ALBERT

Beschreibung: Introduction: Allogeneic hematopoietic cell transplantation (HCT) is curative therapy for sickle cell disease (SCD). Good outcomes have spurred an increase in the use of HCT for SCD, including an increasing number of trials using alternative donors. As survival improves, assessment of long-term outcomes and potential late effects (LEs) in this patient population is critical. We evaluated the data reported to the Center for International Blood and Marrow Transplant Research (CIBMTR) to study incidence and risk factors for LEs following HCT for SCD. Methods: Patients reported to the CIBMTR with a diagnosis of SCD who had undergone their first HCT between 1996 and June 2015 were included in this analysis. Patients with graft failure were excluded. We performed a descriptive analysis of patient, disease, donor, and transplant-related factors. The cumulative incidence (CI) of LEs was estimated at 1, 3, and 7 years post-HCT. The number of pre- versus post-HCT SCD-specific disease complications was computed. Overall survival (OS) probabilities were calculated using the Kaplan-Meier method. Multivariable Cox regression analysis was used to evaluate risk factors related to OS and LEs. Results: The study population consisted of 355 patients. The median age at HCT was 10 years (range 15 years of age was associated with significantly inferior OS (mortality HR 7.26, 95% CI 3.57-14.77). Multivariable analysis for LEs demonstrated an increased risk of diabetes (HR 7.29, 95% CI 2.94-18.08) and pulmonary abnormalities (HR 5.90, 95% CI 1.14-30.42) with unrelated donor, while older age at HCT was associated with avascular necrosis (HR 14.19, 95% CI 1.86-108.47), diabetes (HR 3.45, 95% CI 1.69-7.05), and congestive heart failure (HR 8.02, 95% CI 1.13-56.94). SCD-related symptoms overall decreased from pre- to post-HCT (Table 1), most notably acute chest syndrome, vaso-occlusive pain crises, and stroke. Conclusions: Patients with SCD who have undergone HCT for SCD in recent years have excellent OS, confirmed in this CIBMTR multicenter dataset, with diminished SCD-related symptom burden post-HCT. However, they remain at-risk for a myriad of LEs, with risk factors including older age at HCT and unrelated donor, necessitating systemic organ-based follow up post-HCT. Continued follow-up of this patient population is critical to provide appropriate counseling for medical providers, patients, and families considering HCT as a treatment option for SCD. Disclosures Shaw: Therakos: Other: Speaker Engagement.

Beschreibung: Background: Recent data have shown that pre-transplant FDG-PET is prognostic in DLBCL patients undergoing autologous stem cell transplantation (ASCT). We retrospectively analyzed data on patients with DLBCL treated with ASCT to assess the impact of pre-transplant FDG-PET on relapse-free survival (RFS) and overall survival (OS). Methods: We reviewed medical records of 32 patients with DLBCL who underwent ASCT using high dose busulfan, cyclophosphamide, and etoposide (Bu/Cy/VP) at Cleveland Clinic from June 2008 to December 2012 and had both a relapse FDG-PET as well as a pre-transplant FDG-PET available for review. All images were interpreted by a staff nuclear medicine radiologist blinded to the outcomes. Visual analysis was performed using the Deauville five-point scale and semiquantitative analysis was done by measuring the maximum standardized uptake value (SUVmax). ΔSUVmax was calculated by determining the difference between the SUVmax at the time of relapse and the SUVmax immediately prior to transplant. Patients were grouped into pre-transplant Deauville score 1-3 or 4-5. Baseline characteristics were compared between groups using the Chi-square test or Wilcoxon rank test. Cox proportional hazards analysis was used to identify prognostic factors. Outcomes were calculated from the date of ASCT. Overall survival (OS) and relapse-free survival (RFS) were estimated using the Kaplan-Meier method and compared using the log-rank test Results: The median age of the patients at transplant was 57 and 69% were male. There was no significant difference in baseline characteristics of patients who had a Deauville score 1-3 compared to patients who had a Deauville score 4-5 including mean age, gender, race, Karnofsky performance status, number of prior chemotherapy regimens, prior radiation therapy, and IPI at diagnosis and transplant. There was a trend towards significance in the median SUVmax at relapse in the Deauville 1-3 group compared to the Deauville 4-5 group (11.1 vs. 18.1, p=0.08) and a significant difference in the median pre-transplant SUVmax (2.3 vs. 8.1, p6 vs. 6) prior to transplant is predictive of poor RFS. Pre-transplant PET is a powerful tool for identifying DLBCL patients at high risk for treatment failure with ASCT and could be used to risk-stratify patients in prospective clinical trials of novel transplant strategies. Figure 1. OS of DLBCL patients undergoing ASCT based on pre-transplant Deauville score. Figure 1. OS of DLBCL patients undergoing ASCT based on pre-transplant Deauville score. Figure 2. RFS of DLBCL patients undergoing ASCT based on pre-transplant SUVmax. Figure 2. RFS of DLBCL patients undergoing ASCT based on pre-transplant SUVmax. Disclosures Smith: celegene, spectrum, genentech: Honoraria. Majhail:Gamida Cell Ltd.: Consultancy; Anthem Inc.: Consultancy.

Beschreibung: Proteasome inhibitors (PIs) capitalize on the constitutive activation of NF-KB in AML cells and increase chemosensitivity to anthracyclines and cytarabine. We combined the second generation PI, ixazomib, with the standard AML salvage regimen of MEC (mitoxantrone, etoposide, cytarabine). The primary objectives of this study were to determine the dose limiting toxicity (DLT), maximum tolerated dose (MTD), and phase 2 dose of ixazomib in combination with MEC in relapsed/ refractory (R/R) AML. Secondary objectives included evaluating the efficacy of this combination and correlating response to the gene expression profile and CD74 expression, which may identify a subset of leukemias in which NF-KB is operative with increased sensitivity to PI (Attar et al. CCR 2008; 14: 1446-54). Methods: Patients (pts) were treated at Cleveland Clinic and University Hospitals of Cleveland from Oct 2014 to present. An IND was approved by the FDA, and the protocol was approved by each institutional review board. Eligibility: age 18-70 yrs, R/R AML, and cardiac ejection fraction ≥ 45%. The fraction of blasts positive for CD74 was assessed by flow cytometry. Samples were stored for gene expression profiling pre- and post-treatment (at the time of response assessment). Pts received MEC: mitoxantrone (8 mg/ m2), etoposide (80 mg/m2), and cytarabine (1000 mg/m2) intravenous (IV) Days 1-6. Ixazomib, provided by Takeda, was given orally on Days 1, 4, 8, and 11 and was dose escalated using a standard 3x3 design. Dose levels (DLs): 1 (1.0 mg), 2 (2.0 mg), 3 (3.0 mg), 4 (3.7 mg). An additional 18 pts were to be treated at the MTD. One cycle of treatment was administered. Response was assessed by bone marrow aspirate/ biopsy by Day 45 and complete remission (CR) was defined by IWG criteria (Cheson 2006). Toxicities were graded according to NCI CTCAE v 4.03. Toxicities secondary to neutropenia or sepsis were not considered DLTs. DLTs included: (1) ≥ Grade 4 non-hematologic toxicity (NHT) with the exception of nausea, vomiting/ alopecia and drug-related fevers; (2) any ≥ Grade 3 neurologic toxicity; (3) grade 4 platelet or neutrophil count 50 days beyond the start of chemotherapy and not related to leukemia; (4) any Grade 4 NHT 〉 grade 2 by 45 days beyond the start of chemotherapy. Grade 2, 3, and 4 hyperbilirubinemia were redefined as 1.5-〈 10x upper limits of normal (ULN), 10-20 x ULN, and 〉 20 x ULN. Results: Of 23 pts enrolled, 22 are evaluable. The median age was 58 yrs (range 31-70), 12 (52%) were male and the median baseline WBC was 2.56 K/ uL (range 0.1-62.9). The median time from initial diagnosis to registration was 7.1 months (range 1.4-36.8) and 7 pts (30%) had a history of an antecedent hematologic disorder. Thirteen pts were in 1st relapse and 10 pts were refractory to their last therapy. One pt had received a prior allogeneic hematopoietic cell transplant (AHCT), 7 pts had FLT3 ITD mutations and 7/ 21 pts (33%) had adverse cytogenetics per CALGB 8461 criteria at the time of relapse. At DL1, 1 DLT occurred (grade 4 thrombocytopenia), so this DL was expanded to 6 pts. At DL2, 2 pts developed Grade 4 thrombocytopenia; therefore, the MTD of ixazomib was 1.0 mg. The most common grade 3-5 NHTs in the dose escalation phase were febrile neutropenia (100%), hypoalbuminemia (25%), hypokalemia (42%), hypotension (33%), and respiratory failure (33%). No adverse events in the dose escalation phase were attributed to ixazomib alone. The overall response rate was 55% [CR/ CR with incomplete count recovery (CRi)], and 9 pts proceeded to AHCT. Five of these 9 pts remain alive with a median follow-up of 12.8 months. Five pts had CD74 expression performed. Two pts had high levels of CD74 expression (〉 80%); and both achieved CRi. Myeloid mutation panel data was available in 14 pts. Previous data has demonstrated the number of mutations in DNTMT3A, TP53, ASXL1, and NRAS (0, 1, 〉1) is associated with a worse response to salvage therapy (Advani et al, abstract 3825, ASH 2015). Seven pts had at least one of these mutations and 6 of the 7 achieved CR/ CRi. Conclusions: The combination of MEC and ixazomib was well-tolerated and produced an overall response rate of 55% in patients with relapsed/ refractory AML irrespective of molecular mutation status. The combination is safe with a similar toxicity profile to MEC alone. CD74 expression may represent a biomarker for response to this therapy. Results from gene expression profiling will be complete by the time of the meeting and will be presented. Disclosures Mukherjee: Novartis: Consultancy, Honoraria, Research Funding; Ariad: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding. Caimi:Genentech: Speakers Bureau; Gilead: Consultancy; Roche: Research Funding; Novartis: Consultancy. Maciejewski:Alexion Pharmaceuticals Inc: Consultancy, Honoraria, Speakers Bureau; Apellis Pharmaceuticals Inc: Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Honoraria, Speakers Bureau. Sekeres:Millenium/Takeda: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees.

Beschreibung: Acute undifferentiated leukemia (AUL) and mixed phenotype acute leukemia (MPAL) are acute leukemias of ambiguous lineage representing less than 5% of all adult leukemias. Ontogenetically, they are thought to be caused by precursor lesions in early pluripotent hematopoietic progenitor cells having the ability to differentiate into both lymphoid and myeloid lineages. In contrast, common lymphoid and myeloid leukemias are likely derived from precursor lesions in committed progenitor cells. The molecular characteristics of the cell of origin of these leukemias have not been fully characterized. Given the ambiguous classification of these disorders, we used NGS to evaluate the molecular profiles of this unique subset of leukemias. Our panel tested for the 60 most commonly mutated genes in myeloid malignancies (MM), which can be used to further elucidate driver mutations that play a role in the pathogenesis of this unique entity. Molecular data was available for 18 of 35 patients (pts) (51%), of whom 8 were T/myeloid, 7 were B/myeloid, and 3 were AUL. 14 pts out of the 18 had samples at the time of initial diagnosis, 3 AUL cases harbored mutations commonly seen in MM, including one patient with DNMT3A and a germ line JAK3 mutation, another with U2AF1 and PHF6 mutations, and one pt with SF3B1 and MECOM mutations. Of the 5 B/myeloid cases, 4 had only one mutation detected by the sequencing panel, including TET2, PTPN11, KDM6A, and PHF6, and one had no mutations, but did have complex cytogenetics. Of interest, we identified four patients with T/myeloid MPAL that harbored a FLT3-ITD mutation. Notably, one of these cases had additional DNMT3A and TET2 mutations while another case had a WT1 mutation. We assert that the mutational data for MPAL supports that T-myeloid MPAL encompasses a borderland between early T precursor (ETP)-ALL/AML in addition to more typical cases of T-ALL/AML given its similar immunophenotype to ETP ALL (CD117, CD13 and CD33 positive). The overlap between these two entities is illustrated in the figure below. With this immunophenotyping and molecular profiling we propose a new provisional entity, ETP-myeloid MPAL in addition to already existing ETP ALL. Of 1250 pts with acute leukemia diagnosed from 1997-2016 at Cleveland Clinic, 35 had immunophenotypic characteristics of ambiguous leukemia based on WHO criteria. The median age at diagnosis was 50 years, and 22 (63%) were male. There were 31 MPAL (16 T/myeloid, 15 B/myeloid) and 4 AUL cases. Among the 31 MPAL patients, 2 were mixed lineage chimera (subclones), and 29 had true biphenotypic features. 48% of the cohort had normal cytogenetics at diagnosis, 23% had other cytogenetic abnormalities, 14% had complex karyotype, 9% had MLL gene rearrangement, and 6% had t(9;22). 62% of pts were treated with acute lymphoblastic leukemia (ALL) directed induction chemotherapy (IC), while 38% were treated with acute myelogenous leukemia (AML) directed IC. Rates of complete remission (CR) were significantly higher in pats treated with ALL-IC regimen (82%) versus AML-IC regimen (23%) (p=.003). In our study, two cases with the recurrent lymphoid mutations WT1 and KDM6A, that achieved CR with upfront ALL-IC, while one case with FLT3-ITD, DNMT3A, and TET2 mutations achieved CR with AML-IC treatment. Pts

Beschreibung: Reduced intensity conditioning for allogeneic hematopoietic cell transplantation (alloHCT) has become a standard approach for older patients and for those with co-morbidities that prohibit myeloablative conditioning. The optimal conditioning regimen for patients with AML or MDS undergoing such transplants is not clear. Therefore we performed a single center, retrospective analysis comparing busulfan (100 mg/m2/day on days -5, -4, -3, -2) and fludarabine (40 mg/m2/day on days -5, -4, -3, -2) (BuFlu) versus fludarabine (30 m2/day on days -5, -4, -3) and 400 cGy total body irradiation (200 cGy on days -1 and 0) (FluTBI) conditioning. All of the BuFlu transplants were performed as inpatient hospitalizations while all of those with FluTBI were performed as an outpatient. A total of 71 patients in two cohorts were included. The first study cohort consisted of 38 patients (23 AML, 15 MDS) who received FluTBI from 3/2004-4/2010, and the second included 33 (20 AML, 13 MDS) patients conditioned with FluBu from 6/2010-12/2013. The groups had similar disease risk and HCT comorbidity index scores. The BuFlu patients were older (median age 65 [range, 34-73] vs. 61[range, 44-70] years, P=0.03), but there were no other differences in patient or disease characteristics. All patients received peripheral blood stem cells as the graft source. The donor sources were 53% matched related (MRD) and 47% matched unrelated (MUD) for FluTBI patients and 58% MRD and 42% MUD for BuFlu patients. The BuFlu group received more red blood cell (RBC) transfusions (median 4 vs. 2, P=0.02), but there were no differences in platelet transfusion requirements. Platelet recovery was longer for patients receiving BuFlu than FluTBI (median 16 vs. 12 days, P=0.004), but there was no difference in cumulative incidence of neutrophil recovery. The respective median number of days hospitalized in the first 100 days post-transplant was 22 vs. 10 days (P

Beschreibung: INTRODUCTION: High dose busulfan (Bu) is an integral component of many commonly-used preparative regimens for both allogeneic and autologous transplantation. Data on the efficacy and toxicity of q6 vs. q24 hour dosing are of significant clinical interest. In order to facilitate a therapeutic dose-monitoring protocol, we transitioned from q6 to q24 Bu dosing as part of our standard Bu/Cy/VP ASCT preparative regimen for patients with Hodgkin (HL) and Non-Hodgkin Lymphoma (NHL) in July 2012. We present comparative outcomes of q24 Bu dosing vs historical controls receiving q6 Bu. METHODS We retrospectively reviewed 400 consecutive eligible lymphoma patients who underwent ASCT from 2007-2013 with Bu/Cy/VP. All patients received Cy 60 mg/kg IV over 4 hours on days -3 and -2 and VP 60 mg/kg as continuous infusion on days -5 and -4. Bu was given at a dose of either 0.8 mg/kg q6 (N = 307) x 14 doses for patients transplanted between 2007-July, 2012 or 2.8 mg/kg q 24 hours (N = 93) on days -9 through -6 for subsequent patients. Outcomes assessed from date of transplant were: relapse, non-relapse mortality (NRM), relapse-free survival (RFS) and overall survival (OS). Toxicity was assessed using pulmonary and liver function tests (PFTs and LFTs) at specified time-points before and after ASCT. In addition, for a subset of 22 patients receiving q24 Bu, we measured serial Bu serum levels after the first dose of Bu with an in-house liquid chromatography-tandem mass spectrometry assay using turbulent flow online extraction technology (Bunch, et al. J Chromatogr B Analyt Technol Biomed Life Sci, 2010. 878(31): p. 3255-8) and subsequently determined the cumulative Bu area-under the curve (AUC). RESULTS Baseline patient and disease characteristics of patients dosed with q6 and q24 Bu were similar. The median age was 55 (range 20-78) years; 63% were males. 18% had HL and 82% had NHL with a comparable distribution of subtypes in both groups. Patients in both groups had comparable rates of prior chemotherapy regimens and of complete/partial remission at the time of ASCT. Due to a change in institutional guidelines, plerixafor was more commonly incorporated in peripheral blood stem cell mobilization regimen in the q24 group compared to q6 cohort (70% vs. 39%, P

Beschreibung: Allogeneic HCT is a potentially curative but high risk therapy for patients with hematologic malignancies. HCT recipients are typically followed closely by their transplant center within the first 100 days, and with advances in supportive care, day 100 survival has continued to improve significantly over time. Longer term survival, however, remains a challenge and the factors that predict for later mortality are not well understood. We thus undertook this retrospective analysis to identify prognostic factors for 1-and 2-year survival among day 100 survivors. Of 413 patients that underwent a first allogeneic HCT from 2006 to 2014, 355 survived 〉100 days post-transplant. Diagnoses included acute myeloid leukemia (N=163), myelodysplastic syndrome (N=89), acute lymphoblastic leukemia (N=62), chronic myeloid leukemia (N=34), or undifferentiated/biphenotypic leukemia (N=7). 34% of patients had high risk, 18% intermediate, and 48% low risk disease by American Society for Blood and Marrow Transplantation (ASBMT) RFI risk category. Median age at transplant was 50 years (range, 18-73). The majority of patients were Caucasian (89.6%). Median household income was $49,980 (range 13,316-112,530) and median distance from transplant center was 46 miles (range, 1-1055). 40% patients had a high HCT co-morbidity index, 32% intermediate and 28% low. 152 (43%) patients underwent a matched related donor, 148 (42%) matched unrelated donor, 36 (10%) umbilical cord blood (UCB), 13 (3%) haplo-identical, and 6 (2%) mismatched unrelated donor transplants. The majority of patients (75%) underwent a myeloablative transplant and bone marrow (BM) (53%) was the primary graft source. Cox proportional hazards was used to identify prognostic variables for 1- and 2-year mortality in the 355 surviving patients using baseline characteristics and factors evaluated at day 100. Baseline characteristics as described above included patient, disease, transplant, and socioeconomic/psychosocial factors. Additional variables evaluated at day 100 included number of readmissions, days hospitalized, GVHD rates, infections, relapse within the first 100 days of transplant, and QOL measures as assessed by the Functional Assessment of Cancer Therapy Bone Marrow Transplantation (FACT-BMT), scored at baseline and day 100. 1- and 2-year mortality was 71%, and 54%, respectively, compared to a day 100 mortality of 86%. Among day 100 survivors, the most common causes of death within the first 2 years were relapse (N=78, 54%), followed by infection (N=24, 17%), pulmonary or other organ failure (N=23, 16%), and GVHD (N=16, 11%). In multivariable analysis evaluating risk factors for mortality among the day 100 survivors, lower income (HR 1.25, P=0.013), high risk ASBMT RFI (HR 1.75, P=0.03), relapse (HR 7.84, P

Beschreibung: Molecular mutations are routinely incorporated into the risk stratification of newly diagnosed acute myeloid leukemia (AML) patients (pts). However, their prognostic impact in relapsed AML has not been well characterized. To better understand the landscape and prognostic impact of molecular mutations in relapsed AML, we retrospectively examined pts with AML in first relapse. Methods: We performed multi-amplicon targeted deep sequencing on samples from bone marrow and peripheral blood of pts diagnosed with AML in first relapse at our institution between the years 2002-2013. A multiple gene sequencing panel of 64 genes that have been described as recurrently mutated in myeloid malignancies was applied. Genes were analyzed individually and grouped based on their functional pathways: RNA splicing, RNA-helicase family, DNA methylation/epigenetic, transcription factors, signal transduction/ receptors, histone/ chromatin modification, cohesion complex. Cytogenetic (CG) risk was ascribed by CALGB/Alliance 8461 criteria. The primary endpoints were response to salvage therapy and overall survival from relapse (OS-R). Binary logistic and proportional hazards models were used for univariable and multivariable analyses. Multivariable analyses of individual genes and functional groups used a stepwise variable selection algorithm and were based on the genes and gene groups found to be significant in univariable analysis at p 〈 0.20. Results: Data from 74 pts were analyzed. The median age at diagnosis was 61 years (range 27-77). CG risk at diagnosis: good (17%), intermediate (42%), miscellaneous (15%), poor (26%). At the time of relapse, 68% of pts received intensive salvage chemotherapy [i.e. MEC (mitoxantrone, etoposide, cytarabine), high dose cytarabine], 14% supportive care, and 19% low dose therapy. Sixteen percent of pts received an allogeneic hematopoietic stem cell transplant. The most common mutations were found in NPM1 (16%), DNTM3A (15%), IDH2 (14%), and PHF6 (10%). Overall, 19 pts (26%) had no mutations, 25 (34%) had 1, 12 (16%) had 2, 11 (15%) had 3, and 7 (9%) had 〉 3 mutations. Fifty-two percent of pts achieved a complete remission (CR) or CR with incomplete count recovery (CRi) with salvage therapy (95% CI: 39-64%) and median OS-R was 5.2 months. In multivariable analyses, the number of mutations (0, 1, 〉1) in DNMT3A, TP53, NRAS, and ASXL1 (panel 1) was the only factor found to be independently associated with worse OS-R and response to salvage therapy (p〈 0.0001 and 0.03, respectively). Adjusting for age, CG risk, and treatment, the number of mutations in panel 1 remained a significant predictor of OS-R (p=0.003) but not of response to salvage therapy (p=0.23). Multivariable analyses of panel 1 and conventional CG risk suggested that both factors contained prognostic information (p 〈 0.0001 and 0.07, respectively); and that a modified CG risk classification system could be defined using a simple scoring algorithm that assigns points to each conventional CG risk group and the number of panel 1 mutations that are proportional to the corresponding regression coefficients from the model and then summing the number of points present (Table 1). Based on the scoring system, 3 prognostic groups can be defined (Figure 1). Table 1. Scoring Algorithm Factor Points CG Risk  Good 0  Intermediate 2  Miscellaneous 2  Poor 3 Number of mutations in panel 1  0 0  1 3  〉1 6 Conclusions: Molecular mutations are prognostic for OS-R and may help identify patients who would benefit from novel therapies at the time of relapse. Specific predictive mutations included genes related to DNA methylation and histone modification suggesting that targeting these specific factors may improve outcome. Figure 1. Prognostic Groups Figure 1. Prognostic Groups Disclosures Carew: Boehringer Ingelheim: Research Funding. Sekeres:Celgene Corporation: Membership on an entity's Board of Directors or advisory committees; TetraLogic: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees.

Beschreibung: Healthcare disparities, such as race/ethnicity and SES, can impact access to care and outcomes in cancer patients. ASCT is standard therapy for high-risk relapsed and refractory lymphoma, but is a highly specialized and resource-intensive procedure. The association of race and SES with outcomes in lymphoma patients undergoing ASCT has not been described previously. We conducted a retrospective cohort study of 687 consecutive ASCT recipients with Hodgkins (N=154, 22%) and non-Hodgkins (N=533, 78%) lymphoma transplanted between 2003 and 2013 at our institution. Zip code of residence was used to obtain median annual household income based on 2010 US Census data. Patients were categorized into low SES (1/KPS 1 year, however, mortality in the low SES group in primarily mediated through non-relapse causes. Our study highlights the need for active interventions to mitigate health care disparities in this high risk population. Table. 5-year outcomes after ASCT for lymphoma by SES Outcomes All patients, N=687 1-yr survivors, N=551 Low SES High SES P-value Low SES High SES P-value Relapse mortality 29% 25% 0.03 16% 18% 0.53 NRM 16% 12% 0.18 14% 9% 0.07 OS 55% 64% 0.004 70% 74% 0.07 PFS 41% 47% 0.01 57% 58% 0.25 Figure 1. OS for all patients and 1-year survivors Figure 1. OS for all patients and 1-year survivors Figure 2. Figure 2. Disclosures Hill: Celgene: 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; Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Honoraria, Membership on an entity's Board of Directors or advisory committees. Majhail:Gamida Cell Ltd.: Consultancy; Anthem Inc.: Consultancy.

Beschreibung: Background: High-dose chemotherapy (HDCT) followed by autologous stem cell transplantation (ASCT) is a standard treatment both as consolidation after induction chemotherapy and as second-line therapy depending on the histologic subtype of NHL. BEAM (BCNU, etoposide, cytarabine, and melphalan) is a commonly used conditioning regimen for NHL but often fails to produce durable remission, likely due to inherent chemoresistance. Many B-cell NHL subtypes including diffuse large B-cell lymphoma and double-hit lymphoma are resistant to chemotherapy-induced apoptosis by overexpression of Bcl-2. Venetoclax is an orally administered selective Bcl-2 inhibitor with significant single agent activity in CLL and mantle cell lymphoma. In addition, the efficacy of venetoclax is potentiated by combination with rituximab [Seymour 2018, Kater 2018] and multiple lines of preclinical data show synergistic efficacy with a range of both novel and conventional antineoplastic agents [Johnson-Farley 2015, Li 2015]. Study Design and Methods: This is a single arm, open-label, dose-escalation phase I trial to evaluate the safety of venetoclax in combination with BEAM (V-BEAM) conditioning chemotherapy. Key inclusion criteria include patients with pathologically confirmed NHL, regardless of specific histology, who have received one prior systemic therapy and are eligible for and proceeding with HDCT followed by ASCT. The trial employs a standard 3+3 cohort-based dose escalation design of venetoclax (800 mg daily days -7 through -6 on dose level 1, 800 mg daily days -7 through -5 on dose level 2, 800 mg daily days -7 through -4 on dose level 3, 800 mg daily days -7 through -3 on dose level 4, and 800 mg daily days -7 through -2 on dose level 5) with standard doses of BEAM followed by ASCT. The primary objectives are to assess safety, describe dose-limiting toxicities, engraftment of stem cells and to identify the recommended phase II dose. Secondary objectives include evaluation of progression-free survival (PFS) and overall survival (OS) compared to historical controls treated with BEAM as part of ASCT. Neutrophil and platelet engraftment will be estimated with cumulative incidence and compared to controls with Gray test. OS and PFS will be estimated with Kaplan-Meier and compared to controls with the log-rank test. As of 8/1/2019, the first dosing cohort of 3 patients have been enrolled and successfully completed study treatment. There are 3 patients in screening to be enrolled in dose level 2. Additional accrual will be presented at the time of the meeting. Clinical trial information: NCT03713580. Disclosures Anwer: Seattle Genetics: Membership on an entity's Board of Directors or advisory committees; In-Cyte: Speakers Bureau. Gerds:Celgene Corporation: Consultancy, Research Funding; Sierra Oncology: Research Funding; Pfizer: Consultancy; Incyte: Consultancy, Research Funding; CTI Biopharma: Consultancy, Research Funding; Roche: Research Funding; Imago Biosciences: Research Funding. Majhail:Nkarta: Consultancy; Atara Bio: Consultancy; Mallinckrodt: Honoraria; Incyte: Consultancy; Anthem, Inc.: Consultancy. Hill:TG therapeutics: Research Funding; Abbvie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Genentech: Consultancy, Research Funding; Kite: Consultancy, Honoraria; Gilead: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; AstraZeneca: Consultancy, Honoraria; Celegene: Consultancy, Honoraria, Research Funding; Seattle Genetics: Consultancy, Honoraria; Takeda: Research Funding; Amgen: Research Funding. OffLabel Disclosure: Our trial in progress is investigating the use of venetoclax in combination with BEAM conditioning chemotherapy prior to autologous stem cell transplantation. Venetoclax is not currently approved in this setting.