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Bocchi, V., M. G. Strillacci, A. Zecconi, et al. "191 SEARCHING FOR THE IN VIVO TRANSCRIPTOME BLUEPRINT OF COMPETENT BOVINE OOCYTES." Reproduction, Fertility and Development 28, no. 2 (2016): 226. http://dx.doi.org/10.1071/rdv28n2ab191.
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Gene expression in early stage embryos relies mostly on post-transcriptional control of maternal transcripts accumulated during oocyte maturation. However, while the building process to obtain a competent oocyte is now better understood, it is still not clear what transcriptome blueprint composes a competent oocyte. The aim of the study was to compare the mRNA expression pattern between oocytes collected from fertile heifers and repeat breeders by using RNAseq. Oocytes were collected by ovum pickup from 3 heifers that were 11–15 months of age and became pregnant at the following oestrus and from 4 adult cows with an age of 4 to 7 years, classified as repeat breeders after they failed to become pregnant for a minimum of 3 consecutive AI. To obtain oocytes from follicles with the same degree of development, at time 0 all follicles visible through transrectal ultrasound examination were removed by transvaginal aspiration. Five days later oocytes were collected by ovum pick up from the newly formed follicles with diameters >5 mm. Oocytes from each animal were pooled and sequenced as a single sample. Total RNA was extracted by RNeasy Micro Kit (Qiagen, Valencia, CA, USA). Amplified cDNA, was prepared starting from total RNA using the Ovation RNA-Seq System V2 (Nugen Technologies, San Carlos, CA, USA). After library preparation with TruSeq DNA Sample Prep kit (Illumina, Madison, WI, USA), sequencing was performed on an Illumina HiSEqn 2000. Galaxy and Chipster open web-based platforms were used to analyse the data. We identified 49 differentially expressed genes. Heifers’ oocytes mRNA pattern indicated greater potential to sustain cell division. In particular, oocytes expressed more Keratin 14 (a gene involved in cell proliferation) and kinesin family member 20B (a protein involved in cytokinesis). More competent oocytes also have a greater ability to repair single-strand breaks due to the high levels of endo/exonuclease (5′-3′), endonuclease G-like. This may reflect greater capacity to neutralise DNA damage and, therefore, greater ability to preserve and transmit high-quality DNA. Repeat breeders portray a different landscape; their greater expression of Jun oncogene, Heat shock protein 1, Stimulated by retinoic acid gene6, arylhydrocarbon receptor nuclear translocator, fibromodulin, and aryl-hydrocarbon receptor repressor suggest that these oocytes have been subjected to environmental stress during oocyte maturation. Their greater expressions of inhibin α, stearoyl-CoA desaturase, junctional adhesion molecule 2 have been previously shown to correlate with a reduced oocyte developmental potential. Furthermore, the Cannabinoid receptor protein 1 expression suggests a compromised ion function that can lead to a failed activation of the development program. Finally, the greater expression of Ubiquilin3 and Heat shock protein 1 led to high protein and mRNA degradation, respectively, suggesting that these oocytes are deprived of essential components to sustain embryo growth. In conclusion our data provide the first detailed snapshot of the mRNA pattern defining the differences between a competent oocyte and an incompetent oocyte in vivo. Study supported by PRIN 2008, 2009 and EU-Quantomics.
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Pinato, David James, Francesco A. Mauri, Paolo Spina, et al. "Quantitative comparison of PD-L1 immuno-histochemical assays in hepatocellular carcinoma: The Blueprint-HCC study." Journal of Clinical Oncology 36, no. 5_suppl (2018): 91. http://dx.doi.org/10.1200/jco.2018.36.5_suppl.91.
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91 Background: Programmed cell death ligand 1 (PD-L1) expression by immunohistochemistry (IHC) enriches for responses to PD-1/PD-L1 inhibitors, however its role as a predictive biomarker in hepatocellular carcinoma (HCC) is inconclusive, with no consensus on any particular assay. We evaluated the performance of 4 different PD-L1 detection assays previously published in landmark clinical studies. Methods: PD-L1 IHC was performed on 4 serial sections from tissue microarray (TMA) blocks containing 100 archival cases of HCC that included tumour and surrounding non-tumorous tissue. Antibody clones E1LN3, 28-8, 22c3, SP263 were compared on the basis of percentage and intensity of staining in malignant cells (M) to generate an H-score (range 0-300). Immune cells infiltrating (ICI) and at the periphery, in non-tumorous tissue (ICP) were scored on a 4-tier system (0-3). Results: Patients were 76% males, 20% HCV-positive, 64% cirrhotic with a median age of 67 years. Median tumour size was 4 cm, 70% of patients had T1-T2 tumours and 48% were of grade 2. The proportion of PD-L1 positive cases according to M-ICI-ICP pattern was 2-6-2% for E1LN3, 10-18-19% for 28-8, 9-22-18% for 22c3 and 5-14-13% for SP263. Pairwise comparison of M H-scores revealed heterogeneity across antibodies, with highest concordance between E1L3N/SP263 (R2 = 0.95), E1L3N/22c3 (R2 = 0.65), 22c3/SP263 (R2 = 0.66) and increasing discordance for 28-8/22c3 (R2 = 0.44), E1L3N/28-8 (R2 = 0.29), and 28-8/SP263 (R2 = 0.26). Detection of PD-L1-positive immune infiltrates using a semi-quantitative scoring system revealed significantly different scores in pairwise non-parametric comparisons of ICI (p < 0.05) but not ICP (p > 0.05 for chi-square test). Conclusions: In the Blueprint-HCC study we demonstrated that quantification of PD-L1 protein levels in tumour cells, intra-tumoural and peri-tumoural infiltrate is characterised by inter-assay discordance in HCC. This has profound implications in the clinical development of predictive correlates of efficacy to immunotherapy in HCC. Sources of such discordance should be explored.
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Roper, Michael. "Effective Knowledge Management: A Best Practice Blueprint20036Sultan Kermally. Effective Knowledge Management: A Best Practice Blueprint. Chichester: John Wiley & Sons 2002. 194 pp., ISBN: ISBN 0 470 844493 3 £24.95." Journal of Documentation 59, no. 1 (2003): 118–19. http://dx.doi.org/10.1108/00220410310458082.
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Othman, Zarith Sofiah, Nurhuda Ismail, Ahmad Khudzairi Khalid, and Norbaiti Tukiman. "Module Development for STEM Education Achievement: A Case Study at the Secondary School Level." Journal of Computational and Theoretical Nanoscience 17, no. 2 (2020): 1085–89. http://dx.doi.org/10.1166/jctn.2020.8771.
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STEM Education through the Malaysia Education Blueprint 2013–2025 (PPPM 2013–2025) is an important agenda in the transformation of education to prepare the younger generation for the challenges of the 21st century. Over the years, STEM was carried out, but there are still some issues which contribute towards the failure in achieving a policy percentage set of 60% science and 40% literary studies in secondary schools. The target to increase the number of Science students was not achieved. Therefore, this study was conducted to produce a STEM@IDEAS module as an alternative to increase students’ interest and understanding in solving the synopsis of learning in science, technology and mathematics (STEM). The module STEM@IDEAS focuses in competition design and generating prototype products through a variety of synopsis statements. STEM practices provide students with various trainings such as application of knowledge, skills and assessment to solve synopsis. This study has five (5) STEM practice steps and a total of three (3) modules which will be applied using the STEM elements. Furthermore, the STEM@IDEAS module was tested on several groups of four secondary school students around Pasir Gudang, Johor. A questionnaire was used to evaluate if STEM@IDEAS modules are in line with STEM and its impact on students. This survey uses a Likert scale of 0 to 4 to evaluate starting from 0 (strongly disagree) up to 4 (strongly agree) for each question submitted in each section. The STEM@IDEAS module and the above study are expected to be a source of interest and an alternative way for schools to support the nation’s education policy in strengthening the education development plans towards the nation’s progress.
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Maggio, Meg. "The Hong Kong Basic Law: Blueprint for “Stability and Prosperity” under Chinese Sovereignty? Edited by Ming K. Chan and David J. Clark. [New York: M. E. Sharpe, 1991. 310 pp. ISBN 0-87332-835-3.]." China Quarterly 153 (March 1998): 169–71. http://dx.doi.org/10.1017/s030574100000312x.
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Robinson, JoAnn L. "A Blueprint for the Promotion of Prosocial Behavior in Early Childhood. E. Chesebrough, P. King, T. P. Gullotta, & M. Bloom (Eds.). New York: Springer, 2004, $65.00 (Hardcover), 320 pp., ISBN 0-30648-186-3." Journal of Primary Prevention 27, no. 4 (2006): 445–46. http://dx.doi.org/10.1007/s10935-006-0044-x.
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Gotlib, Jason, Deepti H. Radia, Tracy I. George, et al. "Pure Pathologic Response Is Associated with Improved Overall Survival in Patients with Advanced Systemic Mastocytosis Receiving Avapritinib in the Phase I EXPLORER Study." Blood 136, Supplement 1 (2020): 37–38. http://dx.doi.org/10.1182/blood-2020-137413.
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Introduction: Advanced systemic mastocytosis (AdvSM) comprises a heterogeneous group of clonal mast cell neoplasms, primarily driven by KIT D816V. Measures of AdvSM response, including the International Working-Group for Myeloproliferative Neoplasms Research and Treatment and European Competence Network on Mastocytosis (IWG-MRT-ECNM) criteria, are based on improvements in mast cell-related organ damage (C-findings), and further sub-classified by the extent of reduction in measures of mast cell disease (e.g. serum tryptase level, bone marrow mast cell burden). However, assessment of some C-findings lacks precision (such as splenomegaly and its resolution). Normalization of C-findings may not be an adequate surrogate for important clinical outcomes such as overall survival (OS). We evaluated whether pure pathologic response (PPR) criteria based on changes in bone marrow mast cells, serum tryptase, and complete blood count was more closely correlated with OS compared to the modified IWG-MRT-ECNM (mIWG-MRT-ECNM) criteria. Methods: As an exploratory post-hoc analysis of the phase 1 EXPLORER study of avapritinib in AdvSM, we evaluated responses lasting ≥12 weeks by both mIWG-MRT-ECNM and PPR criteria. At baseline, evaluability for mIWG-MRT-ECNM response required ≥1 evaluable C-findings; PPR required presence of bone marrow mast cell aggregates and/or serum tryptase ≥20 ng/mL. Per PPR, morphologic complete remission (mCR) is absence of bone marrow mast cell aggregates, serum tryptase &lt;20 ng/mL and full (or partial [mCRh]) hematologic recovery; morphologic partial remission (mPR) is ≥50% reduction in bone marrow mast cells and serum tryptase level. OS was analyzed by Kaplan-Meier method and was time from first dose to death. OS comparisons were by log-rank test, performed for best response and landmark analyses at various cycles. Results: As of the data cut-off of August 30, 2019, 80 patients enrolled including 62 with AdvSM (7 with aggressive SM [ASM], 44 SM with an associated hematologic neoplasm [SM-AHN] and 11 with mast cell leukemia [MCL]). Ten (16%) AdvSM patients (7 ASM, 3 SM-AHN) were not response evaluable (RE) per mIWG-MRT-ECNM criteria, due to a lack of an evaluable C-finding at baseline, and 4 additional AdvSM patients were recently enrolled and were not yet response evaluable. Of the 48 RE patients (3 ASM, 35 SM-AHN and 10 MCL) the best overall response rate (ORR) per mIWG-MRT-ECNM was 77% (8% CR, 19% CRh, 42% partial response [PR], and 8% clinical improvement [CI]). Non-responders had stable disease (SD; 21%) or were not evaluable (NE) due to insufficient (&lt;13 weeks) follow-up (2%). Responders (CR/CRh/PR/CI) had 18-month OS of 85% (CR/CRh, 100%; PR, 77%; CI, 75%; Figure 1A); non-responders had 18-month OS of 48% (SD, 53%; NE, 0%) (P=0.042). Per PPR criteria, the best ORR was similar at 79%; however, a greater proportion of patients were assessed as being in a complete remission (15% mCR, 27% mCRh and 38% mPR). Non-responders by PPR all had SD (21%). This demonstrates that elimination of measurable mast cell burden can be discordant with complete C-finding resolution. Responders (mCR/mCRh/mPR) by PPR had 18-month OS of 88% (mCR/mCRh: 100%; mPR: 72%; Figure 1B); non-responders (all SD) had 18-month OS of 21% (P=0.0001). Eventually, all 62 AdvSM patients will be evaluable by PPR criteria, including those 10 patients without mIWG evaluable C-findings at baseline; however, 5 patients had insufficient follow-up at the time of analysis. For the 57 AdvSM patients with sufficient follow up, the best ORR per PPR criteria was similar at 77% (14% mCR, 26% mCRh and 37% mPR). Overall, no patients had a best response of progressive disease based on mIWG or PPR criteria. Landmark analyses of PPR at the end of 6 cycles showed a trend in 18-month OS of mCR/mCRh&gt;mPR&gt;SD in patients with similar starting avapritinib doses of ≥200 mg daily (n=48 of 57 PPR-evaluable patients). Conclusions : In the phase I EXPLORER study, response assessment in AdvSM using PPR criteria increases the evaluable population, significantly correlates with OS, and should be explored as a potential primary endpoint for future trials. Disclosures Gotlib: Blueprint Medicines Corporation: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Chair of the Response Adjudication Committee and Research Funding, Research Funding; Deciphera: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: co-chair of the Study Steering Committee and Research Funding. Radia:Blueprint Medicines Corporation: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees, Other: Education events. George:Blueprint Medicines Corporation: Consultancy, Other: I have received no funding for this research. ARUP Laboratories, owned by the University of Utah, has received funding; Allakos: Consultancy; Deciphera: Other: consultancy, but has received no financial compensation for the past 12 months; Celgene: Consultancy. Robinson:Blueprint Medicines Corporation: Research Funding. Drummond:Jazz: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Pfizer: Consultancy, 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, Speakers Bureau; Gilead: 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, Speakers Bureau; Takeda: Membership on an entity's Board of Directors or advisory committees; Astellas: Membership on an entity's Board of Directors or advisory committees; Blueprint Medicine Corporation: Research Funding. Bose:Incyte Corporation: Consultancy, Honoraria, Research Funding, Speakers Bureau; Kartos Therapeutics: Honoraria, Research Funding; Astellas Pharmaceuticals: Research Funding; NS Pharma: Research Funding; Pfizer, Inc.: Research Funding; Promedior, Inc.: Research Funding; Constellation Pharmaceuticals: Research Funding; Celgene Corporation: Honoraria, Research Funding; CTI BioPharma: Honoraria, Research Funding; Blueprint Medicines Corporation: Honoraria, Research Funding. Hexner:Samus Therapeutics: Research Funding; Novartis: Research Funding; American Board of Internal Medicine: Other: member of the hematology exam committee; Blueprint Medicines Corporation: Other: serves on a data safety monitoring committee, Research Funding. Winton:Blueprint Medicines Corporation: Research Funding; Samus Therapeutics: Research Funding; Incyte Corporation: Research Funding. Horny:Novartis: Consultancy; Blueprint Medicines Corporation: Consultancy. Tugnait:Blueprint Medicines Corporation: Current equity holder in publicly-traded company, Ended employment in the past 24 months. Schmidt-Kittler:Blueprint Medicines Corporation: Current equity holder in publicly-traded company, Ended employment in the past 24 months. Evans:Blueprint Medicines Corporation: Current equity holder in publicly-traded company, Ended employment in the past 24 months. Lin:Blueprint Medicines Corporation: Current Employment, Current equity holder in publicly-traded company. Mar:Blueprint Medicines Corporation: Current Employment, Current equity holder in publicly-traded company. Deininger:Leukemia & Lymphoma Society: Research Funding; Bristol-Myers Squibb: Consultancy, Honoraria, Other, Research Funding; Ariad: Consultancy, Honoraria, Other; Incyte: Consultancy, Honoraria, Other, Research Funding; Novartis: Consultancy, Other, Research Funding; Medscape: Consultancy; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Fusion Pharma: Consultancy; Blueprint Medicines Corporation: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: part of a study management committee, Research Funding; DisperSol: Consultancy; Galena: Consultancy, Honoraria, Other; Celgene: Research Funding; Gilead Sciences: Research Funding; SPARC: Research Funding; Sangamo: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria, Other, Research Funding. DeAngelo:Incyte Corporation: Consultancy; Glycomimetics: Research Funding; Forty-Seven: Consultancy; Amgen: Consultancy; Novartis: Consultancy, Research Funding; Pfizer: Consultancy; Abbvie: Research Funding; Jazz: Consultancy; Autolos: Consultancy; Shire: Consultancy; Takeda: Consultancy; Blueprint Medicines Corporation: Consultancy, Research Funding; Agios: Consultancy.
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Maltin, C. A., G. E. Lobley, C. M. Grant, et al. "Factors influencing beef eating quality 2. Effects of nutritional regimen and genotype on muscle fibre characteristics." Animal Science 72, no. 2 (2001): 279–87. http://dx.doi.org/10.1017/s1357729800055776.
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AbstractEighteen purebred steers of three genotypes, Aberdeen Angus (AA), Charolais (CH) and Holstein (HO), were divided within genotype into three groups of six animals and offered one of three different levels of feeding either moderate (M/M) or high (H/H) both for 20 weeks or moderate for the first 10 weeks followed by high for the remaining 10 weeks (M/H). Growth rates during the final 10 weeks of the experimental period differed between dietary regimen (M/M = 0·87; M/H = 1·25; and H/H = 1·02 kg/day; s.e.d. = 0·08;P< 0·001). Over the entire 20 week experimental period animals offered the M/M level of feeding grew more slowly (0·97 kg/day) than those offered the M/H and H/H level of feeding (1·20 kg/day; s.e.d. = 0·06;P< 0·001). Mean growth rates for CH, HO and AA steers were 1·21, 1·13 and 1·03 kg/day (s.e.d. = 0·06;P< 0·05). The animals were all slaughtered at a fixed age of 18 months, according to the Meat and Livestock Commission Blueprint for beef and, 48 h post mortem, samples of m. longissimus lumborum (LL) and m. vastus lateralis (VL) were removed for analyses.Muscle fibres were classified histochemically, according to their contractile and metabolic properties, and muscle fibre size was measured. Fibre type frequency was calculated and, in LL, the total fibre number of the muscle was estimated. There was little impact of feeding level, or consequentially growth rate, on muscle fibre frequency and size. The effects seen were confined mainly to LL where there were significant differences between the M/M and H/ H groups with respect to fast twitch glycolytic fibres (mean % frequency (M/M = 40·1 and H/H = 44·3; s.e.d. = 1·4;P< 0·01); mean % area (M/M = 51·9 and H/H 56·0; s.e.d. = 1·5;P< 0·05)) and apparent total fibre number (M/ M = 35·0; and H/H = 41·9 ✕ 104; s.e.d. = 1·7;P< 0·05) which were greater in H/H than in M/M groups. However, in both LL and VL the predominant differences were related to genotype; in particular, overall fibre size was smallest in CH, while slow oxidative (SO; type I) fibre area was highest in AA. For LL, analysis across all animals showed a positive relationship between SO area, % area, % frequency and overall acceptability of meat at 14 days as evaluated by a trained sensory panel. No such relationship was observed for VL. The data suggest that in this study manipulation of feeding level has only a small impact on muscle fibre characteristics and that the differences between genotype and muscle type may be more important in determining the variability of overall acceptability than growth rate.
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Gotlib, Jason R., Deepti Radia, Daniel J. DeAngelo, et al. "Avapritinib, a Potent and Selective Inhibitor of KIT D816V, Improves Symptoms of Advanced Systemic Mastocytosis (AdvSM): Analyses of Patient Reported Outcomes (PROs) from the Phase 1 (EXPLORER) Study Using the (AdvSM) Symptom Assessment Form (AdvSM-SAF), a New PRO Questionnaire for (AdvSM)." Blood 132, Supplement 1 (2018): 351. http://dx.doi.org/10.1182/blood-2018-99-112017.
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Abstract Introduction: The KIT D816V oncogene is a key driver in 90-95% of patients with systemic mastocytosis (SM), a group of mast cell (MC) neoplasms including indolent SM (ISM), smoldering SM (SSM) and AdvSM. Debilitating symptoms related to MC proliferation and degranulation characterize ISM and SSM and are also prominent in AdvSM, which is further complicated by SM-related organ damage and decreased survival. Currently, there are no approved agents that selectively target KIT D816V, and there are limited tools to assess symptom improvement in SM. Avapritinib, a highly potent and selective inhibitor of the KIT D816V mutant, showed substantial clinical activity in AdvSM (83% overall response rate (ORR) per modified IWG-MRT-ECNM criteria) in the Phase 1 EXPLORER study [Deininger, et al, EHA, 2018]. We present results using a novel PRO questionnaire, the AdvSM-SAF, developed in accordance with FDA guidance, to assess changes in symptoms in the Part 2 dose expansion phase of EXPLORER. Methods: Patients (pts) received avapritinib at the recommended Phase 2 dose (300 mg once daily [QD]) in continuous 28-day (d) cycles. Pts completed the AdvSM-SAF and 2 additional PROs used in other cancers, the Patient Global Impression of Symptom Severity (PGIS) and the European Organization for Research and Treatment of Cancer Quality of Life (QLQ). PROs and KIT D816V mutant allele fraction (MAF) in blood were assessed serially as follows: AdvSM-SAF daily, from 7 d before first avapritinib dose, ie, baseline (BL: Cycle [C]1 Day [D]1) and through C12, using an electronic diary; PGIS and QLQ at BL (C1D1) and on D1 of each cycle through C12; and KIT D816V mutant allele fraction (MAF) at BL and on D1 of C3, 7, 11, and then every 6 cycles. The AdvSM-SAF assesses severity of 8 symptoms (pruritus, flushing, spots, nausea, vomiting, diarrhea, abdominal pain, fatigue) on a 0-10 scale, and 2 items assess frequency of diarrhea and vomiting. Results are analyzed as a Total Symptom Score (TSS), combining all 8 severity items (maximum symptom score=80), and as a GI domain (combining 4 symptoms: nausea, vomiting, diarrhea, abdominal pain; maximum score 40) and Skin domain (combining 3 symptoms: pruritus, flushing, spots; maximum score 30). Analyses were based on 7 d average scores. AdvSM-SAF data were summarized at BL (C1D-7 to C1D-1), and over the 7-d interval prior to C3D1 and C7D1, and correlated with QLQ, PGIS and KIT D816V MAF. Results: As of 22 June 2018, 25 pts were treated in Part 2 of the study; 24 are ongoing, and enrollment and follow-up continues. The median duration of avapritinib treatment was 5.7 mo (range, 1.7+ to 10.3+ mo). AdvSM-SAF scores for 24 pts with data are shown the Table. Mean BL TSS, GI and Skin scores were 22.6, 9.1, and 7.1. The most severe BL symptom was fatigue (mean score of 6.4). Among 21 pts with scores at C3D1 and 12 pts with scores at C7D1, mean reductions from BL TSS, GI and Skin scores were 6.4, 3.9, and 1.5 points, and 11.1, 5.7, and 4.4 points, respectively, indicating further improvement with continued treatment. Symptom reductions were seen for all 8 items at C3D1. Further symptom improvement was observed for 6 of 8 items from C3D1 to C7D1. Reductions in AdvSM-SAF TSS, GI and Skin scores significantly correlated with improvement in QLQ Emotional (EF) and Cognitive functioning (CF) scales (p values for Pearson Correlation Coefficients <0.0001, <0.0001, and 0.04 with EF and <0.0001, 0.0001, and 0.04 with CF, respectively). Among 18 pts with BL PGIS (mean 3.2, SD 1.15, range 1-5), improvement in PGIS was highly associated with improvement in GI score (p value 0.0004). Decreases in KIT D816V MAF correlated with reduction in TSS (p value 0.04). Conclusions: Avapritinib treatment resulted in meaningful symptom improvement as measured by the AdvSM-SAF in overall symptoms (TSS), GI and skin domains, and all individual symptoms, and improvement continued with longer duration of treatment. Reduction in AdvSM-SAF scores correlated with improvements in other PRO instruments, PGIS and QLQ, supporting the AdvSM-SAF as a useful new tool to assess symptoms in pts with AdvSM. Reduction in AdvSM-SAF scores also correlated with decreases in KIT D816V MAF, indicating that reductions in disease burden may correlate with reduced disease symptoms and improved quality of life. These data warrant further development of avapritinib in AdvSM, as well as in ISM and SSM where symptom burden and poor quality of life are the predominant disease manifestations. Disclosures Gotlib: Deciphera: Consultancy, Honoraria, Research Funding; Blueprint Medicines: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Promedior: Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Kartos: Consultancy; Incyte: Consultancy, Honoraria, Research Funding; Gilead: Consultancy, Research Funding. Radia:Novartis: Speakers Bureau; Blueprint: Consultancy. DeAngelo:Glycomimetics: Research Funding; Shire: Honoraria; Pfizer Inc: Consultancy, Honoraria; Incyte: Consultancy, Honoraria; Amgen: Consultancy; Novartis Pharmaceuticals Corporation: Consultancy, Honoraria; Takeda: Honoraria; ARIAD: Consultancy, Research Funding; BMS: Consultancy; Blueprint Medicines: Honoraria, Research Funding. Bose:CTI BioPharma: Research Funding; Celgene Corporation: Honoraria, Research Funding; Pfizer, Inc.: Research Funding; Blueprint Medicines Corporation: Research Funding; Incyte Corporation: Honoraria, Research Funding; Astellas Pharmaceuticals: Research Funding; Constellation Pharmaceuticals: Research Funding. Conlan:Blueprint Medicines: Employment. Oren:Blueprint Medicines: Employment. Shi:Blueprint Medicines: Employment. Deininger:Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Blueprint: Consultancy.
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Goodhart, William. "The Hong Kong Basic Law—Blueprint for “Stability and Prosperity” under Chinese Sovereignty?. Edited by Ming K. Chan and David J. Clark. [New York: M. E.Sharpe East Gate Books. 1991. xv + 310 pp. ISBN 0-87332-835-3. $45]." International and Comparative Law Quarterly 41, no. 4 (1992): 963–64. http://dx.doi.org/10.1093/iclqaj/41.4.963.
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Bowyer-Bower, T. A. S., and David Pearce. "Blueprint 3: Measuring Sustainable Development." Geographical Journal 162, no. 1 (1996): 114. http://dx.doi.org/10.2307/3060278.
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Beckerman, Wilfred. "Blueprint 3: measuring sustainable development." International Affairs 70, no. 3 (1994): 560. http://dx.doi.org/10.2307/2623760.
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Walsingham, Jean. "Blueprint 3 — Measuring sustainable development." Agricultural Systems 52, no. 4 (1996): 525–26. http://dx.doi.org/10.1016/s0308-521x(96)80457-4.
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Owens, Peter L. "Blueprint 3: measuring sustainable development." Applied Geography 14, no. 3 (1994): 282. http://dx.doi.org/10.1016/0143-6228(94)90043-4.
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Owens, Susan. "Blueprint 3: Measuring sustainable development." Global Environmental Change 5, no. 1 (1995): 78–79. http://dx.doi.org/10.1016/0959-3780(95)90015-2.
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Oetjen, Karolyn, Cai Chen, Christian Bradley, et al. "Neoantigen Landscape of Relapsed Acute Leukemia Following Allogeneic Stem Cell Transplantation." Blood 132, Supplement 1 (2018): 4595. http://dx.doi.org/10.1182/blood-2018-99-115501.
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Abstract INTRODUCTION: The potent graft versus leukemia (GVL) effect of allogeneic stem cell transplantation (allo-SCT) is considered as a blueprint for cellular immunotherapy. However, failure of GVL leads to relapse of underlying leukemia, the major cause of death after allo-SCT. In solid tumors, higher tumor mutation burdens are associated with better response to check point inhibitors which implies the importance of neoantigen specific T-cell functions in cancer immunity. In contrast, the frequencies of somatic mutations in acute leukemia are generally low, therefore the role of neoantigens in GVL remains undetermined. Here, we developed a platform to screen for potential neoantigens by performing whole exome sequencing (WES) and RNA sequencing (RNAseq) in matched samples: leukemic blasts at relapse after allo-SCT, recipient T cell controls, and donor cells. METHODS: Leukemic blasts from patients in relapse were enriched by flow sorting from bone marrow aspirate or peripheral blood samples. Recipient T cells were isolated from pre-transplant peripheral blood as germline controls, and donor monocytes or CD34-positive cells were used as hematopoietic-lineage cell controls. WES was performed to 100X coverage, paired with RNAseq 40M reads per sample. Somatic mutations were detected with mutect and mpileup, followed by annotation with SnpEff. High confidence somatic mutations were subjected to pVAC-seq for neoantigen predictions. RESULTS: Six patients with relapsed acute leukemia (AML 5, ALL 1) after allo-SCT and their transplant donors (matched sibling 3, haplo-identical 3) had suitable samples available for analysis. On average, somatic mutations were identified in 297 genes (range 108- 609) by comparing leukemic blasts and germline control T cells. Among those mutations, potential candidates of neoantigen were identified in five out of six subjects. Allele frequencies of mutant genes varied. Most of neoantigens were predicted to bind HLA of both class I (median 5, range 0-15) and class II (median 6, range 0-12). One subject had only HLA class II restricted peptides as predicted neoantigens. Of interest majority of antigens were derived from molecules known to play important roles in leukemia or tumor biology which include ETV6, CCNY, IDH2, PTPN11, SF3B1, and TP53. Evolution analysis of neoantigen showed an emergence of new antigens in relapsed leukemia while a few driver gene mutations persisted after allo-SCT (Figure). CONCLUSION: Our in-silico analysis demonstrated the possibility that somatic mutation in acute leukemia could serve as putative neoantigens applicable for novel immunotherapy after allo-SCT. The binding capacity of mutant peptides to class I and II HLA implies the importance of both CD4 and CD8 contributions to anti-neoantigen immunity. Next, we will search for neoantigen specific T cells exerting an anti-leukemia effect to validate the GVL potential of these mutations in allo-SCT. Figure. Figure. Disclosures No relevant conflicts of interest to declare.
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Stirrups, Robert. "A blueprint for hope." Lancet Respiratory Medicine 7, no. 7 (2019): 565. http://dx.doi.org/10.1016/s2213-2600(19)30135-3.
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Kosarewicz, Agata, Lisa Königsmaier, and Thomas C. Marlovits. "The blueprint of the type-3 injectisome." Philosophical Transactions of the Royal Society B: Biological Sciences 367, no. 1592 (2012): 1140–54. http://dx.doi.org/10.1098/rstb.2011.0205.
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Type-3 secretion systems are sophisticated syringe-like nanomachines present in many animal and plant Gram-negative pathogens. They are capable of translocating an arsenal of specific bacterial toxins (effector proteins) from the prokaryotic cytoplasm across the three biological membranes directly into the eukaryotic cytosol, some of which modulate host cell mechanisms for the benefit of the pathogen. They populate a particular biological niche, which is maintained by specific, pathogen-dependent effectors. In contrast, the needle complex, which is the central component of this specialized protein delivery machine, is structurally well-conserved. It is a large supramolecular cylindrical structure composed of multiple copies of a relatively small subset of proteins, is embedded in the bacterial membranes and protrudes from the pathogen's surface with a needle filament. A central channel traverses the entire needle complex, and serves as a hollow conduit for proteins destined to travel this secretion pathway. In the past few years, there has been a tremendous increase in an understanding on both the structural and the mechanistic level. This review will thus focus on new insights of this remarkable molecular machine.
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Jawhar, Mohamad, Nicole Naumann, Sebastian Kluger, et al. "Inhibitory Effects of Midostaurin and Blu-285 on Myeloid Progenitor Cells Derived from Patients with Multi-Mutated KIT D816V+ Advanced Systemic Mastocytosis." Blood 128, no. 22 (2016): 1964. http://dx.doi.org/10.1182/blood.v128.22.1964.1964.
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Abstract Recent data have highlighted that the molecular pathogenesis of advanced systemic mastocytosis (advSM) is complex. In addition to the phenotypically most important mutations in KIT, e.g. KIT D816V in 80-90% of patients, one or more additional mutations, e.g. in SRSF2, ASXL1, RUNX1, CBL, JAK2 and others, are present in 60-70% of patients (Jawhar et al., Leukemia 30, 2016). In individual patients, a complex mutational profile is detected not only in mature mast cells (MCs) but also in myeloid progenitors derived from granulocyte-macrophage colony-forming progenitor cells (CFU-GM), indicating multi-lineage involvement of all identified mutations in the vast majority of patients (Jawhar et al., Leukemia 29, 2015). Midostaurin, a multi-targeted kinase inhibitor, has demonstrated an overall response rate of 60% in advSM patients (Gotlib et al., NEJM 374, 2016). BLU-285 is a highly selective KIT D816V kinase inhibitor which has demonstrated biochemical activity on the mutated KIT enzyme (KIT D816V IC50 = 0.27 nM). In the current study, we sought to a) investigate the inhibitory effects of midostaurin and BLU-285 on single-cell-derived CFU-GM from bone marrow mononuclear cells derived from multi-mutated KIT D816V+ advSM patients and b) correlate the midostaurin CFU-GM data with clinical and various response parameters in midostaurin-treated advSM patients. The mutational status of CFU-GM colonies (median colonies per patient, n=20; range 10-30) was analyzed for KIT D816V and additional mutations by PCR followed by Sanger Sequencing. In 10 multi-mutated advSM patients (aggressive SM [n=8] or mast cell leukemia [n=2] with an associated hematological neoplasm), CFU-GM colonies were screened prior to midostaurin (month 0, n=10) and, if available, at month 6 on midostaurin (n=8). At month 0, a median of 90% (range, 40-100) CFU-GM colonies were KIT D816V+, while at month 6 a median of 70% (range, 5-100) CFU-GM colonies were KIT D816V+. A significant relative reduction (≥50%) in the proportion of KIT D816V+ colonies at month 6 was observed in 4/8 (50%) patients. Midostaurin-naïve CFU-GM were incubated with midostaurin at concentrations up to 1000 nM and showed a dose-dependent significant reduction (≥50%) of KIT D816V+ colonies in 1/7 (14%) patients. Overall, the in vitro effects correlated with the in vivo effects of midostaurin on CFU-GM and established IWG-MRT-ECNM response criteria (e.g. mast cell infiltration in BM, serum tryptase level) and KIT D816V allele burden in peripheral blood. Midostaurin-naïve CFU-GM from 7/10 (70%) patients were also incubated with different concentrations of BLU-285 ranging from 0 to 75 nM. A dose-dependent, significant relative reduction (≥50%) of KIT D816V+ CFU-GM colonies was observed at concentrations between 45 and 75nM in 5/7 (71%) patients. Of interest, 3/5 (60%) in vitro responders to BLU-285 were resistant to midostaurin (in vivo and in vitro) while CFU-GM colonies from 2 patients resistant to BLU-285 were also resistant to midostaurin. In addition to KIT D816V, recurrent molecular aberrations (median 2/patient, range 1-3) were identified in all patients, most frequently in SRSF2 (n=9), TET2 (n=7) and ASXL1 (n=4). Neither drug had an effect on the relative frequency of additional mutations in CFU-GM colonies. In summary, we conclude that a) the relative reduction of KIT D816V+ CFU-GM colonies between month 0 and month 6 on midostaurin correlates with clinical response, b) the CFU-GM colony assays may provide useful information for prediction of response to midostaurin, c) the highly selective KIT D816V inhibitor BLU-285 has significant activity against KIT D816V, even in cases which are resistant to midostaurin, and d) neither drug had an effect on the prognostically relevant additional mutations. Disclosures Evans: Blueprint Medicines: Employment, Equity Ownership. Gardino:Blueprint Medicines Corporation: Employment. Lengauer:Blueprint Medicines Corporation: Employment.
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Laug, Dylan, Stacey M. Glasgow, and Benjamin Deneen. "A glial blueprint for gliomagenesis." Nature Reviews Neuroscience 19, no. 7 (2018): 393–403. http://dx.doi.org/10.1038/s41583-018-0014-3.
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Ravella, Revathi, Elizabeth Ren Zhang-Velten, Farrukh T. Awan, et al. "CAR T-Cell Therapy in Relapsed/Refractory Diffuse Large B-Cell Lymphoma (R/R DLBCL): A 'Real-World' Analysis of Patterns of Failure and Role of Bridging Therapy." Blood 136, Supplement 1 (2020): 22–23. http://dx.doi.org/10.1182/blood-2020-141445.
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Introduction:In R/R DLBCL patients receiving CAR T-cell therapy (CAR-T), bridging therapy (BT) with chemotherapy, targeted therapy, and/or radiation therapy (RT) is often administered during the manufacturing window after collection and prior to CAR-T infusion to aid in tumor debulking and/or control symptomatic disease. However, little is known about the optimal type of BT and specifically, the impact BT may have on patterns of failure. Thus, we sought to compare the patterns of failure in patients who received CAR-T for R/R NHL at a single-institution based on the type of BT received. We hypothesize that bridging RT decreases the risk of local recurrence in sites treated with RT prior to CAR-T therapy. Methods: An IRB-approved single-institution retrospective review was performed of all R/R DLBCL patients who underwent leukapheresis for planned CAR-T with axicabtagene ciloleucel (axi-cel). 20 patients were identified, of whom 1 died before CAR-T infusion and 3 died before day +30 post-CAR-T (D+30) PET/CT scans due to CAR-T related toxicities (n=2) or disease progression (n=1). Of the 16 patients who had D+30 PET/CT scans, demographic, disease, and treatment characteristics, as well as toxicity and survival outcomes, were collected and analyzed. PET/CT scans immediately before CAR-T, as well as D+30, D+90, 6 months, and 1-year post-CAR-T infusion were analyzed, with response assessment per the Lugano classification. FDG-avid (Lugano 4 or 5) lesions on pre-CAR-T scan were recorded as index lesions and compared to residual or new FDG-avid lesions on all available post-CAR-T scans. Results: Of the 16 patients who had D+30 PET/CT scans, 4 received no BT, 6 received bridging chemotherapy, 5 received bridging RT (median 30 Gy in 10 fxs), and 1 received a Bruton's tyrosine-kinase inhibitor (BTKi) on a clinical trial. At last follow up, 11/15 (73%) were alive (3/4 with no BT, 3/5 with bridging chemotherapy, 4/5 with RT, 1/1 with BTKi) and 8/15 (53%) were without disease progression (3/4 with no BT, 3/5 with chemotherapy, 2/5 with RT, 0/1 with BTKi); one patient was lost to follow up. Grade 3-4 cytokine release syndrome (CRS) occurred in 1/4 (25%) patients without BT, 2/6 (33%) patients with bridging chemotherapy, and 0/5 (0%) patients with bridging RT. Grade 3-4 immune effector cell-associated neurotoxicity syndrome (ICANS) occurred in 1/4 (25%) patients without BT, 2/6 (33%) patients treated with bridging chemotherapy, and 1/5 (20%) patients treated with bridging RT. Complete patient, disease, and treatment characteristics, as well as outcomes and toxicities, are summarized in Table 1. 6/16 (38%) patients had metabolic complete response (CR) at D+30 and 6/13 (46%) at D+90. In comparison among type of BT received, D+30 and D+90 CR rates, respectively, were 1/4 (25%) and 2/3 (67%) for no BT, 4/6 (67%) and 3/5 (60%) for bridging chemo, and 1/5 (20%) and 1/4 (25%) for bridging RT. In analysis of patterns of failure, there were 48 total index lesions identified on pre-CAR-T PET/CT scans. Of those, 20 received no BT, 15 were treated with bridging chemotherapy, 7 with bridging RT, 6 with bridging BTKi. On D+30 PET/CT, the rates of CR were 16/20 (80%) in lesions without BT, 8/15 (53%) in lesions treated with bridging chemo, 6/7 (86%) in lesions with bridging RT. By D+90, the rates of CR were 7/9 (78%) in lesions without BT, 8/11 (73%) in lesions treated with bridging chemo, and 3/3 (100%) of lesions treated with bridging RT. Of the 50 lesions noted on D+30 PET/CTs, 18 (36%) were index lesions on pre-CAR-T PET/CT, and only 4/28 (14%) lesions on D+90 PET/CT were initial index lesions. Conclusions: Patients who require BT before CAR-T have higher relapse rates, likely reflecting more aggressive disease biology. Bridging RT to CAR-T appears to be safe and effective in providing local control, even at palliative doses, but may not impact overall outcomes. Due to small sample size and retrospective biases, comparison among bridging treatments is limited, and the optimal bridging strategy remains unknown. However, these data suggest that bridging RT should be considered in sites where local control is a priority, such as symptomatic sites or sites where recurrence may cause significant morbidity. Radiating all sites of active disease pre-CAR-T may not improve outcomes though as the predominant pattern of failure appears to be distant. The optimal timing and combination strategies with RT and CAR-T for R/R DLBCL needs to be explored prospectively. Disclosures Awan: MEI Pharma:Consultancy;Karyopharm:Consultancy;Genentech:Consultancy;Astrazeneca:Consultancy;Abbvie:Consultancy;Janssen:Consultancy;Pharmacyclics:Consultancy;Sunesis:Consultancy;Gilead Sciences:Consultancy;Kite Pharma:Consultancy;Dava Oncology:Consultancy;Celgene:Consultancy;Blueprint medicines:Consultancy.Desai:Boston Scientific:Consultancy, Other: Trial Finding.
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Bigler, Bill. "A blueprint for regenerating firms." Long Range Planning 29, no. 5 (1996): 652–62. http://dx.doi.org/10.1016/0024-6301(96)00059-3.
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DeAngelo, Daniel J., Brian A. Jonas, Jane L. Liesveld, et al. "Uproleselan (GMI-1271), an E-Selectin Antagonist, Improves the Efficacy and Safety of Chemotherapy in Relapsed/Refractory (R/R) and Newly Diagnosed Older Patients with Acute Myeloid Leukemia: Final, Correlative, and Subgroup Analyses." Blood 132, Supplement 1 (2018): 331. http://dx.doi.org/10.1182/blood-2018-99-114286.
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Abstract Background Binding of E-selectin (E-sel) to sialyl Lex on the leukemic cell surface activates cell survival pathways and promotes chemotherapy resistance in AML. Expression of the E-sel ligand (E-sel-L) is associated with increased relapse and poor survival. Uproleselan (GMI-1271), a novel E-sel antagonist, disrupts cell survival pathway activation, enhances chemotherapy response and protects from toxicity with improved survival in vivo. We added uproleselan to mitoxantrone, etoposide, cytarabine (MEC) chemotherapy for R/R AML patients (pts) and to cytarabine and idarubicin (7+3) induction for older, treatment naïve (TN) AML pts. Here we report on final outcomes and correlative studies. Methods A Phase (Ph) 1/2 trial evaluated safety and efficacy of escalating doses of upro (5-20 mg/kg) combined with MEC in pts with R/R AML. The recommended Ph 2 dose (RP2D) was 10 mg/kg. Ph 2 added pts ≥60 yrs with TN AML treated with upro and 7+3. Uproleselan was given 24 hrs prior, every 12 hrs during and 48 hrs post chemotherapy. Responders could receive consolidation therapy (1 cycle MEC or 1-3 cycles IDAC) with uproleselan. Baseline E-sel-L expression on AML blasts (CD45+,SSC) and leukemic stem cells (LSC, CD34+CD38-CD123+) in blood and bone marrow (BM) was assessed by flow cytometry, for percentage of blasts binding to E-sel-Fc chimeric protein and HECA452 (antibody to sialyl Lex). Post-induction measurable residual disease (MRD-/MRD+) was assessed locally. Results 91 pts were enrolled (Ph 1 R/R=19; Ph 2 R/R=47. TN=25). Median age in R/R pts was 59 yrs (26-84) with 22/66 (33%) primary refractory, 22 (33%) CR1<6 months (m); 17% prior SCT; 50% had adverse risk (ELN). Uproleselan was well tolerated, with no increase in adverse events. Grade 3/4 mucositis was 2% at RP2D. R/R CR/CRi rate was 41% (RP2D), 39% (all doses), 30% (primary refractory/CR1<6m). 11/16 (69%) evaluable pts were MRD- . 42/66 (64%) received further anti-leukemic therapy including 17 (26%) SCT. At RP2D, median (95%CI) OS was 8.8 m (5.7-11.4); remission duration was 9.1 m (3.2-15.2); 1-year OS was 35%. For R/R/MRD-, 1-year OS was 73%. E-sel-L was detectable on BM blasts in all 36 evaluable pts: median expression 26% (1-85) of blasts. In a subset of MRD evaluable pts (N=10), E-sel-L expression was higher in those who were MRD- (55% vs 35%). Functional E-sel binding was higher in those achieving CR/CRi (N=14, p=0.003, at 12 hrs; p=0.001 at 48 hrs post uproleselan). In BM blasts (Figure N=36), LSC expression of E-sel-L correlated with blast E-sel-L (R2=0.75, p<0.0001), consistent with hypothesis that E-sel/E-sel-L interaction may be an LSC mechanism of chemoresistance. R/R responders (CR/CRi) also had higher LSC/E-sel-L expression than non-responders (41% [0-98] vs 19% [0.7-83] p=0.06). Median OS for LSC/E-sel-L ≥10% (N=22) vs LSC/E-sel-L <10% (N=14) was 12.7m (8.3-NR) and 5.2 m (2.3-9.4), respectively (p<0.006). Median age in TN pts was 67 yrs (60-79). 48% had adverse risk (ELN) and 52% secondary AML (sAML). Uproleselan was well tolerated, with no increase in adverse events, no Grade 3/4 mucositis, and mortality 8% (30d) and 12% (60d). CR/CRi was 72% (all), and 69% (sAML). 5/9 (56%) evaluable pts were MRD-. 19/25 (76%) proceeded to further anti-leukemic therapy; 11 (44%) proceeded to SCT. Median (95% CI) EFS, OS, and remission duration were 9.2 m (3.0-12.6), 12.6 m (9.9-NR), and 10.4 m (7.1-17.8) respectively; 1-year OS was 52%. For sAML, median (95% CI) EFS and OS were 7.7 m (1.1-9.5) and 10.5m (4.4-NR), respectively. For TN/MRD-, 1-year OS was 60%. E-sel-L was detectable on BM blasts in all 24 evaluable pts: median expression 31% (2-92) of blasts. In a subset of MRD evaluable pts (N=8), E-sel-L expression was higher in those who were MRD+ (35% vs 8%). In BM blasts (Figure N=24), LSC expression of E-sel-L correlated with blast E-sel-L (R2=0.87, p<0.0001). TN responders (CR/CRi) had LSC/E-sel-L expression similar to non-responders (21% [0-96] vs 21% [0-94] p=NS). Median OS for LSC/E-sel-L ≥10% (N=15) vs LSC/E-sel-L <10% (N=7) was 10.5 m (4.4-NR) and not reached, respectively (p=NS). Conclusion The addition of uproleselan to chemotherapy was well tolerated, with low oral mucositis rates, high remission rates, high MRD- and transplant rates, and promising survival outcomes in pts with R/R and TN AML. High E-sel-L expression is associated with improved remission and survival with uproleselan treatment in R/R AML. Phase III studies in pts with R/R and (older) TN AML are underway. Figure. Figure. Disclosures DeAngelo: Shire: Honoraria; Amgen: Consultancy; BMS: Consultancy; ARIAD: Consultancy, Research Funding; Blueprint Medicines: Honoraria, Research Funding; Takeda: Honoraria; Glycomimetics: Research Funding; Novartis Pharmaceuticals Corporation: Consultancy, Honoraria; Amgen: Consultancy; Novartis Pharmaceuticals Corporation: Consultancy, Honoraria; Incyte: Consultancy, Honoraria; Glycomimetics: Research Funding; Blueprint Medicines: Honoraria, Research Funding; Pfizer Inc: Consultancy, Honoraria; Shire: Honoraria; BMS: Consultancy; Takeda: Honoraria; Incyte: Consultancy, Honoraria; Pfizer Inc: Consultancy, Honoraria; ARIAD: Consultancy, Research Funding. Jonas:Glycomimetics: Research Funding; Genentech/Roche: Research Funding; Celgene: Consultancy, Research Funding; Accelerated Medical Diagnostics: Research Funding; Daiichi Sankyo: Research Funding; Incyte: Research Funding; Esanex: Research Funding; Tolero: Consultancy; Kalobios: Research Funding; LP Therapeutics: Research Funding; Amgen: Consultancy; Pharmacyclics: Research Funding; Forma: Research Funding; AbbVie: Consultancy, Research Funding. Liesveld:Onconova: Other: DSMB; Abbvie: Honoraria. Bixby:GlycoMimetics: Research Funding. Advani:Glycomimetics: Consultancy; Novartis: Consultancy; Amgen: Research Funding; Pfizer: Honoraria, Research Funding. Marlton:GlycoMimetics: Research Funding; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Astellas: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees. O'Dwyer:Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Research Funding; Onkimmune: Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Research Funding; Glycomimetics: Research Funding; Abbvie: Membership on an entity's Board of Directors or advisory committees. Fogler:GlycoMimetics: Employment, Equity Ownership. Wolfgang:GlycoMimetics: Employment, Equity Ownership. Magnani:GlycoMimetics: Employment, Equity Ownership, Membership on an entity's Board of Directors or advisory committees. Thackray:GlycoMimetics: Employment, Equity Ownership. Becker:GlycoMimetics: Research Funding.
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Richardson, Sarah J., James Michael Fisher, and Andrew Teodorczuk. "The Future Hospital: a blueprint for effective delirium care." Future Hospital Journal 3, no. 3 (2016): 178–81. http://dx.doi.org/10.7861/futurehosp.3-3-178.
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Siddiqui, Maria Tariq, Rashmi Kanagal-Shamanna, Kiran Naqvi, et al. "Clinical Outcomes with Hypomethylating Agents in Patients with Myelodysplastic Syndrome/Myeloproliferative Neoplasm with Ring Sideroblasts and Thrombocytosis (MDS/MPN-RS-T); A Case Series." Blood 136, Supplement 1 (2020): 18–19. http://dx.doi.org/10.1182/blood-2020-142084.
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INTRODUCTION: Myelodysplastic syndrome/myeloproliferative neoplasm with ring sideroblasts and thrombocytosis (MDS/MPN RS-T), formerly called refractory anemia with ring sideroblasts and thrombocytosis (RARS-T), is a disease entity characterized by the presence of anemia, thrombocytosis, bone marrow dysplasia with ring sideroblasts and large atypical megakaryocytes. Given the rarity of MDS/MPN-RS-T, there is little data on the efficacy and clinical outcomes of different therapies in this patient population. Prior case reports and series suggest treatment with erythropoietin-stimulating agents (ESAs) and lenalidomide can be effective in this disease, but there is no data detailing the activity of hypomethylating agents (HMA). The aim of this study is to evaluate the outcomes with HMAs in patients with MDS/MPN-RS-T. MATERIALS AND METHODS: A retrospective review was conducted of patients presenting to MD Anderson Cancer Center between March 2005 and January 2020 at with the diagnosis of MPS/MPN RS-T per World Health Organization (WHO) criteria and 52 patients were identified. Of the 52 patients, 16 patients had received either decitabine or azacitidine in the course of their disease. Of those, 4 were excluded for either receiving HMAs prior to presentation or proceeding to transplant after only 1 cycle of HMA. The data presented is on the remaining 12 patients. Outcomes evaluated included erythroid response, duration of response, response rate, disease progression, overall survival (OS) and progression free survival (PFS). Disease progression was defined as increasing transfusion dependence, development of myelofibrosis (MF) or transformation to acute myeloid leukemia (AML). Overall survival was defined as time from the date of treatment initiation to the date of last follow-up or censorship date. Progression-free survival was defined as the time from the date of starting treatment to the date of progression of disease. RESULTS: Twelve patients who received HMAs with WHO defined MDS/MPN RS-T were included. Median age was 66 years (51-77) with 7 males (58%). Patient characteristics are detailed in Table 1. Ten patients (83%) were transfusion dependent at the time of HMA therapy initiation. The median number of prior therapies was 2 (range 0-5). A total of 6 patients had received prior ESAs and 3 had received prior lenalidomide. HMAs were used as 1st line treatment in 2 patients (17%), 2nd line in 2 patients (17%), 3rd line in 3 patients (25%), 4th line in 4 patients (33%), 5th line in 1 patient (8%) and 6th line in 1 patient (8%). Nine patients (75%) received azacitidine (of which 1 was in conjunction with ruxolitinib), 2 patients (17%) received decitabine, and 1 patient (8%) received decitabine and then azacitidine (in combination with an investigational agent). Median duration of treatment was 8.5 months (range 0-53). Response was achieved in 3 patients with an overall response rate (ORR) of 25%. Per 2015 International Working Group (IWG) MDS/MPN overlap syndrome response criteria, 1 patient achieved complete response (CR) and 2 patients reached hematological improvement in the erythrocyte lineage (HI-E). Median duration of response was 7 months (range 4-21). For the remaining 9 patients, 2 remain on HMA therapy with stable disease, 1 died during treatment, 3 developed failure/loss of response and proceeded to allogeneic stem cell transplantation and 3 had disease progression, with a median follow-up time of 38 months; median OS from therapy initiation was 46 months (Figure 1). Disease progression was seen in a total of 5 patients (42%, 2 patients from the responder group), with increased transfusion dependence in 1 patient (8%), worsening cytogenetics in 1 patient (8%), increased bone marrow blast count in 1 patient (8%), development of myelofibrosis after 8 months in 1 patient (8%) after introduction of HMA therapy and transformation to AML in 1 patient (8%) 46 months after initiating HMAs (Table 2). CONCLUSION: Treatment with HMAs can induce responses in up to 25% of patients, including transfusion independence, even in heavily pre-treated patients with prior exposure to lenalidomide, with a median response duration of 7 months. Disclosures Sasaki: Daiichi Sankyo: Consultancy; Otsuka: Honoraria; Pfizer Japan: Consultancy; Novartis: Consultancy, Research Funding. Jabbour:Genentech: Other: Advisory role, Research Funding; AbbVie: Other: Advisory role, Research Funding; Amgen: Other: Advisory role, Research Funding; Pfizer: Other: Advisory role, Research Funding; BMS: Other: Advisory role, Research Funding; Adaptive Biotechnologies: Other: Advisory role, Research Funding; Takeda: Other: Advisory role, Research Funding. Pemmaraju:MustangBio: Honoraria; DAVA Oncology: Honoraria; Affymetrix: Other: Grant Support, Research Funding; Blueprint Medicines: Honoraria; Stemline Therapeutics: Honoraria, Research Funding; SagerStrong Foundation: Other: Grant Support; Novartis: Honoraria, Research Funding; Celgene: Honoraria; Daiichi Sankyo: Research Funding; Plexxikon: Research Funding; Samus Therapeutics: Research Funding; Roche Diagnostics: Honoraria; AbbVie: Honoraria, Research Funding; LFB Biotechnologies: Honoraria; Incyte Corporation: Honoraria; Pacylex Pharmaceuticals: Consultancy; Cellectis: Research Funding. Kadia:Cyclacel: Research Funding; Amgen: Research Funding; Novartis: Honoraria; Ascentage: Research Funding; Celgene: Research Funding; Pfizer: Honoraria, Research Funding; BMS: Honoraria, Research Funding; Abbvie: Honoraria, Research Funding; Incyte: Research Funding; JAZZ: Honoraria, Research Funding; Cellenkos: Research Funding; Pulmotec: Research Funding; Genentech: Honoraria, Research Funding; Astra Zeneca: Research Funding; Astellas: Research Funding. Ravandi:Abbvie: Consultancy, Honoraria, Research Funding; Xencor: Consultancy, Honoraria, Research Funding; BMS: Consultancy, Honoraria, Research Funding; AstraZeneca: Consultancy, Honoraria; Astellas: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding; Macrogenics: Research Funding; Jazz Pharmaceuticals: Consultancy, Honoraria, Research Funding; Orsenix: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria. Daver:Daiichi Sankyo: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol-Myers Squibb: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Karyopharm: Research Funding; Servier: Research Funding; Genentech: Research Funding; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Astellas: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novimmune: Research Funding; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Trovagene: Research Funding; Fate Therapeutics: Research Funding; ImmunoGen: Research Funding; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Jazz: Consultancy, Membership on an entity's Board of Directors or advisory committees; Trillium: Consultancy, Membership on an entity's Board of Directors or advisory committees; Syndax: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; KITE: Consultancy, Membership on an entity's Board of Directors or advisory committees; Agios: Consultancy, Membership on an entity's Board of Directors or advisory committees. Borthakur:PTC Therapeutics: Research Funding; Incyte: Research Funding; Novartis: Research Funding; Abbvie: Research Funding; Jannsen: Research Funding; GSK: Research Funding; Cyclacel: Research Funding; BioLine Rx: Research Funding; BMS: Research Funding; AstraZeneca: Research Funding; Polaris: Research Funding; Treadwell Therapeutics: Consultancy; Nkarta Therapeutics: Consultancy; BioTherix: Consultancy; BioLine Rx: Consultancy; PTC Therapeutics: Consultancy; Xbiotech USA: Research Funding; Argenx: Consultancy; FTC Therapeutics: Consultancy; Curio Science LLC: Consultancy; Oncoceutics: Research Funding. Verstovsek:Genentech: Research Funding; CTI Biopharma Corp: Research Funding; NS Pharma: Research Funding; Novartis: Consultancy, Research Funding; Roche: Research Funding; Incyte Corporation: Consultancy, Research Funding; PharmaEssentia: Research Funding; Protagonist Therapeutics: Research Funding; AstraZeneca: Research Funding; Promedior: Research Funding; Celgene: Consultancy, Research Funding; Gilead: Research Funding; Sierra Oncology: Consultancy, Research Funding; ItalPharma: Research Funding; Blueprint Medicines Corp: Research Funding. Bose:Incyte Corporation: Consultancy, Honoraria, Research Funding, Speakers Bureau; Astellas Pharmaceuticals: Research Funding; Pfizer, Inc.: Research Funding; Kartos Therapeutics: Honoraria, Research Funding; NS Pharma: Research Funding; Promedior, Inc.: Research Funding; Constellation Pharmaceuticals: Research Funding; CTI BioPharma: Honoraria, Research Funding; Blueprint Medicines Corporation: Honoraria, Research Funding; Celgene Corporation: Honoraria, Research Funding. Kantarjian:Novartis: Research Funding; AbbVie: Honoraria, Research Funding; Takeda: Honoraria; Astex: Research Funding; Daiichi-Sankyo: Research Funding; Immunogen: Research Funding; Cyclacel: Research Funding; Ariad: Research Funding; Actinium: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding; BMS: Research Funding; Agios: Honoraria, Research Funding; Jazz Pharma: Research Funding. Garcia-Manero:Jazz Pharmaceuticals: Consultancy; Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Merck: Research Funding; Amphivena Therapeutics: Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Novartis: Research Funding; Acceleron Pharmaceuticals: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Research Funding; Helsinn Therapeutics: Consultancy, Honoraria, Research Funding; Astex Pharmaceuticals: Consultancy, Honoraria, Research Funding; AbbVie: Honoraria, Research Funding; H3 Biomedicine: Research Funding; Onconova: Research Funding.
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Facchini, Peter J., Jillian M. Hagel, David K. Liscombe, et al. "Opium poppy: blueprint for an alkaloid factory." Phytochemistry Reviews 6, no. 1 (2007): 97–124. http://dx.doi.org/10.1007/s11101-006-9042-0.
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Ananthaswamy, Anil. "Quantum entanglement holds together life's blueprint." New Scientist 207, no. 2769 (2010): 9. http://dx.doi.org/10.1016/s0262-4079(10)61708-3.
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Garcia, Jacqueline S., Helen I. Gandler, Geoffrey Fell, et al. "Targeting MET and FGFR in Relapsed or Refractory Acute Myeloid Leukemia: Preclinical, Clinical, and Correlative Studies." Blood 134, Supplement_1 (2019): 2549. http://dx.doi.org/10.1182/blood-2019-126224.
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Background: Increased expression of hepatocyte growth factor (HGF), causing activation of its receptor MET, is found in a subset of patients with acute myeloid leukemia (AML). Inhibition of HGF-MET signaling with the specific MET kinase inhibitor crizotinib led to a transient therapeutic effect in AML cells; however, resistance rapidly emerged via increased HGF expression due to activation of alternative kinase pathways such as FGFR1 (Kentsis et al., Nat Medicine, 2012). Thus, simultaneous inhibition of activated MET and FGFR represents a potential therapeutic opportunity to forestall resistance to MET inhibition, in part by promoting downregulation of oncogenic STAT transcription factors. The MET/RON inhibitor merestinib and the pan-FGFR inhibitor LY2874455 are investigational small molecules. While they have been tested as single agents in phase 1 solid tumor cancer trials, they have neither been tested individually or in combination in AML patients (pts). Methods: We are conducting a phase 1 combination study to determine the safety and tolerability of dose-escalated merestinib and LY2874455 in pts with R/R AML or secondary AML. Eligible pts include AML pts ≥ 18 y inappropriate for intensive chemotherapy, for whom no approved available therapy exists, and ECOG ≤ 2. A merestinib safety lead-in cohort (dose level (DL) 0) assessed merestinib alone (n=6) at a dose of 80 mg daily for a 28-day cycle (Cycle 0). In the absence of ≥ gr 3 adverse events (AEs), LY2874455 10 mg twice daily on days 1-21 was added to merestinib on day 1 of Cycle 1. Subsequent cohorts (DL 1-3) included a 7-day lead-in (day -6 through day 0) of merestinib alone (80 mg or 120 mg per assigned DL) for pharmacodynamic studies. DL1 is merestinib 80 mg daily for days 1-28 and LY2874455 10 mg po BID days 1-21. DL2 is merestinib 120 mg daily for days 1-28 and LY2874455 10 mg po BID days 1-21. DL3 is merestinib 120 mg daily for days 1-28 plus LY2874455 12 mg po BID days 1-28. Dose-limiting toxicity (DLT) is defined as non-hematologic AEs ≥ gr 3 (excluding fatigue or reversible electrolyte abnormalities), gr 4 infection, or gr 4 neutropenia > 42 days in absence of disease. Results: The merestinib safety lead-in cohort consisted of 7 pts (2M, 5F) with a median age 76 y (range, 46-80) and a diagnosis of refractory (n=2) or relapsed (n=5) AML. One pt was replaced due to insufficient treatment doses administered. Four of 6 pts with available pre-treatment samples had adverse risk baseline mutations (TP53, RUNX1 and ASXL1) and 4 of 7 had poor risk cytogenetics including complex karyotype (n=3) and del 5q (n=1). Median duration on study was 2.4 months (90% CI, 0.8-5.6 months). AEs included 1 DLT due to gr 3 elevation of ALT and AST during merestinib monotherapy phase, which resolved with dose interruption and did not recur after dose modification. Other AEs were gr 3 bacteremia (n=1), gr 3 febrile neutropenia (n=1), gr 2 emesis (n=2), gr 2 nausea (n= 3), gr 3 diarrhea (n=1), gr 3 hypophosphatemia (n=2), gr 3 hyponatremia (n=1) and gr 3 QTc prolongation (n=1). SAEs included gr 4 ARDS (n=1), gr 3 back spasms (n=1), and gr 3 bruising (n=1), all considered to be unrelated to study drug. Five of 6 evaluable pts had LY2874455 added to their treatment per protocol; 1 progressed at the end of merestinib-lead in. In this safety cohort, 1 achieved a CR (after 28 days of merestinib only), 4 had stable disease, and 1 had disease progression. The pt with a CR remained on merestinib monotherapy until progression at the end of cycle 4, at which point LY2874455 was added per protocol. Notably, this responder had baseline normal cytogenetics and mutations in DNMT3A (R882H), FLT3 (N676K), NPM1 (W288fs), TET2 (E227fs) and TET2 (L1231P). This activating FLT3 (N676K) mutation was not detected by repeat NGS with > 200X mean at remission. Exploration of the phosphorylation state of key signaling molecules (STAT3, STAT5, FGFR, and MET) potentially modified by merestinib and LY2874455 inhibitors was carried out in pts with circulating disease (Fig 1). The responder (pt 5) exhibited reduced signaling in pSTAT3, pSTAT5, pFGFR, and pMET during merestinib monotherapy concomitant with clearance of blasts, though this effect was lost shortly before relapse. Conclusions: Preliminary clinical data suggest that merestinib is tolerable and the safety of adding dose-escalated LY2874455 is under investigation. Correlative studies to evaluate the significance of changes in HGF production and in STAT3/5 target genes are on-going. Disclosures Garcia: Abbvie: Research Funding; Genentech: Research Funding. Neuberg:Pharmacyclics: Research Funding; Madrigal Pharmaceuticals: Equity Ownership; Celgene: Research Funding. Winer:Jazz Pharmaceuticals, Pfizer: Consultancy. Galinsky:AbbVie Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Pfizer Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Merus Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; ABIM: Other: Member of specialty oncology board. DeAngelo:Glycomimetics: Research Funding; Blueprint: Consultancy, Research Funding; Amgen, Autolus, Celgene, Forty-seven, Incyte, Jazzs, Pfizer, Shire, Takeda: Consultancy; Abbvie: Research Funding; Novartis: Consultancy, Research Funding. Frank:Janpix, Roche-Genentech, Biolojib Design: Research Funding. Stone:Argenx, Celgene, Takeda Oncology: Other: Data and Safety Monitoring Board/Committee: ; Novartis, Agios, Arog: Research Funding; AbbVie, Actinium, Agios, Argenx, Arog, Astellas, AstraZeneca, Biolinerx, Celgene, Cornerstone Biopharma, Fujifilm, Jazz Pharmaceuticals, Amgen, Ono, Orsenix, Otsuka, Merck, Novartis, Pfizer, Sumitomo, Trovagene: Consultancy. OffLabel Disclosure: Merestinib and LY2874455 are investigational small molecular inhibitors that were tested in combination in a phase 1 clinical trial in AML.
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Garcia-Manero, Guillermo, Koji Sasaki, Guillermo Montalban-Bravo, et al. "Final Report of a Phase II Study of Guadecitabine (SGI-110) in Patients (pts) with Previously Untreated Myelodysplastic Syndrome (MDS)." Blood 132, Supplement 1 (2018): 232. http://dx.doi.org/10.1182/blood-2018-99-116838.
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Abstract Introduction: The hypomethylating agents (HMA) are the standard of care for a majority of patients with higher-risk MDS. SGI-110 is a second generation HMA that molecularly is a dinucleotide derivative of decitabine and therefore a more potent inhibitor of DNA methyltransferase activity. SGI-110 is currently being studied in front-line AML and second-line MDS multicenter studies. Here we present results of a single arm phase II trial of SGI-110 for patients with previously untreated MDS. Methods: Patients, age 18 or older, with adequate renal and hepatic functions, with int-2 or high risk MDS by IPSS or more than 10% blasts in bone marrow were eligible. One prior cycle of azacitidine or decitabine was allowed. No prior other therapies were allowed. SGI-110 was administered at a dose of 60 mg/m2 SC daily x 5 days every 4 weeks. The study was designed with stopping rules for response, toxicity, and mortality (first 3 months). A maximum of 100 patients could be treated. Results: From 11/14/2014 to 7/31/2018, 94 patients have been treated. Median age was 69 years (22.7-91.9), 72 patients (77%) had INT-2, 13 patients (14%) high risk. Median % of marrow blasts was 10 (range, 0-20). Median white blood cell count and platelet count were 2.5 (×106/L), and 52 (×106/L) respectively. Twenty two patients (23%) were diploid, 36 (38%) complex, and 33 (35%) others. Mutation distribution was as follows: TP53, 29 (31%); ASXL1, 26 (28%); TET2, 20 (21%); RUNX1, 19 (20%); RAS, 12 (13%); DNMT3A, 10 (11%); EZH2, 9 (10%); SRSF2, 6 (7%); PHF6, 4 (4%); BCOR, 3 (3%); CEBPA, 3 (3%); SF3B1, 3 (3%); IDH2, 3 (3%); BRAF, 2 (2%); CBL 2 (2%); MPL, 2 (2%); NPM1, 2 (2%); U2AF1, 2 (2%); WT1, 2 (2%); CREBBP, 1 (1%); ETV6, 1 (1%); FLT3-ITD, 1 (1%); GATA2, 1 (1%); IDH1, 1 (1%); SETBP1, 1 (1%); ZRSR2, 1 (1%). The median number of cycles received was 5 (range 1 - 32). Ninety four (100 %) patients are evaluable for toxicity. Early mortality was 0%. Common toxicities were fatigue (61%), infection (46%), nausea (27%), pain (19%), and constipation (16%), mucositis (16%), dyspnea (15%), local injection toxicity (15%), and diarrhea (12%). Eighty seven (93%) patients were evaluable for response. The median number of cycles to response was 3 (range 1 - 11). Overall response rate was 53 (61%); CR 19 (22%), CRp 3 (3%), HI 31 (36%), SD 5 (6%), NR 27 (31%), and died 2 (2%). With a median follow-up of 15 months, the median OS was 15 months and the median EFS was 14 months (Figure 1). By UVA, higher ACE-27 score showed tendency of lower rates of response (p=0.063; hazard ratio [HR], 1.383; 95% confidence interval [CI], 0.982-1946). However, MVA did not show any prognostic factors for response. By MVA characteristics associated with survival were: complex karyotype (p=0.036; HR, 2.345; 95% CI, 1.055-5.210), and response to therapy (p=0.003; HR, 0.272; 95% CI, 0.114-0.648). In conclusion: SGI-110 is well tolerated in previously untreated MDS. ORR appears to be better than expected compared to azacitidine or decitabine. Longer follow-up and randomized trials will be needed to understand effect on survival. Figure. Figure. Disclosures Sasaki: Otsuka Pharmaceutical: Honoraria. Bose:Incyte Corporation: Honoraria, Research Funding; CTI BioPharma: Research Funding; Celgene Corporation: Honoraria, Research Funding; Astellas Pharmaceuticals: Research Funding; Constellation Pharmaceuticals: Research Funding; Blueprint Medicines Corporation: Research Funding; Pfizer, Inc.: Research Funding. Daver:Pfizer: Consultancy; Karyopharm: Research Funding; Novartis: Consultancy; Daiichi-Sankyo: Research Funding; Karyopharm: Consultancy; ARIAD: Research Funding; Novartis: Research Funding; Incyte: Research Funding; Incyte: Consultancy; BMS: Research Funding; Otsuka: Consultancy; Alexion: Consultancy; Sunesis: Consultancy; Pfizer: Research Funding; Sunesis: Research Funding; ImmunoGen: Consultancy; Kiromic: Research Funding. Ravandi:Bristol-Myers Squibb: Research Funding; Sunesis: Honoraria; Orsenix: Honoraria; Amgen: Honoraria, Research Funding, Speakers Bureau; Astellas Pharmaceuticals: Consultancy, Honoraria; Xencor: Research Funding; Seattle Genetics: Research Funding; Abbvie: Research Funding; Orsenix: Honoraria; Astellas Pharmaceuticals: Consultancy, Honoraria; Bristol-Myers Squibb: Research Funding; Jazz: Honoraria; Seattle Genetics: Research Funding; Abbvie: Research Funding; Jazz: Honoraria; Sunesis: Honoraria; Amgen: Honoraria, Research Funding, Speakers Bureau; Macrogenix: Honoraria, Research Funding; Macrogenix: Honoraria, Research Funding; Xencor: Research Funding. Cortes:Pfizer: Consultancy, Research Funding; Astellas Pharma: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Daiichi Sankyo: Consultancy, Research Funding; Arog: Research Funding. DiNardo:Celgene: Honoraria; Agios: Consultancy; Karyopharm: Honoraria; Abbvie: Honoraria; Bayer: Honoraria; Medimmune: Honoraria. Pemmaraju:SagerStrong Foundation: Research Funding; Affymetrix: Research Funding; plexxikon: Research Funding; daiichi sankyo: Research Funding; samus: Research Funding; celgene: Consultancy, Honoraria; abbvie: Research Funding; cellectis: Research Funding; stemline: Consultancy, Honoraria, Research Funding; novartis: Research Funding. Kadia:Novartis: Consultancy; Amgen: Consultancy, Research Funding; Jazz: Consultancy, Research Funding; Abbvie: Consultancy; Pfizer: Consultancy, Research Funding; BMS: Research Funding; Amgen: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Celgene: Research Funding; BMS: Research Funding; Celgene: Research Funding; Novartis: Consultancy; Jazz: Consultancy, Research Funding; Abbvie: Consultancy; Takeda: Consultancy; Takeda: Consultancy.
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Brown, Patrick A., Lingyun Ji, Xinxin Xu, et al. "A Randomized Phase 3 Trial of Blinatumomab Vs. Chemotherapy As Post-Reinduction Therapy in High and Intermediate Risk (HR/IR) First Relapse of B-Acute Lymphoblastic Leukemia (B-ALL) in Children and Adolescents/Young Adults (AYAs) Demonstrates Superior Efficacy and Tolerability of Blinatumomab: A Report from Children's Oncology Group Study AALL1331." Blood 134, Supplement_2 (2019): LBA—1—LBA—1. http://dx.doi.org/10.1182/blood-2019-132435.
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First relapse of B-ALL in children and AYAs is a vexing clinical problem with high rates of subsequent relapse and death using conventional treatment approaches. This is especially true in patients with early relapse [high risk (HR), defined as marrow relapse <36 months from diagnosis or isolated extramedullary relapse <18 months from diagnosis] and those with late relapse and minimal residual disease (MRD) of ≥0.1% at the end of re-induction chemotherapy [intermediate risk (IR)]. Allogeneic hematopoietic stem cell transplant (HSCT) is considered the treatment of choice for this population, but many relapsed patients are not able to proceed to HSCT due to adverse events (AEs) from chemotherapy and/or inability to achieve the MRD-negative second remission known to be associated with optimal HSCT outcomes. The CD3-CD19 BiTE® blinatumomab has single agent efficacy in relapsed/refractory B-ALL (pediatrics and adults) and MRD-positive B-ALL (adults), and a favorable toxicity profile. The primary aim of this study was to compare disease-free survival (DFS) of HR/IR first relapse B-ALL patients aged 1-30 years randomized following re-induction chemotherapy (Block 1 of UKALLR3/mitoxantrone arm) to receive either two intensive chemotherapy blocks (Blocks 2 and 3 of UKALLR3; Control Arm A) or two 4-week blocks of blinatumomab, each followed by one week of rest (Blina cycles 1 and 2; Experimental Arm B). Patients with ≥25% marrow blasts after Block 1 were ineligible for randomization. After randomized therapy, patients on both arms proceeded to HSCT. Secondary aims included comparisons of the following between Arms A and B: AEs, MRD response (by flow cytometry, central lab), overall survival (OS) and ability to proceed to HSCT. During a planned interim analysis (data cut-off 6/30/19) by the Data Safety and Monitoring Committee, the HR/IR randomization was stopped early. While the improvement in DFS for Arm B did not cross the predefined superiority threshold at the time of interim analysis, the combination of improved DFS, superior OS, lower toxicity, and superior MRD clearance for Arm B relative to Arm A was judged to provide sufficiently compelling evidence to establish a new standard of care. A total of 208 HR/IR patients were randomized (Arm A: 103, Arm B: 105). Baseline characteristics were comparable between arms (Table 1). With median follow up of 1.4 years, the intent-to-treat (ITT) 2-year DFS (% ± standard error) was 41.0 ± 6.2% for Arm A vs. 59.3 ± 5.4% for Arm B (p=0.05, 1-sided per pre-specified statistical plan)(Figure 1A). The ITT 2-year OS was 59.2 ± 6.0% for Arm A vs. 79.4 ± 4.5% for Arm B (p=0.005, 1-sided)(Figure 1B). Among patients with detectable MRD (≥0.01%) at the completion of Block 1 chemotherapy, the proportion that achieved undetectable MRD (<0.01%) after Block 2 (Arm A) vs. Blina cycle 1 (Arm B) was 21% vs. 79% (p<0.0001)(Table 2). The rates of MRD response were similar with Block 3 or Blina cycle 2 (Table 2). Post-induction toxic deaths occurred in 4 patients on Arm A (all infections) vs. none on Arm B (p=0.05). Relative rates of CTCAEv4 grade ≥3 febrile neutropenia, infections, sepsis and mucositis were strikingly higher for Block 2/3 (Arm A) vs. Blina cycle 1/2 (Arm B): 44%/46% vs. 4%/0%, 41%/61% vs. 10%/11%, 14%/21% vs. 1%/2%, and 25%/7% vs. 0/1% respectively (p<0.001 for all comparisons except mucositis for Block 3 vs. Blina cycle 2, p=0.16). For Arm B, the rate of selected blinatumomab-related AEs in cycle 1/2 were: Cytokine release syndrome (CRS) 22%/1% (grade ≥3 1%/0%); seizure 4%/0% (1%/0%); other neurotoxicity (e.g., cognitive disturbance, tremor, ataxia, dysarthria) 14%/11% (2%/2%). All blinatumomab-related AEs fully resolved. The rate of patients successfully proceeding from randomization to HSCT (data cut-off 9/30/19) was strikingly different between arms. On Arm A, only 45% (44 of 98 who received randomized therapy) proceeded to HSCT. On Arm B, 73% (75 of 103 who received randomized therapy) proceeded to HSCT (p<0.0001). In conclusion, for children and AYA patients with HR/IR first relapse of B-ALL, blinatumomab is superior to standard chemotherapy as post-reinduction consolidation prior to HSCT, resulting in fewer and less severe toxicities, higher rates of MRD response, greater likelihood of proceeding to HSCT and improved disease-free and overall survival. Patients remain in follow up, and prospectively defined analyses of longer-term outcomes will be forthcoming. Disclosures Brown: Jazz: Membership on an entity's Board of Directors or advisory committees; Servier: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees. Borowitz:Beckman Coulter: Honoraria. Raetz:Pfizer: Research Funding. Zugmaier:Amgen: Employment, Other: holds stock, Patents & Royalties: & other intellectual property. Gore:Amgen: Consultancy, Equity Ownership, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel expenses; Novartis: Consultancy, Other: Service on Data Safety Monitoring Committee; travel, accommodations, expenses; Roche/Genentech: Consultancy, Honoraria, Other: travel expenses; Anchiano: Equity Ownership, Other: spouse employment and company leadership; Blueprint Medicines: Equity Ownership; Celgene: Equity Ownership, Other: DSMC member; Clovis: Equity Ownership; Mirati: Equity Ownership; Sanofi Paris: Equity Ownership. Pulsipher:Medac: Honoraria; Miltenyi: Research Funding; Bellicum: Consultancy; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Jazz: Other: Education for employees; Adaptive: Membership on an entity's Board of Directors or advisory committees, Research Funding; CSL Behring: Membership on an entity's Board of Directors or advisory committees; Amgen: Other: Lecture. Hunger:Amgen: Consultancy, Equity Ownership; Bristol Myers Squibb: Consultancy; Jazz: Honoraria; Novartis: Consultancy. Loh:Medisix Therapeutics, Inc.: Membership on an entity's Board of Directors or advisory committees. OffLabel Disclosure: Investigational use of blinatumomab
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Guru Murthy, Guru Subramanian Guru, Scott H. Kaufmann, Aniko Szabo, et al. "A Multisite Phase Ib Study of Pevonedistat, Azacitidine and Venetoclax (PAVE) for the Treatment of Subjects with Acute Myelogenous Leukemia (AML)." Blood 134, Supplement_1 (2019): 3837. http://dx.doi.org/10.1182/blood-2019-131728.
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Background: Outcomes of patients with AML have remained poor despite the availability of cytotoxic chemotherapy, hypomethylating agents (HMAs) and targeted therapies. HMAs, such as azacitidine, in combination with Bcl-2 inhibitors like venetoclax have demonstrated response rates of 67% in newly diagnosed AML and 21% in relapsed/refractory (RR) AML (DiNardo et al. Blood 2019 and Am J Hematol 2018). While the combination of azacitidine and venetoclax is efficacious in AML, preclinical studies indicate potential mechanisms of drug resistance including overexpression of MCL-1, an anti-apoptotic protein (Konopleva et al. Cancer Cell. 2006). Pevonedistat is a first in class inhibitor of Nedd8 activating enzyme that has demonstrated activity against AML (Swords RT et al. Blood. 2010). Pevonedistat induces NOXA, a pro-apoptotic protein leading to neutralization of MCL-1 inducing apoptosis (Wang et al. Biochem Biophys Res Commun. 2017). Preclinical studies evaluating the combination of pevonedistat and venetoclax against AML cell lines have demonstrated synergistic effect (Knoor KL et al. Cell Death Differ. 2015). Hence, we hypothesize that the addition of pevonedistat to the combination of azacitidine and venetoclax would enhance the therapeutic efficacy by overcoming resistance to apoptosis. Study design and methods: This is an investigator-initiated phase Ib study evaluating the safety of pevonedistat, azacitidine and venetoclax. Patients aged 18 years or above with morphologically documented AML (de novo, secondary or therapy-related), ECOG performance status 0-2 and adequate organ function are eligible for the study. Major exclusion criteria are patients with isolated extramedullary relapse, hematopoietic cell transplantation (HCT) within 100 days of enrollment, active acute GVHD, veno-occlusive disease, acute promyelocytic leukemia, liver cirrhosis and severe liver impairment. While the dose escalation phase is available only for patients with RR-AML, the dose expansion phase can also include newly diagnosed AML patients who are ineligible for intensive induction. The study is planned to be conducted at Medical College of Wisconsin, Mayo Clinic and University of Pennsylvania. The primary endpoint is to determine the recommended phase 2 dose (RP2D) and toxicity profile of pevonedistat, azacitidine and venetoclax. The secondary endpoints include determination of response rates, duration of response, survival and pharmacokinetics. Exploratory endpoints include correlation of response rates with AML genomic profile, correlation of pretreatment levels of BCL2, BCLXL, MCL1, BAX or BAK with response, determination of changes in NOXA (PMAIP1) mRNA and protein expression pre-and post-pevonedistat treatment, evaluation of BH3 mimetic profiling on bone marrow samples by flow cytometry and assessing the sensitivity of leukemia and leukemic stem/progenitor cells to pevonedistat ex vivo. The study will follow 3+3 design with dose escalation (Arms A and B), de-escalation in case of dose limiting toxicity (DLT) (arms Z and Y) and dose expansion phase (figure 1). Patients will be entered sequentially to each dose level, starting with dose level 0. The DLT observation period for dose-escalation will be 1 cycle. The maximal tolerated dose (MTD) will be defined as the highest dose level at which none of the first 3 treated subjects, or no more than 1 of the first 6 treated subjects experiences a DLT. A minimum of 9 and a maximum of 24 patients will be needed for the dose escalation phase and 6 patients for the dose expansion phase. Response rate, duration of response and exploratory endpoints will be analyzed using descriptive statistics. Kaplan-Meier method will be used to determine survival. Disclosures Guru Murthy: Cardinal Health Inc.: Honoraria. Michaelis:Incyte: Consultancy, Research Funding; Pfizer: Equity Ownership, Research Funding; Novartis: Consultancy; Macrogeneics: Research Funding; Millenium: Research Funding; BMS: Research Funding; Celgene: Consultancy, Research Funding; JAZZ: Other: Data Safety Monitoring Board, uncompensated, Research Funding; TG Therapeutics: Consultancy, Research Funding; Janssen: Research Funding; ASTEX: Research Funding; Bioline: Research Funding. Abedin:Jazz Pharmaceuticals: Honoraria; Agios: Honoraria; Helsinn Healthcare: Research Funding; Pfizer Inc: Research Funding; Actinium Pharmaceuticals: Research Funding. Runaas:Agios: Honoraria; Blueprint Medicine: Honoraria. Atallah:Jazz: Consultancy; Novartis: Consultancy; Takeda: Consultancy, Research Funding; Pfizer: Consultancy; Jazz: Consultancy; Helsinn: Consultancy; Helsinn: Consultancy.
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Amrein, Philip C., Karen K. Ballen, Kristen E. Stevenson, et al. "Phase I Study of Ixazomib Added to Chemotherapy in the Treatment of Acute Lymphoblastic Leukemia in Older Adults." Blood 136, Supplement 1 (2020): 41–42. http://dx.doi.org/10.1182/blood-2020-139661.
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Introduction: While progress has been made in the treatment of childhood leukemia, the outlook for patients &gt;60 years of age with acute lymphoblastic leukemia (ALL) is poor with complete remission rates (CR) of approximately 60% and 3-year survivals (OS) of less than 15%. Intensified treatment in a later CALGB trial showed little improvement with a CR=61% and 5-year OS=6% (Stock, Cancer 2013). Ixazomib is an oral proteasome inhibitor, which has shown single agent activity and promising combination activity in pediatric ALL patients (Messinger, Blood 2012). We sought to assess the safety and tolerability, as well as early efficacy of adding ixazomib to a current MGH-DFCI/HCC multi-agent regimen for older adults with ALL. Methods: Patients aged 51 to 75 years of age with newly diagnosed B-ALL and T-ALL were screened for eligibility. Patients with mature ALL (including Burkitt's) were excluded. Patients with Philadelphia chromosome positive ALL (BCR-ABL1+) were eligible, and dasatinib was added to the chemotherapy on Day 10 for these patients. The chemotherapy treatment schedule from induction through maintenance is outlined in Table 1. A standard 3 + 3 patient cohort dose escalation design was used to determine the maximum tolerated dose (MTD) of ixazomib during induction for these patients, the primary objective of the trial. After consolidation I, patients in complete remission (CR) with a suitable donor were offered a hematopoietic stem cell transplantation (HSCT) as per institutional guidelines. Those not going to HSCT continued therapy as noted in the table. Results: There were 19 patients with B-ALL enrolled, none with T-ALL. Among these patients, 7 harbored BCR-ABL1 rearrangements. The median age was 65 years, 74% were male, and 90% had a performance status 0 or 1. The MTD was 2.3 mg of ixazomib, as 2 patients at 3.0 mg developed DLT's: a grade 3 peripheral neuropathy and a grade 5 acute kidney injury (Table 2). Grade 3 and 4 toxicities encountered at any time consisted mainly of grade 4 neutropenia in 13 patients and grade 4 thrombocytopenia in 12 patients. One patient experienced grade 3 neutropenia and 5 patients experienced grade 3 thrombocytopenia. Two patients with grade 2 neuropathy did not meet the definition of DLT. Among the 19 patients, 15 (79%, [95% confidence interval (CI), 54-94%]) achieved CR (14) or CRi (1), and 5 patients went on to HSCT. The median follow-up time was 2 years (range, 1-5) for 8 patients remaining alive. The 1-year overall survival estimate was 53% [95% CI, 29-72%], while the 2-year overall survival estimate was 47% [95% CI, 24-67%]. Conclusions: A dose of 2.3 mg of ixazomib in combination with induction chemotherapy among older patients with ALL was well-tolerated and associated with a promising rate of complete remission. Disclosures Amrein: Takeda: Research Funding; AstraZeneca: Consultancy, Research Funding; Amgen: Research Funding. Brunner:Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Research Funding; AstraZeneca: Research Funding; Forty-Seven Inc: Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Novartis: Research Funding. Hobbs:Novartis: Honoraria; Celgene/BMS: Honoraria; Jazz: Honoraria; Constellation: Honoraria, Research Funding; Incyte: Research Funding; Merck: Research Funding; Bayer: Research Funding. Neuberg:Celgene: Research Funding; Pharmacyclics: Research Funding; Madrigak Pharmaceuticals: Current equity holder in publicly-traded company. Fathi:Takeda: Consultancy, Research Funding; Agios: Consultancy, Research Funding; PTC Therapeutics: Consultancy; Amphivena: Consultancy; Astellas: Consultancy; Daiichi Sankyo: Consultancy; Novartis: Consultancy; Newlink Genetics: Consultancy; Pfizer: Consultancy; Blueprint: Consultancy; Trillium: Consultancy; Kura Oncology: Consultancy; Forty Seven: Consultancy; Jazz: Consultancy; Boston Biomedical: Consultancy; BMS/Celgene: Consultancy, Research Funding; Kite: Consultancy; Trovagene: Consultancy; Amgen: Consultancy; Seattle Genetics: Consultancy, Research Funding; Abbvie: Consultancy. OffLabel Disclosure: MLN 9708, ixazomib is FDA approved for multiple myeloma. In this trial it is used to treat acute lymphoblastic leukemia.
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Cattaneo, Adriano. "Breastfeeding in Europe: a blueprint for action." Journal of Public Health 13, no. 2 (2005): 89–96. http://dx.doi.org/10.1007/s10389-004-0089-3.
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Kvasnicka, Hans Michael, Juergen Thiele, Carlos E. Bueso-Ramos, Philomena Colucci, Dilan Paranagama, and Srdan Verstovsek. "Ruxolitinib (RUX) Induced Meaningful and Directional Changes in the Bone Marrow Microenvironment of Patients with Myelofibrosis Enrolled in the COMFORT-I Study." Blood 134, Supplement_1 (2019): 2948. http://dx.doi.org/10.1182/blood-2019-124343.
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Background The oral Janus kinase (JAK) 1/JAK2 inhibitor RUX has been shown to induce a reduction in bone marrow (BM) fibrosis in patients (pts) with myelofibrosis (MF) compared with placebo. MF is characterized by clonal proliferation of hematopoietic progenitor cells (HPCs) and amplification of cytokine-producing megakaryocytes (MEGs) and macrophages (MACs). Evidence suggests that the pro-inflammatory microenvironment, fostered by the hematopoietic clone, results in BM stromal alterations (including BM fibrosis and osteosclerosis), which can, in turn, influence the hematopoietic niche. The objective of this analysis was to evaluate BM changes in order to characterize the long-term effects of RUX on BM stromal alterations, cytokine-producing cells (ie, MEGs and MACs), and plasma cells (surrogates of inflammation) in a cohort of pts with intermediate-2 or high-risk primary MF, post-polycythemia vera MF, or post-essential thrombocythemia MF who were enrolled in the phase 3 COMFORT-I study. Methods This analysis included 57 pts (36 originally randomized to RUX, 21 crossover [CO] from placebo). All pts were required to have a baseline (BL) BM biopsy and ≥1 subsequent BM observation. CO pts were re-baselined; if CO occurred at <36 wks or ≥36 wks, the Week 0 BM or Week 48 BM, respectively, was used as the BL observation. For fibrosis and osteosclerosis, sections were stained with standard procedures. Specific immunohistochemical (IHC) stains were used to assess MEGs (CD61); plasma cells (MUM1); and activated MACs, including CD68 to identify M1 and anti-inflammatory M2 subtypes, and CD163, a very specific marker for the M2 subtype. Evaluations included IHC and morphometric assessment of CD34+ HPCs. European consensus guidelines were used to grade BM fibrosis and cellularity (Haematologica. 2005;90:1128-1132). Each parameter was graded, by consensus, based on independent review by 3 expert pathologists. A 0-3 grading system was used for fibrosis, osteosclerosis, plasma cells, MEG clustering/atypia, and CD68/163 MACs. Changes from BL to last BM observation are reported. These changes were categorized as improved, stable, or worsened. Improvement/worsening was defined as ≥1 grade reduction/increase from BL or a change in abnormal/normal status. Improvement was assessed in pts with BL values 1-3 or abnormal, stability in pts with BL values 0-2 or normal, and worsening in pts with BL values 0-2 or normal. Results Pt characteristics are summarized in the Table. With respect to age-adjusted cellularity at BL, most marrows were hypercellular, with a notable increase in the proportion of normocellular and hypocellular marrows by the last observation (Figure). In most pts, BM fibrosis was either stable or improved; 21.6% of pts had worsening fibrosis. Similarly, the majority of pts had stable (62.7%) or improved (20.6%) osteosclerosis at the last observation compared with BL. Assessments of megakaryopoiesis revealed stabilization or improvement in MEG clustering in all pts; MEG atypia was improved or stable in the majority of pts. Similarly, RUX resulted in normalization of CD68+ and CD163+ MACs in 21.4% and 25.0% of pts, respectively. The proportion of pts with normal CD34+ clustering/frequency increased from 72.5% at BL to 86.3% at the last visit. With respect to evidence of decreased inflammation in the BM microenvironment, the majority of pts (71.4%) with abnormal plasma cells at BL had a normal level of plasma cells by the last observation, and only 9.7% had evidence of worsening. Conclusions These results extend previous observations on the effect of RUX on the BM in pts with MF. RUX treatment resulted in improvements in the HPCs, atypical MEGs, and activated MACs that are classically thought to produce the inflammatory cytokines that drive BM stromal alterations. These improvements in myeloproliferation were associated with improvement/stabilization of BM fibrosis and sclerosis in the majority of pts. There were also directional improvements in BM plasma cells, a surrogate of inflammation in the BM microenvironment. The MF phenotype is derived from clonal myeloproliferation and a secondary inflammatory state, which results in BM stromal alterations and a constellation of symptoms. The disease-modifying properties of RUX are likely attributable to its ability to address not only myeloproliferation through inhibition of JAK2, but also the secondary inflammatory state through inhibition of JAK1. Disclosures Kvasnicka: Novartis: Honoraria, Research Funding; Takeda: Honoraria; Incyte: Honoraria, Research Funding. Thiele:Sanofi: Consultancy, Honoraria, Other: Remuneration; Incyte: Consultancy, Honoraria, Other: Remuneration, Research Funding; AOP Orphan Pharmaceuticals: Consultancy, Research Funding; Novartis: Consultancy, Honoraria, Other: Remuneration, Research Funding; Shire: Research Funding. Bueso-Ramos:Incyte: Consultancy. Colucci:Incyte: Employment, Equity Ownership. Paranagama:Incyte: Employment, Equity Ownership. Verstovsek:Genetech: Research Funding; Blueprint Medicines Corp: Research Funding; Gilead: Research Funding; Promedior: Research Funding; CTI BioPharma Corp: Research Funding; Novartis: Consultancy, Research Funding; Sierra Oncology: Research Funding; Pharma Essentia: Research Funding; Astrazeneca: Research Funding; Ital Pharma: Research Funding; Protaganist Therapeutics: Research Funding; Constellation: Consultancy; Pragmatist: Consultancy; Incyte: Research Funding; Roche: Research Funding; NS Pharma: Research Funding; Celgene: Consultancy, Research Funding.
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Garcia-Manero, Guillermo, Koji Sasaki, Guillermo Montalban-Bravo, et al. "A Phase II Study of Nivolumab or Ipilimumab with or without Azacitidine for Patients with Myelodysplastic Syndrome (MDS)." Blood 132, Supplement 1 (2018): 465. http://dx.doi.org/10.1182/blood-2018-99-119424.
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Abstract Introduction: Myeloid cells express PD1 and CTL-A. The expression of these molecules is activated by treatment with a hypomethylating agent (HMA) both in cell lines and patient samples. We hypothesized that treatment of patients with MDS with immune checkpoint inhibitors (ICPI) blocking CTLA or PD1 with or without azacitidine could have activity both in front line and relapsed MDS. Methods: To study this, we designed a basket exploratory phase 2 trial of ICPI in MDS. Patients with MDS age 18 or older with adequate renal and hepatic function without history of autoimmune disorders were eligible. Patients were divided into front-line and HMA-failure cohorts. Front-line patients were treated in two different cohorts: AZA + nivolumab (Nivo) and AZA + ipilimumab (Ipi). Patients in the HMA failure cohort were treated in 2 cohorts: single agent Nivo and single agent Ipi. In the HMA failure cohort, patients were first treated with single agent ICPI, and after 6 cycles (or earlier if evidence of progression), the use of azacitidine was allowed to test the concept of re-sensitization. If there was no response, azacitidine was added back. Cohorts could enroll a max of 20 patients with stopping rules for toxicity and response. Nivolumab was administered at a dose of 3 mg/kg on days 1 and 15 every 4-week cycle and ipilimumab at 3 mg/kg on day 1 every 3-week cycle. Azacitidine was used at the standard dose. When combined with azacitidine, nivolumab was administered on days 6 and 20 every 4-week cycle and ipilimumab on day 6 every 4-week cycle. Results: From 11/12/2015 to 8/10/2017, 76 patients were treated. 41 pts (54%) on front-line cohort and 35 (46%) on HMA failure. The median age was 71 years (range, 39.5-85.7). IPSS risk was Low 3 patients (4%), INT-1 30 patients (40%), INT-2 28 patients (37%), High 11 (15%), and unknown 4 (5%). 29 patients (38%) had complex karyotype; 17 patients (22%), diploid; 25 (33%), other; 5 (7%), insufficient metaphases. Next generation sequencing on whole bone marrow extracted DNA was performed using a 28 or 81-gene panel. Distribution of mutations was as follows: ABL, 4 (5%); ASXL1, 17 (22%); BRAF, 2 (3%); CBL 2 (3%); DNMT3A, 7 (9%); IDH1, 2 (3%); IDH2, 4 (5%); IKZF2, 1 (1%); JAK2, 1 (1%); KIT, 2 (3%); NPM1, 1 (1%); RAS, 14 (18%); RUNX1, 15 (20%); 1, SF3B1, 1 (3%); SRSF2, 2 (3%); TET2, 12 (16%); TP53, 22 (29%); U2AF1, 1 (1%). Median number of marrow blasts was 7% (range, 0-18). Median WBC and platelets was 2.9 (range, 0.5-48.2) and 46 (range, 2-319), respectively. 20 patients were treated with AZA+Nivo, 21 with AZA+Ipi, 15 with Nivo, and 20 with Ipi. In summary, toxicities were as follows; skin rash, 26 (11%); fatigue, 22 (9%); pain, 16 (7%); infection, 14 (6%); febrile neutropenia, 13 (5%); pruritus, 14 (6%); diarrhea, 11 (5%); constipation, 9 (4%); nausea, 10 (4%), ALT elevations, 8 (3%); anorexia, 7 (3%); cough, 7 (3%). Early mortality was observed in 1 patient (1%). Overall response was observed in 15/20 (75%), 15/21 (71%), 2/15 (13%), and 7/20 (35%) of pts treated with AZA+Nivo, AZA+Ipi, Nivo, and Ipi, respectively; CR/CRp was observed in 10/20 (50%), 8/21 (38%), 0 (0%), and 3 (15%) in pts treated with AZA+Nivo, AZA+Ipi, Nivo, and Ipi, respectively. In addition, clearance of detectable mutations through the course of therapy was observed in 3 (15%) pts treated with Ipi, 4 (20%) with AZA+Nivo and 3 (14%) with AZA+Ipi. The median cycle received was 4 cycles (range, 1-25). Among 37 patients with response, the median cycle to response was 3 cycles (range, 1-10). With a median follow up of 20 months, the median overall survival were 12 months, not reached, 8 months, and 8 months with AZA+Nivo, AZA+Ipi, Nivo, and Ipi, respectively (Figure 1A; Figure 1B). Event-free survival were 10 months, not reached, 7 months, 6 months with AZA+Nivo, AZA+Ipi, Nivo, and Ipi, respectively. One-year survival rates were 50%, 68%, 25%, and 45%, respectively. The median event-free survival were 16 months and 7 months in the frontline and HMA failure cohort, respectively (p=0.096); the median overall survival were 17 months and 8 months in the frontline and HMA failure cohort, respectively (p=0.030). Conclusion: The incorporation of ICPI is feasible in MDS. These agents have significant activity as single agents and in combination in MDS with an acceptable toxicity profile and significant response and survival outcomes, particularly with ipilimumab. Further randomized studies are needed. Disclosures Sasaki: Otsuka Pharmaceutical: Honoraria. Daver:Novartis: Research Funding; ARIAD: Research Funding; Karyopharm: Consultancy; Kiromic: Research Funding; Sunesis: Consultancy; Otsuka: Consultancy; Incyte: Consultancy; BMS: Research Funding; Daiichi-Sankyo: Research Funding; Alexion: Consultancy; Pfizer: Research Funding; Incyte: Research Funding; Novartis: Consultancy; ImmunoGen: Consultancy; Pfizer: Consultancy; Sunesis: Research Funding; Karyopharm: Research Funding. DiNardo:Medimmune: Honoraria; Karyopharm: Honoraria; Celgene: Honoraria; Abbvie: Honoraria; Agios: Consultancy; Bayer: Honoraria. Ravandi:Xencor: Research Funding; Bristol-Myers Squibb: Research Funding; Astellas Pharmaceuticals: Consultancy, Honoraria; Sunesis: Honoraria; Seattle Genetics: Research Funding; Macrogenix: Honoraria, Research Funding; Sunesis: Honoraria; Macrogenix: Honoraria, Research Funding; Orsenix: Honoraria; Jazz: Honoraria; Abbvie: Research Funding; Orsenix: Honoraria; Seattle Genetics: Research Funding; Amgen: Honoraria, Research Funding, Speakers Bureau; Astellas Pharmaceuticals: Consultancy, Honoraria; Jazz: Honoraria; Amgen: Honoraria, Research Funding, Speakers Bureau; Abbvie: Research Funding; Bristol-Myers Squibb: Research Funding; Xencor: Research Funding. Bose:Astellas Pharmaceuticals: Research Funding; CTI BioPharma: Research Funding; Blueprint Medicines Corporation: Research Funding; Celgene Corporation: Honoraria, Research Funding; Pfizer, Inc.: Research Funding; Incyte Corporation: Honoraria, Research Funding; Constellation Pharmaceuticals: Research Funding. Pemmaraju:abbvie: Research Funding; Affymetrix: Research Funding; SagerStrong Foundation: Research Funding; daiichi sankyo: Research Funding; novartis: Research Funding; plexxikon: Research Funding; samus: Research Funding; stemline: Consultancy, Honoraria, Research Funding; celgene: Consultancy, Honoraria; cellectis: Research Funding. Cortes:novartis: Research Funding. Kadia:Takeda: Consultancy; Novartis: Consultancy; Pfizer: Consultancy, Research Funding; Abbvie: Consultancy; Amgen: Consultancy, Research Funding; Celgene: Research Funding; Takeda: Consultancy; Celgene: Research Funding; Pfizer: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; Jazz: Consultancy, Research Funding; Jazz: Consultancy, Research Funding; Abbvie: Consultancy; BMS: Research Funding; BMS: Research Funding; Novartis: Consultancy. Konopleva:Stemline Therapeutics: Research Funding. Colla:Abbvie: Research Funding.
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Hui, Gavin, Abdullah Ladha, Edna Cheung, et al. "Routine Use of Gemtuzumab Ozogamicin in 7+3-Based Inductions for All "Non-Adverse" Risk AML." Blood 136, Supplement 1 (2020): 36–37. http://dx.doi.org/10.1182/blood-2020-142691.
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Introduction: The addition of gemtuzumab ozogamicin (GO) to 7+3 chemotherapy for newly diagnosed acute myeloid leukemia (AML) has been shown to significantly improve event-free survival (EFS) for cytogenetically favorable-risk AML, with marginal benefit for intermediate-risk AML, and no benefit for cytogenetically adverse-risk AML. Of note, with the exception of mutated FLT3-ITD, little is known about the impact of GO in ELN 2017-defined genotypically adverse-risk AML, and a recent randomized trial found no EFS benefit for 7+3+GO in patients (pts) with genotypically favorable-risk, NPM1-mutated AML. Since 2017, our institution incorporated GO into 7+3-based inductions for all "non-adverse" risk AML pts, as defined by wild-type FLT3 and no abnormalities on rapid FISH analysis for del(5q)/monosomy 5, del(7q)/monosomy 7, and del(20q). We report our experience treating all pts with "non-adverse" risk AML-as defined by this algorithm-with 7+3+GO. Methods: An institutional database was queried in order to identify all pts ≥18 years old who received 7+3-based chemotherapy for newly diagnosed AML between 2017 and 2020; pts who received the FDA-approved fractionated dose of GO were included in the analysis. Data collection included demographic variables, karyotype/FISH, targeted PCR analyses, and multigene NGS panels for AML-related mutations including, but not limited to, mutations in FLT3, NPM1, CEBPA, TP53, RUNX1, and ASXL1. Outcome data included response to induction, relapse, and death, as well as hematopoietic cell transplant (HCT) rates, conditioning regimens, and post-transplant complications. Results: Between January 2017 and July 2020, 96 pts received 7+3-based induction at our institution. Of these, 29 (30%) received 7+3 in combination with GO. Median age at diagnosis was 46 years (range 23-66), with 17 (59%) males. Sixteen (55%) pts had ELN favorable-risk AML (5 [31%] by cytogenetics and 11 [69%] by genotype), 6 (21%) pts had ELN intermediate-risk AML, and 7 (24%) pts had ELN adverse-risk AML (4 [57%] by cytogenetics and 3 [43%] by genotype). Median time from diagnosis to start of induction was 4 days (range 0-43). For cytogenetically adverse-risk pts, median time from diagnostic bone marrow biopsy to receipt of adverse karyotype results was 8 days (7-14). Median time from start of induction to receipt of multigene NGS results for all pts was 15 days (3-32). Overall, 22 (76%) pts achieved remission. All genotypically adverse-risk pts (1 with mutated TP53 and 2 with mutated RUNX1) were refractory to induction, while 3 of 4 (75%) cytogenetically adverse-risk pts (1 with t(6;9), 1 with monosomy 7, and 2 with 11q23 abnormalities) achieved remission. Eight of the 29 (28%) pts proceeded to HCT, including 4 adverse-risk pts. Of the adverse-risk pts, all received myeloablative conditioning prior to HCT and 3 (75%) developed veno-occlusive disease (VOD), with 2 (50%) requiring defibrotide therapy. In favorable/intermediate-risk pts, 4 (18%) proceeded to HCT (2 intermediate-risk pts in first remission and 2 favorable-risk pts in second remission). Of these, 2 (50%) received myeloablative conditioning and 1 (25%) developed VOD. At last follow-up, 23 of 29 pts (79%) remained alive, with a median overall survival not reached (range 1-29 months) and a median EFS of 20 months (9-31). The percentage of ELN favorable-, intermediate-, and adverse-risk pts who remained event-free at last follow-up was 75%, 33%, and 43%, respectively. Discussion: This single-center, retrospective cohort describes the outcomes of pts with "non-adverse" risk AML who received induction chemotherapy with 7+3+GO according to a pre-defined algorithm. Using this algorithm, 30% of all pts receiving 7+3-based inductions received GO. Of these, nearly 25% were ultimately found to have adverse-risk AML as defined by ELN 2017 criteria, largely driven by long turn-around times for karyotyping and NGS multigene panel results. No patient with genotypically adverse-risk AML by ELN criteria responded to induction chemotherapy, and 75% of cytogenetically adverse-risk pts who proceeded to HCT developed VOD. Routine use of 7+3+GO induction outside of the context of cytogenetically favorable-risk AML remains controversial, and further study is needed to define the role of GO, particularly for pts with ELN genotypically adverse-risk AML. Table Disclosures Gotlib: Blueprint Medicines Corporation: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Chair of the Response Adjudication Committee and Research Funding, Research Funding; Deciphera: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: co-chair of the Study Steering Committee and Research Funding. Liedtke:Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria; GSK: Membership on an entity's Board of Directors or advisory committees; Adaptive: Membership on an entity's Board of Directors or advisory committees; Caelum: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees. Muffly:Adaptive: Research Funding; Amgen: Consultancy; Servier: Research Funding. Mannis:AbbVie, Agios, Bristol-Myers Squibb, Genentech: Consultancy; Glycomimetics, Forty Seven, Inc, Jazz Pharmaceuticals: Research Funding.
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Condit, Celeste M. "How the public understands genetics: non-deterministic and non-discriminatory interpretations of the “blueprint” metaphor." Public Understanding of Science 8, no. 3 (1999): 169–80. http://dx.doi.org/10.1088/0963-6625/8/3/302.
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Critics have worried that recent mass media coverage of genetics encourages genetic determinism and discriminatory attitudes in the public. They have identified the “blueprint” metaphor as one major component of public discourse that encourages such undesirable public opinions. To assess public interpretations of popular discourse about genetics, this audience study exposed 137 college students to sample genetics news articles and asked for their interpretations of the “blueprint” metaphor and of genetics in general. A larger group, the plurality, offered non-deterministic interpretations and perspectives on genetics. A small minority offered discriminatory interpretations, whereas a plurality offered explicit antidiscriminatory interpretations and opinions. Non-deterministic views were based on interpretations of the blueprint metaphor that understood genes as operating in a partial and probabilistic fashion, and that interpreted genes as malleable through individual will or technological intervention.
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O'Sullivan, Jennifer, Jason A. Taylor, Aaron T. Gerds, et al. "Molecular Analysis in the Pacritinib Dose-Finding PAC203 Study in Patients with Myelofibrosis Refractory or Intolerant to Ruxolitinib." Blood 134, Supplement_1 (2019): 4214. http://dx.doi.org/10.1182/blood-2019-129254.
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PAC203 is a global multicenter dose-finding study of pacritinib (PAC), an oral JAK2/IRAK1 inhibitor in patients with primary or secondary myelofibrosis refractory or intolerant to ruxolitinib, including patients with severe thrombocytopenia. Patients were randomized 1:1:1 (PAC 100mg QD, 100mg BID or 200mg BID) and stratified by baseline platelet count. The mutational landscape of this patient group is not well characterised, and the impact of mutation status on disease response and hematologic parameters is unknown. We carried out baseline mutational analysis on 105 (of total 164 recruited; 161 treated) patients using an ISO accredited Illumina TruSeq Custom Amplicon Panel, including 32 gene mutation hotspots and exons (~36,000 bp, 287 amplicons). CALR mutation screening was carried out independently. Accepted coverage was achievement of a depth of ≥100 reads per base in ≥95% of targeted bases. Median follow-up time for this cohort was 163 (28-476) days. 57% of patients had a diagnosis of primary myelofibrosis (PMF), whereas 27% and 15% had post-polycythemia vera MF (PPV-MF) and post-essential thrombocythemia MF (PET-MF), respectively. The median baseline platelet count was 64.5 x109/L, with <50 x109/L in 38.3% of patients and baseline Hb <10g/dL in 67.8% of patients. The median age was 67.5 (37-87) years. The majority of patients were JAK2 V617F-mutated (77%), followed by MPL-mutated (8.6%), with a notably low incidence of CALR-mutated (8.6%; type 1 CALR n=6, type 2 CALR n=3) and "triple-negative" (4.8%) cases. Non-myeloproliferative neoplasm driver mutations (NDM) were present in 77.1% (n=81) with ≥3 NDMs in 18.1% of patients. Similar to previous reports, the most prevalent NDMs were TET2 and ASXL1 (n=27 and n=25 respectively). Splicing factor (SF) mutations were mutually exclusive and detected in 32.3% of patients: SF3B1 [13], U2AF1 [14], SRSF2 [6], ZRSR2 [1]. RAS pathway mutations (KRAS/NRAS) were found at a higher frequency than previously in MF cohorts; 16.2% (n=17). SF mutations were present in more PMF (45.6%) than PPV-MF (3.7%, n=1/27) or PET-MF patients (33.3%, n=5/15), P=.002. SF3B1-mutated patients had higher trial entry platelet counts (66.7% platelets ≥100x109/L, P=.014). Baseline red cell transfusion dependency was more often associated with U2AF1 mutations 24.1% (n=7/29) as compared with red cell transfusion independence, 4.5% (n=2/44), P=.047 and U2AF1-mutated patients had lower baseline hemoglobin <10g/dL (n=11/12), P=.015. Overall, 41 (39%) of patients had a high molecular risk mutation (HMR; IDH1/2, SRSF2, ASXL1, SRSF2, U2AF1Q157), and 8 patients had TP53 mutations. In those with molecular analysis available, the highest rates of ≥35% SVR were observed in the 200mg BID arm: 11.1% (n=4/36) followed by 3.2% (n=1/32) in 100mg BID arm and 0% (n=0/30) in 100mg QD arm). Rates of TSS reduction ≥50% were similar across arms. There were no significant correlations between mutations and SVR or TSS response. More grade 3/4 anemia occurred in TET2-mutated patients (OR 5.7, 95% CI 1.6-20.4, P=.007). RAS pathway mutations were associated with grade 3/4 thrombocytopenia (OR 4.4, 95% CI 1.3-14.8, P=0.016). Treatment discontinuation was not influenced by mutation status. In summary, the PAC203 cohort is molecularly high risk, with a high incidence of HMR and low incidence of CALR mutations. We identified novel associations between mutation profiles and hematologic events in this population with advanced MF. Disclosures Taylor: Baxalta: Research Funding; CTI BioPharma: Employment, Equity Ownership. Gerds:Roche: Research Funding; Incyte: Consultancy, Research Funding; Pfizer: Consultancy; CTI Biopharma: Consultancy, Research Funding; Imago Biosciences: Research Funding; Sierra Oncology: Research Funding; Celgene Corporation: Consultancy, Research Funding. Buckley:CTI BioPharma: Employment, Equity Ownership. Harrison:Incyte: Speakers Bureau; Novartis: Honoraria, Research Funding, Speakers Bureau; Promedior: Honoraria; Celgene: Honoraria, Speakers Bureau; AOP: Honoraria; Sierra Oncology: Honoraria; Janssen: Speakers Bureau; Gilead: Speakers Bureau; Roche: Honoraria; CTI: Speakers Bureau; Shire: Speakers Bureau. Oh:Novartis: Consultancy; Incyte: Membership on an entity's Board of Directors or advisory committees; Blueprint Medicines: Membership on an entity's Board of Directors or advisory committees. Mead:CTI: Honoraria, Research Funding; Bristol Myers-Squibb: Consultancy; Novartis: Consultancy, Honoraria, Other: Travel/accommodation expenses, Research Funding, Speakers Bureau; Celgene: Consultancy, Research Funding; Pfizer: Consultancy.
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Abrams, John M. "An emerging blueprint for apoptosis in Drosophila." Trends in Cell Biology 9, no. 11 (1999): 435–40. http://dx.doi.org/10.1016/s0962-8924(99)01646-3.
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Wood, Christopher. "Pearce, David (ed.), "Blueprint 3: Measuring Sustainable Development" (Book Review)." Town Planning Review 66, no. 2 (1995): 213. http://dx.doi.org/10.3828/tpr.66.2.j1024176427770v5.
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Adam, Marc T. P., Henner Gimpel, Alexander Maedche, and René Riedl. "Design Blueprint for Stress-Sensitive Adaptive Enterprise Systems." Business & Information Systems Engineering 59, no. 4 (2016): 277–91. http://dx.doi.org/10.1007/s12599-016-0451-3.
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Zuvanov, Luíza, Diogo Maciel Duarte Mota, Ana P. U. Araujo, and Ricardo DeMarco. "A blueprint of septin expression in human tissues." Functional & Integrative Genomics 19, no. 5 (2019): 787–97. http://dx.doi.org/10.1007/s10142-019-00690-3.
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Hook, Brian. "The Hong Kong Basic Law: Blueprint for “Stability and Prosperity” under Chinese Sovereignty? Edited by Ming K. Chan and David J. Clark. [Armonk, NY: M. E. Sharpe, 1991. 310 pp. $45.00. ISBN 0 87332 835 3.] - Education and Society in Hong Kong: Toward One Country and Two Systems. Edited by Gerard A. Postiglione with Julian Leung Yat Ming [Armonk, NY: M. E. Sharpe, 1991. 320 pp. $45.00. ISBN 0 87332 743 8.]." China Quarterly 134 (June 1993): 371–73. http://dx.doi.org/10.1017/s0305741000029842.
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WACKERS, F., and T. BATEMAN. "Blueprint of the certification examination in nuclear cardiology." Journal of Nuclear Cardiology 4, no. 2 (1997): 164–68. http://dx.doi.org/10.1016/s1071-3581(97)90066-0.
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Whitworth, Pat W., Mark Gittleman, Stephanie Akbari, et al. "Chemosensitivity and endocrine sensitivity prediction by MammaPrint and BluePrint in the Neoadjuvant Breast Registry Symphony Trial (NBRST)." Journal of Clinical Oncology 32, no. 26_suppl (2014): 29. http://dx.doi.org/10.1200/jco.2014.32.26_suppl.29.
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29 Background: Classification into molecular subtypes is important for the selection of therapy for patients with breast cancer. Previous analyses demonstrated that breast cancer subtypes have distinct clinical outcome (Gluck, BCRT 2013). The aim of the prospective NBRST study is to measure chemosensitivity as defined by pathologic complete response (pCR), or endocrine sensitivity as defined by partial response (PR) and metastasis-free survival in molecular subgroups. Methods: The study includes women aged 18 to 90 with histologically proven breast cancer, who are scheduled to start neoadjuvant chemotherapy (NCT) or neoadjuvant endocrine therapy (NET), and who provide written informed consent. Additional inclusion criteria include no excision biopsy or axillary dissection, no confirmed distant metastatic disease, and no prior therapy for breast cancer. Treatment is at the discretion of the physician adhering to NCCN approved regimens. Results: Of 336 patients, T1-4 N0-3, had definitive surgery and the overall pCR rate was 24%. 32/167 (19%) IHC/FISH ERPR+/Her2- patients were reclassified by BluePrint (31 Basal). 43/95 (45%) IHC/FISH Her2+ patients were reclassified by BluePrint (25 Luminal and 18 Basal). 3/74 (3%) IHC/FISH triple-negative patients were not Basal by BluePrint. Of 45 (13%) patients classified as Luminal A 32 received NCT; one patient (3%) had a pCR; 13 patients received NET and 9 (70%) had a PR. Of 116 (35%) patients classified as Luminal B, 111 received NCT and seven (6%) had a pCR. The pCR rate (17/149 (11%)) in IHC/FISH ERPR+/HER2- patients was higher. Fifty-five (16%) are BluePrint HER2 and received NCT (51 plus trastuzumab); 27 (49%) had a pCR compared to 35/95 (37%) in IHC/FISH HER2+ patients. One-hundred twenty (36%) are BluePrint Basal and received NCT; 46 (38%) had a pCR, similar to the pCR percentage seen in the 74 patients designated triple-negative by IHC/FISH. Conclusions: Molecular subtyping using MammaPrint and BluePrint leads to a reclassification of 23% (78/336) of tumors. BluePrint reclassification resulted in better grouping of patients into expected response groups compared to local surrogate subtyping with immunostains.
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Jacobson, Caron A., Alex F. Herrera, Lihua E. Budde, et al. "Initial Findings of the Phase 1 Trial of PBCAR0191, a CD19 Targeted Allogeneic CAR-T Cell Therapy." Blood 134, Supplement_1 (2019): 4107. http://dx.doi.org/10.1182/blood-2019-128203.
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Background: Adoptive engineered autologous cellular immunotherapy has had a significant impact on the lives of some patients with advanced hematologic malignancies. However, the use of these therapies on a larger proportion of patients has been limited by variability of the final cell product, feasibility concerns, cost, and toxicity. Off-the-shelf allogeneic (allo) products offer the opportunity to address some of these concerns. Allo products have their own theoretical limitations, including the potential for graft-versus-host disease (GvHD) causing additional toxicity and host-versus-graft rejection limiting efficacy. PBCAR0191, an anti-CD19 allogeneic CAR T cell, was designed to limit the risk of GvHD by specifically inserting a CD19 specific CAR into the TRAC (T cell receptor alpha constant) locus in cells harvested from healthy donors. Those cells are then expanded, a CD3 elimination step is performed, followed by another expansion, and then PBCAR0191 is vialed and frozen for shipment then thawing, dilution, and infusion at the treatment site. To reduce the risk of PBCAR0191 rejection and increase the chances of cell expansion, lymphodepletion prior to dosing is required. This phase 1 3+3 dose escalation study is designed to identify an optimal dose of PBCAR0191 for efficacy evaluation. Methods: In each of 3 dose levels (3 x 105, 1 x 106, and 3 x 106 CAR-T+ cells/kg), up to 6 patients may be enrolled in each of 2 cohorts (Non-Hodgkin Lymphoma (NHL) and Acute Lymphoblastic Leukemia (ALL)). Eligibility requirements include adequate organ function, confirmed diagnosis to fit one of the cohorts, evaluable disease, at least 2 prior standard treatment regimens, no immunodeficiencies, no CNS disease, no active infections or other major medical issues requiring intervention, and no active GvHD. Eligible patients may have received allogeneic stem cell transplant or another CAR-T therapy. Lymphodepletion was administered on day -5 to day -3 using fludarabine 30mg/m2/day and cyclophosphamide 500mg/m2/day. Cells were administered on day 0. Correlative serum and PBMC samples were taken, while patients remained on study, on days 0, 1, 3, 7, 10, 14, 28, 42, 60 and every 30 days until 180 and then every 90 days until day 360. Assessment of response compared to baseline was performed on day 14 (optional for NHL only), and days 28, 60, 90, 180, 270, and 360, until progression. Results: Three patients with advanced NHL were enrolled and treated in DL1 between April 25, 2019 and May 24, 2019. Two males (one MCL, one DLBCL) and 1 female (DLBCL) ages 34 - 64 (median 64) years were treated. Two screen failures occurred, both patients with ALL, due to non-compliance (1) and loss of CD19 surface expression (1). One patient enrolled post disease progression after treatment with Axicabtagene ciloleucel. No significant toxicity was observed, including no serious adverse events and no dose-limiting toxicities with all patients having a minimum follow-up of 28 days (median 60 days). Two of the three patients experienced objective tumor response by Lugano criteria, at day 14 and day 28, respectively. Both patients progressed due to new lesions (on day 28 and day 60, respectively). The third patient has not met the definition of response, but has had evidence of central necrosis, decreased tumor size, and decreased PET-avidity at day 28, in the context of post-infusion tumor site pain and mild CRS symptoms. Peripheral blood analysis for CAR-T expansion has identified preliminary evidence of cell expansion with a low absolute numbers quantified, likely due to the low dose level at which treatment was initiated. Peripheral blood serum analysis for IFN-gamma, IL-6, and IL-15 indicate preliminary evidence of cell expansion, though not definitive. Conclusions: Further enrollment of patients into DL2 is ongoing. Data from DL2 entered by early October will be included in a presentation in the meeting. Findings to date indicate preliminary evidence of short-lived cell-mediated anti-tumor effect and preliminary evidence of cell expansion in vivo, which will be evaluated more fully at DL2 and DL3. Disclosures Jacobson: Bayer: Consultancy, Other: Travel Expenses; Humanigen: Consultancy, Other: Travel Expenses; Kite, a Gilead Company: Consultancy, Honoraria, Other: Travel Expenses, Research Funding; Novartis: Consultancy, Honoraria, Other: Travel Expenses; Precision Biosciences: Consultancy, Other: Travel Expenses; Pfizer: Consultancy, Research Funding; Celgene: Consultancy, Other: Travel Expenses. Herrera:Adaptive Biotechnologies: Consultancy; Gilead Sciences: Consultancy, Research Funding; Seattle Genetics: Consultancy, Research Funding; AstraZeneca: Research Funding; Merck: Consultancy, Research Funding; Genentech, Inc.: Consultancy, Research Funding; Pharmacyclics: Research Funding; Immune Design: Research Funding; Kite Pharma: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding. Budde:F. Hoffmann-La Roche Ltd: Consultancy. DeAngelo:Amgen, Autolus, Celgene, Forty-seven, Incyte, Jazzs, Pfizer, Shire, Takeda: Consultancy; Novartis: Consultancy, Research Funding; Glycomimetics: Research Funding; Abbvie: Research Funding; Blueprint: Consultancy, Research Funding. Heery:Precision BioSciences: Employment. Stein:Amgen: Consultancy, Speakers Bureau; Stemline: Speakers Bureau; Celgene: Speakers Bureau. Jain:Kite/Gilead: Consultancy. Shah:Celgene/Juno: Honoraria; Kite/Gilead: Honoraria; Incyte: Research Funding; Jazz Pharmaceuticals: Research Funding; Pharmacyclics: Honoraria; Adaptive Biotechnologies: Honoraria; Spectrum/Astrotech: Honoraria; Novartis: Honoraria; AstraZeneca: Honoraria.
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Rausch, Caitlin R., Adam DiPippo, Prithviraj Bose, and Dimitrios P. Kontoyiannis. "Breakthrough Invasive Fungal Infections (bIFI) Are Uncommon in Patients with Newly Diagnosed Acute Leukemia Receiving Primary Antifungal Prophylaxis." Blood 136, Supplement 1 (2020): 31–32. http://dx.doi.org/10.1182/blood-2020-142559.
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Introduction: Mold-active primary antifungal prophylaxis (PAP) is widely recommended in neutropenic patients (pts) with newly diagnosed acute myeloid leukemia (AML) and high-risk myelodysplastic syndrome (MDS) who undergo remission-induction chemotherapy (RIC). Posaconazole (PCZ) prophylaxis resulted in fewer invasive fungal infections (IFIs) when compared to fluconazole and was associated with a survival advantage in this population (Cornely et al, 2007). Similarly, pts with acute lymphoblastic leukemia (ALL) undergoing RIC are also at risk of IFI due to prolonged neutropenia. Although PCZ is the preferred agent for PAP, the incorporation of targeted agents into acute leukemia therapy calls for more individualized choices in PAP. Other mold-active agents including voriconazole (VCZ) and isavuconazole (ISA) or the echinocandins are alternatives which may be preferred in individual settings due to variations in toxicity, patient co-morbidities, drug interactions, and cost. Little contemporary data exists to compare the incidence of breakthrough IFI (bIFIs) in pts with AML or ALL receiving PCZ, VCZ, or ISA as prophylaxis during RIC. Methods: We reviewed the medical records of all consecutive pts with newly diagnosed AML/MDS or ALL treated at our institution from 3/2016-7/2019. Included pts received high-intensity chemotherapy, or a lower-intensity venetoclax (VEN)-containing regimen, for RIC. Therapy with high-dose (&gt; 1g/m2/day) cytarabine (HiDAC), continuous cytarabine plus an anthracycline (3+7), or HyperCVAD was considered high-intensity therapy. Patients receiving PCZ, VCZ, or ISA for &gt; 5 days beginning during induction therapy were included. Baseline evidence of prior mold infection and treatment with a concomitant echinocandin were not allowed. Echinocandin use preceding mold-active PAP was allowed, however prior use of an amphotericin B product was not. bIFI were defined according to ECMM criteria (Cornely et al, 2019). Results: We identified 232 pts with AML/MDS (n=186), ALL (n=43), and biphenotypic leukemia (n=3). Among the AML/MDS pts, 31% (n=57) received a lower-intensity VEN-containing regimen, while 69% (n=129) received a high-intensity regimen with or without VEN. Nearly all pts with ALL and biphenotypic leukemia received high-intensity RIC with HyperCVAD or a HiDAC containing regimen. Of the 232 pts, PCZ (n=111), VCZ (n=84), or ISA (n=37) were used as PAP, respectively (Table 1). Most pts (n=157; 68%) received an echinocandin for a median of 6 days (range, 0-38), prior to transitioning to a mold-active triazole. Ten (4.3%) pts had a bIFI (6 proven, 1 probable, 3 possible) during induction therapy while receiving PAP (Table 2) including 9 (4.8%) pts with AML/MDS and 1 (2.3%) patient with ALL. An equal number of pts with bIFI were receiving lower-intensity, VEN-based therapy, or high-intensity therapy. Among the 84 pts receiving VCZ, 4 (4.8%) had a bIFI (4 proven); 3 pts (2.7%) receiving PCZ had a bIFI (2 proven, 1 possible); 3 pts (8.1%) receiving ISA had a bIFI (1 probable, 2 possible). C. glabrata (n=3), and C. krusei, Cryptococcus spp. and Fusarium spp. (one each) accounted for the 6 proven bIFIs. One patient had both C. glabrata and C. krusei fungemia. The probable bIFI was pneumonia with a positive Aspergillus GM from BAL. The 3 possible bIFI were pneumonia (n=2) and sinusitis (n=1). Eight pts (80%) were neutropenic (ANC &lt; 500 cells/mm3) for &gt;14 days at the time of bIFI, 1 pt was neutropenic for &gt;7 days, and 1 pt had ANC &gt; 500 cells/mm3. Seven pts with bIFI received a prior echinocandin for a median of 3 days (range, 0-15) prior to initiation of triazole PAP. Seven pts were neutropenic for &lt; 7 days (n=2), 7-14 days (n=3), or &gt; 14 days (n=2) at the time of azole initiation. bIFI occurred after a median of 20 days (range, 5-72) of azole PAP and a median of 24 days (range, 12-71) from the initiation of RIC. One patient with bIFI deceased within 42 days of starting RIC and did not achieve a response after RIC (bIFI-related mortality: 0.44%). Conclusion: The incidence (&lt;5%) and mortality (&lt; 0.5%) due to bIFI in a contemporary cohort of pts with newly diagnosed acute leukemia receiving PAP is low. bIFI occurred late in induction therapy and most often in pts with &gt; 14 days of neutropenia. Prophylaxis with VCZ, PCZ, or ISA, with or without a prior echinocandin, appear to be comparable options for PAP in pts with newly diagnosed AML or ALL undergoing RIC. Disclosures Bose: CTI BioPharma: Honoraria, Research Funding; Astellas Pharmaceuticals: Research Funding; Celgene Corporation: Honoraria, Research Funding; Constellation Pharmaceuticals: Research Funding; Kartos Therapeutics: Honoraria, Research Funding; Incyte Corporation: Consultancy, Honoraria, Research Funding, Speakers Bureau; Promedior, Inc.: Research Funding; Pfizer, Inc.: Research Funding; NS Pharma: Research Funding; Blueprint Medicines Corporation: Honoraria, Research Funding. Kontoyiannis:Gilead Sciences: Honoraria; United Medical: Honoraria; Astellas Pharma: Consultancy; Cidara Therapeutics: Consultancy; Amplyx Pharmaceuticals: Consultancy; Mayne Pharma: Consultancy; Pharma Pharmaceutical Industries: Consultancy; Merck & Co.: Consultancy, Honoraria. OffLabel Disclosure: Voriconazole and isavuconazole are approved for the treatment of invasive fungal infections rather than the prevention, as discussed in this abstract.
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Wang, Xiaoli, Raajit K. Rampal, Cing Siang Hu, et al. "The Genetic Architecture of Myeloproliferative Neoplasms-Blast Phase (MPN-BP) Stem Cells." Blood 134, Supplement_1 (2019): 1677. http://dx.doi.org/10.1182/blood-2019-128836.
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MPN-BP originates from a leukemic stem cell (LSC) that is capable of recreating and serial passaging the leukemia in NSG mice (Wang Blood 2018). The genomic architecture of these LSCs has not been well characterized. We therefore performed mutational profiling using capture-based next generation sequencing of primary MPN-BP patient samples and xenografts following their transplantation into NSG mice. All 7 patients with MPN-BP studied had 2-6 known oncogenic gene mutations. T cell-depleted mononuclear cells (MNC, 1-10×106) containing 50-3850 leukemia initiating cells based upon limiting dilution analysis were transplanted into 1-3 NSG mice per patient sample. 1-7 months after transplantation, the mice were sacrificed. 23.3±5.5% leukemic cell chimerism was detected in each mouse. Leukemic cells from xenografts were then selected and sequenced. As shown in Figure 1, primary MNCs from 6 of 7 patients contained 1-3 mutations involving TET2, JAK2V617F, TP53, MPL, KRAS with a variant allele frequency (VAF) ≥45% marking founder clones. Leukemic cells in primary xenografts possessed each of their founder mutations, suggesting clonality and that MPN-BP originates within the LSC compartment. Additionally 1-2 gene mutations with 0.1-9.6% VAF (subclonal mutations) were present in primary samples from 3 of these 6 patients (Pts 1, 6, 7) but their VAF (15.5-71.1%) in xenografts surpassed that present in primary cells. Moreover, a distinct oncogenic mutation in TP53(p.R175G) not present in Pt 7's primary cells was detected in leukemic cells from one of the 3 individual xenografts (VAF: 51.8%). There was also one patient (Pt 4) with primary cells that did not harbor any founder mutations but contained 4 subclonal mutations (VAF: MYB, 6.9%; KRAS, 9.6%, PTPN11, 29.5%; ASXL1(p.T848fs*19), 35.6%). In the xenografts, the VAFs of MYB (0%) and PTPN11 (12.2%) were reduced, while the VAFs of the other 2 subclonal mutations were increased to 77.4% (KRAS) and 48.8% (ASXL1). These findings suggest that multiple genetically distinct LSC clone/subclones exist in patients with MPN-BP that are capable of engrafting NSG mice and have the potential in the future to participate in leukemia progression and/or relapse. All 7 patients originally had a JAK2V617F+ MPN, but 3 of the MPN-BP cells were JAK2V617F¯. Among the remaining 4 patients whose primary cells retained JAK2V617F, the VAF was decreased in leukemic cells within the xenografts. These findings indicate that in JAK2V617F+ MPNs which evolve to MPN-BP, that the MPN-BP may either arise from stem cells distinct from the original JAK2V617F+ MPN stem cells with the acquisition of additional genetic events or progress from the clonal proliferation of distinct JAK2V617F¯ LSCs. Thus, JAK2V617F might play a limited role in either MPN-BP initiation or its progression. Four patients had distinct oncogenic TP53 mutations in primary cells which represented a clonal (VAF: Pt 2, 63.5%; Pt 5, 59.6%) or a subclonal mutation (Pts 1, 7) with a very low VAF (2.5%, 0.4%). The VAF for TP53 mutations were each increased in paired xenograft from 3 patients (Pt 2: 99.8%; Pt 1: 15.5%; Pt 7: 3.8%). These observations support a consistent proliferative advantage of LSCs carrying TP53 mutations in MPN-BP irrespective of how small the original LSC subclone is in the primary cells. Pt 3 and Pt 4 both had a KRAS mutation in their primary cells (VAF: Pt 3, 45.7%; Pt 4, 9.6%). For Pt 3, although the VAF of the KRAS mutation remained the same in the leukemic cells of the primary NSG recipient (44.4%), it increased to 90.2% in a secondary NSG recipient which was characterized by a higher leukemic cell burden (1.8-fold) and shorter survival (12 days less) than the primary NSG recipient. The VAF of KRAS mutation in Pt 4 also reached 77.4% in leukemic cells in the primary xenograft. These data suggest that acquisition of a KRAS mutation in LSCs may not only promote LSC clonal expansion, but also confer enhanced LSC self-renewal capacity. Finally, 4 distinct TET2 mutations were present as a founder mutation in primary cells of 3 patients but their VAF was unchanged or only slightly increased in leukemic cells in paired xenografts, suggesting that TET mutations are not involved in either LSC clonal expansion or disease progression. We conclude that TP53 and/or KRAS mutations appear to play an important role in the development of MPN-BP and may serve as potential targets for the development of effective treatment. Disclosures Rampal: Agios, Apexx, Blueprint Medicines, Celgene, Constellation, and Jazz: Consultancy; Constellation, Incyte, and Stemline Therapeutics: Research Funding. Hoffman:Merus: Research Funding.
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Verstovsek, Srdan, Anne Jacobson, Jeffrey D. Carter, and Tamar Sapir. "Facilitating Team-Based Care Coordination and Collaboration in Myelofibrosis: Findings from a Quality Improvement Study in Three US Community Oncology Systems." Blood 136, Supplement 1 (2020): 32–33. http://dx.doi.org/10.1182/blood-2020-136432.
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Background Care coordination can be especially challenging in the setting of rare malignancies such as myelofibrosis (MF), where hematology/oncology teams have limited experience working together to implement rapidly evolving standards of care. In this quality improvement (QI) initiative, we assessed barriers to patient-centered MF care in 3 community oncology systems and conducted team-based audit-feedback (AF) sessions within each system to facilitate improved care coordination. Methods Between 1/2020 and 3/2020, 31 hematology/oncology healthcare professionals (HCPs) completed surveys designed to characterize self-reported practice patterns, challenges, and barriers to collaborative MF care in 3 community oncology systems (Table 1). Building on findings from the team-based surveys, 39 HCPs from these centers participated in AF sessions to reflect on their own practice patterns and to prioritize areas for improved MF care delivery. Participants developed team-based action plans to overcome identified challenges, including barriers to effective risk stratification, care coordination, and shared decision-making (SDM) for patients with MF. Surveys conducted before and after the small-group AF sessions evaluated changes in participants' beliefs and confidence in delivering collaborative, patient-centered MF care. Results Team-Based Surveys: HCPs identified managing MF-associated anemia and other disease symptoms (42%), providing individualized care despite highly variable clinical presentations (29%), and developing institutional expertise despite low patient numbers (16%) as the most pressing challenges in MF care. For patients who are candidates for JAK inhibitor therapy, HCPs reported most commonly relying on current guidelines (71%) and clinical evidence (61%) to guide treatment selection. HCPs also considered drug safety/tolerability profiles (55%), personal or institutional experience (13%), and out-of-pocket costs for patients (13%); no participants (0%) reported incorporating patient preference into their decision-making. Teams were underutilizing SDM and patient-centered care resources; fewer than 50% reported providing tools to support adherence (48%), visual aids for patient education (47%), financial toxicity counseling (40%), resources for managing MF-related fatigue (36%), or counseling to reduce risk factors for CVD, bleeding, and thrombosis (26%). Small-Group AF Sessions: Across the 3 oncology centers, teams participating in the AF sessions (Table 1) shared a self-reported caseload of 97 patients with MF per month. HCPs reported a meaningful shift in beliefs regarding the importance of collaborative care: following the AF sessions, 100% of HCPs agreed or strongly agreed that collaboration across the extended oncology care team is essential for achieving MF treatment goals, an increase from 71% prior to the AF sessions (Figure 1). Participants also reported increased confidence in their ability to perform each of 6 aspects of evidence-based, collaborative, patient-centered care (Figure 2). In selecting which aspects of patient-centered care to address with their clinical teams, HCPs most commonly prioritized individualizing treatment decision-making based on patient- and disease-related factors (57%), followed by providing adequate patient education about treatment options and potential side effects (24%) and engaging patients in SDM (18%). To achieve these goals, 73% of HCPs committed to sharing their action plans with additional clinical team members; others committed to creating a quality task force to oversee action-plan implementation (15%) and securing buy-in from leadership and stakeholders (9%). Conclusions As a result of participating in this community-based QI initiative, hematology/oncology HCPs demonstrated increased confidence in their ability to deliver patient-centered MF care and improved commitment to team-based collaboration. Remaining practice gaps and challenges can inform future QI programs. Study Sponsor Statement The study reported in this abstract was funded by an independent educational grant from Incyte Corporation. The grantors had no role in the study design, execution, analysis, or reporting. Disclosures Verstovsek: ItalPharma: Research Funding; CTI Biopharma Corp: Research Funding; Promedior: Research Funding; Gilead: Research Funding; NS Pharma: Research Funding; Celgene: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Genentech: Research Funding; Sierra Oncology: Consultancy, Research Funding; PharmaEssentia: Research Funding; AstraZeneca: Research Funding; Incyte Corporation: Consultancy, Research Funding; Blueprint Medicines Corp: Research Funding; Protagonist Therapeutics: Research Funding; Roche: Research Funding.
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Zhao, Mansuo, Yibing Yang, and Hong Yan. "An adaptive thresholding method for binarization of blueprint images." Pattern Recognition Letters 21, no. 10 (2000): 927–43. http://dx.doi.org/10.1016/s0167-8655(00)00052-0.
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