines: Honoraria, Research Funding; CTI BioPharma: Honoraria, Research Funding; Celgene Corporation: Honoraria, Research Funding; BMS: Honoraria, Research Funding; Incyte Corporation: Honoraria, Research Funding; Astellas: Research Funding; NS Pharma: Research Funding; Promedior: Research Funding. Kantarjian: Ipsen Pharmaceuticals: Honoraria; Amgen: Honoraria, Research Funding; Precision Biosciences: Honoraria; Astellas Health: Honoraria; Astra Zeneca: Honoraria; Immunogen: Research Funding; Daiichi-Sankyo: Research Funding; KAHR Medical Ltd: Honoraria; Aptitude Health: Honoraria; Pfizer: Honoraria, Research Funding; Ascentage: Research Funding; NOVA Research: Honoraria; BMS: Research Funding; Jazz: Research Funding; Novartis: Honoraria, Research Funding; AbbVie: Honoraria, Research Funding; Taiho Pharmaceutical Canada: Honoraria. Cortes: Novartis: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Bio-Path Holdings, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees; Sun Pharma: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; Bristol Myers Squibb, Daiichi Sankyo, Jazz Pharmaceuticals, Astellas, Novartis, Pfizer, Takeda, BioPath Holdings, Incyte: Consultancy, Research Funding.
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Deligeorgakis, D., M. Trachana, P. Pratsidou-Gertsi, D. Dimopoulou, A. B. Haidich, and A. Garyfallos. "AB0976 CAPTURING THE ENTHESITIS RELATED ARTHRITIS CONTEMPORARY PROFILE OF NORTHERN GREEK PATIENTS IN THE ERA OF BIOLOGICS." Annals of the Rheumatic Diseases 79, Suppl 1 (2020): 1782.1–1783. http://dx.doi.org/10.1136/annrheumdis-2020-eular.2946.
Full textAbstract:
Background:Enthesitis-Related Arthritis (ERA) is a subtype of Juvenile Idiopathic Arthritis (JIA) subtype with an estimated prevalence ranging from 8% to 37.4%. The improvement of the disease course and outcome has been related with the introduction of biologic Disease-Modifying Antirheumatic Drugs (bDMARDs) and the uninterrupted monitoring following the transition of young patients to adult rheumatology settings.Objectives:To capture the contemporary ERA profile in Northern Greek patients by analyzing the characteristics and treatment outcome in the era of bDMARDs.Methods:This retrospective cohort study included patients who had been monitored on a 3-month schedule for ≥12 months, from 2000 to 2017. The periodic metric assessment included the disease status and burden by applying contemporary tools in respect to activity, clinical remission (CR) and damage (cJADAS, JSpADA, Wallace criteria for CR and JADI, respectively).Results:Forty-three patients, mainly male (60%) with a mean age at disease onset of 10.75 (SD:2.75) years were enrolled. The predominant joints were the hip, ankle and sacroiliac (56%, 49% and 46%, respectively). Median lag time from diagnosis to bDMARDs initiation was 8.5 months. Patients with sacroiliitis were more likely to receive bDMARDs (hazard ratio [HR]:3.26, 95% confidence interval [CI]: 1.35, 7.88). Thirty six patients (84%) achieved clinical remission (CR) on medication (CRONM), within a median time of 11 months and correlated with compliance (HR:3.62, 95%CI: 1.34, 9.76). Twenty patients (47%) experienced a flare following CR, mainly as a single episode (75%). The median flare-free survival following remission on and off medication (CROFFM) was 42 and 34 months, respectively. At the last evaluation, both median baseline cJADAS (8), and JSpADA (2) dropped to 0, while 13 patients (30%) were in CROFFM, 17 (40%) in CRONM, and 13 (30%) had persistent disease activity. The median percentage of CR per patient was 54% and no patient had JADI >0.Conclusion:Early administration of bDMARDs and compliance to monitoring and treatment improved the long-term outcome in ERA. Axial involvement emerged as a negative prognostic factor with an increased need for bDMARDs and diminished rates of CR.Disclosure of Interests:Dimitrios Deligeorgakis: None declared, Maria Trachana: None declared, Polyxeni Pratsidou-Gertsi: None declared, Despoina Dimopoulou: None declared, Anna Bettina Haidich: None declared, Alexandros Garyfallos Grant/research support from: MSD, Aenorasis SA, Speakers bureau: MSD, Novartis, gsk
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Goldstein, D., J. Shannon, C. Brown, et al. "ABC; An AGITG trial of fixed dose rate (FDR) gemcitabine (gem) and cisplatin for patients (pts) with advanced biliary tract cancer (ABC)." Journal of Clinical Oncology 25, no. 18_suppl (2007): 15015. http://dx.doi.org/10.1200/jco.2007.25.18_suppl.15015.
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15015 Background: No standard regimen exists for pts with ABC. Previous studies suggest that FDR optimises gem activity. This study evaluated the activity of FDR gem with low dose cisplatin using a previously identified schedule. Methods: Single arm, multi- centre phase II trial, planned to enrol 45 pts > 18 years, ECOG PS = 2, with previously untreated histologically / cytologically confirmed, inoperable locally advanced or metastatic ABC. Treatment consisted of FDR gem 1000 mg/m2 (10 mg/m2/min) and cisplatin 20 mg/m2 days 1& 8 q21 days until progression or intolerable toxicity. The primary end point was response rate (RR) by RECIST. Secondary end points included tolerability and safety, progression free and overall survival (PFS, OS) and response duration (RD). Results: 50 pts were enrolled from Feb 05 to Oct 06. Mean age was 60y (39–78); 88% had ECOG PS 0–1; 54% were female. Primary sites were gall bladder 45%, biliary tree 51%, ampulla 4%. Distant metastases were present in 63%. Past treatments included biliary stent in 29%, bypass in 6%, and an external drain in 4%. With a minimum follow-up of 12 weeks, best response was a confirmed PR in 11 pts (RR 22%, 95% CI 11 - 36) and SD (after 4 cycles) in 11 pts (22%), 1 (2%) unevaluable. CA19–9 responses occurred in 6 of 33 pts (18%). Median OS was 7 mo (0.3–13), PFS 4.4 mo (0.3–13), and RD 8 mo (5–12). One year survival rate was 30%. The median number of cycles was 4 (1–16). Treatment was delayed at least once in 45% of pts; mean delay 9d. Grade 3/4 (NCI/CTC) toxicities included infection 9%, fatigue 9%, anorexia/nausea 11%, vomiting 9%, anaemia 9%, neutropenia 28%, thrombocytopenia 15%, abnormal ALP 25%, GGT 47%, AST 6%. There was 1 treatment related death (hematemesis with grade 4 thrombocytopenia). Exploratory analysis of CA 19–9 and its association with response assessment and overall survival will be presented in June. Conclusions: This combination was well tolerated. The observed response rate is consistent with the expected 35% rate and may be superior to that expected with gem monotherapy. Further testing of this dose and scheduling is warranted. The authors thank Lilly for an unrestricted grant to conduct this study. [Table: see text]
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Xiong, YiYing, Fan Qian, Fen Huang, et al. "Mesenchymal Stem Cells Vs. Mesenchymal Stem Cells Combined With Cord Blood For Treating Engraftment Failure Following Autologous Hematopoietic Stem Cell Transplantation: A Pilot Prospective Study." Blood 122, no. 21 (2013): 3693. http://dx.doi.org/10.1182/blood.v122.21.3693.3693.
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Abstract Background Engraftment failure (EF) is a formidable complication after autologous hematopoietic stem cell transplantation (auto-HSCT). Mesenchymal stem cells (MSCs) and cord blood (CB) have been found to support hematopoiesis. Thus, we designed a multicenter randomized clinical trial to investigate the effects and safety of MSCs alone or combined with CB infusion for patients with EF. Methods Twenty-two patients were randomly assigned to receive the treatment with MSCs alone (MSCs group, n=11) or MSCs combined with CB (CB group, n=11). MSCs were administered once every 2 weeks (2 doses were a cycle) in both groups, and single-unit CB was administered at the same day with the first application of MSCs in CB group; After one cycle of treatments (within 28 days), the patients who did not response to MSCs would receive the therapeutic schedule in CB group, and those patients with partial response (PR) in MSCs group and those without complete response (CR) in CB group would continue another cycle of MSCs treatment. If patients did not obtain CR after two cycles of treatments (within 56 days), they would receive other treatments including allogeneic HSCT. Results After the first treatment cycle, the effect rates were not significant difference in MSCs and CB groups (7/11 vs. 9/11, P=0.635), and the median time of hematopoietic reconstruction was 22 (18-28) and 17 (13-22) days, respectively (P=0.036) in MSCs and CB group. There was statistically significant difference regarding neutrophil engraftment, with 17 (range 9-28) and 8 (range 6-14) days respectively (P=0.030), but no difference regarding platelet engraftment, with 21 (range 18-28) and 18 (range 11-21) days respectively (P=0.092) between MSCs and CB groups. After two cycles of treatments, 17 patients obtained CR, 2 PR and 3 NR. CB chimerisms were not detected by short tandem repeat (STR) at +15 and +30 days after CB infusion. None of the patients experienced any adverse events of grade 3/4 with the Common Terminology Criteria for Adverse Events v3.0 (CTCAE v3.0) and acute GVHD or chronic GVHD during the period of study treatment and follow-up. One patient with PR in MSCs group and 1 NR in CB group received allogeneic HSCT at +249 and +273 days after auto-HSCT because of EF and primary disease relapse, respectively. At a median follow-up time of 345 (range 129–784) days post-transplantation, 16 patients remained alive, 3 died of relapse of primary diseases and 1 died of CMV pneumonia following allo-HSCT. None of patients developed EBV-DNA viremia and EBV-associated diseases in two groups. The 2-year overall survival, disease-free survival and tumor relapse post-transplantation were 75.2% (95% CI, 63.2-87.2%), 79.5% (95% CI, 70.1-88.9%) and 20.5% (95% CI, 11.1-29.9%) respectively. Conclusions Our data suggest that ex-vivo-expanded MSCs derived from HLA-mismatched BM alone or combined with unrelated CB are effective to EF after auto-HSCT. CB can facilitate the effect of MSCs to EF. Both two strategies do not result in GVHD or increase the risk of primary diseases relapse in patients with EF. This trial was registered at www.clinicaltrials.govas#NCT01763099. Disclosures: Liu: It was supported by 863 Program (No. 2011AA020105) and National Public Health Grand Research Foundation (Grant No. 201202017).: Research Funding; It was supported by National Natural Science Foundation of China (Grant No.81000231, No.81270647) and Science and Technology Program of Guangzhou of China (11A72121174). : Research Funding.
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Holte, Harald, Sirpa Leppä, Magnus Bjorkholm, et al. "R-CHOEP-14 × 6 Followed by Systemic CNS Prophylaxis for Diffuse Large B-Cell Lymphoma/Follicular Lymphoma Grade 3 with Age Adjusted IPI Score 2–3: Final Results of a Nordic Lymphoma Group Phase 2 Study Including 156 Patients Aged 18–65 Years." Blood 116, no. 21 (2010): 2805. http://dx.doi.org/10.1182/blood.v116.21.2805.2805.
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Abstract Abstract 2805 CHOP – based chemotherapy for aggressive lymphomas in patients with age-adjusted International Prognostic Index (IPI) score of 2–3 resulted in a historical 3-year progression free survival of approximately 30% in a previous Nordic phase III study. The aim of the present study is to determine whether an intensified regimen with chemoimmunotherapy and CNS prophylaxis improves outcome. Methods: From October 2004 to June 2008 patients were included in a phase II study. Inclusion criteria: 1) Age 18–65 years. 2) Newly diagnosed de novo diffuse large B-cell lymphoma (DLBCL) or follicular lymphoma (FL) grade III. 3) No clinical sign of CNS disease and negative CSF cytology/flow cytometry by lumbar puncture. 4) No HIV infection. 5) WHO performance score 0–3. 6) Adequate organ functions. Schedule: Six courses of R-CHOEP14. Pegfilgrastim 6 mg sc. day four of each cycle. One course of high dose cytarabine 12 g/m2 (6 g/m2 for patients 60–65 years). One course of high dose methtrexate 3 g/m2 (1 g/m2 for patients 60–65 years). Biopsy and/or 18FDG PET/CT imaging of residual masses after fulfilled therapy was recommended, but not mandatory. Radiotherapy was given to residual masses of uncertain significance. Results. Demographic data:.156 eligible patients were included (97 males). Median age: 54 years (range 20–64). Histology: DLBCL: 145, FL grade 3: 12 (three patients no data). Age adjusted IPI score: 2: 117; 3: 39. Stage III-IV: 150 patients. LDH elevated: 151 patients. Performance status 2–3: 51 patients. B-symptoms were registered in 97 patients, more than one extranodal site in 42 and bulky lesions (≥ 10 cm) in 68. Median observation time for patients alive at last follow up was 36 months. Toxicity: Three toxic deaths are registered, one large bowel perforation, one fulminant hepatic necrosis and one septic shock. Hematological toxicity grade 4 was seen in 78% of the patients, infection grade 4 in 8%. Radiotherapy was given to 16% of the patients. Response: Response rates at end of therapy: CR/CRu: 69%, PR: 22%, SD: 1%, PD: 4.5%. Seventeen patients (7%) were not treated according to protocol, either due to lack of response (6 patients) or due to toxicity (eleven patients). The majority of the PR patients were considered to have residual masses and not viable tumour tissue. Survival: Three year overall survival was 80% (95% CI +/− 6.5%) and three year treatment failure free time 67% (95% CI +/−8.0%). CNS events: Seven patients had a CNS relapse, all but one were isolated (4 intracerebral, 3 meningeal). All CNS relapses occurred within 6 months after inclusion. Conclusions: The results are promising with a low three year treatment failure rate, a low toxic death rate and fewer CNS events than expected. The CNS events might be further reduced by earlier CNS prophylaxis. The study was supported by an unrestricted grant from Amgen Disclosures: Holte: Roche: Honoraria, Research Funding; Amgen: Honoraria, Research Funding. LeppÃ: Roche: Honoraria. Bjorkholm:Roche: Research Funding. Jyrkkiö:Roche: Honoraria. Kolstad:Roche: Honoraria; Amgen: Honoraria. Fosså:Roche: Honoraria. φstenstad:Roche: Honoraria; Amgen: Honoraria. Eriksson:Amgen: Research Funding.
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Scanlon, M., V. Pridmore, M. Davis, A. Cooper, and A. Beauchamp. "Can Pharmacists Fill the Primary Care Provider Gap in Recommending Breast Screening?" Journal of Global Oncology 4, Supplement 2 (2018): 159s. http://dx.doi.org/10.1200/jgo.18.11300.
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Background and context: BreastScreen Victoria (BSV) provides free breast screening to women aged 40+, targeting women aged 50-74. The program reduces breast cancer deaths by up to 28%. Primary care is important in improving uptake of breast screening. In particular, a recommendation from a health professional is a strong influencer. Many general practitioners (GPs) recommend screening, however, it is important to expand recruitment to other health professionals given many women do not visit a GP regularly. Community pharmacists and pharmacy staff may be a trusted source of health information, and are potentially an underutilized opportunity to promote breast screening to women. Based on this gap, BSV developed a three month pharmacy-based screening awareness campaign that was trialed in community pharmacies throughout 2017/18. The campaign is based on a UK community pharmacy model that was shown to successfully increase public awareness about cancer screening. Aim: BSV aims to diversify the types of health professionals that recommend screening to reach women who do not visit a GP regularly. The aim of the pharmacy-based breast screening awareness campaign is to: • build capacity of pharmacy staff to deliver breast screening messages to their communities • increase awareness of breast screening in women aged 50-74 • increase awareness of breast screening among family and friends of women Strategy/Tactics: BSV's pharmacy-based breast screening awareness campaign was trialed in 4 community pharmacies in 2017. Each pharmacy received a grant of up to $1550 which enabled them to: • allow pharmacy staff to attend training to increase their knowledge of breast screening and the campaign • display BreastScreen collateral throughout the store to provide information and prompt queries • initiate conversations and answer questions about breast screening • monitor campaign activity via a number of methods Outcomes: • Posttraining, 100% of staff were confident in promoting breast screening to customers • Staff across 4 pharmacies had 638 conversations about breast screening with customers (average 160/pharmacy). The majority were with women in the target age group • Most pharmacies suggested shortening the campaign to 2 months • All pharmacies said the funding was a critical motivator to participation • All pharmacies stated that the campaign was worthwhile, and allowed them to participate in health promotion Two additional trials are scheduled to test a reduced campaign duration and funding model. Results will be available later in 2018 What was learned: • Many women do not visit their GP regularly • Community pharmacists and pharmacy staff are an underutilized opportunity to promote breast screening • Delivering cancer screening messages through community pharmacies is an effective way to reach women aged 50-74 • Pharmacy funding and training are critical in enabling pharmacies to deliver a breast screening awareness campaign
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Borchmann, Peter, Alden A. Moccia, Richard Greil, et al. "Tolerability and efficacy of BrECADD versus BEACOPP in advanced stage classical Hodgkin lymphoma: GHSG HD21, a randomized study." Journal of Clinical Oncology 42, no. 17_suppl (2024): LBA7000. http://dx.doi.org/10.1200/jco.2024.42.17_suppl.lba7000.
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LBA7000 Background: We hypothesized that therapy with the novel BrECADD regimen (brentuximab vedotin, etoposide, cyclophosphamide, doxorubicin, dacarbazine, dexamethasone) guided by positron emission tomography after two cycles (PET2) could improve the treatment of advanced-stage classical Hodgkin lymphoma (AS-cHL). The HD21 trial aimed at demonstrating superiority over the intensified BEACOPP regimen (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, prednisone) in terms of treatment-related morbidity (TRMB) and non-inferiority (NI) in terms of progression-free survival (PFS). This is the first report of the final confirmative analysis of the HD21 trial. Methods: HD21 is an international, open-label, randomized phase III trial including AS-cHL patients 18-60 years at diagnosis. Patients were randomized to receive individualized 4 or 6 cycles of either BEACOPP or BrECADD guided by PET2 results. The co-primary endpoints included TRMB and PFS, which had been successfully established recently. Testing for superiority was planned with mature follow-up of four years. An adjusted alpha level of 0.047 was required to cross the efficacy boundary for superiority. The trial was conducted in accordance with ICH-GCP (NCT02661503) and supported by a research grant from Takeda Oncology. Results: The ITT (intention-to-treat) cohort for the efficacy analysis consisted of 1482 patients, of which 742 were randomized to receive BrECADD and 740 to BEACOPP. Median age was 31.1 years (range 18 to 60), 44% were female. PET2 was negative in 424 (57.5%) and 426 (58.2%) patients for BrECADD or eBEACOPP, respectively, and these were scheduled for 4 treatment cycles. With median follow-up of 48 months, 4y-PFS was 94.3% for BrECADD (95%-CI 92.6-96.1), and 90.9% for BEACOPP (95%-CI 88.7-93.1). The hazard ratio was 0.66 [95% CI 0.45-0.97], p=0.035). PFS benefit of BrECADD was driven by a reduction in early treatment failures, i.e., primary progression within 3 months (5 vs. 15) or early relapse between months 3 and 12 (11 vs. 23) and observed across all investigated subgroups. PET2-negative patients in the BrECADD group showed a 4-year PFS of 96.5%. 4-year OS was 98.5% for BrECADD and 98.2% for BEACOPP. Analyses of gonadal function demonstrated significantly higher follicle stimulating hormone recovery rates after one year in both men (67% vs. 24%) and women (89% vs. 68%) with higher birth-rates in the BrECADD group (n=60 vs. n=43). Conclusions: BrECADD is significantly more effective than BEACOPP and is associated with an unprecedentedly high 4-year PFS, reducing the risk of progression, relapse or death by a third. Together with an abbreviated treatment duration of only 3 months for the majority of patients and a favorable tolerability, treatment with PET2-individualized BrECADD sets a new benchmark for the treatment of adult patients with AS-cHL. Clinical trial information: NCT02661503 .
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Matuschek, Christiane, Tanja Fehm, Maria Hufnagel, et al. "Abstract P3-10-22: Preoperative radiotherapy versus postoperative radiotherapy after neoadjuvant chemotherapy in high-risk breast cancer: a prospective, randomized, international multicentre Phase III trial—NeoRad." Clinical Cancer Research 31, no. 12_Supplement (2025): P3–10–22—P3–10–22. https://doi.org/10.1158/1557-3265.sabcs24-p3-10-22.
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Abstract Background: Preoperative radiotherapy is a well-established treatment for various tumor types (rectal cancer, sarcoma, bronchial carcinoma). Promising studies on preoperative radiotherapy also exist for breast cancer, but most of them were not randomized or very old. Recent studies suggest that preoperative radiotherapy followed by immediate reconstruction or flap reconstruction is a low-complication method. There is evidence that the immunogenic effects of radiotherapy may lead to improved immune recognition of tumor cells. These potential immunogenic effects make preoperative radiotherapy a promising modality in interdisciplinary cancer therapy. In addition, preoperative radiotherapy may obviate the need to irradiate implants, expanders, or autologous transplants. NeoRad (NCT04261244, GBG116) is a multicenter, prospective, international randomized Phase III trial. It aims to investigate whether pre- versus postoperative radiotherapy after neoadjuvant chemotherapy (NACT) improves disease-free survival in patients with high-risk breast cancer and show superiority of preoperative radiotherapy (PRT) of the experimental treatment schedule in terms of disease-free survival (DFS). In addition, several secondary endpoints (cosmetic outcomes, quality of life, overall survival, etc.) will be assessed to better understand the benefits and risks of preoperative radiotherapy compared to the current standard of care. Study Design: Only patients with high-risk breast cancer who are eligible for NACT will be enrolled and randomly assigned in a 1:1 ratio to two study arms. In the standard arm, patients will undergo surgery, sentinel lymph node biopsy, possibly axillary dissection or targeted axillary dissection according to current S3/AGO guidelines. After surgery, patients will receive adjuvant radiotherapy +/- lymphatic pathways and, if indicated, systemic treatment according to S3/AGO guidelines. In the experimental arm, patients will receive whole-breast irradiation (WBRT) +/- lymphatic pathway irradiation after NACT. Approximately 3-6 weeks after radiotherapy, patients will undergo surgery including sentinel lymph node biopsy or axillary dissection, followed, if indicated, by post-neoadjuvant systemic therapy according to S3/AGO guidelines. Enrolment in post-neoadjuvant studies is allowed. To assess the response to NACT before radiotherapy, a biopsy of the primary tumor and suspicious lymph nodes is recommended in the experimental arm. An interim analysis on wound healing will be conducted after 100 patients have received breast-conserving surgery or autologous flap reconstruction (in both arms combined) and after 40 and 100 patients have been reconstructed with an implant (also combined from both arms). The recruitment period will be four years. The total study duration, including follow-ups, is ten years. Recruitment: The first patients were enrolled in 02/24 at the University Hospital of Düsseldorf. A total of 1826 patients will be recruited across 40 centers within 4 years. Funding: This study was supported by a grant from Deutsche Krebshilfe. Citation Format: Christiane Matuschek, Tanja Fehm, Maria Hufnagel, Vesna Bjelic-Radisic, Michael Untch, Michael Golatta, Danny Jazmati, Thorsten Kühn, David Krug, Jens Blohmer, Carsten Denkert, Beyhan Ataseven, Carolin Nestle-Krämling, Stefanie Corradini, Jens Huober, Jens Huober, Eugen Ruckhaeberle, Andreas Hartkopf, Theresa Link, Kerstin Rhiem, Elmar Stickeler, Claus Hanusch, Jörg Heil, Christine Solbach, Mattea Reinisch, Inga Bekes, Johannes Holtschmidt, Valentina Nekljudova, Sibylle Loibl, Wilfried Budach. Preoperative radiotherapy versus postoperative radiotherapy after neoadjuvant chemotherapy in high-risk breast cancer: a prospective, randomized, international multicentre Phase III trial—NeoRad [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2024; 2024 Dec 10-13; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2025;31(12 Suppl):Abstract nr P3-10-22.
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Cherng, Hua-Jay J., Raamis Khwaja, Rashmi Kanagal-Shamanna, et al. "Retrospective Single-Institution Analysis of Patients with Chronic Lymphocytic Leukemia with TP53 alterations Treated First-Line with Bruton's Tyrosine Kinase Inhibitor-Based Therapy." Blood 138, Supplement 1 (2021): 394. http://dx.doi.org/10.1182/blood-2021-146432.
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Abstract Introduction Long-term follow up of prospective studies has shown that continuous Bruton's tyrosine kinase inhibitor (BTKi) therapy leads to durable remissions in previously untreated TP53-altered CLL. Additionally, combining BTKi with the BCL2 inhibitor venetoclax (VEN) achieves deep remissions with similar rates of undetectable measurable residual disease in these high-risk patients (pts) compared to those with wildtype TP53. Without randomized data, it is unclear which pts would benefit most from combined targeted therapy over BTKi monotherapy. It is also unknown how size of the TP53-altered clone influences efficacy of BTKi therapy. We performed a retrospective analysis of pts with CLL with baseline deletion 17p [del(17p)] and/or mutated TP53 (TP53-m) treated with BTKi +/- VEN +/- CD20 mAb in the first-line setting. Methods Pts with CLL/SLL and pretreatment testing (FISH and TP53 sequencing by NGS assay in &gt;95% of pts with 1% limit of detection) performed at our institution (MDACC) demonstrating del(17p) and/or TP53-m who received first-line BTKi-based therapy were included. Pts started treatment between March 2012 and June 2021. The primary endpoint was progression-free survival (PFS) from therapy start. Pts were categorized into those who received first-line BTKi +/- CD20 mAb versus combined BTKi and fixed-duration VEN +/- CD20 mAb. Outcomes were analyzed by baseline characteristics, including size of the TP53-altered clone (% cells with del(17p) and variant allele frequency [VAF] for TP53-m). Results A total of 140 pts with TP53 alteration who received first-line BTKi-based treatment for CLL were included. Pretreatment characteristics are summarized in Table 1. The median follow-up was 3.0 years (range, 0.1 to 9.0). Overall, a total of 38 (27%) pts experienced a progression event, 18 (13%) pts died, and 10 (7%) experienced RT. The 4-year PFS rate was 72.7% and median PFS was 6.3 years (Fig. 1A). The 4-year OS rate was 87.2% (Fig. 1B). A total of 112/140 (80%) pts had pretreatment del(17p). The median % of cells with del(17p) was 60.5% (range, 3.5-99). TP53-m was noted in 100 of the 120 (83%) tested. There were 120 unique TP53 mutations, of which 115 had an available VAF; the median VAF was 34.1% (range, 1-99.5). Among the pts tested for both del(17p) and TP53-m (n=120), 42 (35%) pts had a single alteration [del(17p) or single TP53-m] and 78 (65%) had multiple alterations [both del(17p) and TP53-m or multiple TP53-m]. By univariable analyses, no baseline characteristic was significantly associated with PFS. PFS was not different for TP53-m pts based a VAF threshold of 10% (Fig. 2A) and del(17p) pts based on a threshold of 25% cells affected (Fig. 2B). No baseline characteristic was associated with OS. A total of 101 (72%) pts received a BTKi +/- CD20 mAb without VEN; 39 (28%) received BTKi and VEN (+/- CD20 mAb) (4 pts included who did not get VEN due to early study withdrawal or data censoring). PFS was significantly longer for BTKi + VEN pts vs. BTKi only pts (p=0.009, Fig. 3A) with a HR of 0.18 (95% CI 0.04-0.77) and there was a trend for longer OS in BTKi + VEN pts (p=0.092, Fig. 3B) with a HR of 0.21 (95% CI 0.03-1.57). BTKi + VEN pts were less likely to harbor TP53-m (69% v 90%, p=0.008) or multi-alteration TP53 (44% v 75%, p&lt;0.001), but no other baseline characteristics were significantly different (Table 1). A total of 28/140 (20%) pts received a CD20 mAb. There was no significant association of CD20 mAb with PFS (p=0.54). Conclusions We report favorable 4-year PFS and OS rates of 72.7% and 87.2% in a large retrospective cohort of pts with TP53-altered CLL receiving first-line BTKi-based therapy. The clone size either by % FISH+ or by TP53-m VAF was not associated with PFS, which may reflect the high efficacy of BTKi. PFS appears longer for pts treated with BTK + VEN compared to BTKi only pts, and there was a trend towards improved OS. Though the BTKi + VEN group had lower rates of TP53-m and multiple TP53 alterations, neither characteristic was associated with shorter PFS. Heterogeneity in patient follow-up and response assessment schedule across this pt cohort could be a confounding factor. Whether combination fixed-duration BTKi + VEN is preferable over sequential treatment with these agents remains an unanswered question; this is especially pertinent in pts with high-risk genomics. Therefore, studies dedicated to enrolling such patients are needed to formally clarify optimal treatment for these high-risk patients. Figure 1 Figure 1. Disclosures Burger: Beigene: Research Funding, Speakers Bureau; TG Therapeutics: Other: Travel/Accommodations/Expenses, Research Funding, Speakers Bureau; Novartis: Other: Travel/Accommodations/Expenses, Speakers Bureau; AstraZeneca: Consultancy; Gilead: Consultancy, Other: Travel/Accommodations/Expenses, Research Funding, Speakers Bureau; Pharmacyclics LLC: Consultancy, Other: Travel/Accommodations/Expenses, Research Funding, Speakers Bureau; Janssen: Consultancy, Other: Travel/Accommodations/Expenses, Speakers Bureau. Thompson: Genentech: Other: Institution: Advisory/Consultancy, Honoraria, Research Grant/Funding; Amgen: Other: Institution: Honoraria, Research Grant/Funding; Janssen: Consultancy, Honoraria; Pharmacyclics: Other: Institution: Advisory/Consultancy, Honoraria, Research Grant/Funding; Adaptive Biotechnologies: Other: Institution: Advisory/Consultancy, Honoraria, Research Grant/Funding, Expert Testimony; Gilead: Other: Institution: Advisory/Consultancy, Honoraria; AbbVie: Other: Institution: Advisory/Consultancy, Honoraria, Research Grant/Funding. Ferrajoli: Janssen: Other: Advisory Board ; AstraZeneca: Other: Advisory Board, Research Funding; BeiGene: Other: Advisory Board, Research Funding. Sasaki: Daiichi-Sankyo: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Research Funding. Kantarjian: Immunogen: Research Funding; Aptitude Health: Honoraria; Daiichi-Sankyo: Research Funding; Astra Zeneca: Honoraria; Amgen: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding; NOVA Research: Honoraria; Jazz: Research Funding; KAHR Medical Ltd: Honoraria; BMS: Research Funding; AbbVie: Honoraria, Research Funding; Ipsen Pharmaceuticals: Honoraria; Astellas Health: Honoraria; Ascentage: Research Funding; Novartis: Honoraria, Research Funding; Precision Biosciences: Honoraria; Taiho Pharmaceutical Canada: Honoraria. Wierda: Juno Therapeutics: Research Funding; KITE Pharma: Research Funding; Loxo Oncology, Inc.: Research Funding; Miragen: Research Funding; Cyclacel: Research Funding; Sunesis: Research Funding; Acerta Pharma Inc.: Research Funding; Pharmacyclics LLC, an AbbVie Company: Research Funding; Oncternal Therapeutics, Inc.: Research Funding; Karyopharm: Research Funding; Gilead Sciences: Research Funding; Xencor: Research Funding; Janssen: Research Funding; Genentech: Research Funding; AstraZeneca: Research Funding; GSK/Novartis: Research Funding; Genzyme Corporation: Consultancy; AbbVie: Research Funding. Jain: Beigene: Honoraria; Janssen: Honoraria; Servier: Honoraria, Research Funding; AbbVie: Honoraria, Research Funding; Incyte: Research Funding; Genentech: Honoraria, Research Funding; Precision Biosciences: Honoraria, Research Funding; TG Therapeutics: Honoraria; AstraZeneca: Honoraria, Research Funding; Fate Therapeutics: Research Funding; Pharmacyclics: Research Funding; Cellectis: Honoraria, Research Funding; ADC Therapeutics: Honoraria, Research Funding; Aprea Therapeutics: Research Funding; Pfizer: Research Funding; Adaptive Biotechnologies: Honoraria, Research Funding; Bristol Myers Squibb: Honoraria, Research Funding.
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Palladini, Giovanni, Paolo Milani, Simone Celant, et al. "The Italian Medicines Agency Prospective Registry of Bortezomib-Based Treatment in AL Amyloidosis." Blood 136, Supplement 1 (2020): 22. http://dx.doi.org/10.1182/blood-2020-141563.
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Background: There is no licensed therapy for light chain (AL) amyloidosis; however, bortezomib (B) is considered standard upfront treatment. Existing data on safety and efficacy of B in AL amyloidosis derive from clinical trials and retrospective series from few referral centers and only partly reflect real-world practice. In 2011, the Italian Medicines Agency (AIFA) started a program to grant access to upfront B to patients with AL amyloidosis. Treated patients had to be enrolled in an online registry and prospectively followed during therapy. We report the treatment experience in this real-world setting. Methods: AL amyloidosis diagnosis required tissue typing with mass spectrometry or immuno-electron microscopy. Patients samples could be sent to the Pavia specialized center for typing, but patients were not treated under the supervision of the referral center. Subjects with multiple myeloma were excluded. Variables were collected at baseline and hematologic and cardiac responses were assessed after 8 weeks (approximately 2 cycles) according to the International Society of Amyloidosis criteria. The cox proportional model has been adopted to assess the risk of treatment discontinuation according to the baseline characteristics. Results: A total of 754 patients were treated between May 2011 and October 2019 and 605 were included in the analysis. Most common reasons for exclusion were retrospective data collection (45%), and incomplete data set (31%). Median age was 67 years (range 26-89 years). 82% of patients had heart involvement. Cardiac stage was I in 18% of subjects, II in 45%, IIIa in 21%, and IIIb, in 16%. Sixty-seven percent of patients had renal involvement, and 13% and 14% had severe (glomerular filtration rate [eGFR] between 30 and 15 mL/min) and end-stage (eGFR &lt;15 mL/min) renal insufficiency, respectively. Differential free light chain level (dFLC) was &gt;180 mg/L in 41% of cases. Bortezomib was administered with dexamethasone (D) alone in 41% of patients, with cyclophosphamide and D (CyBorD) in 44%, and with melphalan and D (BMDex) in 13% of subjects. Other combinations were used in 2% of patients. In the overall population, the initial dose of B was attenuated (&lt;1.3 mg/m2) in 22% of patients. The proportion of patients receiving attenuated dosage was higher in stage III patients (38%). Fourteen percent of subjects required B dose reduction during therapy, while B dosage could be increased in 7% of patients who started at a reduced dose. A twice-weekly B schedule at treatment initiation was used in 22% of all subjects and in 16% of stage III patients. Fourteen percent of patients initially treated with the twice weekly schedule needed to be shifted to the once weekly schedule. After 8 weeks (approximately 2 cycles) the overall hematologic response rate was 58% (CR 3%, VGPR 20%) and cardiac response was attained in 14% of patients. The median number of cycles performed was 3 (range 1-9), median duration of monitored treatment was 4.3 months. Treatment was discontinued during monitoring due to achievement of satisfactory response or completion of maximum (9) allowed number of cycles in 3% of cases, progression in 14%, death in 8%, and toxicity in 1% of patients. The cause of discontinuation was defined as independent of drug and disease in the remaining 25.1% of subjects. Risk of treatment discontinuation was lower in patients who could tolerate a 1.3 mg/m2 dose of B from cycle 1 (HR 0.70, 95%CI 0.54-0.91). Second-line therapy with immunomodulators (most commonly lenalidomide) was started in 14% of patients. Conclusions: Patients with AL amyloidosis start treatment at an advanced stage and early deaths are common. The rate of severe/end-stage renal failure was higher (27%) than expected, possibly indicating that these patients are less likely to be referred to specialized centers. Remarkably, outside referral centers B is commonly administered with D alone. Dose reductions are frequently applied, but dosage can be escalated during therapy. Response rates at 8 weeks are comparable to those reported in other large studies and early cardiac responses are possible. To the best of our knowledge this is the only study prospectively evaluating treatment with B in a real-world setting. Treatment registries under the supervision of regulatory agencies are precious tools to assess common therapeutic practice in rare disease, to evaluate candidate comparators for future trials, and to assess unmet medical needs. Disclosures Palladini: Celgene: Other: Travel support; Jannsen Cilag: Honoraria, Other. Milani:Janssen: Other: Speaker honoraria; Celgene: Other: Travel support; Pfizer: Other: Speaker honoraria. Nuvolone:Janssen: Honoraria. OffLabel Disclosure: Bortezomib in AL amyloidosis
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Sonneveld, Pieter, Emilie Asselberg-Hacker, Sonja Zweegman, et al. "Dose Escalation Phase 2 Trial Of Carfilzomib Combined With Thalidomide and Low-Dose Dexamethason In Newly Diagnosed, Transplant Eligible Patients With Multiple Myeloma. A Trial Of The European Myeloma Network." Blood 122, no. 21 (2013): 688. http://dx.doi.org/10.1182/blood.v122.21.688.688.
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Abstract Background A proteasome inhibitor (PI) combined with an immune-modulatory dexamethasone has significant activity in replapse and newly diagnosed Multiple Myeloma (MM). Carfilzomib is an effective 2nd generation PI. We report an update of a Phase 2 trial using Carfilzomib combined with Thalidomide and Dexamethasone in newly diagnosed MM. Introduction This investigator sponsored, dose escalation phase 2 trial was designed to investigate Carfilzomib © combined with Thalidomide (T) and Dexamethasone (D) (CTD) for induction and consolidation treatment in patients with newly diagnosed symptomatic MM, who were transplant candidates. Patients with measurable disease, aged 18 to 65 were eligible. Fifty patients in cohort 1 received 4 cycles of Carfilzomib at 20 mg/m2 i.v. on days 1 & 2 followed by 27 mg/m2 on days 8, 9, 15, 16 of cycle 1 and on days 1, 2, 8, 9, 15 & 16 of all subsequent 28-day cycles, Thalidomide 200 mg p.o. days 1 through 28 of a 28 day cycle and Dexamethasone 40 mg p.o. on days 1, 8, 15 & 22 of a 28 day cycle. In cohort 2 (20 patients) the dose of Carfilzomib was escalated from 27 mg/m2 to 36 mg/m2 in the same schedule. In cohort 3 (20 patients) the dose of Carfilzomib increased to 45 mg/m2 in the same schedule. Stem cell harvest was performed with cyclophosphamide 2 g/m2 and G-CSF. Patients received high-dose Melphalan (HDM, 200 mg/m2) and autologous stem cell transplantation (ASCT), followed by consolidation therapy: 4 cycles of Carfilzomib 27 mg/m2 days 1, 2, 8, 9, 15 & 16 of a 28 day cycle, (cohort 1) or 36 mg/m2 days 1, 2, 8, 9, 15 & 16 of a 28 day cycle (cohort 2), Thalidomide 50 mg days 1-28 of a 28 day cycle and Dexamethasone 20 mg days 1, 8, 15, 22 of a 28 day cycle. The primary endpoint was very good partial response (VGPR) after 4 CTD cycles: secondary endpoints were complete response (CR), stringent CR (sCR), VGPR and overall response (≥ PR) according to IMWG criteria pre- and post HDM, progression-free (PFS) and overall survival (OS). Results 90 patients were included as of 1st April 2013. We here report the response of cohorts 1+2 (n=70) with a median follow-up of 22 and 7 months respectively. Median age was 58 yrs and ISS stages I/II/III were 27%/40%/27%, respectively. Six (9%) patients had renal failure with serum creatinine > 2 mg/dL. Of 70 patients in cohorts 1 and 2, 8 patients stopped treatment during/after induction and 4 patients after HDM because of refusal (n=2), toxicity (n=4) non-eligibility (n=2) or progression (n=4). 39 patients completed protocol treatment with 19 still on treatment. Overall response rate on protocol treatment was 96%. After induction therapy response was 19% (CR/sCR), 60% (≥ VGPR) and 93% (≥ PR), respectively. The CR/sCR rate increased to 30% after HDM and to 49% after consolidation. CR/sCR rate was not different across ISS staged I/II/III. In addition, response was similar in poor risk FISH (gain 1q or t(4;14) or del17p: 26% of patients) and standard risk FISH (all other). Progression-free survival (PFS) f 70 patients is 74%, overall survival (OS) is 7%. Stem cell harvest was successfully accomplished with >3x10*6 CD34+ yield in 60/60 patients and HDM/ASCT was performed with complete hematologic recovery in 53/53 patients. This regimen was well tolerated. Safety analysis for all 3 cohorts showed non-hematological toxicity CTC Grade 3+4 in < 5%, mainly infections and skin lesions. Other toxicities were Grade 2 ≤ or less than 5% including cardiac symptoms. Purified myeloma plasma cells, obtained in 39 patients at diagnosis were used for gene expression profiling and exome sequencing. The prognostic impact of the EMC-92 gene classifier on outcome with CTd will be presented. Conclusion Carfilzomib combined with thalidomide and dexamethasone is a safe and rapidly effective regimen for newly diagnosed MM. This trial was registered as NTR2422. Carfilzomib and an unrestricted study grant were provided by ONYX Pharmaceuticals. Disclosures: Sonneveld: Janssen-Cilag: Honoraria; Celgene: Honoraria; Onyx: Honoraria; Janssen-Cilag: Research Funding; Millenium: Research Funding; Onyx: Research Funding; Celgene: Research Funding. Palumbo:Amgen: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Janssen Pharmaceuticals: Consultancy, Honoraria; Millenium: Consultancy, Honoraria; Onyx: Consultancy, Honoraria. Lokhorst:Genmab A/S: Consultancy, Research Funding; Celgene: Honoraria; Johnson-Cilag: Honoraria; Mudipharma: Honoraria.
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Ahlgrimm, Manfred, Evi Regitz, Klaus-Dieter Preuss та ін. "Single Nucleotide Polymorphisms (SNPs) of FCγRIIA and FCγRIIIA in Patients with Diffuse Large B-Cell Lymphoma Have No Impact On Treatment Outcome of Elderly Patients with Diffuse Large B-Cell Lymphoma (DLBCL) Treated with CHOP with and without Rituximab: Results From the RICOVER-60 Trial of the German High-Grade Non-Hodgkin Lymhoma Study Group (DSHNHL)." Blood 114, № 22 (2009): 3956. http://dx.doi.org/10.1182/blood.v114.22.3956.3956.
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Abstract Abstract 3956 Poster Board III-892 BACKGROUND During the last decade the outcome of patients with diffuse large B-cell lymphoma (DLBCL) has significantly improved by the addition of rituximab (R) to the standard chemotherapy with cyclophosphamide, doxorubicin, vincristine, and prednisolone (CHOP). Despite this improvement in response rates, event- progression and overall survival, about one third of the patients with DLBCL will eventually fail. The main therapeutic efficacy of rituximab is not fully elucidated. One major effector mechanism is by antibody dependent cellular cytotoxicity (ADCC) mediated by cell-bound rituximab via its FCg part that activates effector cells by binding to their Fcg receptor (FCγR). Three classes and eight subclasses of FCγR have been described. SNPs have been detected for FcgRIIA at amino acid position (AA) 131 where histidin is substituted by arginin (131 R/H) and for FCγRIIIA at position 158, where phenylalanine is substituted by valine (158 V/F). These SNPs have an increased affinity to Fcg and induce a stronger ADCC which explains better responses to rituximab treatment in follicular lymphoma. The aim of this study was to determine the impact of FCγRIIA and FCγRIIIA SNPs on the outcome R-CHOP chemotherapy in elderly patients with newly diagnosed DLBCL. PATIENTS AND METHODS In the RICOVER-60 therapy study 1222 elderly patients (aged 61-80 years) were randomly assigned to 6 or 8 cycles of CHOP, both with or without rituximab (Pfreundschuh et al., Lancet Oncology 2008). The control group (n=100) consisted of anonymous healthy blood donors of Saarland University Institute of Transfusion Medicine. Available for this study were peripheral blood samples from 570 patients who were representative for the entire RICOVER-60 population. The 2 FCgR SNPs FCγ-RIIa AA 131 R/H and FCγ-RIIIa 158 V/F were determined and univariate and multivariate analyses adjusting for the IPI-relevant risk factors (LDH, ECOG performance status, advanced stage and >1 extranodal involvement) were performed for the entire study population and separately for patients receiving or not receiving rituximab. RESULTS Frequencies of FCγ-RIIa and FCγ-RIIIa polymorphisms were not different in healthy controls compared to DLBCL patients. In our statistical analyses finaly 512 patients were included. The characteristic for the groups were for group 1 (6x CHOP-14) 127 patients (24.8%), for group 2 (8x CHOP-14) 122 patients (23.83%), for group 3 (6x CHOP-14+8x rituximab) 124 patients (24.22%) and for group 4 (8x CHOP-14 + 8x rituximab) 139 patients (27.15%) [fisher test (included vs excluded): p=0.4691]. The median age at admission was the same for included and excluded patients. The gender characteristics for the included patients were well balanced [fisher test (included vs excluded): p=1.0000]. The median observation time for the included vs. excluded patients was 40.25 months vs. 34.50 months. This verification shows that the collective of included patients represents the whole RICOVER-60 population. Statistical analyses of overall survival, 3 year event-free survival and 3 year overall-survival were done for the complete RICOVER-60 population. 3-year event-free survival was 47.2% after six cycles of CHOP-14 (95% CI 41.2-53.3), 53.0% (47.0-59.1) after eight cycles of CHOP-14, 66.5% (60.9-72.0) after six cycles of R-CHOP-14, and 63.1% (57.4-68.8) after eight cycles of R-CHOP-14. 3-year overall survival was 67.7% (62.0-73.5) for six cycles of CHOP-14, 66.0% (60.1-71.9) for eight cycles of CHOP-14, 78.1% (73.2-83.0) for six cycles of R-CHOP-14, and 72.5% (67.1-77.9) for eight cycles of R-CHOP-14. Compared with treatment with six cycles of CHOP-14, overall survival improved by -1.7% (-10.0-6.6) after eight cycles of CHOP-14, 10.4% (2.8-18.0) after six cycles of R-CHOP-14, and 4.8% (-3.1-12.7) after eight cycles of R-CHOP-14. In summary, event-free, progression free, overall survival and complete remission rates were not different among patients with FCγ-RIIa (AA 131R/H) and FCγ-RIIIa (AA 158 V/F) SNPs, irrespective of whether the entire RICOVER-60 population was analysed or when patients treated with and without rituximab were analysed separately. CONCLUSIONS FCγ-RIIa and FCγ-RIIIa SNPs have no influence on the outcome of patients treated with CHOP-14 with or without rituximab. Therefore, modifications of schedule and dose of rituximab according to the underlying FCγ-R SNPs are not justified. Supported by a HOMFOR grant of Saarland University Medical School, Homburg, Germany Disclosures: Pfreundschuh: Roche MabThera Advisory Board: Consultancy, Honoraria.
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Laubach, Jacob P., Fredrik Schjesvold, Mário Mariz, et al. "Efficacy and Safety of the Panobinostat-Bortezomib-Dexamethasone Combination in Relapsed or Relapsed/Refractory Multiple Myeloma: Results from the Randomized Panorama 3 Study." Blood 136, Supplement 1 (2020): 4–6. http://dx.doi.org/10.1182/blood-2020-140697.
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Background Panobinostat (Pano), a pan-histone deacetylase inhibitor, is approved for the treatment of relapsed or relapsed/refractory multiple myeloma (RRMM) in combination with bortezomib and dexamethasone (FVd) in patients who have received ≥2 prior lines of therapy, including bortezomib and an immunomodulatory agent (IMiD). The pivotal phase 3 PANORAMA 1 trial, which used intravenous (i.v.) bortezomib, demonstrated significant progression-free survival benefit with FVd compared with placebo-Vd; however, adverse events (AEs) were also more frequent (San-Miguel J. et al., Lancet Oncol. 2014). The randomized phase 2 PANORAMA 3 study was conducted to optimize FVd by comparing three regimens with varying dose and schedule of Pano and by incorporating subcutaneous (s.c.) bortezomib. Methods PANORAMA 3 (NCT02654990) was a randomized, open-label, international, multicenter phase 2 study conducted in compliance with the Declaration of Helsinki. Eligible patients were ≥18 years old with 1‒4 prior lines of therapy, including an IMiD. Patients refractory to bortezomib were excluded. Patients were randomized 1:1:1 to Pano 20 mg three times weekly (TIW; the currently approved dosing regimen; Days 1, 3, 5, 8, 10, 12), Pano 20 mg twice weekly (BIW; Days 1, 4, 8, 11), or Pano 10 mg TIW (Days 1, 3, 5, 8, 10, 12), all administered in 21-day cycles. Randomization was stratified by number of prior treatment lines (1 vs 2 vs 3 or 4) and by age at screening (≤75 vs &gt;75 years). For Cycles 1-4, all patients ≤75 years old received s.c. bortezomib 1.3 mg/m2 BIW (Days 1, 4, 8, 11) and oral dexamethasone 20 mg (Days 1, 2, 4, 5, 8, 9, 11, 12). Patients aged ≤75 years from Cycle 5 onwards, and patients &gt;75 years for all cycles, received bortezomib 1.3 mg/m2 weekly (Days 1 and 8) and dexamethasone 20 mg on Days 1, 2, 8, and 9. Patients were treated until progressive disease or death, or until discontinuation due to toxicity or withdrawal of consent. The primary endpoint was overall response rate (ORR; IMWG 2011 criteria) after up to 8 treatment cycles by Independent Review Committee assessment. Secondary endpoints included best response, time to response (TTR), duration of response (DOR) and safety. Results In total, 248 patients were randomized (Pano: 20 mg TIW, N=82; 20 mg BIW, N=83; 10 mg TIW, N=83) and 241 patients received treatment (Pano: 20 mg TIW, N=79; 20 mg BIW, N=82; 10 mg TIW, N=80). Mean (SD) age was 65 (9) years; 55% of patients were male. Overall, patients had a median (range) time since diagnosis of 49 months (7‒242) and a median (range) of 2 (1-4) prior lines of therapy; 17% and 2% of patients were refractory to lenalidomide and pomalidomide, respectively. In total, 68% of patients had relapsed and 32% had relapsed/refractory disease. High-risk molecular findings were present in 15% of patients, with either del(17p) or t (4;14) at screening by fluorescence in situ hybridization. For the Pano 20 mg TIW, 20 mg BIW, and 10 mg TIW arms, respectively, median (range) number of treatment cycles completed was 9 (1; 50), 8 (1; 40) and 7 (1; 39); ORR (95% CI) after up to 8 treatment cycles was 62% (51; 73), 65% (54; 75), and 51% (39; 62); median TTR was 1, 2, and 3 months, with a median (95% CI) DOR of 22 (14, not estimable), 12 (9, 21), and 11 (6, 14.5) months. Best responses are presented in Table 1. In the Pano 20 mg TIW, 20 mg BIW, and 10 mg TIW arms, respectively, treatment-related AEs Grade ≥3 were reported in 78%, 72%, and 54% of patients; serious AEs were reported in 54%, 48%, and 44% of patients; and discontinuations due to AEs occurred in 29.5%, 28%, and 15% of patients, respectively. Most common treatment-emergent AEs (≥20% patients) are presented in Table 2. Grade ≥3 diarrhea occurred in 11.5%, 10%, and 5% of patients, respectively. There were 14 (6%) on-treatment deaths during the study (20 mg TIW, n=5; 20 mg BIW, n=3; 10 mg TIW, n=6), with none causally related to therapy and with 12 of 14 directly attributable to progressive disease. Conclusion In patients with RRMM, the 20 mg TIW and 20 mg BIW dosing regimens provided favorable outcomes, with most durable and deepest responses observed in the 20 mg TIW arm. The rate of AEs, including diarrhea, with Pano 20 mg TIW was lower than those observed with the same dosing regimen in PANORAMA 1, suggesting s.c. administration of bortezomib improves tolerability compared with i.v. administration. Moreover, all three regimens of FVd proved generally manageable; Pano 20 mg TIW had greatest efficacy, while 10mg TIW proved best tolerated. Disclosures Schjesvold: Celgene, Amgen, Janssen, Oncopeptides: Research Funding; Amgen, Celgene, Janssen, MSD, Novartis, Oncopeptides, Sanofi, Takeda: Consultancy; Amgen, Celgene, Janssen, MSD, Novartis, Oncopeptides, Sanofi, SkyliteDX, Takeda: Honoraria. Dimopoulos:Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Personal fees, Speakers Bureau; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Personal fees, Research Funding, Speakers Bureau; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Personal fees, Research Funding, Speakers Bureau; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Personal fees, Research Funding, Speakers Bureau; BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Personal fees. Lech-Marańda:Roche, Amgen, Gilead: Speakers Bureau; Roche, Novartis, Takeda, Janssen-Cilag, Amgen, Gilead, AbbVie, Sanofi: Consultancy. Spicka:Celgene, Amgen, Janssen-Cilag, Takeda, Bristol-Myers Squibb, Novartis, Sanofi: Consultancy, Honoraria, Speakers Bureau. Hajek:Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Abbvie: Consultancy, Honoraria; PharmaMar: Consultancy, Honoraria; BMS: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Consultancy, Research Funding; Oncopeptides: Consultancy. Wróbel:Roche: Honoraria, Research Funding; Takeda, Celgene, Janssen, Amgen, AbbVie, Teva, Sandoz: Consultancy, Honoraria. Sureda Balari:Takeda: Consultancy, Honoraria, Speakers Bureau; Merck Sharpe and Dohme: Consultancy, Honoraria, Speakers Bureau; Sanofi: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Gilead/Kite: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Incyte: Consultancy; Celgene: Consultancy, Honoraria; BMS: Speakers Bureau; Roche: Honoraria; Celgene/Bristol-Myers Squibb: Consultancy, Honoraria. Beksac:Janssen&janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sanofi: Speakers Bureau; Takeda: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Deva: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Goncalves:Janssen, Takeda, Amgen, Bayer, Novartis, Merck, Bayer, Celgene, GSK, BMS: Research Funding; Janssen: Consultancy, Speakers Bureau. Bladé Creixenti:Celgene: Honoraria; Amgen: Honoraria; Oncopeptides: Honoraria; Takeda: Honoraria; Janssen: Honoraria. Chari:Bristol Myers Squibb: Consultancy; Pharmacyclics: Research Funding; Novartis: Honoraria; Oncopeptides: Consultancy; Takeda: Consultancy, Research Funding; Antengene: Consultancy; Sanofi Genzyme: Consultancy; Seattle Genetics: Consultancy, Research Funding; Secura Bio: Consultancy; Adaptive Biotechnology: Honoraria; Array BioPharma: Honoraria; Karyopharm: Consultancy; Glaxo Smith Kline: Consultancy; Amgen: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; The Binding Site: Honoraria. Lonial:JUNO Therapeutics: Consultancy; Merck: Consultancy, Honoraria, Other: Personal fees; Abbvie: Consultancy; GSK: Consultancy, Honoraria, Other: Personal fees; BMS: Consultancy, Honoraria, Other: Personal fees, Research Funding; Janssen: Consultancy, Honoraria, Other: Personal fees, Research Funding; Novartis: Consultancy, Honoraria, Other: Personal fees; Takeda: Consultancy, Other: Personal fees, Research Funding; Amgen: Consultancy, Honoraria, Other: Personal fees; Onyx: Honoraria; Genentech: Consultancy; Karyopharm: Consultancy; Sanofi: Consultancy; TG Therapeutics: Membership on an entity's Board of Directors or advisory committees; Millennium: Consultancy, Honoraria. Spencer:Haemalogix: Consultancy, Honoraria, Other: Grant/Research Support; Secura Bio: Consultancy, Honoraria; Pharmamar: Other; Abbvie: Consultancy, Honoraria, Other: Grant/Research Support; Janssen: Consultancy, Honoraria, Other: Grant/Research Support, Speakers Bureau; Roche: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; TheraMyc: Consultancy, Honoraria; Amgen: Consultancy, Honoraria, Other: Grant/Research Support; BMS: Honoraria, Other: Grant/Research Support, Research Funding, Speakers Bureau; Sanofi: Consultancy, Honoraria; Servier: Consultancy, Other: Grant/Research Support; Takeda: Honoraria, Other, Speakers Bureau; Antegene: Consultancy, Honoraria. Maison-Blanche:Chiesi Pharmaceutical, Sanofi, Novartis: Honoraria. Moreau:Novartis: Honoraria; Sanofi: Consultancy, Honoraria; Celgene/Bristol-Myers Squibb: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Takeda: Honoraria; Abbvie: Consultancy, Honoraria; Amgen: Consultancy, Honoraria. Richardson:Celgene/BMS, Oncopeptides, Takeda, Karyopharm: Research Funding. San-Miguel:Amgen, BMS, Celgene, Janssen, MSD, Novartis, Takeda, Sanofi, Roche, Abbvie, GlaxoSmithKline and Karyopharm: Consultancy, Membership on an entity's Board of Directors or advisory committees.
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Andrade Sr., Marcio M., Ilda Murillo-Florez, Anel Montes-Limon, Beatriz de Rueda, Jose-Maria Grasa, and Pilar Giraldo. "Association Of Stringed Response and Immunoparesis Normalization After Bortezomib-Based Therapy Is Related To Better Outcomes In Multiple Myeloma." Blood 122, no. 21 (2013): 5354. http://dx.doi.org/10.1182/blood.v122.21.5354.5354.
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Abstract Background Proteasoma inhibitors have proven to be one of the major advances on multiple myeloma (MM) therapy. Their principal effect in growth inhibition of MM cells is achieved not only through the inhibition of proteasomes but also by preventing the adhesion of myeloma cells to stromal cells, induction of cytokines by the microenvironment, decrease angiogenic activity and a direct apoptotic effect on MM cells. Actually it is part of the first-line standard of care therapy for patients with MM. On the other hand, multiple strategies have been developed for trying to predict response or improve the assessment of response and follow-up of MM patients. Currently, the International Myeloma Working Group (IMWG) criteria of response include immunophenotype and immunoparesis analysis. The HevyLiteTM and FreeLiteTM assays (The Binding Site Ltd. Birminghan. UK) permit a separate quantification of the amount of kappa- and lambda-bound to a given immunoglobulin (HLC) and the free light chains kappa or lambda amount quantification (FLC), both being excellent tools for immunoparesis assessment. Aims To analyze the usefulness of immunoparesis analysis by HevyLiteTM and FreeliteTM in patients who receive bortezomib-based therapy in our institution. Patients and Methods A retrospective chart review was performed including the patients diagnosed with secretor IgA or IgG MM who received therapy with bortezomib either at relapse or as first-line therapy. General clinical characteristics, therapy schedules, number of cycles, response to therapy according IMWG criteria and relapse were recorded. For the analysis, only patients with at least 4 cycles of bortezomib based regimen and HLC and/or FLC analysis performed between 4-12 weeks after complete therapy were included. Period of study: June 2004 to April 2013. Results At the end of study a total of 67 MM patients had received bortezomib-based therapy, 63 of them completed 4 or more cycles and were included in the analysis. Male/Female ratio: 31/32, mean age: 66.9 years old (46-81), therapeutic schedules were: bortezomib-prednisone: 3 (4.7%), bortezomib-dexametasone: 33 (51.6%), bortezomib-melfalan-prednisone: 18 (28.1%), bortezomib-dexametasone-lenalidomide: 8 (12.5%) and bortezomib-talidomide-dexametasone: 1 (1.6%). 55% of patients received at least 6 cycles of therapy. Immunoglobulin Myeloma subtype: IgAL: 13 (20.4%) patients, IgAK: 10 (15.6%) patients, IgGK: 32 (50.8%) patients and IgGL: 8 (14.1%) patients. A total of 46 (73%) patients showed an abnormal HLC ratio at diagnosis and 48 (76,2%) had immunoparesis before therapy; a total of 47 (74.6%) registered an abnormal FLC ratio at diagnosis. The response to therapy was: 15 (23.8%) of cases achieved a stringent complete response (SR), 3 (4.8%) a very good partial response (VGPR), 36 (57.1%) obtained a partial response (PR) and 9 (14.3%) patients had not-response/progressive-disease. At the time of post-therapy evaluation, 26 (37%) of patients had normalized FLC-ratio, 15 (23.8%) maintain the SR, 1 (1,6%) patient in VGPR and 5 (11.1%) in PR and 1 (1.6%) of non-responder patients. Normalization of HLC-ratio was only observed in patients with SR and VGPR: 13 (20.6%). Regarding the immunoparesis analysis, only 15 (23.8%) of patients with immunoparesis recovered the immune restitution (IR) at the end of therapy, of which 8 (11.7%) were SR patients, 2 VGPR and 5 PR patients. At the end of the study 47(71.4%) patients relapsed, 5 (11.11%) are on maintenance therapy and 11(17.4%) after a median follow-up of 29 months (9-94) without therapy not-relapsed; the association of SR with IR was related to a less tendency to relapse and need of therapy, 7/8 patients who achieved this status are not-relapsed. Conclusion In our cohort, patients who achieved a SR with a normalization of immunoparesis shows a clear tendency to less incidence of relapse; probably reflecting a better response with not only an undetectable monoclonal protein but also the recovery of the immune function. Even in small cohorts, the immunoparesis recovery analysis through HLC quantifications seems to be an useful tool to determine a new level of response. More investigations on this field are warranted. This work has been partially supported by a grant from Fundación para el Estudio de la Hematología y hemoterapia en Aragón (FEHHA) Disclosures: No relevant conflicts of interest to declare.
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Chiappella, Annalisa, Patrizia Pregno, Pier Luigi Zinzani, et al. "The Combination of Bortezomib and Rituximab Is Effective and Safe in Relapsed/Refractory Indolent Non Follicular and Mantle-Cell Non Hodgkin Lymphoma: a Phase II Multicenter Study by Intergruppo Italiano Linfomi." Blood 114, no. 22 (2009): 3758. http://dx.doi.org/10.1182/blood.v114.22.3758.3758.
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Abstract Abstract 3758 Poster Board III-694 Introduction The combination of Bortezomib (B) and Rituximab (R) has been shown in vitro synergistic apoptosis and enhanced NFkB depletion in Mantle Cell Lymphoma (MCL) and Marginal Zone Lymphoma (MZL) cells. Rituximab in combination with Bortezomib is well tolerated without overlapping toxicities. Our study was aimed to evaluate safety and efficacy of the association of Rituximab and Bortezomib in relapsed/refractory indolent non follicular and mantle cell lymphoma patients not eligible to high dose chemotherapy and ASCT. The study was designed according to Simon's two stage Optimal Design and the primary endpoint was the achievement of an Overall Response Rate (ORR) > 40%. Patients and methods From September 2006 to March 2008, 54 patients were enrolled into the study. Histology was centrally reviewed in all cases: 49 diagnosis fulfilled the inclusion criteria and were evaluable for the analysis. Clinical characteristics were as follows: 28 males and 21 females; median age 68 years (range 50-74); 16 lymphocytic/lymphoplasmacytic (LL), 8 MZL and 25 MCL; seven stage I-II disease, nine III and 33 IV; 33 were BM positive; according to IPI 36 patients were at low-intermediate risk and 18 at intermediate-high/high risk; 11 patients had 1 and 38 > 2 prior lines of chemotherapy; 15 were R-naïve patients and 34 R-pretreated, 21 patients had refractory disease (<1 yr from the last therapy) and 28 were in relapse (> 1 yr). The treatment plan was: one course of 4 weekly doses of Rituximab (375 mg/sqm) and Bortezomib (1.6 mg/sqm IV bolus) followed by 2 courses of 4 weekly IV bolus of B (1.6 mg/sqm) as single agent. Responding (CR+ PR) and stable disease patients were planned to be given three further courses with the same schedule. Results ORR was 26/49 (53%). Responses were as follows: 13 CR (26.5%) and 13 PR (26.5%). ORR by histology was: 6/16 (37.5%) in LL, 4/8 (50%) in MZL and 16/25 (64%) in MCL respectively. Pretreatment with Rituximab did not adversely affect the ORR: 21/34 (62%) in R-pretreated patients and 5/15 (33%) in R-naïve patients (p .06). ORR was higher in relapsed patients compared with refractory ones: 18/28 (64%) and 8/21 (38%) (p .06). With a median follow-up of one year, Overall Survival (OS) was 93% (95%CI: 79.7-97.9) and 1-year Progression free survival (PFS) was 45% (95%CI: 30-59) (Figure 1). A total of 233 courses were delivered with a median of 4.7 courses per patient. Twenty-eight patients completed the treatment plan and 21 were withdrawn from the study because of: 17 PD during treatment and 4 AE (1 concomitant gastric neoplasia, 1 neurotoxicity grade II, 1 pleural effusion and 1 toxic death due to interstitial pneumonia). Grade 3-4 CTC haematological toxicity was rare with neutropenia in 5% of the courses and thrombocytopenia in <2%. Grade 3-4 CTC cumulative non hematological toxicity was observed in 4.7% of all courses delivered. The most frequent of these were: neurotoxicity grade II in 13 patients and grade III in 5, with complete recover or return to grade I in all of them but one; infections were detected in 3 patients (pneumonia), constipation grade III in 2 and diarrhoea grade > III in 5. Conclusions This study suggests that the combination of Rituximab and Bortezomib is feasible and effective in relapsed/refractory indolent non follicular lymphoma and MCL. This treatment combination is a good therapeutic option without chemotherapy mainly in MCL and MZL also in Rituximab pretreated patients. Our data suggest a promising PFS in this subset of heavily pretreated patients. The combination of Rituximab plus Bortezomib should be explored in further and larger studies. Disclosures: Vitolo: Roche: lecture fees. Off Label Use: Bortezomib was provided free by Jansen-Cilag who gave a research grant to support the study.
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Shanafelt, Tait D., Victoria Wang, Neil E. Kay, et al. "A Randomized Phase III Study of Ibrutinib (PCI-32765)-Based Therapy Vs. Standard Fludarabine, Cyclophosphamide, and Rituximab (FCR) Chemoimmunotherapy in Untreated Younger Patients with Chronic Lymphocytic Leukemia (CLL): A Trial of the ECOG-ACRIN Cancer Research Group (E1912)." Blood 132, Supplement 1 (2018): LBA—4—LBA—4. http://dx.doi.org/10.1182/blood-2018-120779.
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Abstract BACKGROUND: Chronic lymphocytic leukemia (CLL) is one of the most common lymphoid malignancies, accounting for ~11% of all hematologic neoplasms. Over the last 15 years, a series of phase 3 trials have established that chemoimmunotherapy (CIT) with fludarabine, cyclophosphamide, and rituximab (FCR) improves both progression free survival (PFS) and overall survival (OS) compared with chemotherapy alone. FCR is the gold standard for young fit patients with treatment naïve CLL. In parallel with the advances in CIT, a profound increase in the understanding of CLL B-cell biology led to new therapeutic approaches.1 Among these, ibrutinib (an irreversible inhibitor of Bruton's Tyrosine Kinase [BTK]) has had the largest impact on clinical practice to date. Initial trials of ibrutinib demonstrated robust and durable efficacy in patients with relapsed/refractory disease. Subsequent phase 3 trials showed improved PFS and OS with ibrutinib relative to chlorambucil in previously untreated, older CLL patients. Despite these advances, the efficacy of ibrutinib as a first-line treatment for younger CLL patients (i.e. <70) relative to the most efficacious CIT regimens, such as FCR, is unknown. METHODS: Eligible patients were treatment-naive individuals with CLL who were age <70 and required therapy. Patients with deletion 17p- were excluded from participating given the poor response of these patients to FCR therapy. Participants were randomly assigned in a 2:1 ratio to receive ibrutinib (420 mg/day until disease progression) and rituximab (50 mg/m2 on day 1 of cycle 2; 325 mg/m2 on day 2 of cycle 2; 500 mg/m2 on day 1 of cycles 3-7) or six courses of intravenous fludarabine (25 mg/m2 ) and cyclophosphamide (250 mg/m2) days 1-3 with rituximab (50 mg/m2 on day 1 of cycle 1; 325 mg/m2 on day 2 of cycle 1; 500 mg/m2 on day 1 of cycles 2-6) every 28-days. The planned accrual was 519 patients. Hematologic toxicity was graded according to the 2008 IWCLL Working Group scale. All other adverse events were graded according to the NCI Common Toxicity Criteria (version 4). The primary endpoint was PFS with a secondary endpoint of overall survival (OS). Analysis was by intention to treat. The first planed interim analysis for PFS was scheduled to occur 24-27 months after full accrual with the first interim analysis for OS scheduled to occur if the boundary for PFS was crossed. The primary analysis was a stratified logrank test applied to all patients as randomized. Treatment effect p-values are one-sided. The study was approved by the Central Institutional Review Board for the National Cancer Institute, conducted in accordance with the principles of the Declaration of Helsinki, and registered with ClinicalTrials.gov (NCT02048813). RESULTS: A total of 529 patients were accrued between January 31, 2014 and June 9, 2016. 354 patients were assigned to ibrutinib and rituximab (IR) and 175 to FCR. Nineteen patients did not start protocol therapy. The first interim analysis was performed September 2018. With median follow-up of 33.4 months, we observed 77 PFS events and 14 deaths. The hazard ratio (HR) for PFS favored IR over FCR (HR=0.352; 95% CI 0.223-0.558; p<0.0001) which crossed the pre specified boundary. The HR for OS also favored the IR arm (HR=0.168, 95% CI 0.053-0.538; p=0.0003, pre-specified boundary for superiority p=0.0005). Kaplan-Meier estimates for PFS and OS are shown in Figure 1A and 1B. In subgroup analysis for PFS, IR was superior to FCR independent of age, sex, performance status, disease stage or the presence/absence of del11q23. With current follow-up, IR was also superior to FCR for IGHV unmutated patients (HR=0.262; 95% CI 0.137-0.498; p<0.0001) but not IGHV mutated patients (HR=0.435; 95% CI 0.140-0.1350; p=0.07). Grade 3 and 4 treatment-related adverse events were observed in 58% of IR and 72% of FCR treated patients (p=0.0042). Specifically, FCR was more frequently associated with grade 3 and 4 neutropenia (FCR: 69 [44%] of 158 vs. IR: 80 [23%] of 352; p<0·0001) and infectious complications (FCR: 28/158 [17.7%] vs. IR: 25/352 [7.1%]; p<0.0001). CONCLUSIONS: The combination of ibrutinib and rituximab provides superior PFS and OS relative to FCR for patients with previously untreated CLL age <70. These findings have immediate practice changing implications and establish ibrutinib-based therapy as the most efficacious first-line therapy for patients with CLL. Disclosures Shanafelt: Mayo Clinic: Patents & Royalties: Physician Well-being Index, Medical Student Well-being Index, Well-being index; Celgene: Research Funding; GlaxoSmithKline: Research Funding; Genentech: Research Funding; Abbvie: Research Funding; Pharmacyclics: Research Funding; Janssen: Research Funding. Kay:Janssen: Membership on an entity's Board of Directors or advisory committees; Morpho-sys: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees; Cytomx Therapeutics: Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Tolero Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Research Funding; Acerta: Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees; Agios Pharm: Membership on an entity's Board of Directors or advisory committees; Infinity Pharm: Membership on an entity's Board of Directors or advisory committees. O'Brien:Amgen: Consultancy; Astellas: Consultancy; Celgene: Consultancy; GlaxoSmithKline: Consultancy; Janssen: Consultancy; Aptose Biosciences Inc.: Consultancy; Vaniam Group LLC: Consultancy; Abbvie: Consultancy; Alexion: Consultancy; Kite Pharma: Research Funding; Regeneron: Research Funding; Acerta: Research Funding; Gilead: Consultancy, Research Funding; Pharmacyclics: Consultancy, Research Funding; TG Therapeutics: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Sunesis: Consultancy, Research Funding. Barrientos:Pharmacyclics/AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Bayer: Membership on an entity's Board of Directors or advisory committees; astra Zeneca: Membership on an entity's Board of Directors or advisory committees. Erba:Seattle Genetics: Consultancy, Research Funding; Pfizer: Consultancy, Other: grant; Novartis: Consultancy, Speakers Bureau; Pfizer: Consultancy, Other: grant; Pfizer: Consultancy, Other: grant; Incyte: Consultancy, Speakers Bureau; Agios: Consultancy, Speakers Bureau; Agios: Consultancy, Speakers Bureau; Astellas: Research Funding; Janssen: Research Funding; Janssen: Research Funding; Amgen: Research Funding; Amgen: Research Funding; Novartis: Consultancy, Speakers Bureau; Astellas: Research Funding; Incyte: Consultancy, Speakers Bureau; Astellas: Research Funding; Pfizer: Consultancy, Other: grant; Novartis: Consultancy, Speakers Bureau; Juno: Research Funding; Juno: Research Funding; Novartis: Consultancy, Speakers Bureau; MacroGenics: Consultancy; MacroGenics: Consultancy; Amgen: Research Funding; Takeda/Millenium: Research Funding; Amgen: Research Funding; Takeda/Millenium: Research Funding; Seattle Genetics: Consultancy, Research Funding; Jazz: Consultancy, Speakers Bureau; Immunogen: Consultancy, Research Funding; Seattle Genetics: Consultancy, Research Funding; Jazz: Consultancy, Speakers Bureau; Seattle Genetics: Consultancy, Research Funding; Celgene: Consultancy, Speakers Bureau; Takeda/Millenium: Research Funding; Immunogen: Consultancy, Research Funding; Takeda/Millenium: Research Funding; Glycomimetics: Consultancy, Other: Chair, Data and Safety Monitoring Committee; Celgene: Consultancy, Speakers Bureau; MacroGenics: Consultancy; Daiichi Sankyo: Consultancy, Research Funding; MacroGenics: Consultancy; Glycomimetics: Consultancy, Other: Chair, Data and Safety Monitoring Committee; Daiichi Sankyo: Consultancy, Research Funding; Juno: Research Funding; Juno: Research Funding; Agios: Consultancy, Speakers Bureau; Agios: Consultancy, Speakers Bureau; Incyte: Consultancy, Speakers Bureau; Incyte: Consultancy, Speakers Bureau; Jazz: Consultancy, Speakers Bureau; Immunogen: Consultancy, Research Funding; Jazz: Consultancy, Speakers Bureau; Celgene: Consultancy, Speakers Bureau; Immunogen: Consultancy, Research Funding; Glycomimetics: Consultancy, Other: Chair, Data and Safety Monitoring Committee; Celgene: Consultancy, Speakers Bureau; Daiichi Sankyo: Consultancy, Research Funding; Glycomimetics: Consultancy, Other: Chair, Data and Safety Monitoring Committee; Daiichi Sankyo: Consultancy, Research Funding. Stone:Juno: Consultancy; Macrogenics: Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Research Funding; FujiFilm: Consultancy; Sumitomo: Consultancy; Ono/Theradex: Consultancy; Otzuka/Astex: Consultancy; Pfizer: Consultancy; Roche: Consultancy; AbbVie: Consultancy, Research Funding; Actinium: Membership on an entity's Board of Directors or advisory committees; Agios: Consultancy, Research Funding; Amgen: Membership on an entity's Board of Directors or advisory committees; Argenx: Membership on an entity's Board of Directors or advisory committees; Arog: Consultancy, Research Funding; Astellas: Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Consultancy; Celator / Jazz: Consultancy; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Cornerstone: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees. Tallman:ADC Therapeutics: Research Funding; Daiichi-Sankyo: Other: Advisory board; BioSight: Other: Advisory board; AbbVie: Research Funding; Cellerant: Research Funding; AROG: Research Funding; Orsenix: Other: Advisory board.
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Niesvizky, Ruben, Scott Ely, Maurizio DiLiberto, et al. "Multicenter Phase II Trial of the Histone Deacetylase Inhibitor Depsipeptide (FK228) for the Treatment of Relapsed or Refractory Multiple Myeloma (MM)." Blood 106, no. 11 (2005): 2574. http://dx.doi.org/10.1182/blood.v106.11.2574.2574.
Full textAbstract:
Abstract Background: Depsipeptide is a cyclic compound with histone deacetylase inhibitory activity as well as antiproliferative and apoptotic effects. Dysregulation of the cell cycle and apoptosis control have been implicated as critical events behind the genesis of MM. Previously, we demonstrated that depsipeptide induces apoptosis in vitro in MM cell lines; those containing t (11q13-cyclin D1) were most sensitive. In vivo studies of primary MM cells treated with depsipeptide show evidence of cell cycle modulation. Here, we report the preliminary results of a Phase II trial which evaluates the safety and efficacy of depsipeptide in MM patients (pts) with documented progressive disease. Methods: To date, 12 pts with relapsed or refractory MM Stage IIIa with progressive disease documented after 4 (mean 3) lines of therapy (Rx) were treated. Mean age 63 years (range 54–74). Baseline mean levels: WBC 4.6 K/uL (range 3.2–5.9); platelets 193 K/uL (63–272); hemoglobin 11g/dL (8–14); albumin 3.8 g/dL (range 2.7–4.6); creatinine 1.0 mg/dL (range 0.6–1.5); LDH 197 u/L (range 156–245); calcium 9.1 mg/dL (range 8.2–10.2). Pretreatment FISH in 9 pts identified 2 with del 13q14 including one with t(11;14), one patient with tetrasomy 11, one with trisomy 11 and 6 normals. Conventional cytogenetics identified one with inversion 9. Depsipeptide was administered IV at 13 mg/m2 as a 4-hr infusion on days 1, 8 and 15 of a 28 day cycle. Cardiac monitoring included pre and post Rx EKG as well as serum troponin-I levels. Results: 11 of 12 pts had stable disease (SD) measured by SPEP or free light chain measurement after receiving one to 6 cycles of depsipeptide; 2 of these pts continue with SD with ongoing Rx (including one patient in cycle 7), 5 discontinued the trial with SD, and 4 progressed after completion of 1 to 2 cycles. Preliminary results indicate that the drug has been well tolerated apart from thrombocytopenia (grade 3) reported in 2 pts necessitating dose reductions; one patient had ST-segment depression (grade 1) noted by EKG. Toxicities commonly associated with depsipeptide administration including fatigue and nausea (grade 2) were reported in 4 and 5 pts, respectively. Conclusions: Depsipeptide treatment was generally well tolerated at the dose and regimen used. Results suggest that the drug is active in pts with advanced MM producing stabilization of disease in those who had progressive relapsed and refractory disease after numerous cycles of prior chemotherapy. Clinical beneffit was noted with improvement of hypercalcemia and pain in 2 pts. Correlative IHC (CD138/Ki-67, BCL-2, MCL-1, CD56, cleaved caspase 3, nuclear cyclin D1 and D3, nuclear p18, p21, p27) and gene array studies are being conducted in these pts and will be reported. Future studies will evaluate depsipeptide at other dosing schedules and combinations with other agents such as bortezomib. Patient accrual continues by the NY Phase II Trial Consortium. Supported by The LLS SCOR grant, RFP S03-058 SAIC-Frederick, NCI K24 CA100287-02 and NCI K23 CA109260-01
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Hilgendorf, Inken, Nils Winkelmann, Jochen J. Frietsch, et al. "Treosulfan, Fludarabine and Cytarabine As Conditioning before Allogeneic Hematopoietic Stem Cell Transplantation." Blood 132, Supplement 1 (2018): 5702. http://dx.doi.org/10.1182/blood-2018-99-118259.
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Abstract Background: The combination of treosulfan witth fludarabine was successfully introduced into toxicity-reduced conditioning regimens for hematopoietic stem cell transplantation (HCT). However, the risk of post-HCT relapse remains of concern. Here we report for the first time on the results of an individual treatment approach with treosulfan, fludarabin and cytarabine as conditioning for allogeneic HCT in patients with AML, MPN or MDS. Methods: 22 patients were treated with fludarabine 30 mg/m² given on day -6 to day -2, treosulfan 14 g/m² administered on days -4 to day -2 and cytarabin 2g/m² given on days -6 and -5. GvHD-prophylaxis consisted of cyclosporine A and methotrexate or MMF. In addition, antithymocyte globulin was applied in case of an unrelated donor. One patient received bone marrow and the remaining patients received peripheral blood stem cells from matched related donors (9%), matched unrelated donors (73%) or mismatched unrelated donors (18%). All patients were considered to have high risk of relapse because of unfavourable cytogenetic features and/or insufficient or missing response to previous treatment. Three patients (14 %) with CML after blast crisis received the combination because of the reported high relapse rate (46%) after three-day scheduled conditioning with treosulfan [1]. In addition, patients were considered to be ineligible for myeloablative standard conditioning because of multi-morbidity (n = 4; 18% with HCT-CI >2) and/or age >55 years (n = 14; 64%). Results: The median age of patients was 59 (35-68) years. Patients suffered from acute myeloid leukemia (n = 14, 64%), myeloproliferative neoplasia (n = 6, 27%) or myelodysplasic syndrome (n = 2, 9%). The conditioning regime was well tolerated and nearly all patients engrafted and achieved complete donor-type chimerism, except for one who died very early from sepsis. Another patient with underlying myelofibrosis suffered from secondary graft failure on day 100. Two patients developed aGVHD °III/ IV. None of the patients suffered from veno-occlusive disease or severe chronic GVHD. Overall survival and event-free survival at one year reached 60.2% and 59.6%, respectively. Six patients died from infectious disease, two from relapse and one patient from acute GVHD °IV. Conclusion: The combination of cytarabine with the established conditioning of treosulfan and fludarabine is feasible in patients with high risk of relapse and ineligible for myeloablative standard conditioning. Holowiecki J, Giebel S, Wojnar J et al. Treosulfan and fludarabine low-toxicity conditioning for allogeneic 334 haematopoietic stem cell transplantation in chronic myeloid leukaemia. Br J Haematol 335 2008; 142(2): 284-92. Disclosures Hilgendorf: Novartis: Other: Travel support, Research Funding; Medac: Other: Travel support, Research Funding. Frietsch:Deutsche Krebshilfe: Research Funding. Scholl:Abbivie: Other: Travel support; MDS: Other: Travel support; Novartis: Other: Travel support; Carreras Foundation: Research Funding; Pfizer: Membership on an entity's Board of Directors or advisory committees; Jazz Pharma: Membership on an entity's Board of Directors or advisory committees; Deutsche Krebshilfe: Research Funding; Alexion: Other: Travel support. Hochhaus:Novartis: Research Funding; Bristol-Myers Squibb: Research Funding; Incyte: Research Funding; Takeda: Research Funding; Pfizer: Research Funding. Casper:Medac: Membership on an entity's Board of Directors or advisory committees, Other: travel grant, Research Funding.
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Ribera, Josep-Maria, Olga Garcia, Jordi Ribera, et al. "Ponatinib and Chemotherapy in Adults with De Novo Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia. Final Results of Ponalfil Clinical Trial." Blood 138, Supplement 1 (2021): 1230. http://dx.doi.org/10.1182/blood-2021-148310.
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Abstract Background and objective. The combination of HyperCVAD and ponatinib resulted in a high molecular response rate and survival in adults with Ph+ ALL, suggesting improved outcome compared with combinations of chemotherapy with first- or second-generation tyrosine kinase inhibitors (TKI) (Jabbour E, et al, Lancet Haematol. 2018;5:e618-e627). The Spanish PETHEMA group conducted the phase 2 PONALFIL trial, which incorporates ponatinib to the same chemotherapy as that of the ALL Ph08 trial that used imatinib as TKI (Ribera JM et al. Cancer 2019;125:2810-17). Final results of this trial are reported. Patients and method. PONALFIL trial (NCT02776605) combined ponatinib (30 mg/d) and induction chemotherapy (vincristine, daunorubicin, prednisone) followed by consolidation (high-dose methotrexate, high-dose ARA-C, mercaptopurine, etoposide) and allogeneic hematopoietic stem cell transplantation (alloHSCT). Ponatinib was scheduled after alloHSCT only for patients (pts) with persistence/reappearance of MRD. Response to therapy (complete morphological [CR], molecular [complete -CMR- or major -MMR-] after induction and before alloHSCT) (assessed by centralized BCR-ABL1/ABL1 ratio), disease-free survival (DFS), overall survival [OS]) and toxicity were analyzed. The following genetic studies were performed: 1. Additional gene abnormalities (Copy Number Alteration [CNA] analysis by SNP array Affymetrix 750K), 2. ABL1 mutation status at diagnosis (Sanger sequencing), 3. T315I mutation at diagnosis (allele-specific PCR). A propensity score comparison with the results of the ALL Ph08 trial was performed. Results. Median age was 49 (19-59) years (y), and 13/30 pts were female. One pt showed CNS involvement at diagnosis. ECOG score was &lt;2 in 90% of pts. Median WBC count was 6.4 x10 9/L (0.6-359.3), Hb 90 g/L (63-145), platelets 38 x10 9/L (11-206). Immunologic phenotype was common in 26 cases, with p190 isoform in 20 pts (67%), p210 in 9 (30%) and p230 in 1 (3%). CR was attained in 30/30 pts, CMR in 14/30 (47%), MMR in 5/30 (17%) and no molecular response in 11/30 (37%). Two pts withdrew the trial during induction (thrombosis of central retina artery and severe intestinal infection, one case each). Consolidation was given to 28 pts, 2 pts withdrew the trial (physician's decision and lack of molecular response, one case each) and 26 pts received alloHSCT (20 in CMR, 6 in MMR). No relapses before HSCT were detected. One pt died by severe GVHD and two withdrew the trial (grade IV hepatic toxicity:1, protocol deviation after molecular relapse:1). One pt relapsed in BM after HSCT. Ponatinib was given after HSCT in 4/26 pts and dasatinib in 1/26 due to MRD reappearance, and 1/26 received dasatinib in CMR because of refusal to receive CNS prophylaxis, whereas 20/26 pts did not receive any TKI therapy after HSCT. Twenty-nine pts are alive (median follow-up 2.3y, range 1.3-4). 2y DFS and OS probabilities were 97% (91%-100%) and 97% (91%-100%) (Figure 1). Among 7/16 pts without CMR after consolidation and genetic material available, 4 showed IKZF1 deletion (IKZF1 plus in 2), 1 showed CDKN2A/B and PAX5 deletion and 2 did not show any CNA. Among 5/19 pts with molecular relapse, 3 showed IKZF1 deletion (1 being IKZF1 plus), and 2 pts did not show any CNA. No ABL1 mutations or T315I mutation at diagnosis were found. Propensity score with 1:1 matching identified 30 pts in each cohort (variables: age, gender, ECOG, WBC, CNS involvement, cytogenetic risk and BCR/ABL isoform). 2y DFS rates for PONALFIL and ALL Ph08 trials were 97% and 62%, (p=0.005), and 2y OS rates were 97% and 66% (p=0.001) (Figure 2). 107 adverse events (AE) were registered in 20 pts (21 severe in 11 pts), prompting to withdrawn of the trial in 3 (thrombosis of central retina artery, severe bowel infection, grade IV hepatic toxicity). The most frequent AE were hematologic (28%), gastrointestinal (14%), hepatic (11%), infections (7%), and cutaneous (5%). Cardiovascular events occurred in 2 patients (angor pectoris and thrombosis of central artery of the retina). Conclusions. The results of the PONALFIL trial show a high antileukemic efficacy with acceptable toxicity profile and compare favorably with the same chemotherapy schedule and imatinib. Supported in part by grant 2017 SGR288 (GRC) Generalitat de Catalunya and "La Caixa" Foundation. Figure 1. OS (A) and DFS (B). PONALFIL. Figure 2. OS (A) and DFS (B). PONALFIL vs. ALL Ph08. Figure 1 Figure 1. Disclosures Ribera: AMGEN: Consultancy, Research Funding, Speakers Bureau; NOVARTIS: Consultancy, Speakers Bureau; TAKEDA: Consultancy, Research Funding, Speakers Bureau; ARIAD: Consultancy, Research Funding, Speakers Bureau; SHIRE: Consultancy, Speakers Bureau; Pfizer: Consultancy, Research Funding, Speakers Bureau. Esteve: Novartis: Consultancy, Research Funding; Pfizer: Consultancy; Abbvie: Consultancy; Bristol Myers Squibb/Celgene: Consultancy; Novartis: Research Funding; Jazz: Consultancy; Astellas: Consultancy. Mercadal: Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Gilead Sciences, Inc.: Honoraria, Speakers Bureau. Martínez-López: Roche, Novartis, Incyte, Astellas, BMS: Research Funding; Janssen, BMS, Novartis, Incyte, Roche, GSK, Pfizer: Consultancy. OffLabel Disclosure: This trial includes Ponatinib in off-label indication.
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Wu, Christina C. N., Fitzgerald Lao, Hongying Li, et al. "Inhibition of Wnt Signaling By Dimethyl Fumarate Results in in Vitro and in Vivo Clearance of Chronic Lymphocytic Leukemia Cells and Has Additive Activity with Ibrutinib." Blood 124, no. 21 (2014): 4683. http://dx.doi.org/10.1182/blood.v124.21.4683.4683.
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Abstract Background: Small molecules that inhibit B cell survival pathways are effective treatments for patients with chronic lymphocytic leukemia (CLL). However, such therapies are not curative, and resistance can develop in some patients. Combination therapies with agents that inhibit several CLL survival pathways may allow for more complete responses, and help prevent treatment resistance. Previous data has shown that the pro-survival Wnt pathway is highly active in CLL and is a negative prognostic factor, and therefore is an attractive target for novel therapies to combine with agents like ibrutinib. Dimethyl fumarate (DMF) is an orally bioavailable fumaric acid ester with immunomodulatory properties, including inhibition of the NF-kB signaling cascade. DMF has been evaluated as a systemic treatment of psoriasis as well as multiple sclerosis. Our group previously observed anti-CLL effects of DMF, mediated in part through oxidative stress. Herein we describe a novel mechanism of action of DMF and ibrutinib, mediated by inhibition of the Wnt signaling pathway. Methods: Effects of DMF and ibrutinib on Wnt signaling were determined using a cell-based LEF/TCF beta-lactamase reporter gene FRET assay. In vitro activity was assessed in primary CLL from patients with indolent and aggressive disease. In vivo activity was evaluated in Rag2-/- gamma chain-/- immunodeficient (RG-KO) mice, which were engrafted with human CLL cells by intraperitoneal injection. DMF and/or ibrutinib were administrated to mice by oral gavage, at clinically used doses and schedules. Results: Both DMF and ibrutinib have an alpha-beta unsaturated ketone that can react with essential free cysteines in the Wnt-driven LEF1 transcription factor. This effect was confirmed by a cell-based reporter gene assay in which DMF inhibited LEF/TCF dependent gene expression at low μM levels. Ibrutinib also inhibited Wnt signaling activity in the same assay. In short term cultures, DMF was cytotoxic to primary CLL cells from patients with both indolent and aggressive disease, at low uM concentrations. The combination of DMF and ibrutinib resulted in a higher degree of CLL cell clearance than achieved by either agent alone (p < 0.05 after multiple comparison adjustments, Dunnet’s method). To evaluate the effect in a preclinical CLL xenograft animal model, we administered DMF by oral lavage to RG-KO mice engrafted with human CLL cells. Doses ranging from 3 to 30 mg/kg BID for 7 days resulted in dose dependent clearance of CLL cells compared to vehicle controls, without observable toxicity to the recipient animals. Moreover, the combination of DMF and ibrutinib resulted in a higher degree of CLL cell clearance than achieved by either agent alone. Preliminary FACS analyses revealed that DMF selectively targets CLL subpopulations of cells with aggressive characteristics, as assessed by CD38 expression. Further molecular analyses of predictive or correlative biomarkers are ongoing. Conclusions: DMF inhibits Wnt signaling, and has single agent activity as a treatment for CLL. The combination of DMF and ibrutinib is more effective than either agent alone, particularly in aggressive disease, and is well tolerated. Clinical trials of DMF in CLL are warranted, and are planned. This work is supported by a Leukemia and Lymphoma Society Specialized Center of Research Grant (7005-14) and by the CLL Research Consortium (5P01CA081534-14). Disclosures No relevant conflicts of interest to declare.
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Kimby, Eva, Stephanie Rondeau, Anna Vanazzi, et al. "Rituximab Plus Lenalidomide Versus Rituximab Monotherapy in Untreated Follicular Lymphoma Patients in Need of Therapy. First Analysis of Survival Endpoints of the Randomized Phase-2 Trial SAKK 35/10." Blood 128, no. 22 (2016): 1099. http://dx.doi.org/10.1182/blood.v128.22.1099.1099.
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Abstract Background: The randomized phase-2 trial SAKK 35/10 was conducted by the Swiss Group for Clinical Cancer Research (SAKK) and the Nordic Lymphoma Group (NLG) to compare the activity of single-agent rituximab versus rituximab plus lenalidomide in the first-line treatment of symptomatic follicular lymphoma (FL). The results of primary endpoint (complete remission [CR/CRu] at week 23) assessment were previously reported, showing that addition of lenalidomide to rituximab results in a significantly higher CR/CRu rate at the expected cost of increased but manageable toxicity (Kimby et al. Blood 2014.124 (21):799; Zucca et al. Hematol Oncol 2015. 33(s1): 105). Here we report the first analysis of secondary endpoints, progression-free survival (PFS), time to next anti-lymphoma treatment (TTNT), CR duration, as well as CR/CRu rate at 30 months (CR30). Methods: 154 patients (pts) with grade 1 to 3a FL, untreated and in need of systemic therapy, were randomized to receive either rituximab (375mg/m2 at week 1, 2, 3, 4, 12, 13, 14 and 15) or rituximab (same schedule) plus lenalidomide (15 mg daily, from 14 days before the first until 14 days after the last rituximab administration). The sample size was calculated to allow the detection of a 20% increase of the CR/Cru rate with 90% power and type I error 0.10; a one-sided Z-test for proportions was used to compare the two arms. Treatment was discontinued in pts who did not achieve at least a 25% reduction in the sum of products of tumor diameters at week 10. Primary and secondary endpoints were defined according to the NCI international standardized criteria (Cheson et al 1999). Results: 77 pts (median age 63 years, 52% with stage IV and 47% with poor-risk FLIPI score) were allocated in the single-agent rituximab arm and 77 (median age 61 years, 48% with stage IV and 47% with poor-risk FLIPI score) in the combination arm. A higher CR/CRu rate in the combination arm was documented both by the investigator assessment (36% vs 25%) and by the independent response reviewers of CT scans (61% vs. 36%). Adverse events of grade ≥3 were more common (56% vs 22% of pts) in the combination arm, including neutropenia (23% vs 7%). At a median follow up of 3.1 years, a longer CR duration was seen for the pts in the combination arm (median not reached vs 2.3 years) as well as a longer PFS (median not reached vs. 2.3 years), these differences were not statistically significant. The CR30, recently identified as a reliable surrogate of PFS (Sargent et al. Hematol Oncol 2015. 33(s1): 166), was significantly improved by the addition of lenalidomide to rituximab (42% vs 19%, p=0.001). Moreover, TTNT was significantly longer with the combination (median not reached vs 2.1 years, p=0.02) [Figure1]. Overall survival rates at 3 years were 93% and 92%, respectively. Conclusions: The SAKK 35/10 randomized trial confirmed that lenalidomide plus rituximab is an active and feasible initial treatment for FL pts in need of therapy. Addition of lenalidomide significantly increased the CR/CRu rate at week 23 (primary endpoint) and was maintained throughout 30 months. Although the trial was not powered to detect survival differences (secondary endpoints), a significantly better TTNT and a trend towards prolonged PFS and CR duration was seen in the combination arm. The excellent overall survival in both arms suggests that chemotherapy-free strategies should be further explored. Figure 1. Time to next anti-lymphoma therapy by treatment arm Figure 1. Time to next anti-lymphoma therapy by treatment arm Disclosures Kimby: Jansen: Membership on an entity's Board of Directors or advisory committees, Other: Honoraria for lecture at educational session; Celgene: Other: Honoraria for lecture. educational meeting; Pfizer: Other: Research grant; Roche: Other: Honoraria for lecture in educational meetings; Gilead: Honoraria, Other: honoraria for educational lecture in meeting sponsored by Gilead. Mey:roche: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Honoraria, Research Funding. Wahlin:Roche: Consultancy. Hernberg:Roche: Consultancy, Honoraria. de Nully Brown:Roche: Research Funding. Ferreri:Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Zander:Bristol Myers, Celgene, Amgen, Mundipharma, Janssen-Cilag, Takeda Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees.
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Knight, Thomas G., Melissa Aguiar, Myra Robinson, et al. "Financial Toxicity Intervention Improves Quality of Life in Hematologic Malignancy Patients." Blood 136, Supplement 1 (2020): 21. http://dx.doi.org/10.1182/blood-2020-136578.
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Background: Financial toxicity (FT) has been consistently demonstrated to a be a major contributor to morbidity and mortality in a variety of cancers. However, the vast majority of research examining this issue has been in solid tumors, and there has been less investigation of how this concept applies in malignant hematology and even fewer studies looking at an interventional model. This pilot study attempts to identify patients at high-risk due to FT in a busy clinical environment and improve clinical outcomes with comprehensive intervention. Methods: All patients seen at the Malignant Hematology Clinic at the Levine Cancer Institute, a tertiary hospital-based specialty practice, were surveyed at their visits over a six-month period. All patients were aged ≥18 years and diagnosed with hematologic malignancy or bone marrow failure syndrome. The survey consisted of the PROMIS Global-10 measure and two questions from the COST measure. FT was defined as scoring 5 or less (maximum: 10) in agreement with the COST questions: "I know that I have enough money in savings, retirement, or assets to cover the costs of my treatment" and "I am satisfied with my current financial situation." Patients with FT were entered into the interventional cohort and scheduled for a visit with a nurse navigator where they completed a standardized worksheet to identify gaps in care and opportunities for grant funding/other assistance. Patients were seen by a clinical pharmacist for copay review and discussion of assistance programs. Finally, patients were offered the services of a community pro-bono financial planner for help with budgeting, asset management, and general financial advice. Patients were tracked longitudinally for assistance provided, changes in PROMIS scores, and clinical outcomes. Categorical variables, including responses to survey questions, were summarized with frequencies and proportions, while continuous variables were summarized with medians and ranges. Correlation of FT screening scores and COST scores was assessed with Spearman's correlation. Baseline versus post-intervention PROMIS scores were compared with paired t-tests, while McNemar tests for agreement were used to compare ER and IP utilization 3 months prior versus post intervention. Results: A total of 107 patients were included in the intervention. Specific characteristics of the intervention population are listed in Table 1. FT screening scores were found to correlate with the full COST measure (Spearman correlation = 0.45, p &lt;.001). Patients in the intervention cohort had high rates of noncompliance due to inability to afford prescription medications (16.8%), OTC medications (15.9%), and doctor visits (6.5%). In order to pay for their care, patients reported reducing spending on food and clothing (48.6%), using savings to cover OOP expenses (51.4%), and partially filling prescriptions (11.2%) (Table 2). In terms of the intervention, 37.4% of patients were found to qualify for and were helped to obtain grants from external foundations. The median value of these grants was $850 (range: $100-$17,850). Through manufacturer's assistance and other programs, the clinical pharmacy team was able to obtain free or greatly reduced cost medications for the qualified patients at a median retail value of $197,158 (range: $29,909-$639,801). Gas cards, food pantry assistance, and transportation assistance were also supplied to patients who qualified at a median value of $300 ($100-$300). 58 patients (54.2%) expressed interest and were scheduled with a pro-bono financial counselor. The intervention resulted in statistically significantly higher quality of life when measured by PROMIS physical and mental health scores, compared to baseline scores (Table 3) (all p &lt;.001). There was no significant difference found when looking at patients with at least one ER visit 3 months prior and post intervention (10.3% vs 6.5% p=.317). There was no difference between inpatient visits/days pre and post intervention. Conclusions: Using a quick screening method for FT in a busy clinical environment is feasible and allows identification of an extremely high-risk population. Intervening on FT in a comprehensive way including navigators, pharmacists, and financial counselors is effective and leads to increased quality of life. Disclosures Knight: Foundation for Financial Planning: Research Funding. Ai:Celgene: Speakers Bureau; Incyte: Speakers Bureau. Chojecki:Incyte: Research Funding; Novartis: Other: Investigator Meeting Attendance. Copelan:Amgen: Membership on an entity's Board of Directors or advisory committees. Grunwald:Forma Therapeutics: Research Funding; Premier: Consultancy; Premier: Consultancy; Celgene: Consultancy; Abbvie: Consultancy; Pfizer: Consultancy; Abbvie: Consultancy; Trovagene: Consultancy; Premier: Consultancy; Astellas: Consultancy; Astellas: Consultancy; Genentech/Roche: Research Funding; Celgene: Consultancy; Celgene: Consultancy; Janssen: Research Funding; Merck: Research Funding; Cardinal Health: Consultancy; Amgen: Consultancy; Amgen: Consultancy; Agios: Consultancy; Merck: Consultancy; Merck: Consultancy; Amgen: Consultancy; Merck: Consultancy; Cardinal Health: Consultancy; Pfizer: Consultancy; Cardinal Health: Consultancy; Daiichi Sankyo: Consultancy; Astellas: Consultancy; Daiichi Sankyo: Consultancy; Trovagene: Consultancy; Pfizer: Consultancy; Forma Therapeutics: Research Funding; Genentech/Roche: Research Funding; Genentech/Roche: Research Funding; Janssen: Research Funding; Forma Therapeutics: Research Funding; Trovagene: Consultancy; Incyte: Consultancy, Research Funding; Incyte: Consultancy, Research Funding; Incyte: Consultancy, Research Funding; Agios: Consultancy; Daiichi Sankyo: Consultancy; Agios: Consultancy; Abbvie: Consultancy.
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Navani, Vishal, Moira Graves, Giovana Marchett, Hiren Mandaliya, Nikola Bowden, and Andre Van der Westhuizen. "243 Real world exposure survival relationship of pembrolizumab in metastatic melanoma." Journal for ImmunoTherapy of Cancer 8, Suppl 3 (2020): A262. http://dx.doi.org/10.1136/jitc-2020-sitc2020.0243.
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BackgroundDespite the paradigm shift heralded by immune checkpoint blockade (ICB), only a small proportion of patients have a meaningful response. Dose selection of ICB agents was significantly based on in-silico modelling.1 Trial data has shown that clearance of these agents varies over time, with a reduction in clearance associated with improved best overall response (BOR).2, 3 Real world data has shown patients with higher exposure to ICB, manifested as higher plasma trough concentrations, experience improved BOR and longer survival.4 This study aimed to determine the relationship between longitudinal ICB exposure and BOR, progression free survival (PFS) and overall survival (OS) in patients with metastatic melanoma receiving pembrolizumab monotherapy.Methods28 patients with metastatic melanoma receiving weight based pembrolizumab (2 mg/kg Q3w) had serial pharmacokinetic trough draws prior to their next scheduled dose, up to a maximum of 22 cycles. BRAF mutation positive patients were pre-treated with BRAFi/MEKi therapy, otherwise pembrolizumab was given first line. Plasma trough levels were determined using the Abcam® pembrolizumab ELISA kit.The cohort was split by best overall response (BOR), determined by iRECIST. No statistically significant differences were determined, using one-way ANOVA. The cohort was stratified into high versus low pembrolizumab trough concentrations, split by the median. Trough is an established surrogate for drug exposure.5 Kaplan-Meier survival analysis for progression-free and overall survival was performed based on pembrolizumab drug exposure groups.ResultsMedian follow up was 32.5 months. Complete responders (CR) (n=11) had 29.8% higher geometric mean pembrolizumab trough levels (90.8 mcg/mL) than partial responders (PR) (n=9) (63.7 mcg/mL, p=ns). CR patients had 16.1% higher trough levels than patients with progressive disease (PD) (n= 6) (76.2 mcg/mL, p=ns). 2 patients with stable disease had mean trough pembrolizumab levels of 106.4 mcg/mL.The high pembrolizumab exposure group experienced significantly longer median OS (not reached versus 48 months, p=0.021) (figure 1), than the low exposure group. No significant difference was found in mean PFS between the groups (49.2 versus 37.9 months, p=ns) (figure 2). The median PFS was not reached in either group.Abstract 243 Figure 1OS Kaplan-Meier survival curves stratified for the group with the 50% highest trough concentrations (red) and 50% lowest trough concentrations (blue). The median OS for high pembrolizumab exposure group was not reached, which was significantly longer than the low pembrolizumab exposure median of 48 months (p=0.021)Abstract 243 Figure 2PFS Kaplan-Meier survival curves stratified for the group with the 50% highest trough concentrations (red) and 50% lowest trough concentrations (blue). The mean PFS for the high pembrolizumab exposure group was 49.2 months, which was not significantly longer than low pembrolizumab exposure mean PFS of 37.9 months. The median PFS was not reached in either group.ConclusionsA positive exposure survival relationship for pembrolizumab in metastatic melanoma is described in a real world setting. Whether this relationship indicates a true causal effect of variation in drug exposure on clinical outcomes remains to be determined. Further pharmacokinetically driven dosing studies are required to identify whether therapeutic drug monitoring of pembrolizumab in the clinic is a necessity.AcknowledgementsThis study was funded by a Hunter Medical Research Institute Project Grant (HMRI983) - Hunter Cancer Biobank Serial Blood Collection Project.Ethics ApprovalThis study was approved by the Hunter New England Health Local Health District (14/12/10/4.02) and University of Newcastle Human Research Ethics Committee institutional review board (H-2018-0159).ConsentWritten informed consent was obtained from the patient for publication of this abstract and any accompanying images. A copy of the written consent is available for review by the Editor of this journal.ReferencesLeven C, Padelli M, Carre JL, Bellissant E, Misery L. Immune checkpoint inhibitors in melanoma: a review of pharmacokinetics and exposure-response relationships. Clin Pharmacokinet 2019.Liu C, Yu J, Li H, et al. Association of time-varying clearance of nivolumab with disease dynamics and its implications on exposure response analysis. Clin Pharmacol Ther. 2017;101(5):657–666.Li H, Yu J, Liu C, et al. Time dependent pharmacokinetics of pembrolizumab in patients with solid tumor and its correlation with best overall response. J Pharmacokinet Pharmacodyn 2017;44(5):403–414.Basak EA, Koolen SLW, Hurkmans DP, et al. Correlation between nivolumab exposure and treatment outcomes in non-small-cell lung cancer. Eur J Cancer 2019;109:12–20.FDA CfDEaRC. Guidance for Industry. Exposure-Response Relationships — Study Design, Data Analysis, and Regulatory Applications. In: Administration FaD, ed.
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Lynggaard, Line Stensig, Sofie Gottschalk Højfeldt, Lisbeth Moeller, et al. "NOR-GRASPALL2016 (NCT03267030): Asparaginase Encapsulated in Erythrocytes (eryaspase) - a Promising Alternative to Peg-Asparaginase in Case of Hypersensitivity." Blood 136, Supplement 1 (2020): 13–14. http://dx.doi.org/10.1182/blood-2020-139373.
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Introduction: Asparaginase is an essential part of the treatment of acute lymphoblastic leukemia (ALL). Hypersensitivity occurred in 16.8% (clinical allergy (13.8%) or silent inactivation (3.0%)) of patients treated with pegylated asparaginase (PEG-asp) in the NOPHO ALL2008 cohort (Hoejfeldt et al 2018). Hypersensitivity (clinical allergy or silent inactivation) is the most common cause of truncated asparaginase therapy, and truncated treatment has been associated with decreased event-free survival (Silverman et al 2001). Asparaginase encapsulated in erythrocytes (eryaspase) is an alternative formulation of asparaginase aiming to prolong the half-life of asparaginase and to reduce toxicity e.g. hypersensitivity, since the erythrocyte membrane prevents activation of the immune system and protects asparaginase against elimination. A phase 2 study has demonstrated prolonged asparaginase enzyme activity (AEA) and significantly reduced incidence of hypersensitivity in patients with ALL, who had a prior exposure to other asparaginase preparations (NCT01518517). The aim of the NOR-GRASPALL 2016 study is to evaluate the safety and efficacy of eryaspase in combination with multiagent chemotherapy according to the NOPHO ALL2008 protocol and the ALLTogether Pilot study. Antileukemic treatment in these protocols include 4-8 doses of PEG-asp as first line treatment. Methods: NOR-GRASPALL 2016 is a phase 2 multinational multicentre trial conducted in the Nordic/Baltic countries. It is a single-arm study for non-high-risk patients with ALL and hypersensitivity to PEG-asp. Eryaspase (150 U/kg) is scheduled to complete the intended course of asparaginase (1-7 doses). AEA-measurements are used as biomarkers for treatment efficacy. Results: Since August 2017, 36 children and two adults were included in the study. Median age was 6.0 years (IQR: 3.3;8.7). 37 patients (97.4%) had clinical allergy to PEG-asp of whom 59.5% (n=22) had a severe allergic reaction. One patient (3.3%) was included due to silent inactivation. AEA-measurements were available in all patients but one (n=37), and in none of these patients AEA was detectable following PEG-asp treatment. In total, 171 doses of eryaspase were administered. A total of 34 of the 36 patients (94.7%) had AEA &gt;100 U/L and 27 patients (71.1%) had AEA-levels &gt;400 U/L 14 days after first eryaspase administration (expected nadir). The median AEA-level was 798 U/L [IQR: 387;864]. In total 90.7% of all samples collected 14 days after eryaspase administration had AEA &gt;100 U/L and 69.3% had AEA &gt;400 U/L. The median AEA-level was 621U/L [IQR: 331;962]. Adverse events with relation to eryaspase were reported in 8 of 36 patients (22%). Six patients experienced a possible allergic reaction to eryaspase; one patient had a severe allergic reaction, three patients developed a rash and two patients had "drug fever", deemed related to eryaspase. Three of these six patients (50%) had low AEA-levels after developing allergic symptoms, the remaining patients (50%) had AEA-levels comparable with all other patients in the study. Four patients experienced adverse events related to eryaspase; two patients with mild hyperlipidaemia and two with hepatoxicity. No other severe adverse events with relation to eryaspase have been reported. Final study results will be provided at the meeting. Conclusion: Eryaspase consistently demonstrated prolonged AEA in patients who developed hypersensitivity reactions to PEG-asp. Treatment with eryaspase was well tolerated. We conclude that eryaspase is a promising alternative to PEG-asp in case of hypersensitivity. Disclosures Schmiegelow: Jazz Pharmaceuticals: Other: Speaker and/or Advisory Board Honoraria ; Amgen: Other: Speaker fee; Medscape: Other: Speaker fee; Servier: Other: Educational grant. Speaker and/or Advisory Board Honoraria . Albertsen:Erytech Pharma: Other: Sponsor of the investigator initiated study: NOR-GRASPALL 2016. No financial benefits..
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Rathod, H., K. Adam, R. Ghorpade, A. Venugopalan, M. Saluja, and A. Chopra. "AB1663 MUSCULOSKELETAL (MSK) PAIN IN VILLAGE BHIGWAN (INDIA) IN 2022- CHANGE OVER 25 YEARS: WHO COMMUNITY ORIENTED PROGRAM FOR CONTROL OF RHEUMATIC DISEASES (COPCORD) 1996-2022." Annals of the Rheumatic Diseases 82, Suppl 1 (2023): 2066.2–2067. http://dx.doi.org/10.1136/annrheumdis-2023-eular.4692.
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BackgroundCOPCORD population surveys (Stage I) have reported the prevalence of MSK pain and rheumatic disorders in several countries. A crude point prevalence rate of 18.2% for MSK pain (adult) was reported by the maiden COPCORD India survey (1996) in rural Bhigwan (Pune) and was continued to date with a free-of-cost local rheumatology clinic and a health education program. Several other factors (development, environment, Chikungunya epidemic 2006, Covid pandemic 2019) are likely to impact the epidemiology of MSK disorders and thus we carried out a resurvey in Bhigwan from April to July 2022. We present early results of MSK pain and related factors.ObjectivesTo describe and measure the current MSK pain and rheumatic disorders in Bhigwan rural population and further assess the transformation over time (1996 to 2022).MethodsThe resurvey (Stage I) was carried out using the methods of the previous survey (Bhigwan COPCORD model 1996). Trained voluntary health workers (HW) completed a house-to-house cross-sectional survey (Phase 1) of the adult population(≥ 18 years) and identified current and/or past MSK pain respondents. Pain due to recent trauma (< 3 months) was excluded. Concurrently, the respondents were also evaluated (Phase 2) for pain descriptors and other relevant issues. Rheumatologists examined (Phase 3) the respondents to make a clinical diagnosis, order relevant investigations, and begin treatment. A follow-up was scheduled. The target population was estimated at 8117 (Government records). The database was created using an indigenous software program. Standard population analysis was carried out. Crude point prevalence rates (95% confidence intervals) are presented. Further analysis is being done.Results6970 population (85.9% response, 50% males) was surveyed. The age-gender distribution pattern was comparable with the India rural census 2011; 63% in 18-44 years age groups (Bhigwan). Paradoxically, only 7.6% current population in sharp contrast to about 55% in 1996 admitted working (physically) in fields; now dependent upon temporary migrant labor (not in the survey). 32% population possessed mobile phones. Five hundred eighty-six pain respondents (women 69%) were identified; 46% belonged to the 45-64 years age group. The MSK pain prevalence was 8.2% (7.5%, 8.8 %); male 2.5 (2.2 %,2.9%). female 5.6% (5.1, 6.2). 14.2% population used tobacco in some form, mostly oral; 36.3% of MSK pain respondents (58% women). Hypertension in 7.9%, diabetes in 4.7%, thyroid disorders in 1.6%, and rectal hemorrhoids in 1% was self-reported in the population; correspondingly 25%, 12%, 2.5%, and 3% were reported by the MSK pain cohort. Past history of Chikungunya in 5.7% and COVID-19 in 7.4% of the total population was reported. On univariate analysis, MSK pain was significantly associated (p < 0.0001, Chi-square) with Chikungunya, COVID-19, tobacco use, fieldwork, and low education status. Prevalence rates for disease groups were 1.38% (1.12. 1.68) for inflammatory arthritis, 3.66% (3.23, 4.13) for degenerative arthritis and 2.87 % (2.49, 3.29) for non-specific rheumatism/arthritis. Self-reported data, subject recall, and limited investigations were important concerns.ConclusionThe current COPCORD survey shows that despite a substantial reduction from 1996, MSK pain continues to be a predominant and important self-reported illness in the Bhigwan rural community. Undoubtedly, the lives and livelihoods of the Bhigwan people and their MSK landscape have been transformed substantially. Interestingly, the burden of other non-communicable diseases seems increased. Further research studies will be required to unravel the role of Chikungunya and COVID-19, and other risk factors in MSK disorders.References[1]Joshi, Chopra. (COPCORD Bhigwan Model Surveys). J Rheumatol 2009;36:614-22[2]Chopra A. (COPCORD World). Rheumatol 2013; 52(11):1925-8[3]Chopra et al. (Bhigwan survey 1996).J Rheumatol 2002; 29: 614-621.AcknowledgementsFunded by an ILAR grant 2022 and ARCF-Centre for Rheumatic Diseases (CRD) Pune India, CRD personnel, Bhigwan Administration, leaders and population.Disclosure of InterestsNone Declared.
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Falanga, Anna, Marina Marchetti, Sara Gamba, et al. "Hypercoagulation Screening as Marker of Occult Cancer in a Population of Healthy Blood Donors: The Hypercan Prospective Study." Blood 128, no. 22 (2016): 2604. http://dx.doi.org/10.1182/blood.v128.22.2604.2604.
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Abstract INTRODUCTION and AIM: The HYPERCAN study is an ongoing prospective Italian multicenter trial, designed to test whether the persistence of a laboratory hypercoagulation abnormalities may predict early cancer diagnosis in healthy subjects (Project A), or prognosis and response to therapy in patients with cancer (Project B). The aim of this abstract is to present a preliminary analysis of data collected for project A. MATERIAL AND METHODS: A large healthy population of Italian blood donors from Bergamo and Milan areas (North Italy) is prospectively enrolled after informed written consent and followed-up for 5 years for the occurrence of cancer. As established by a monitoring schedule, blood donors are periodically screened for a series of serological, biochemical and clinical parameters, and tested for viral infections. We plan to enroll 10,000 donors of both gender, age range 35-65, in 5 years. Blood samples from each study subject are collected at enrollment and after 8-10 months, and processed to obtain plasma, buffy coat, and serum subsamples, which are stored in a dedicated biobank until testing for hypercoagulation biomarkers. Demographic and clinical data are collected, including age, gender, body mass index (BMI), current medications, relevant comorbidities, routine hematological and biochemical workup. In addition, subjects are asked to fill in a questionnaire on lifestyle, smoke and dietary habits. An identification of all malignant tumors, according to the categories 140-208 (International Classification of Diseases) is carried out every 6 months. RESULTS: Between April 2012 and June 2016, 6,607 blood donors (70% males; median age 48 years) have been recruited. Routine biochemical and hematological workups are into the normal range values in more than 90% of subjects. The analysis of questionnaires reveals that 57% of the donors were not smokers, 15% regular smokers, 28% ex-smokers; 49% of them were moderate/low alcohol consumer (≥ 2 drink/die). The crude incidence of all malignant cancers in the Bergamo/Milan area is 552 cases/100,000 persons/year in males and 382 cases/100,000 person/year in females. According to the Cancer Registry, 57 cancer cases (38 males and 19 females) are to be expected in the general population in the age range 35-65 years, after a median follow-up of 2.5 years. In our population, at June 2016, after a median follow-up of 2.5 years, we recorded a total of 46 cancer cases (35 M / 11 F). Five cases were excluded because diagnosis occurred within 6 months from enrollment (incident cancer cases); the remaining 41 cases included in the analysis were diagnosed with cancer 6-28 months from enrollment (median time to diagnosis = 24.8 months). Median age at diagnosis of cancer was 53 years. The most frequent tumor type in male donors was prostate cancer (25.8%), followed by colo-rectal (19.3%) and thyroid (12.9%) cancers. In female donors, breast cancer was the most frequent (40%). Currently, the enrollment of healthy donors and follow-up is ongoing, as well as the identification of new cancer cases. Next, according to the original plan, samples from 3 matched cancer-free donors for each cancer-case donor (cancer: non-cancer = 1:3 ratio) will be analyzed in parallel for hypercoagulation markers. CONCLUSIONS: This preliminary analysis reveals that the distribution of tumor types in our population reflects the same as reported for the general population of the same geographic area. Second, in our population of healthy blood donors, the incidence of cancer diagnosis is lower than that predicted from epidemiological data. This message supports the concept that a healthy lifestyle can be effective to prevent cancer. Project funded by AIRC "5xMILLE" n. 12237 grant from the "Italian Association for Cancer Research (AIRC)". Disclosures Falanga: Pfizer: Speakers Bureau; Aspen: Speakers Bureau; Janssen: Speakers Bureau.
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Popat, Uday R., Roland Bassett, Peter F. Thall, et al. "Myeloablative Fractionated Busulfan Conditioning Regimen with Sorafenib in Patients with AML: Results of Phase I Clinical Trial." Blood 138, Supplement 1 (2021): 556. http://dx.doi.org/10.1182/blood-2021-152450.
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Abstract Background: Myeloablative conditioning can be given safely to older patients by administering busulfan over a longer period (fractionated busulfan regimen) than the standard four-day regimen. (Popat, et al Lancet Haematology 2018). This longer conditioning regimen duration allows the addition of oral targeted agents like sorafenib, which may be synergistic with conditioning chemotherapy and thus further improve disease control. Therefore, we added sorafenib to fludarabine and fractionated busulfan regimen (f-bu) in a phase 1 dose-finding trial studying 4 different doses of sorafenib with f-bu (NCT03247088). Here we report the results of this trial. Methods: Between 3/2018 and 6/2021, 24 patients with AML aged 18 to 70 years with adequate organ function and 8/8-HLA matched related or unrelated donors were enrolled prospectively. The dose of sorafenib was varied among the four values 200, 400, 600, and 800 mg administered from day -24 to -5. Dose-limiting toxicity (DLT) was defined as grade 3 or higher regimen-related non-hematologic, non-infectious, non-GVHD toxicity occurring between day -24 and day 3. The Bayesian Model Averaging Continual Reassessment Method (BMA-CRM) with target DLT probability 0.30 was used to choose doses for successive cohorts of 3 patients. The first cohort was treated at the lowest sorafenib dose 200, with all successive cohorts' doses chosen adaptively by the BMA-CRM. The doses and schedules of busulfan and fludarabine were fixed, with f-Bu dose targeting an area under the concentration vs time curve (AUC) of 20,000 ± 12% μmol.min given over 3 weeks. The first two doses of busulfan (80 mg/m2 IV each) were administered on days -20 and -13 on an outpatient basis. The last four Bu doses were calculated to give a total course AUC of 20,000 ± 12% μmol.min and were given as inpatient following each dose of Flu 40 mg/m2 on days -6 through -3. GVHD prophylaxis was post-transplant cyclophosphamide (PTCy) 50mg/kg on days 3 and 4 and tacrolimus. Recipients of unrelated donor grafts also received MMF. All patients were eligible to receive post-transplant maintenance sorafenib after engraftment. Results: The median age was 52 years (range, 30-70). Disease status was CR in 16 (66.6%) patients, CRi in 5 (20.8%), and advanced in 3 (12.5%). Adverse risk karyotype was present in 10 (41.7%) patients. MRD was present in 13 (54.2%). 9 (38%) had mutated flt3. The donor was unrelated in 14 (58%), and peripheral blood stem cells were the graft source in 21(87.5%). Due to the absence of DLTs, the BMA-CRM assigned 200mg, 400mg, 600mg, and 800mg of sorafenib, respectively, to the first 4 cohorts, and the next 4 cohorts were given 800mg. Only 2 dose-limiting skin toxicities were seen, one in cohort 3 with 600mg of sorafenib and the second in cohort 6 with 800mg of sorafenib. 800mg was the final recommended phase 2 dose. The median follow-up in 20 surviving patients was 7.6 months and 1-year progression free survival was 89% (95% CI 75-100%). Other outcomes are summarized in Table 1. Conclusion: Sorafenib can be safely added to the fractionated busulfan regimen. Early data on efficacy appear promising, with an 89% PFS at 1 year of follow up. Figure 1 Figure 1. Disclosures Popat: Bayer: Research Funding; Abbvie: Research Funding; Novartis: Research Funding; Incyte: Research Funding. Hosing: Nkarta Therapeutics: Membership on an entity's Board of Directors or advisory committees. Rezvani: Bayer: Other: Scientific Advisory Board ; AvengeBio: Other: Scientific Advisory Board ; Navan Technologies: Other: Scientific Advisory Board; GSK: Other: Scientific Advisory Board ; Virogin: Other: Scientific Advisory Board ; Affimed: Other: License agreement and research agreement; education grant, Patents & Royalties, Research Funding; Pharmacyclics: Other: Educational grant, Research Funding; Caribou: Other: Scientific Advisory Board; GemoAb: Other: Scientific Advisory Board ; Takeda: Other: License agreement and research agreement, Patents & Royalties. Qazilbash: Bristol-Myers Squibb: Other: Advisory Board; Biolline: Research Funding; Amgen: Research Funding; Oncopeptides: Other: Advisory Board; NexImmune: Research Funding; Angiocrine: Research Funding; Janssen: Research Funding. Daver: Daiichi Sankyo: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; ImmunoGen: Consultancy, Research Funding; Astellas: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; Gilead Sciences, Inc.: Consultancy, Research Funding; Trillium: Consultancy, Research Funding; Glycomimetics: Research Funding; Abbvie: Consultancy, Research Funding; Hanmi: Research Funding; Bristol Myers Squibb: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; FATE Therapeutics: Research Funding; Sevier: Consultancy, Research Funding; Novimmune: Research Funding; Trovagene: Consultancy, Research Funding; Novartis: Consultancy; Jazz Pharmaceuticals: Consultancy, Other: Data Monitoring Committee member; Dava Oncology (Arog): Consultancy; Celgene: Consultancy; Syndax: Consultancy; Shattuck Labs: Consultancy; Agios: Consultancy; Kite Pharmaceuticals: Consultancy; SOBI: Consultancy; STAR Therapeutics: Consultancy; Karyopharm: Research Funding; Newave: Research Funding. Ravandi: Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Jazz: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; AstraZeneca: Honoraria; Novartis: Honoraria; Xencor: Honoraria, Research Funding; Taiho: Honoraria, Research Funding; Astex: Honoraria, Research Funding; AbbVie: Honoraria, Research Funding; Agios: Honoraria, Research Funding; Prelude: Research Funding; Syros Pharmaceuticals: Consultancy, Honoraria, Research Funding. Shpall: Magenta: Consultancy; Bayer HealthCare Pharmaceuticals: Honoraria; Magenta: Honoraria; Adaptimmune: Consultancy; Novartis: Consultancy; Navan: Consultancy; Novartis: Honoraria; Takeda: Patents & Royalties; Affimed: Patents & Royalties; Axio: Consultancy. Mehta: CSLBehring: Research Funding; Kadmon: Research Funding; Syndax: Research Funding; Incyte: Research Funding.
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Falanga, Anna, Cristina Verzeroli, Marina Marchetti, et al. "Thrombotic Risk Assessment in a Prospective Cohort of Newly Diagnosed Ambulatory Cancer Patients Candidate to Chemotherapy." Blood 134, Supplement_1 (2019): 3642. http://dx.doi.org/10.1182/blood-2019-129901.
Full textAbstract:
Introduction: The occurrence of venous thromboembolism (VTE) during chemotherapy may result in treatment delays with unfavorable effects on cancer outcome, therefore VTE prevention is a relevant issue. Current guidelines recommend primary thromboprophylaxis in select high-risk cancer outpatients undergoing chemotherapy. Hence, the use of risk assessment models involving both clinical and biological parameters is increasingly important. In this analysis, in a large prospective cohort of patients with newly diagnosed metastatic non-small cell lung (NSCLC), colorectal (CRC), gastric (GC) or breast (BC) cancers, we assessed whether pre-chemotherapy levels of thrombotic biomarkers may help to stratify patients at different risk levels of VTE during the first 6 months of anti-tumor therapy. Methods: The study cohort included patients with advanced cancer enrolled from January 2012 to December 2017 in the HYPERCAN study (ClinicalTrials.gov, ID# NCT02622815), an ongoing Italian prospective, multicenter, observational study (Falanga et al, Thromb Res 2016). Clinical data and blood samples were collected at enrollment and during scheduled follow-up visits. Baseline plasma levels of fibrinogen (Clauss method), d-dimer (immunoturbidimetric assay), prothrombin fragment F1+2 (ELISA), FVIIa-AT (ELISA) and thrombin generation (TG, CAT assay) were measured. The study protocol was approved by the local Ethics Committee. Informed written consent was obtained from all study subjects. The outcome measure of the current analysis is the time to the occurrence of first symptomatic and/or incidental VTE, objectively confirmed. Results: A cohort of 922 patients [median age: 66 (30-92) years] with metastatic NSCLC (n=416), CRC (n=262), GC (n=105) and BC (n=139) was available for analysis. After a median follow-up of 327 days (range 44-1,548), VTE occurred in 122 (76 M/46 F) patients [median age 64 y (range 40-85)] providing a cumulative incidence of 19.7% (CI 95%: 16-23). According to tumor site, VTE frequency was: NSCLC (n= 64, 15.3%) &gt; CRC (n= 38, 14.5%) &gt; GC (n= 12, 11.4%) &gt; BC (n= 8, 5.7%). Biomarkers' analysis of baseline plasma samples from 598 patients showed significantly higher levels of fibrinogen, d-dimer and TG in the cancer cohort compared to healthy control subjects (p&lt;0.01). NSCLC patients had significantly (p&lt;0.001) higher levels of d-dimer compared to CRC and BC patients, and of fibrinogen (p&lt;0.001) compared to CRC, BC and GC patients. Cumulative incidence of VTE at 6 months was 10% (CI 95% 8-12). In particular, patients who had VTE in 6 months presented with significantly higher pre-chemotherapy levels of D-Dimer than VTE-free subjects (p&lt;0.05). Cox-multivariate analysis identified as independent risk factors for VTE, high d-dimer (HR: 2.1, CI 95% 1.2 - 3.7; p=0.008), high peak of TG (HR: 1.8, CI 95% 0.99 - 3.2; p=0.052), and site of primary tumor (non-BC vs BC) (HR: 3.3, CI 95% 1.01 - 10.5; p=0.048). A score for VTE prediction was created with these variables and three risk categories (low, intermediate, and high) were generated. The cumulative incidence of VTE at 6 months in each risk category was 3.9%, 9.8%, and 19%, respectively (low vs high HR: 2.36 p=0.005; intermediate vs high HR 2.16 p=0.006). Differently, the application of the Khorana score failed to identify high risk patients. Conclusions: Our prospective study in a large cohort of metastatic cancer patients shows the high burden of VTE during the first 6 months of chemotherapy. Furthermore, laboratory data from this analysis enable us to create a risk scoring system based on d-dimer and TG together with tumor site, that significantly identifies patients at the highest VTE risk. Further investigation are worth to externally validate this score for clinical use. Project funded by AIRC "5xMILLE multiunit extension program" n. 12237 grant from the "Italian Association for Cancer Research (AIRC)". Disclosures Santoro: Eisai: Consultancy, Speakers Bureau; Novartis: Speakers Bureau; MSD: Speakers Bureau; Servier: Consultancy, Speakers Bureau; Pfizer: Consultancy, Speakers Bureau; BMS: Consultancy; Abb-Vie: Speakers Bureau; Roche: Speakers Bureau; Bayer: Consultancy, Speakers Bureau; AstraZeneca: Speakers Bureau; BMS: Speakers Bureau; Amgen: Speakers Bureau; Celgene: Speakers Bureau; Lilly: Speakers Bureau; Arqule: Consultancy, Speakers Bureau; Gilead: Consultancy, Speakers Bureau; Sandoz: Speakers Bureau; Takeda: Speakers Bureau.