ALBERT

Description: Introduction Numerous genetic abnormalities (including chromosomal translocations, deletions or amplifications, mutations) affect treatment outcomes in multiple myeloma (MM) and explain the heterogeneity in prognosis of MM patients with similar disease and host factors. Hyperdiploidy is associated with favorable outcomes, in contrast to del 17p, del 13, t(4;14), and gain of 1q2, which are associated with unfavorable outcomes. There is conflicting data about the role of overlap in cytogenetic and molecular abnormalities and their impact on prognosis. We sought from our study to determine the influence of overlapping genetic abnormalities in MM patients who received frontline autologous stem cell transplantation (ASCT) consolidation therapy. Methods Between January 2009 and January 2016, we included all consecutive newly diagnosed MM patients who underwent frontline ASCT at The University of Texas MD Anderson Cancer Center. All adult patients (≥18 years) who received high-dose melphalan conditioning regimen and had available conventional cytogenetics and interphase fluorescence in situ hybridization (FISH) studies at diagnosis were eligible. Patients with primary refractory and relapsed disease were excluded. Hyperdiploidy was defined as any extra copy of one or more of the odd chromosomes. High-risk genetic abnormalities are defined presence of del 17p, del 13, t(4;14), and/or 1q21 gain (detected by FISH and/or conventional cytogenetics). Primary and secondary endpoints were progression-free survival (PFS) and overall survival (OS), respectively. Survival estimates were calculated by Kaplan-Meir method, and Cox proportional hazards regression analysis was used to assess the predictors of PFS on univariate and multivariate analysis. Results A total of 494 patients (57% males, 43% females) with a median age of 61 years (range, 33-80) were eligible and included in final analysis. 154 patients (31%) were identified to have any hyperdiploidy and 189 patients (38%) to have any high-risk abnormality. A total of 84 patients (17%) had hyperdiploidy without any high-risk feature and 121 patients (25%) had a high-risk cytogenetic abnormality without hyperdiploidy. With a median follow up of 27 months (range, 1-76) the 2-year PFS and OS of all study group were 71% and 90%, respectively. Among patients with any hyperdiploidy, the 2-year PFS and OS were 72% and 92%. In contrast, for patients with any high-risk genetic feature, the 2-year PFS and OS were 56%and 81%. Acquisition of any high-risk genetic abnormality, age 〉55 years, and international staging system (ISS) stage III were associated with worse PFS in univariate analysis. Further stratification of patients according to overlapping genetic abnormalities showed that the co-existence of hyperdiploidy with any high-risk genetic abnormalities was associated with significantly worse PFS compared to hyperdiploidy without co-exisiting genetic abnormalities (2-year PFS 59% vs 80%, HR 2.9, p=0.003) (Figure). PFS in patients with co-existing hyperdiploidy and high-risk genetic abnormalities was comparable to that in patients with high-risk genetic abnormalities without hyperdiploidy (59% vs. 55%, HR 0.9, 95%CI: 0.6-1.7; p=0.9) (Figure). The effect of high-risk abnormalities on PFS persisted on multivariate analysis, and was reflected on OS as well (Figure). Conclusions Our findings confirm that the co-existence of hyperdiploidy and high-risk genetic features does not abrogate the poor prognosis of MM patients with associated high-risk genetic abnormalities at diagnosis. Patients with hyperdiploidy and high-risk genetic abnormalities have similar outcomes to high-risk MM patients without hyperdiploidy, and should be considered as high-risk patients to guide future risk-adaptive treatment prospective clinical trials. Figure Figure. Disclosures No relevant conflicts of interest to declare.

Description: Outcome of persons 〉65 years with acute myeloid leukemia (AML) is poor. Allogeneic transplant can cure some of these patients but is associated with substantial transplant-related mortality (TRM) and high relapse risk. We analyzed 185 consecutive patients 〉65 years with high-risk AML between 2010 and 2015 who had measurable residual disease (MRD) and molecular risk assessments and who received myeloablative conditioning (MAC, n=42) or reduced-intensity conditioning (RIC, n=143) and a transplant from an HLA-identical sibling (n=66) or a 10/10 loci HLA-matched unrelated donor (MUD, n=119) in order to identify patients who would benefit from allotransplant. MRD was assessed by flow cytometry in bone marrow samples. AML cytogenetic and molecular risk were defined using the 2017 European Leukemia Net genetic risk stratification. The patients who were MRD-negative at time of transplant had a better 2-year cumulative incidence of relapse (CIR 17.6%) and a 2-year overall survival (OS, 69.4%) as compared to the patients in remission but MRD-positive (55.6% CIR, 21.5% OS) or the patients who had morphological evidence of leukemia prior to transplant (48.7% CIR, 19.9% OS), (p

Description: Disease relapse remains the major cause of treatment failure following hematopoietic transplantation for AML/MDS. A major goal is to develop more effective antileukemic regimens without excessive toxicity. Busulfan (Bu)-fludarabine (Flu) is a widely used preparative regimen. We demonstrated that targeting a relatively high busulfan systemic exposure pharmacokinetic (PK) dose adjustment was superior to fixed busulfan dosing. Clofarabine (Clo) has improved antileukemic activity compared to fludarabine. We previously reported a phase I/II study of different dosing combinations of busulfan with Flu and Clo; the best results were obtained with Bu with Flu 10 mg/m2 and Clo 30 mg/m2 daily for four daily doses. We performed a phase III randomized controlled trial to determine if Flu/Clo/Bu improved progression free survival compared to the Flu/Bu regimen. Busulfan was given with PK dose adjustment AUC 6000 mM x min for age

Description: Key Points Ex vivo fucosylation of cord blood cells improves their homing capacities, leading to faster neutrophil and platelet engraftments. This method is quick, safe, and does not require a GMP laboratory; therefore, it can be used widely.

Description: INTRODUCTION: More active high-dose regimens are needed for refractory or poor-risk relapsed non-Hodgkin's (NHL) and Hodgkin's lymphomas (HL), where standard BEAM offers unsatisfactory results. We previously developed a regimen of infusional gemcitabine with busulfan and melphalan (Gem/Bu/Mel), pursuing the inhibition by gemcitabine of DNA damage repair (Nieto et al, BBMT 2012). Since vorinostat induces chromatin relaxation and facilitates access of chemotherapy to DNA, we combined it with Gem/Bu/Mel, which resulted in a safe and markedly synergistic regimen (Nieto et al, BBMT 2015). Still, the addition of vorinostat to GemBuMel induced upregulation of DNA methyltransferase (DNMT) in lymphoma cells, which could be abrogated preclinically by azacitidine, further increasing tumor-cell kill (Valdez et al, Exp Hematol 2012). These observations led us to study the clinical combination of azacitidine with vorinostat/Gem/Bu/Mel. METHODS: Patients ages 12-65 with refractory or poor-risk relapsed lymphomas and adequate end-organ function were eligible. Azacitidine was given on days -8 to -3 at 15-35 mg/m2/day IV (levels 1-3), followed by vorinostat (1,000 mg PO daily, days -8 to -3), gemcitabine (loading dose of 75 mg/m2 followed by infusion at 10 mg/m2/min over 4.5 hours, days -8 and -3), busulfan (target daily AUC of 4,000, days -8 to -5) and melphalan (60 mg/m2/day, days -3 and -2). ASCT was on day 0. Patients with CD20+ tumors received rituximab (375 mg/m2) on day -9. Dose limiting toxicities (DLT) were defined as any G4-5 nonhematological organ toxicity, or as G3 skin or G3 mucositis lasting 〉3 days at peak severity. Dose escalation of azacitidine followed a Bayesian design targeting a maximal DLT probability of 25%. We assessed DNMT-3B levels by Western blot in peripheral blood mononuclear cells drawn at baseline and days -5 and -1 in 8 patients treated at the MTD. RESULTS: Between 11/13 and 6/15, 60 patients were enrolled: 25 DLBCL (10 double hit), 21 HL, 8 T-NHL (3 PTCL, 2 ALCL, 1 AITL, 1 NK/T, 1 panniculitis-like), 4 follicular NHL and 2 mantle cell (Table 1). Table 1. Patient population. Median age (range) 41 (16-65) Primary induction failure / high-risk/refractory relapse 28% / 62% Bulky lesions at relapse/PD 58% Secondary IPI (DLBCL): 0-1 / 〉1 44% / 56% LDH at relapse/PD (DLBCL): High / Normal 50% / 50% Median # prior chemotherapy lines (range) 3 (2-7) Prior xRT 17% PET+ at HDC 32% Status at HDC: 68% CR, 25% PR, 7% unresponsive Patients were treated at levels 1-3, with the MTD of azacitidine established at level 1 (15 mg/m2/day). The DLT was mucositis, observed at the following frequencies: level 1 (N=37): 16%, level 2 (N=18): 28%, level 3 (N=5): 40%. One patient died from early RSV pneumonia at level 3. The toxicity profile at the MTD was manageable: mucositis (40% G2, 32% G3), self-limited transaminitis (16% G2, 16% G3), self-limited elevation of bilirubin not associated with VOD (19% G2, 22% G3) and dermatitis (13% G2). There were no cardiac, pulmonary, renal or CNS toxicities. Neutrophils and platelets engrafted promptly at median days +9 (7-11) and +12 (8-64), respectively. This toxicity profile is identical to the one seen with Gem/Bu/Mel and vorinostat/Gem/Bu/Mel. DNMT-3B levels in PBMNC decreased from baseline to day -1 by a median 58% (19-80%) in 7/8 pts. Response assessment and patient outcomes at median follow-up of 11 months (2-21) at are shown on Table 2 and Figures: Table 2. Activity/outcomes. ORR CR % EFS % OS DLBCL 78% 44% 68% 86% HL 86% 86% 81% 100% T-NHL 100% 100% 87.5% 87.5% CONCLUSIONS: Azacitidine/vorinostat/Gem/Bu/Mel is feasible, with no increased toxicities compared to Gem/Bu/Mel ± vorinostat, and highly active in refractory or poor-risk relapsed HL and NHL. This regimen warrants further study. Figure 1. Figure 1. Disclosures Off Label Use: Azacitidine, vorinostat, gemcitabine, busulfan, melphalan: Use at high doses for lymphoma. . Alousi:Therakos, Inc: Research Funding. Andersson:Otsuka Research and Development, Inc.: Consultancy.

Description: INTRODUCTION: More active high-dose regimens are needed for refractory or poor-risk relapsed Hodgkin's lymphomas (HL), where BEAM offers poor results. Post-BEAM maintenance treatment with brentuximab vedotin (BV) x 48 weeks has recently been shown in the AETHERA trial to prolong progression-free survival (PFS) compared to placebo (2-year PFS 63% vs. 51%). We previously developed a regimen of infusional gemcitabine combined with busulfan and melphalan (Gem/Bu/Mel) pursuing inhibition by Gem of DNA damage repair. The encouraging results we saw in HL patients led us to conduct a phase 2 trial of Gem/Bu/Mel in HL patients at high risk of post-ASCT relapse. METHODS: HL patients ages 12-65 with ≥1 of the following criteria were eligible: Persistent active disease after 1st-line chemotherapy, CR1 〈 1 year, or extranodal disease at relapse/PD. Gem was administered as a loading dose of 75 mg/m2 followed by infusion at a fixed dose rate of 10 mg/m2/min over 4.5 hours on days -8 and -3 (total daily dose of 2,775 mg/m2). Each Gem infusion was immediately followed by the corresponding dose of Bu or Mel. Bu was administered intravenously from days-8 to -5 targeting a daily AUC of 4,000. Mel was infused at 60 mg/m2/day on days -3 and -2. ASCT was on day 0. Post-HDC involved field radiotherapy (IFRT) was considered to lesions 〉5 cm at the time of HDC or persistently PET+ at the 1-month post-HDC evaluation. The trial had 80% power to detect a 2-year PFS increase from 50% to 65%.The concurrent BEAM cohort included all patients eligible for this trial who received BEAM off study due to no financial coverage for ASCT in a trial or patient/physician preference. RESULTS: Eighty patients were enrolled on study between 6/11-04/15 (Table 1). There was no transplant-related mortality (TRM). The toxicity profile was manageable, including mucositis (49% G2, 40% G3), skin (22% G2, 11% G3), self-limited transaminase elevation (30% G2, 19% G3), and hyperbilirubinemia (24% G2, 19% G3) with no cases of VOD. There was 1 case of G2 pneumonitis and none of cardiac, renal or CNS toxicity. Neutrophils and platelets engrafted at median days +10 (8-12) and +12 (9-21), respectively. Eight patients received post-HDC IFRT to mediastinum ± neck ± sternum at 30.6-39.6 Gy, starting on median day +42 (41-53) post-HDC, which was well tolerated. No patients received maintenance BV. Table 1. Patient characteristics Variable Study file (N=80) Concurrent BEAM cohort (N=31) P Median age (range) 31 (13-65) 39 (23-65) 0.02 Primary refractory / poor-risk relapse 41% / 59% 37% / 63% 0.6 # prior relapses 1 80% 70% 0.3 〉1 20% 30% Median # prior chemotherapy lines (range) 2 (2-6) 2 (2-7) 0.3 Prior disease-free interval (months) 12 20% 23% Prior xRT 21% 27% 0.6 Relapse within prior xRT field 10% 3% 0.4 Extranodal relapse/PD 36% 53% 0.08 B symptoms at relapse/PD 11% 10% 0.8 Bulky relapse (any lesion 〉5 cm) 39% 17% 0.02 # risk factors (primary refract/CR11 relapse 50% 73% 0.08 B symptoms 55.6% 70.4% 0.2 Bulky relapse 67% 72% 0.2 Extranodal 67% 72% 0.4 The BEAM cohort included 31 patients treated between 06/11-04/15 (Table 1) with no BV maintenance. There were fewer cases of PET+ tumors at HDC (P=0.003) and of bulky relapses (P=0.02) than the Gem/Bu/Mel file, but was matched for the other risk factors. It had no TRM. Despite a higher number of PET+ tumors at HDC, the Gem/Bu/Mel file had significantly superior 2-year PFS (65% vs. 51%, P=0.03) and 2-year OS (95.5% vs. 70%, P=0.001) than the BEAM cohort. CONCLUSIONS: Gem/Bu/Mel without maintenance BV was safe and effective in patients with refractory or poor-risk relapsed HL, with comparable results to those from the AETHERA trial using BEAM and maintenance BV. A randomized trial is necessary to compare Gem/Bu/Mel and BEAM. Figure 1. Figure 1. Disclosures Off Label Use: Gemcitabine, busulfan and melphalan are not FDA approved at high doses for Hodgkin's lymphoma. Alousi:Therakos, Inc: Research Funding. Andersson:Otsuka Research and Development, Inc.: Consultancy. Fanale:Merck: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Honoraria, Research Funding; Infinity: Membership on an entity's Board of Directors or advisory committees; Spectrum: Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Honoraria, Research Funding; Genentech: Research Funding; Medimmune: Research Funding; Novartis: Research Funding; Bayer: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; Molecular Templates: Research Funding; ADC Therapeutics: Research Funding; Onyx: Research Funding; Gilead: Research Funding.

Description: Adoptive immunotherapy with ex vivo expanded virus-specific T-cell lines from transplant donors has emerged as a potentially curative approach for the treatment of drug-refractory viral infections complicating allogeneic hematopoietic cell transplants (HSCT). In these studies, viral-specific T cells are generated in compliance with current good manufacturing practice (cGMP) following repeated rounds of antigen-driven stimulation over a number of weeks. Such protocols are logistically and technically demanding, requiring access to specialized GMP units and are difficult to apply in urgent clinical settings. The cytokine-capture (gamma-catch) procedure is a fast and simple method that takes

Description: Clinical manifestations of BKV hemorrhagic cystits (HC) following hematopoietic stem cell transplantation (HSCT) range from microscopic hematuria to bladder hemorrhage and renal failure. Pharmacologic treatments for HC have limited efficacy and significant adverse effects. Here, we report the preliminary analysis of adoptive immunotherapy with most closely HLA-matched third party BKV-specific CTL lines (BKV-CTLs) generated by ex vivo expansion.We generated a bank of BKV-specific CTLs from 17 virus-immune healthy donors (mean age, 55; range, 25 to 75 years). Mononuclear cells enriched from donor buffy coats were stimulated with BKV peptide mix from capsid proteins VP1, VP2, VP3, large T antigen (LT) and small T antigen (ST) in the presence of IL-2, IL-7 and IL-15 for 14 days. At the end of culture, the cells were harvested and cryopreserved until use. Patients with symptomatic BKV cystitis after HSCT for leukemia or lymphoma were eligible. Patients with acute GVHD grades II-IV, those receiving 〉0.5 mg/kg systemic steroids/day or on treatment with cidofovir or leflunomide were excluded. A search for the most closely HLA-matched donor was initiated through the MDACC cell therapy donor bank. BKV-specific T cells were infused intravenously directly after thawing. Patients could receive up to 2 infusions. BKV PCR and clinical symptoms were monitored every week for 28 days after infusion. Complete response was defined as complete resolution of symptoms and gross hematuria and partial response (PR) as decrease in grade of HC from 3 (urinary blood clots) or 4 (red cell transfusion requirement/renal impairment) to 2 (macroscopic hematuria) or 3 respectively. Patients with stable disease (SD) or progression had insufficient changes to qualify as PR or had an increase in symptoms or worsening hematuria, respectively. To date, 10 patients (2 HLA-matched related, 5 HLA-matched unrelated and 3 haploidentical HSCT recipients) have received BKV-CTLs for BK cystitis. The median number of BKV-specific CD3+IFN-gamma+ and CD3+IL-2+ T-cells infused was 10e3/kg and 4.8e3/kg, respectively. The ratio of BKV-specific CD4+/CD8+ T cells in the infused product was 7.8 (range 3.1-22.1). There were no infusion-related adverse effects. Based on end-organ response, BKV-CTLs controlled infection in 9/9 evaluable patients with BKV cystitis (4 CRs and 5 PRs)- one patient was not evaluable due to disease relapse, sepsis and anuria. All patients achieved a response by day 14 post-infusion. Two of 5 patients with PR received a second BK CTL infusion from a different donor. One had an initial PR to the first CTL infusion but symptoms progressed after 6 weeks. A second infusion resulted in a PR with reduction in BKV PCR and symptoms. The other patient achieved CR within 28 days of the second infusion. The time to second infusion was 6 and 3 weeks, respectively. The response in all patients was sustained. Following infusion, we detected high frequencies of polyfunctional BKV-specific CD4+ and CD8+ T-cells, capable of producing IL-2, IFN-gamma and TNF-alpha in response to ex vivo stimulation with BKV peptide pools (VP1, VP2, VP3, LT and ST). The response was mainly CD4+ T cell dominant, reflecting the composition of the infused BKV T cell line and consistent with previous reports of a predominantly CD4-mediated T cell response in BKV infection. De novo grade 2-4 acute graft versus host disease (aGVHD) occurred in 1/10 patients. The patient developed grade 2 duodenal GVHD 14 days following infusion. A second patient had recurrence of a prior skin GVHD and developed grade 2 aGVHD 9 days after infusion. Both were successfully treated with 1mg/kg/day systemic steroids. This analysis demonstrates the safety, feasibility and efficacy of administration of most closely HLA-matched BKV CTLs for the treatment of BKV cystitis in HSCT patients. The response rate of 100% in the first 10 patients treated with BKV CTLs is promising. Disclosures Ciurea: Cyto-Sen Therapeutics: Equity Ownership; Spectrum Pharmaceuticals: Other: Advisory Board.

Description: Background: Delayed platelet recovery and secondary thrombocytopenia, defined as a drop in platelet count not due to disease relapse after initial platelet recovery, occur in 5-25% of patients after hematopoietic cell transplantation (HCT) and indicate adverse prognosis. Platelet transfusion to prevent bleeding remains a mainstay of therapy and role of thrombopoietic agents is not known. Eltrombopag, a non-peptide small molecule, thrombopoietin receptor agonist, is licensed for use in refractory ITP and aplastic anemia. In this phase II randomized double blind placebo controlled study, we investigated the safety and efficacy of eltrombopag for post HCT thrombocytopenia. Methods: Patients 35 days or more after HCT were eligible for the study if they had 1) platelet count ≤ 20 x 109/l sustained for 7 days or if they were platelet transfusion dependent, and 2) neutrophil count ≥ 1.5 x 109/l with or without G-CSF in the previous 7 days. Patients were excluded if they had abnormal liver function tests (ALT ≥ 2.5 ULN, or Bilirubin 〉2mg/dl) or had prior venous thrombosis. Patients were randomized to receive placebo or eltrombopag using a Bayesian adaptive algorithm in which the probability of randomization to each arm was based upon the ongoing response rate. Eltrombopag was started at a dose of 50mgs and escalated every 2 weeks to 75mgs, 125 mgs and 150mgs if platelet count was 〈 50 x 109/l. The primary endpoint was platelet count at end of the treatment (8 weeks). A patient was considered responsive if platelet count was ≥ 30 x 109/l. The primary endpoint was evaluated by calculating the Bayesian posterior probability in each arm that the response rate was higher than the other arm. A Beta (0.4, 1.6) prior distribution was assumed for each arm. Given the observed study data, the probability of response in each arm was calculated and the probability that Eltrombopag is superior was computed. Results: Sixty patients were randomized to eltrombopag (n=42) or placebo (n=18) and received at least one dose of drug. 7 patients had an autograft and 53 patients had an allograft. Donor was related for 22 and unrelated for 31 patients. Stem cell source was peripheral blood in 36 patients, bone marrow in 23 patients and cord blood in 1 patient. There were no significant differences in patient characteristics between the 2 treatment arms. The probability that the response rate in the Eltrombopag arm is superior to the response rate in the placebo arm was 0.75, given the observed data. The protocol required this probability to be 〉 0.975 to declare a winner; thus, the results are inconclusive. Fifteen (36%) of patients in eltrombopag arm responded compared to 5 (28%) of patients in placebo arm. A 95% credible interval for response in the Eltrombopag arm is 22% to 50%, and a 95% credible interval for response in the placebo arm is 11% to 48%. 37 patients completed all 8 weeks of therapy; however, all patients (n=60) who received at least one dose of study treatment were included in the intention to treat evaluation of this endpoint. A secondary objective was to compare proportion of patients achieving a platelet count ≥ 50 x 109/l. Response rate was higher in the eltrombopag arm for this endpoint as well: 9 (21.4%) patients achieved success compared with 0 (0%) patients in the placebo arm (p=0.0466; Fisher's exact test). OS, PFS, relapse rate, and non-relapse mortality were similar in two arms. Conclusion: Eltrombopag improves platelet count in patients with post-transplant thrombocytopenia. Disclosures Kim: Eli Lilly: Consultancy; Seattle Genetics, Inc.: Consultancy, Research Funding; Bayer: Consultancy.