Academic literature on the topic 'N 5300.5 UL 2016'

Abstract Introduction: Hemophagocytic lymphohistiocytosis (HLH) is a devastating disorder with protean clinical manifestations caused by the overproduction of T-cell derived cytokines. Cytokine-dependent activation of the Janus family kinases (JAK) is a hallmark of the final common pathway in HLH pathogenesis. Therefore, we initiated a single center, open-label, investigator-initiated trial to assess the efficacy and safety of ruxolitinib in adult patients with secondary HLH. Methods: Adult patients (≥18 years) who fulfilled 5 of 8 diagnostic criteria were eligible. Patients with CNS involvement or an active malignancy were ineligible. Patients who had received any prior systemic therapy (excluding corticosteroids) within 7 days of treatment were ineligible. Patients with normal renal function received oral ruxolitinib 15 mg twice daily on a continuous, 28-day cycle. Dose reductions for renal insufficiency and toxicity are permitted. Treatment was continued indefinitely until disease progression, unacceptable toxicity, or any other conditions for treatment discontinuation were met. The first patient was enrolled in February, 2016 and enrollment is ongoing. The primary endpoint is overall survival at 2 months. Secondary endpoints include the response rate, duration of response, progression-free and overall survival. Adverse events were graded and attributed in accordance with the National Cancer Institute Guidelines for the Cancer Therapy Evaluation Program. Disease parameters evaluable for response included all quantifiable signs and laboratory abnormalities included in the diagnostic criteria for HLH. A complete response (CR) required normalization of all signs and laboratory abnormalities. At least 25% improvement in two or more signs/laboratory abnormalities was required for a partial response (PR). At least a 50% worsening in two or more signs/laboratory abnormalities was considered progressive disease (PD), while failure to fulfill any of these criteria was considered stable disease (SD). Results: A total of 4 patient have been enrolled, all of whom fulfilled at least 5 of 8 diagnostic criteria for HLH. Hemophagocytosis, a pathologic hallmark of HLH, was observed in every patient. At the time of treatment initiation, all patients were anemic [median hemoglobin 7.1 g/dL (range: 6.2-7.5 g/dL)] and thrombocytopenic [median platelet count 47 K/uL (range: 14-107 K/uL)]. Three patients were neutropenic [median ANC 0.95 K/uL (range: 0-1.9 K/uL)]. HLH was secondary to an autoimmune disorder (n=3), infection (n=1), and a homozygous mutation in the STXBP2 gene, recently identified as a causative defect in primary HLH, was observed in one patient. Cytopenias significantly improved within the first week of treatment in all patients. On day +7, the mean increase in hemoglobin was 1.88 g/dL (0.2-3 g/dL), in ANC was 1.53 K/uL (range 0.1-5.3 K/uL) and platelet count was 74 K/uL (range 17-116 K/uL). Neutropenia resolved by day +40 and thrombocytopenia resolved by day +47 in all patients. Three of four patients became transfusion independent within 2 days of treatment initiation. Three of four patients received corticosteroids prior to and after initiation of ruxolitinib. The mean corticosteroid (prednisone equivalent) dose prior to treatment initiation was 225 mg/day (range: 60-391 mg/day) and was 38 mg/day (range: 0-75 mg/day) on day +30. Within 47 days of treatment initiation, corticosteroids were discontinued in 2 patients, and were discontinued in all patients by day +54. Significant improvements in ferritin and sIL-2R were also observed with a median 92.6% decrease in ferritin by day +30 (range 86.4-92.6%) and 86% median decrease in sIL-2R by day +30 (range 66.6-92.7%). All patients achieved at least a PR, and 2 patients remain on treatment (>2 months, >8 months). Two patients discontinued treatment, one for progressive disease (due to recurrent symptoms), and another for drug intolerance (neuropathic foot pain). No severe adverse events have been observed. In addition to the patients enrolled in this study, two additional patients who met eligibility criteria were similarly treated (off study) at another institution. Both of these patients achieved at least a PR and remain on treatment (>8 months, >14 months). Conclusions: Ruxolitinib led to rapid and durable responses and was well tolerated in adult patients with secondary HLH. Disclosures Devata: Affimed: Research Funding. Phillips:Abbvie: Research Funding; Pharmacyclics: Consultancy, Research Funding; Genentech: Consultancy; Bayer: Consultancy; Seattle Genetics: Consultancy; Gilead: Consultancy. Sood:Bayer: Research Funding. Wilcox:Incyte, Corp: Research Funding.

Abstract Background: 30-50% of heavily platelet transfused patients will ultimately develop HLA allo-immunization. Although HLA-matched platelets can be lifesaving for these patients, a substantial proportion of patients receiving partially HLA-matched platelet products develop platelet transfusion refractoriness, putting them at risk for serious bleeding complications. Recent data suggest compliment activation leading to the destruction of platelets bound by HLA allo-antibodies may play a pathophysiologic role in platelet refractoriness. Eculizumab is a monoclonal antibody that binds and inhibits C5 compliment, blocking both the classic and alternative pathways of compliment. Here we investigated whether eculizumab treatment could be used to overcome platelet transfusion refractoriness in HLA allo-immunized patients. Methods: We conducted a one armed; phase II pilot trial (NCT02298933) in which HLA allo-immunized patients with platelet transfusion refractoriness received a single infusion of eculizumab at a dose of 1200mg. Eligible patients included adults age 18-75 with severe thrombocytopenia who had detectable HLA class I antibodies associated with platelet transfusion refractoriness (defined as a post-transfusion corrected count increment (CCI) of <7500/ul and <5000/ul at 10-60 mins and 18-24 hrs respectively that occurred following at least 2 consecutive platelet transfusions). Patients were defined to respond to therapy if one of the first 2 platelet transfusions following eculizumab infusion resulted in a CCI>7500/uL at 10-60 mins and CCI>5000/uL at 18-24 hrs post transfusion. Subjects were taken off study 14 days following eculizumab treatment. Responding patients who developed recurrent platelet refractoriness after planned study withdrawal were eligible to re-enroll on study. All patients were required meningococcal vaccination before eculizumab infusion +/- antibiotic prophylaxis to cover N. meningitidis. Results: As of 8/2016, 8 Eculizumab infusions were administered to 7 HLA allo-immunized subjects (median age 40 yrs, range 24-71) with severe thrombocytopenia associated with platelet transfusion refractoriness. Patients had an underlying diagnosis of SAA (n=3), refractory/relapsed AML (n=2; 1 patient had just finished conditioning for a haplo-identical transplant), relapsed ALL (n=1; post MUD transplant) and high risk MDS (n=1). Compliment, total (CH50) was the most reliable and consistent measure for complement inhibition. After Eculizumab infusion, CH50 decreased to <20U/ml in all treated patients. 3 of 8 (43%) patients had a response to therapy with platelet refractoriness resolving following 4/8 (50%) eculizumab administrations (Figures 1-3). Subject 1 received an additional 2nd treatment with eculizumab 2 months after her 1st response and again had resolution of platelet refractoriness (Figure 1A&1B). In 3 out of 4 cases where platelet refractoriness was overcome, the administered platelet product given immediately after eculizumab treatment expressed an HLA allele for which an HLA antibody had been detected in the patient's serum. Resolution of platelet refractoriness resulted in a clinically meaningful reduction in the requirement for platelet transfusions: the median number of platelet transfusion given 2 weeks before and 2 weeks after the eculizumab infusion in responding patients was 8.5 (range 3-10) and 4.5 (range 3-5) transfusions respectively. For the non-responders, the median number of platelet transfusions given 2 weeks before and 2 weeks after the eculizumab infusion was 8 (range 7-10 ) and 9.5 (range 6-15) transfusions respectively. Conclusions: The preliminary data from this ongoing trial suggest eculizumab may have efficacy in overcoming HLA antibody-associated platelet transfusion refractoriness. Remarkably, we observed eculizumab overcame platelet refractoriness in a subset of HLA allo-immunized patients receiving HLA mismatched platelet products that expressed an HLA allele for which an HLA antibody was detectable in the patient's serum. These data raise the possibility that eculizumab administration could be of therapeutic benefit in patients with platelet refractoriness as a consequence of newly discovered HLA antibodies, buying time for transfusion medicine departments to acquire HLA matched platelets or until platelet recovery occurs following chemotherapy or stem cell transplant. Disclosures No relevant conflicts of interest to declare.

Abstract BACKGROUND: Impact of Plerixafor (P) mobilized stem cells on immune reconstitution of autologous stem cell transplant (ASCT) patients has not been established. Early lymphocyte recovery (Absolute lymphocyte count of > 1 K/uL at day 30 after transplant) has been established to predict outcomes in multiple myeloma (MM) patients. The purpose of this study was to evaluate lymphocyte recovery in MM patients who underwent ASCT with stem cells mobilized with G-CSF vs G-CSF+P. Secondary objective was to evaluate the survival outcomes. METHODS: This is a retrospective analysis of MM patients who underwent first ASCT between 2008 and 2016 with either G-CSF or G-CSF+P mobilization at Karmanos Cancer Institute in Detroit, Michigan. Plerixafor was used per institutional guidelines when the peripheral CD-34+ve cell-count was < 20/ uL on day 5 of G-CSF mobilization. 610 total patients were identified. Mobilization agents used were G-CSF alone (n= 469) or G-CSF+P (n= 141). All patients underwent transplant after Melphalan (M) conditioning and dose of M was at treating physician's discretion (140 vs 200 mg/m2). The primary endpoint was the Absolute Lymphocyte Count at day 30 (ALC30). Secondary endpoints were PFS and OS Univariable and multivariable Cox proportional hazards regression models were fit to assess associations between ten pre chosen predictors( age, race, stage at diagnosis, doublet vs. triplet therapy, lines of treatment, disease status, mobilization agents, melphalan dose, ALC at day 30, post- transplant maintenance) and survival benefit (PFS and OS). RESULTS: Median age of patients was older in G-CSF+P group (62 vs 60 years, p=. 006) and they were more likely to receive triplet therapy (82 vs 72%, p=. 015) for induction compared to G-CSF group (Table 1). Patients in G-CSF group were more likely to receive greater than one line of treatment before transplant (p=. 006). Disease status at transplant was similar between the two groups. G-CSF patients received higher dose of M (at 200mg/ m2) more frequently (69 vs. 58%, p = 0.010) and median cell dose infused was higher in G-CSF group (3.19 vs 2.88 x106 CD 34+ve-cells/Kg, p= 0.001). Primary endpoint, ALC30, was 1.3 K/uL(.1-4.5) and 1.2 K/uL(.1-5.1) for G-CSF and G-CSF+P, respectively (p=. 608). Median day to neutrophil recovery were similar in both groups (ANC of 500 at Day 12). Post-transplant maintenance use was similar between the two groups. The median PFS was 2.46 years (95% CI, 2.14 to 3.15) and 2.77 years (95% CI, 1.99 to 3.27) for G-CSF and G-CSF+P, respectively (HR: 1.128; 95% CI, (.843-1.509); p=. 417) (Figure 1). The median OS was 6.09 years (95% CI, 4.55 to NR) and 3.73 years (95% CI, 3.20 to NR) for G-CSF and G-CSF+P, respectively (HR: 1.638; 95% CI, (1.118-2.399); p=. 011) (Figure 2) .In MVA, higher stage at diagnosis, less than PR before ASCT, and no post-transplant maintenance therapy were associated with worse PFS and OS. More lines of treatment adversely impacted PFS. Use of G-CSF+P for mobilization and Melphalan dose ≤ 200-mg/ m2 adversely impacted OS. ALC30 did not impact PFS or OS in MVA. There were no significant differences in causes of death among the 2 groups. CONCLUSIONS: In this large, retrospective analysis of MM patients mobilized with G-CSF vs G-CSF + P, there was no significant difference in lymphocyte recovery. Higher Melphalan dose resulted in improved OS in the MVA. There was an overall survival difference favoring the G-CSF group, however, differences in baseline characteristics not accounted for in the MVA may be responsible for this observation. A Prospective study comparing these mobilization regimens including patients with similar baseline characteristics is necessary to confirm this finding. Disclosures Deol: Kite Pharmaceuticals: Consultancy; Novartis: Consultancy.

Background:Connective tissue disease-associated interstitial lung disease (CTD-ILD) is a class of refractory diseases.Non-specific treatment with hormone and immunosuppressive agents is mostly used at present, but the effect is limited and the long-term survival rate is not improved [1],while anti-fibrosis treatments (such as Pirfenidone and Nintedanib) have only recently been approved, the long-term efficacy is still unknown.Tofacitinib(TOFA), a JAK inhibitor, has recently been used to treat patients with severe dermatomyositis related interstitial pulmonary disease, with significantly improved survival rate [2-4].A basic study showed that TOFA improved interstitial pulmonary disease in mice by promoting the proliferation of myelogenic inhibitory cells [5].However, whether TOFA can affect the migration and invasion of human lung fibroblasts and further research to reveal the mechanism of its inhibition of pulmonary fibrosis has not been reported.Objectives:To investigate the anti - fibrosis effect of TOFA in CTD-ILD.Methods:Cell migration and invasion AssaysHLFs were incubated with TOFA for 72h, followed by TGF- β1 for 24h.DMEM serum-free medium was used to determine the cell density to 5. 0 × 107/L, 600 uL medium containing 10% fetal bovine serum was added to the lower compartment of Transwell chamber, and 200 uL cell suspension was added to the upper compartment.Incubate in incubator for 12 h.After fixation, staining and sealing, the cells were observed and counted under a microscope. At least 5 random field transmembrane cells were counted in each hole, and the mean value was taken.For the invasion assays, Transwell chamber coated with matrigel was used, and the cell incubation time was 16 h.Results:1. Effect of TOFA on HLFs migration function (Figure 1)Figure 1.Effect of TOFA on HLFs migration function(×200).Mean ± SEM. n = 5.The number of cells passing through the biofilm in the three groups was counted.It can be seen that TGF-β1 group significantly increased compared with control group (*P < 0.0001), and TOFA group significantly decreased compared with TGF- β1 group (#P < 0.0001), suggesting that TOFA can significantly inhibit TGF-β1- induced HLFs migration.2. Effect of TOFA on HLFs invasion function (Figure 2)Figure 2.Effect of TOFA on HLFs invasion function(×200).Mean ± SEM. n = 5.The number of cells passing through the matrigel in the three groups was counted.It can be seen that TGF-β1 group was significantly higher than the control group (*P < 0.0001), and TOFA group was significantly lower than TGF-β1 group(#P < 0.001), suggesting that TOFA can significantly inhibit the invasion function of HLFs induced by TGF-β1.Conclusion:TOFA can effectively inhibit the function of HLFs migration and invasion. Although further studies are needed to elucidate the mechanism by which TOFA inhibit the function of HLFs migration and invasion, our study suggests that TOFA has a potential therapeutic effect for CTD-ILD.References:[1]Aparicio, I.J. and J.S. Lee, Connective Tissue Disease-Associated Interstitial Lung Diseases: Unresolved Issues. Semin Respir Crit Care Med, 2016. 37(3): p. 468-76.[2]Kato, M., et al., Successful Treatment for Refractory Interstitial Lung Disease and Pneumomediastinum With Multidisciplinary Therapy Including Tofacitinib in a Patient With Anti-MDA5 Antibody-Positive Dermatomyositis. J Clin Rheumatol, 2019.[3]Kurasawa, K., et al., Tofacitinib for refractory interstitial lung diseases in anti-melanoma differentiation-associated 5 gene antibody-positive dermatomyositis. Rheumatology (Oxford), 2018. 57(12): p. 2114-2119.[4]Chen, Z., X. Wang, and S. Ye, Tofacitinib in Amyopathic Dermatomyositis-Associated Interstitial Lung Disease. N Engl J Med, 2019. 381(3): p. 291-293.[5]Sendo, S., et al., Tofacitinib facilitates the expansion of myeloid-derived suppressor cells and ameliorates interstitial lung disease in SKG mice. Arthritis Res Ther, 2019. 21(1): p. 184Disclosure of Interests:None declared

Abstract BACKGROUND: Peripheral blood progenitor cell (PBPC) mobilization strategies vary considerably. Optimization of this critical aspect of autologous hematopoietic stem cell transplantation (ASCT) requires efficient use of resources including apheresis kits, machine run time, nursing and cell processing time and consumables. Equally important is the patient experience, which is strongly influenced by collection days and caregiver time that reduces their economic productivity and raises their expenses. We developed a mobilization algorithm designed to collect the target number of cells on day 1 of collection. The algorithm utilizes pre-emptive day 4 plerixafor to maximize collection day peripheral blood (PB) CD34+ cell numbers. METHOD: We analyzed data on all patients with multiple myeloma undergoing PBPC mobilization between March 2014 and July 2016. All patients were mobilized with the intent of collecting sufficient numbers of progenitor cells to permit two ASCT procedures. Patients received filgrastim 10 mcg/kg daily x 4 days. Patients in whom the PB white blood cell (WBC) count was < 50K/uL on day 4 received an extra dose of filgrastim that evening and plerixafor at 0.24 mg/Kg (Figure 1) or a fixed dose of 12mg (Figure 2) if the PBCD34 was < 50/uL. A fixed dose was administered if a patient could be paired with another patient simultaneously undergoing PBPC mobilization. The number of days of apheresis, run time, collection efficiency (CE2) and other relevant variables were analyzed and compared between the standard and fixed dose cohorts. We defined successful mobilization as ≥ 8 million CD34+ cells/Kg (based on our institutional ideal dose of 4 million CD34+ cells/Kg for a single ASCT), optimal mobilization as ≥ 6 million CD34+ cells/Kg (based on the International Myeloma Working Group (IMWG) recommended minimum dose of 3 million CD34+ cells/Kg for an ASCT), suboptimal mobilization as ≥ 2 million but < 6 Million CD34+ cells/Kg, and mobilization failure as < 2 million CD34+ cells/Kg. RESULTS: We identified 105 patients with MM. Median age was 61 years (range, 25 - 76) and 57% were female. Disease status at mobilization included: 7 CR, 14 stringent CR, 5 unconfirmed CR, 52 very good PR (VGPR), and 27 PR. The median day 4 PBCD34+ cell number was 19.9/uL (range, 0.8 - 118.7/uL), and median day 5 PBCD34+ count was 107.8/uL (range, 15.6 - 307.8/uL). Ninety percent of patients required plerixafor of which 16% (n = 17) received the 12 mg fixed dose. The median increase in day 4 to day 5 PBCD34+ cell count for patients receiving plerixafor was 6.6 fold (range, 1.5 - 56.4 fold). In patients not receiving plerixafor, the median increase was 1.8 fold (range, 1.5 - 2.6 fold). The median collection yield was 10.95 million CD34+ cells/Kg (range, 2.9 - 22.5 million CD34+ cells/Kg) no significant difference between patients who received standard dose or fixed dose plerixafor. By the criteria outlined above 96.2% of patients had an optimal mobilization i.e. ≥ 6 million CD34+ cells/Kg sufficient for 2 ASCT procedures with 94.2% achieving this with only 1 day of collection. Per our institutional criteria, 71.4% achieved a successful collection (> 8 million CD34+ cells/Kg) in 1 day. There was no significant difference in days of collection among patients receiving 4 or less cycles of lenalidomide versus those receiving more than 4 cycles (p value = 0.104). The median duration of collection was 399 minutes (range, 180 - 495 minutes) with a median collection efficiency (CE2) of 42.3%. The mean number of days of collection was 1.23 days (range, 1 - 2 days). The median transplanted CD34+ cell dose was 5.48 million CD34+ cells/Kg. All patients had hematopoietic recovery with median neutrophil and platelet engraftment of 11 days and 18 days, respectively. CONCLUSION: The pre-emptive use of plerixafor on day 4 is effective and results in a high percentage of optimal day 1 collections. The cost of a more liberal plerixafor algorithm is offset by the savings incurred from reduced collection day numbers with the majority of patients requiring only 1 day of collection. Cost savings include limiting days away from work and family for the patient and caregiver and decreasing expenses for travel and overnight stays. Reducing collection day numbers also reduces the impact on quality of life for patients, caregivers and family members. Collectively, these data demonstrate utility of the pre-emptive day 4 plerixafor-based mobilization algorithm described here. Disclosures Usmani: Amgen: Consultancy, Research Funding, Speakers Bureau; Sanofi: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Onyx: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; BioPharma: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Pharmacyclics: Research Funding; Britsol-Myers Squibb: Consultancy, Research Funding; Skyline: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Array: Research Funding; Millenium: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Speakers Bureau. Jacobs:Magellan Health: Consultancy; Pharmacyclics: Consultancy, Speakers Bureau. Bhutani:Onyx, an Amgen subsidiary: Speakers Bureau; Bristol-Myers Squibb: Speakers Bureau; Takeda Oncology: Research Funding, Speakers Bureau; Prothena: Research Funding. Avalos:Seattle Genetics: Membership on an entity's Board of Directors or advisory committees.

Abstract Background Induction therapy for acute myeloid leukemia (AML) with a cytarabine-anthracycline regimen (7+3) is well-established; however, there is no standard salvage therapy for patients with relapsed/refractory AML (RR-AML). There is a paucity of data regarding outcomes with salvage regimens in RR-AML that include cladribine, cytarabine, and filgrastim with mitoxantrone (CLAG-M) or without mitoxantrone (CLAG), and mitoxantrone, etoposide, and cytarabine (MEC). We compared outcomes of patients receiving CLAG-M, CLAG or MEC as salvage therapy for RR-AML. Methods A multi-center retrospective study was conducted, including 146 adult RR-AML patients who underwent salvage therapy at the University of Wisconsin and Medical College of Wisconsin from 2009 to 2018. Demographic, clinical and pathologic factors were ascertained at the time of RR-AML diagnosis. The Center for International Blood and Marrow Transplant Research (CIBMTR) response criteria were used. Refractory AML was defined as failure to achieve remission after one or more courses of induction chemotherapy. Minimal residual disease (MRD)-negative was defined by the absence of leukemic cells by morphology and flow cytometry (<0.01%). Data were analyzed using SPSS version 21 (SPSS Inc, Chicago, IL). Bivariate analyses, using chi-square and t-test, and logistic regression analyses were performed for baseline characteristics and response to salvage chemotherapy. Kaplan-Meier analyses, using the log-rank test, were conducted. Cox regression analyses were used to correlate factors with OS. Hazard ratios (HR) with 95% CI were obtained. Statistical significance was considered at P<0.05. Results The study included 146 patients with relapsed (57.5%, n=84) or refractory (42.5%, n=62) AML who received CLAG-M (51%, n=74), MEC (39%, n=57) or CLAG (10%, n=15) salvage chemotherapy. Baseline characteristics were similar between the three groups (all P>0.1). Median age was 60 years (range 22-77 years) and 59% patients were male. AML was classified according to WHO 2016 guidelines as AML with recurrent genetic abnormalities (23%), myelodysplasia (MDS)-related AML (25%), therapy-related AML (8%) and AML not otherwise specified (44%). Cytogenetics were good (5%), intermediate (60%) and poor (36%) with normal (41%), complex (25%), trisomy (8%) and monosomy 5 or 7 (5.5%) being common karyotypes. Among those who had molecular testing (n=119), NPM1 and FLT3-ITD were reported in 21% and 20% patients respectively. AML risk status was good (16%), intermediate (32%) and poor (52%), based on cytogenetic and molecular abnormalities as per ELN 2017 and NCCN 2018 guidelines. Extramedullary disease was present in 13% patients. Prior hematopoietic stem cell transplant (HSCT) was performed in 13% patients. Median lab values prior to salvage regimen were: hemoglobin 9.1 g/dL, platelets 49 K/uL, leukocytes 2.5 K/uL, LDH 231 U/L and bone marrow myeloblasts 28%. Overall response rate was 49% (CLAG-M 55%, n=41/74; MEC 44%, n=25/57, CLAG 40%, n=6/15) with complete remission (CR) rate of 46% (CLAG-M 54%, MEC 37%, CLAG 40%) [P=0.140]. Three percent patients (n=5; CLAG-M=1, MEC=4) had CR with incomplete hematologic recovery (CRi). MRD analysis was available for 83 patients and a trend was seen in MRD-negative CR rates favoring CLAG-M (44%) over MEC (25%) or CLAG (17%) [P=0.128]. Sixty-six patients (45%) received subsequent HSCT (CLAG-M 50%, n=37/74; MEC 44%, 25/57; CLAG 27%, n=4/15) [P=0.245]. At last follow-up, 34% patients were in CR (CLAG-M 42%, MEC 28%, CLAG 20%) [P=0.120]. Fifty (34%) patients were alive at last follow-up (CLAG-M 46%, MEC 23%, CLAG 20%) [P=0.010]. Median OS was 9.7 months (95% CI 6.8-12.6) that was significantly better with CLAG-M (13.3 months, 95% CI 2.4-24.3) compared to MEC (6.9 months, 95% CI 2.9-10.9) or CLAG (6.2 months, 95% CI 2.4-12.6) [P=0.025] Figure 1. In multivariate model adjusted for age, gender and refractory vs relapsed AML, MEC (HR 1.75, 95% CI 1.13-2.71, P=0.013) and CLAG (HR 1.97, 95% CI 1.02-3.79, P=0.043) regimens had worse OS compared to CLAG-M. After adjusting for age, gender, refractory vs relapsed AML and HSCT, CLAG-M remained independent predictor of better OS (HR 0.64, 95% CI 0.42-0.97, P=0.037). Conclusion CLAG-M compared to MEC or CLAG is associated with significantly better OS in RR-AML regardless of age, refractory vs relapsed AML and HSCT. Our findings support the use of CLAG-M as a preferred salvage regimen for RR-AML. Figure 1. Figure 1. Disclosures Atallah: Novartis: Consultancy; BMS: Consultancy; Jazz: Consultancy; Abbvie: Consultancy; Pfizer: Consultancy.

Background: We have previously reported initial high response rates of the BRAF inhibitor, vemurafenib, in patients (pts) with relapsed or refractory hairy cell leukemia (HCL) (Tiacci and Park et al. NEJM 2015). However, complete response (CR) rates were low at 35-40% with detectable minimal residual disease (MRD) in most patients, and a longer follow up revealed a relapse rate of 50% (Park JH et al. Blood 2018, 132;392). Based on the recent data suggesting improved CR rate in combination with rituximab in relapsed HCL (Tiacci et al. Blood 2016, 128:1214), we initiated a phase II clinical trial to investigate the efficacy of vemurafenib and obinutuzumab in patients with newly diagnosed HCL (NCT03410875). Methods: Adult pts with previously untreated HCL who met the treatment initiation criteria (i.e. ANC <1.0k/ul, Hgb <10.0g/dL or PLT <100k/ul) are eligible for the study. Patients received vemurafenib 960mg bid from months 1-4 and obinutuzumab from months 2-4, for a total treatment duration of 4 months. Obinutuzumab was administered at 1000mg IV on days 1, 8, and 15 of month 2, and day 1 of month 3 and 4. Vemurafenib dose reductions were allowed for drug-related adverse events (AEs). Response was assessed at the end of month 4 with bone marrow (BM) biopsy and CT scans. The primary objective was to determine the efficacy of vemurafenib and obinutuzumab combination as assessed by CR rates, and the secondary objectives include assessment of safety, duration of response, MRD negativity, and BRAF allele burden by digital PCR. The study adopted a Simon's minimax 2-stage design and required ≥7 CR in the first 9 pts in the first stage to continue accrual for a total of 28 pts. We report the result of the first 9 pts in the first stage of the study. Results: A total of 11 pts have been enrolled to the study to date. The median age of the patients is 49 years old (range, 35-79). The median pretreatment ANC, Hgb and PLT is 0.7k/ul (range, 0.0-2.6), 11.5g/dL (range, 7.0-15.0), and 83k/ul (range, 21-153), respectively. Nine of 11 pts had a baseline splenomegaly. Nine pts completed all treatments to date, and 2 pts remain on active therapy. Among the 9 pts who completed the treatment, all pts achieved a response with normalization of cytopenia, including 7 pts with MRD negative CR and 2 pts with PR at the end of month four. Two pts with PR at month 4 converted to MRD+ and MRD negative CR by month 7 and 10, respectively, with no further treatment, with the best overall CR rate of 100% (9/9 pts) (Figure). All MRD negative CR had undetectable BRAFV600E by highly sensitive digital PCR. After 1 month of vemurafenib and before the first dose of obinutuzumab, 7 of 9 pts had ANC recovery to >1.0K/ul and 8 of 9 pts had Hgb >10 g/dL and PLT 100k/uL. With a median follow-up of 9.7 months (range, 4.6-15.4), all pts remain in remission with no relapse. The most common vemurafenib-related AEs were rash (73%; Gr2-9%, Gr3-64%), arthralgia (64%; Gr1-27%, Gr2-27%, Gr3-18%), alopecia (45%, all Gr1), dry skin (27%, all Gr1), and fatigue (27%, Gr1). Two pts experienced obinutuzumab infusion reaction but were able to complete all intended doses of obinutuzumab. No case of cutaneous squamous cell carcinomas has been observed. No pt discontinued the therapy due to toxicity but 8 pts had vemurafenib dose reductions due to rash (n=5) and arthralgia (n=2). Conclusion: Vemurafenib and obinutuzumab combination therapy induced a high CR rate of 100% and high rates of MRD negativity (89%) in patients with HCL in the frontline setting and appears to be a promising chemo-free targeted therapeutic approach for HCL. A majority of the pts achieved a normalization of cytopenia within 4 weeks of starting therapy. A longer follow-up is needed to assess durability of remission and degree of immunosuppression compared to cladribine-treated cohorts. Figure Disclosures Park: Kite Pharma: Consultancy; Incyte: Consultancy; GSK: Consultancy; Autolus: Consultancy; AstraZeneca: Consultancy; Allogene: Consultancy; Amgen: Consultancy; Novartis: Consultancy; Takeda: Consultancy. Winer:Jazz Pharmaceuticals, Pfizer: Consultancy. Tallman:Cellerant: Research Funding; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; KAHR: Consultancy, Membership on an entity's Board of Directors or advisory committees; BioLineRx: Consultancy, Membership on an entity's Board of Directors or advisory committees; Nohla: Consultancy, Membership on an entity's Board of Directors or advisory committees; Rigel: Consultancy, Membership on an entity's Board of Directors or advisory committees; Oncolyze: Consultancy, Membership on an entity's Board of Directors or advisory committees; Orsenix: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; ADC Therapeutics: Research Funding; Biosight: Research Funding; Daiichi-Sankyo: Consultancy, Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; UpToDate: Patents & Royalties; Tetraphase: Consultancy, Membership on an entity's Board of Directors or advisory committees; Delta Fly Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees; Cellerant: Research Funding. OffLabel Disclosure: Vemurafenib and obinutuzumab for treatment of hairy cell leukemia

Abstract Background The inflammatory and immune response in tumor microenvironment plays a critical role in cancer progression. Neutrophil-to-lymphocyte ratio (NLR) has been reported as a prognostic factor in solid and lymphoid malignancies. We explored the association of NLR with response to chemotherapy and overall survival (OS) in patients with relapsed/refractory acute myeloid leukemia (RR-AML). Methods A single-center retrospective study was conducted, including 63 adult RR-AML patients who underwent salvage therapy at the University of Wisconsin from 2009 to 2018. Demographic, clinical and pathologic factors were ascertained at the time of RR-AML diagnosis. Refractory AML was defined as failure to achieve remission and <50% reduction in myeloblasts after one or more courses of induction chemotherapy according to the Center for International Blood and Marrow Transplant Research (CIBMTR) reporting criteria. Data were analyzed using SPSS version 21 (SPSS Inc, Chicago, IL). Bivariate analyses, using chi-square and t-test, and Kaplan-Meier analyses, using log-rank test, were performed. Cox regression analyses were conducted to correlate factors with OS. Hazard ratios (HR) and adjusted HR (aHR) with 95% confidence intervals (CI) were obtained. Statistical significance was considered at P<0.05. Results The study included 63 patients with relapsed (57%) or refractory (43%) AML. Median age was 58 years and 59% of patients were male. AML was classified according to WHO 2016 guidelines as AML with recurrent genetic abnormalities (25%), myelodysplasia (MDS)-related AML (25%), therapy-related AML (6%) and AML not otherwise specified (43%). Cytogenetics were good (5%), intermediate (68%) and poor (27%) with normal (46%), complex (17.5%) and trisomy (14%) being common karyotypes. Frequent molecular abnormalities were NPM1 (21%), FLT3-ITD (17.5%), FLT3-TKD (8%), DNMT3A (6%) and CEBPA (5%). AML risk status was good (19%), intermediate (36.5%) and poor (44.5%), based on cytogenetic and molecular abnormalities as defined by the ELN 2017 and NCCN 2018 guidelines. Extramedullary disease was present in 11% of patients. Prior hematopoietic stem cell transplant (HSCT) was performed in 13% of patients. Median values for clinical factors were: hemoglobin 9.2 g/dL, platelets 43 K/uL, leukocytes 1.7 K/uL, neutrophils 262 /uL, lymphocytes 820 /uL and LDH 211 U/L. Median bone marrow cellularity was 50% with 35% myeloblasts. Median NLR was 0.22 (mean 1.54) and 11% patients had NLR of 3 or more. Salvage chemotherapy included MEC (71%), CLAG-M (24%) and CLAG (5%). Complete remission (CR) was noted in 36.5% patients, 8% of patients had CR with incomplete hematologic recovery (CRi) and 55.5% patients were refractory. Thirty patients (48%) received HSCT, of which 40% (n=12/30) were refractory or relapsed. After index salvage regimen, about half of patients received one (33%) or two (16%) lines of further chemotherapy. At last follow-up, 32% of patients were in CR and 62% had relapsed or refractory disease. Nineteen (30%) patients were alive at last follow-up with a median OS of 8.1 months (95% CI 5.0-11.1). Significant correlates of poor OS included MDS-related AML (HR 2.19, 95% CI 1.13-4.27, P=0.021) and therapy-related AML (HR 4.02, 95% CI 1.16-13.90, P=0.028) compared to de-novo AML, poor-risk AML (HR 3.09, 95% CI 1.18-8.10, P=0.022) compared to good-risk AML, refractory to salvage chemotherapy (HR 7.04, 95% CI 3.51-14.14, P<0.001) and high NLR (HR 1.13, 95% CI 1.04-1.23, P=0.003) while HSCT (HR 0.25, 95% CI 0.13-0.48, P<0.001) predicted better OS. Relapsed vs refractory AML was not associated with OS. In age- and gender-adjusted multivariate model, MDS-related AML (aHR 3.85, 95% CI 1.68-8.87, P=0.002), therapy-related AML (aHR 4.72, 95% CI 1.10-20.31, P=0.037), refractory to salvage chemotherapy (aHR 12.93, 95% CI 4.95-33.78, P<0.001), HSCT (aHR 0.12, 95% CI 0.05-0.27, P<0.001) and high NLR (aHR 1.14, 95% CI 1.05-1.25, P=0.004) independently predicted OS. Median OS in patients with NLR of 3 or more was 3.4 months (95% CI 3.2-3.7) versus 9.2 months (95% CI 7.1-11.3) in those with NLR <3 (P=0.040). Conclusion High NLR independently predicts poor OS in RR-AML patients. Our findings warrant further studies with a large prospective cohort to explore the prognostic significance of NLR and incorporate it in AML risk assessment. Disclosures Atallah: BMS: Consultancy; Abbvie: Consultancy; Novartis: Consultancy; Jazz: Consultancy; Pfizer: Consultancy.

Abstract Background: There is no standard therapy for patients (pts) with intermediate (Int)-2 or high risk myelofibrosis (MF) who have failed or are intolerant to Janus kinase (JAK) inhibitors such as ruxolitinib. Second mitochondria-derived activator of caspases (SMAC) mimetics, or inhibitors of apoptosis (IAP) antagonists, lead to increased apoptotic cancer cell death, especially in high TNFα-expressing tumor models. An emerging concept in myeloproliferative neoplasm (MPN) tumor pathobiology is the finding of significantly increased levels of TNFαin pts with MF(Fleischman AG et al, Blood 2011). Objectives: Primary objective: to determine efficacy (IWG-MRT, 2013) of LCL161 as monotherapy for pts with MF. Secondary objectives: to determine safety, durability of response, and changes in symptom burden [Myeloproliferative Neoplasm (MPN)-Total Symptom Score]. Exploratory objectives: to assess JAK2V617F and CALR allele burden; 28-gene panel for molecular mutations via next generation sequencing; and markers of IAP pathway degradation. Methods: We conducted an investigator-initiated, single-center, phase II study of LCL161 for pts with MF in a Simon's Optimal two-stage design. Pts age ≥18, PS=0-2, Int to high risk MF, who were intolerant to, ineligible for, or relapsed/refractory to JAK inhibitors were eligible. There was no threshold requirement for spleen size or platelet (plt) count, and pts with prior allogeneic stem cell transplant (SCT) were eligible. LCL161, an oral (po) drug, was given at starting dose 1500mg po once weekly. Each cycle=28 days. After 3 cycles, bone marrow exam and objective response assessments were performed. Results: From January 2015 to July 2016, 21 pts have been enrolled. Baseline characteristics: Median Age: 72 years [56-81], 86% with primary MF. Baseline laboratory values: Hb 9 g/dL (6.3-12); WBC 5.3 K/uL [1.1-38]; platelets 45 K/uL [6-1365]. JAK2V617F mutations were present in 14(67%), CALR mutations in 3(14%), and MPLW515L mutation in 1(5%) pt. Additionally, the most common other molecular mutations were: TET2(n=4); DNMT3A(n=3); RAS(n=1); EZH2(n=1). 17 (81%) had ≥2 prior therapies. Most common prior therapy was a JAK inhibitor (67%). 2 pts had prior SCT. By IPSS, 14 (67%) were high risk MF; 6(28%) were Int-2. Median number of cycles received=3[1-19], median treatment duration=2.8 months (mos)[0.2-16.7]. 19 pts are alive, with median follow-up of 7 mos[0.2-17.7]. Among 21 pts, 5 have been recently enrolled and have not yet reached 12-week evaluation period; among 16 evaluable pts, 6 pts had 9 objective responses (3 pts achieved 2 separate IWG-MRT 2013 response categories): Clinical improvement (CI) (anemia) in 2 pts; CI (Symptom) in 5 pts; CI (Spleen) in 1 pt; Cytogenetic remission in 1 pt. Grade 3/4 non-hematologic adverse events: syncope, n=2. No pts had cytokine release syndrome. Most common grade 1/2 non-hematologic toxicities: fatigue (n=10), nausea (n=10), dizziness/vertigo (n=9). Dose reductions: 7 pts: 6 pts to dose -1 level (1200 mg po once weekly) and 1 pt to dose -2 (900mg po once weekly); importantly, the most common reason was due to grade 2 fatigue (n=6). 10 pts are now off study [n=5 no response; n=3 toxicity; n=1 transformation to AML; n=1 patient on study proceeded to SCT]. Preliminary, ongoing correlative studies demonstrate on-target inhibition (by Western blot) of CIAP1 in eight pts: strong (n=4) or moderate (n=4); among the 6 clinically responding pts, 4 of 4 of these pts with viable/available samples for analysis demonstrated strong on-target CIAP1 inhibition. Conclusions: In this study, in a cohort of older pts with MF, 67% IPSS high risk, with median plt count of 45 at study entry, in whom 81% had received ≥2 prior therapies, we have observed objective responses in 38% (6/16 evaluable for response). LCL161 has a convenient (po, weekly) dosing schedule, represents a novel target for pts with MPNs, and is able to be administered to pts who have failed or intolerant/ineligible for JAK inhibitor therapy. Notably, grade 2 fatigue was commonly observed, and represents the most common reason for dose reduction and study discontinuation. Based on early responses observed, this study has met criteria for the pre-planned analysis for efficacy (Simon Stage 1) and therefore is able to proceed to Simon Stage 2. This clinical trial is registered at www.clinicaltrials.gov/ct2/show/NCT02098161. Disclosures Carter: PRISM Pharma/Eisai: Research Funding. Cortes:ARIAD: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Teva: Research Funding. DiNardo:Daiichi Sankyo: Other: advisory board, Research Funding; Novartis: Other: advisory board, Research Funding; Abbvie: Research Funding; Celgene: Research Funding; Agios: Other: advisory board, Research Funding. Bose:Novartis: Research Funding. Verstovsek:Incyte Corporation: Membership on an entity's Board of Directors or advisory committees, Research Funding; Genentech: Research Funding; Celgene: Research Funding; AstraZeneca: Research Funding; Geron: Research Funding; NS Pharma: Research Funding; Roche: Research Funding; Bristol-Myers Squibb: Research Funding; Promedior: Research Funding; CTI BioPharma Corp: Research Funding; Galena BioPharma: Research Funding; Pfizer: Research Funding; Seattle Genetics: Research Funding; Gilead: Research Funding; Lilly Oncology: Research Funding.

Background: Allogeneic stem cell transplantation (AlloSCT) from an HLA-matched sibling donor is the only known curative therapy in patients with high-risk SCD (Talano/Cairo, EJH, 2015). Unfortunately only about 15% of high risk patients with SCD have an HLA-matched unaffected sibling donor. T cell depletion has been employed to reduce AGVHD e.g., CD3/CD19 cell depletion (Barfiled RC, et al, Cytotherapy, 2004), αβ T-cell/CD19 cell depletion (Locatelli F, et al, Blood, 2017), CD34+ positive selection (Aversa F, et al, NEJM, 1998). MUD transplantation in high-risk SCD recipients has shown unexpectedly high rates of CGVHD (Shenoy et al, Blood, 2016). We reported a very low incidence of acute and chronic GVHD in pediatric recipients receiving CD34 enriched HPC products with PB MNC addback with 2 x 105 CD3/kg from MUD donors (Geyer/Cairo et al, BJH, 2012). Furthermore, rapid NK cell reconstitution after AlloSCT is associated with a significant improvement in 1yr OS (Pical-Izard, BBMT, 2015; Dunbar et al, Hematologica, 2008). Recently, we reported promising results for high-risk SCD patients at 1 year follow-up after FHI CD34 enriched/PBMNC with addback AlloSCT with the probability of 1-year overall survival (OS) n=17; 88.2% (CI95: 60.6-96.9) (Talano/Cairo, ASH, 2017), expanding the donor pool and hopefully improving outcomes for high-risk patients with SCD. Objective: To investigate donor chimerism, immune cell reconstitution and NK cell function in high-risk patients with SCD following AlloSCT using FHI CD34 enrichment/PBMNC (2 x 105 CD3/kg) addback. Methods: Twenty-one eligible SCD patients (2-<21 yrs) were enrolled. Nineteen patients received hydroxyurea, azathioprine, fludarabine, busulfan, thiotepa, cyclophosphamide, R-ATG, and TLI followed by FHI AlloSCT to date (Talano/Cairo, ASH, 2017). CD34 cells were enriched using the CliniMACS® system, kindly provided by Miltenyi Biotec, with a target dose of 10 x 106 CD34+ cells/kg with a PBMNC addback dose of 2x10*5 CD3/kg in the final product. Whole blood and RBC chimerism (estimated using CD71 to isolate an eythroid lineage-enriched fraction) were determined by STR. Immune cell and subset reconstitution was assessed by flow cytometry as previously described (Geyer/Cairo et al. BJH, 2012). NK function was determined by cytotoxic activity against K562 tumor targets at 10:1 E:T ratio by europium release assay and intracellular LAMP-1 (CD107a) and granzyme B expression by flow cytometry as previously described (Chu/Cairo et al, Can Imm Res, 2015). Results: There was 100% engraftment of neutrophils and platelets. The median day post-HISCT to neutrophil and platelet engraftment was +9 and +19, respectively. Whole blood donor chimerism (mean±SEM) at 1-year, 2-year, and 3-year post-HISCT was 97±1%, 97±1%, 97±1%, respectively (Fig.1). Donor chimerism for CD71+ RBCs (mean±SEM) at 1-year, 2-year, 3-year post-HISCT was 97±2%, 98±1%, 98±1%, respectively (Fig.1). Immune reconstitution of CD3, CD4, CD8, and CD19 was evaluated. The time to recovery of minimally normal levels post-HISCT of CD3 (800 cells/ul), CD4 (400 cells/ul), CD8 (200 cells/ul), and CD19 (200 cells/ul), was approximately 365, 365, 270, and 60 days post-HISCT (Fig.2), respectively. Probability of Grade II-IV AGVHD, CGVHD and 1 year EFS/OS was 6.2%, 6.7% and 90%, respectively. NK reconstitution was rapid and peaked at d+30 (36±9%, 2710cells/ml). NK cytotoxicity against K562 at a E:T=10:1 peaked at d+30 (26±3%) and d+180 (28±3%) vs at pre-t (16±2%) (p<0.01) (Fig. 3A). Consistent with increased NK cytotoxicity, CD56dimCD3- subset was increased at d+30 vs pre- HISCT (p<0.05). The NK activation marker, CD107a peaked at d+30 (38±9%) and d+180 (41±6%) (Fig.3B). More over, reconstituted NK cells expressed higher level of activating receptors NKp46 (24±9%), NKG2D (32±9%) and KIR2DS (8±3%) and inhibitory receptors NKG2A (33±9%), CD94 (28±9%) and KIR2DL2/3 (11±2%) at d+30 compared to other time points. Conclusion: Despite a 5 log depletion of T cells, the PBMNC addback (fixed at 2 x 105 CD3/kg) facilitated rapid donor chimerism and immune reconstitution with a low probability of Grade II-IV AGVHD. The rapid NK reconstitution may have in part contributed to the excellent 1yr OS in the FHI study. (Supported by FDA R01FD004090 (MSC)). Disclosures Cairo: Jazz Pharmaceuticals: Other: Advisory Board, Research Funding, Speakers Bureau; Osuka: Research Funding; Miltenyi: Other: MTA.