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.