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We present a 61-year-old male with FLT3-mutated acute myeloid leukemia treated with midostaurin who developed acute kidney injury requiring hemodialysis and pulmonary renal syndrome. Antibodies to proteinase-3, myeloperoxidase, and glomerular basement membrane were negative. Renal biopsy confirmed acute pauci-immune focal necrotizing glomerulonephritis (GN) with fibrin crescents indicating rapidly progressing glomerulonephritis. He improved with pulse methylprednisolone, intravenous cyclophosphamide, and plasma exchange with resolution of hemoptysis. This case highlights the importance of prompt renal biopsy to guide early initiation of life-saving therapies. To our knowledge, this is the first reported case of ANCA-negative pauci-immune necrotizing GN likely secondary to midostaurin.

Burkitt leukemia/lymphoma (BL) and high-grade B-cell lymphoma (HGBL) have a high incidence of central nervous system (CNS) involvement, which is associated with poor prognosis. The hyper-cyclophosphamide, vincristine, Adriamycin, and dexamethasone plus rituximab (CVAD-R) regimen includes systemic and intrathecal CNS-directed therapy to treat and prevent CNS disease. We report here the long-term safety and efficacy of the hyper-CVAD-R regimen in adults with BL and HGBL, focusing on its efficacy to prevent CNS relapse. Among 79 adults (54 BL, 25 HGBL), the median age was 44 years (25% ≥60 years old), 73% had bone marrow (BM) involvement, and 28% had CNS involvement. The complete response rate was 91% (BL 96%; HGBCL 79%; P = .16). The 5-year relapse-free survival (RFS) and overall survival (OS) rates were 58% and 52%, respectively. The cumulative incidence of relapse (CIR) was 21% (BL 14%; HGBCL 37%, P = .06) and was associated with baseline BM (27% vs 0%; P = .02) and CNS (42% vs 12%; P < .01) involvement. In multivariate analyses, age and CNS involvement were independent predictors for OS and RFS. The 5-year CNS CIR was 6% (BL 4%; HGBL 11%; P = .31); 16% with baseline CNS involvement (P = .03). Our data support the use of hyper-CVAD-R in preventing CNS relapse, especially among high-risk patients with BM or CNS involvement.

Acute lymphoblastic leukemia (ALL) with t(4;11)(q21;q23)-KMT2A-AFF1 is associated with a poor prognosis. The impact of KMT2A rearrangements other than t(4;11) is uncertain, and the benefit of allogeneic stem cell transplantation (HSCT) is unclear. We reviewed adult patients with ALL treated at our institution from 1984 to 2019 and identified 50 out of 1102 (5%) with KMT2A rearrangement, including 42 (84%) with t(4;11)/KMT2A-AFF1 and 8 (16%) with other gene partners. The median age was 45 years (range, 18-78 years); median white blood cell count was 109.0 3 109/L (range, 0.5-1573.0). The complete remission (CR) rate was 88%, and the rate of measurable residual disease negativity by flow cytometry at CR was 41% (76% overall during follow-up). At the last follow-up, 14 patients were alive. The 5-year overall survival (OS) rate was 18% (95% confidence interval [CI], 9% to 35%), with no difference between t(4;11) and other KMT2A rearrangements (P 5 .87). In a 4-month landmark analysis, the 5-year OS rate was 32% (95% CI, 14% to 70%) in patients who underwent HSCT vs 11% (95% CI, 3-39) in others (P 5 .10). Our study confirms the poor prognosis of ALL with any KMT2A rearrangement and the role of HSCT in these patients.

Normal karyotype in therapy-related acute myeloid leukemia (t-AML) is rare and the relative contribution of prior exposure to chemotherapy or radiotherapy to outcomes in these patients remains uncertain. We performed a retrospective study of 742 patients with newly diagnosed AML and normal karyotype (t-AML, n = 61, and non-t-AML, n = 681). Patients with t-AML were older but had a similar mutational profile compared to those with non-t-AML. Overall survival (OS) and relapse-free survival (RFS) were significantly worse for patients with t-AML (P P = 0.02, respectively). Patients with t-AML had a higher cumulative incidence of death in remission (51% versus 16%, P P = 0.21). Both intensive induction and allogeneic hematopoietic stem cell transplantation in first remission were associated with improved OS and RFS in non-t-AML but not in t-AML. Overall, although disease biology appears similar between t-AML and non-t-AML with normal karyotype as indicated by similar risks of relapse, death in remission is the main driver of inferior outcome in t-AML. Careful therapeutic decisions are required to mitigate potential treatment-related toxicity in this rare subgroup of patients with t-AML and normal karyotype.

Summary Background The addition of rituximab to intensive chemotherapy improves outcomes in patients with B-cell acute lymphoblastic leukaemia. Ofatumumab is an anti-CD20 monoclonal antibody that binds to the small extracellular loop of CD20 and has greater in vitro complement-mediated cytotoxicity than rituximab. In this study, we assessed the activity and safety of ofatumumab in combination with chemotherapy in patients with Philadelphia chromosome (Ph)-negative CD20-positive B-cell acute lymphoblastic leukaemia. Methods This was a single-arm, phase 2 trial done at the MD Anderson Cancer Center (Houston, TX, USA). Patients with newly diagnosed, Ph-negative B-cell acute lymphoblastic leukaemia or lymphoblastic lymphoma with CD20 expression of at least 1% were eligible. Patients were treated with up to eight courses of the hyper-CVAD regimen (hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone) on courses 1, 3, 5, and 7 alternating with high-dose methotrexate and cytarabine on courses 2, 4, 6, and 8. Ofatumumab was administered on days 1 and 11 of courses 1 and 3 and on days 1 and 8 of courses 2 and 4 for a total of eight doses. The first dose of ofatumumab was 300 mg intravenously and all subsequent doses were 2000 mg intravenously. Patients received 30 courses of maintenance therapy with 6-mercaptopurine, vincristine, methotrexate, and prednisone (POMP), with four intensification courses (high-dose methotrexate plus L-asparaginase and hyper-CVAD plus ofatumumab on courses 6–7 and 18–19). The primary endpoints were event-free survival, overall response, and overall survival. All enrolled patients were included in the primary and safety analyses. The trial is registered with ClinicalTrials.gov, NCT01363128. Findings Between Aug 26, 2011, and May 18, 2017, 69 patients (67 patients had B-cell acute lymphoblastic leukaemia and two had B-cell lymphoblastic lymphoma; median age 41 years [IQR 32-50]) were enrolled and treated, including 33 (48%) aged between 18 and 39 years. Nine (27%) of 33 patients had Ph-like acute lymphoblastic leukaemia. With a median follow-up of 44 months (26–53), 4-year event-free survival was 59% (95% CI 48–73); 69% (54–87) in adolescents and young adults aged 18–39 years. 4-year overall survival was 68% (58–81); 74% (60–91) in adolescents and young adults. The overall response rate was 98% (64 of 65 patients). The most common non-haematological grade 3 or 4 adverse events were infections (35 [54%] of 65 patients during induction and 53 [78%] of 68 patients during consolidation). Ten (14%) of 69 patients died in complete remission from sepsis (two [3%]), cardiac arrest (one [1%]), therapy-related acute myeloid leukaemia (two [3%]), and haematopoietic stem-cell transplantation complications (five [7%]). None of these deaths were considered related to ofatumumab treatment by the study investigators. Interpretation The combination of hyper-CVAD plus ofatumumab is safe and active in adults with Ph-negative CD20-positive B-cell acute lymphoblastic leukaemia. Modifications of this regimen with the addition of novel monoclonal and bispecific antibody constructs targeting CD19 and CD22 might further improve outcomes and allow reduction in the intensity and duration of chemotherapy. Funding Novartis.

Introduction: Outcome of patients (pts) with CD20-positive B-cell acute lymphoblastic leukemia (B-ALL) has significantly improved with hyper-CVAD (HCVAD) in combination with rituximab with 3-year OS 65% (Thomas et al Blood 2009). Ofatumumab is an anti-CD20 monoclonal antibody with higher capacity of promoting complement-dependent cytotoxicity compared to rituximab. The aim of this study is to compare the outcome of pts with CD20-positive B-ALL who received HCVAD plus ofatumumab (HCVAD-O) or HCVAD plus rituximab (HCVAD-R) therapy. Methods: We reviewed 69 adult pts with newly diagnosed, Philadelphia chromosome (Ph)-negative, CD20-positive B-ALL who were treated with HCVAD-O at our institution between 8/2011 and 5/2017. HCVAD therapy consisted of 4 alternating cycles of hyper-fractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone, plus high-dose methotrexate (MTX) / cytarabine (AraC) with 8 intrathecal injections of MTX/AraC. Ofatumumab was administered at 300mg IV as first dose, and 2000mg IV subsequently. The maintenance phase consisted of 30 cycles of 6-MP, MTX, vincristine, and prednisone (POMP) with 4 intensification courses (high-dose MTX plus L-asparaginase and HCVAD+O) on courses 6-7 and 18-19. Overall survival (OS) was calculated from the start date of treatment to the date of death, or last follow-up. We performed a comparison of survival between pts treated with HCVAD-O and a cohort of 153 historical-control pts treated with HCVAD with or without rituximab between 11/2002 and 7/2012. Historical-control pts were treated with HCVAD alone (N=58) if CD20 expression was 1-19% or HCVAD-R (N=95) if CD20 expression was ≥20%. To adjust for baseline differences of pts characteristics between the cohorts, we performed inverse probability of treatment weighing (IPTW) using propensity scores calculated from pts baseline characteristics. Covariates for the calculation of propensity scores included age, performance status, white blood cell count at diagnosis, the positivity of CD20 expression and adverse-risk cytogenetics (KMT2A-rearrangement, complex karyotype or low-hypodiploidy / near triploidy). Results: The median follow-up for HCVAD-O cohort and historical-control cohort was 44 months (95% CI: 41-53) and 133 months (95% CI: 115-141), respectively. There was no difference in baseline characteristics between HCVAD-O cohort and historical-control cohort (Table 1). The 5-year OS rates were 65% and 51% in HCVAD-O cohort and historical-control cohort, respectively. With the IPTW analysis, the HCVAD-O regimen was associated with better outcome compared with the historical HCVAD/HCVAD-R regimen (HR, 0.74; 95% CI, 0.55-0.99, p = 0.047) (Figure 1). The treatment effect was similar regardless of the level of CD20 positivity, although not statistically significant among each subgroup (CD20 ≥20%, HR 0.73, 95% CI, 0.52-1.04, p = 0.09; CD20 1-19%, HR, 0.68; 95% CI, 0.39-1.20, p = 0.18). Conclusions: The combination of HCVAD plus ofatumumab is highly effective and seems to have offered better outcome than did HCVAD plus rituximab therapy in pts with Ph-negative CD20-positive B-ALL. Additional novel monoclonal/bispecific antibody constructs targeting CD19 and CD22 are expected to further improve the outcome. Disclosures Sasaki: Otsuka: Honoraria; Daiichi Sankyo: Consultancy; Pfizer Japan: Consultancy; Novartis: Consultancy, Research Funding. Konopleva:F. Hoffmann La-Roche: Consultancy, Research Funding; Reata Pharmaceutical Inc.;: Patents & Royalties: patents and royalties with patent US 7,795,305 B2 on CDDO-compounds and combination therapies, licensed to Reata Pharmaceutical; Rafael Pharmaceutical: Research Funding; Amgen: Consultancy; Forty-Seven: Consultancy, Research Funding; AstraZeneca: Research Funding; AbbVie: Consultancy, Research Funding; Agios: Research Funding; Ablynx: Research Funding; Cellectis: Research Funding; Genentech: Consultancy, Research Funding; Ascentage: Research Funding; Sanofi: Research Funding; Stemline Therapeutics: Consultancy, Research Funding; Eli Lilly: Research Funding; Kisoji: Consultancy; Calithera: Research Funding. Short:Takeda Oncology: Consultancy, Honoraria, Research Funding; Amgen: Honoraria; Astellas: Research Funding; AstraZeneca: Consultancy. Jain:Pfizer: Research Funding; Cellectis: Research Funding; Aprea Therapeutics: Research Funding; Servier: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BeiGene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Verastem: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; ADC Therapeutics: Research Funding; Adaptive Biotechnologies: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Genentech: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Research Funding; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Precision Bioscienes: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Incyte: Research Funding; Fate Therapeutics: Research Funding; TG Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees. Ravandi:Macrogenics: Research Funding; Astellas: Consultancy, Honoraria, Research Funding; Jazz Pharmaceuticals: Consultancy, Honoraria, Research Funding; AstraZeneca: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Amgen: Consultancy, Honoraria, Research Funding; Xencor: Consultancy, Honoraria, Research Funding; Orsenix: Consultancy, Honoraria, Research Funding; BMS: Consultancy, Honoraria, Research Funding; Abbvie: Consultancy, Honoraria, Research Funding. Daver:Daiichi Sankyo: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol-Myers Squibb: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Karyopharm: Research Funding; Servier: Research Funding; Genentech: Research Funding; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Astellas: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novimmune: Research Funding; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Trovagene: Research Funding; Fate Therapeutics: Research Funding; ImmunoGen: Research Funding; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Jazz: Consultancy, Membership on an entity's Board of Directors or advisory committees; Trillium: Consultancy, Membership on an entity's Board of Directors or advisory committees; Syndax: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; KITE: Consultancy, Membership on an entity's Board of Directors or advisory committees; Agios: Consultancy, Membership on an entity's Board of Directors or advisory committees. Kadia:Genentech: Honoraria, Research Funding; Cyclacel: Research Funding; Pulmotec: Research Funding; Astellas: Research Funding; Novartis: Honoraria; Celgene: Research Funding; JAZZ: Honoraria, Research Funding; Amgen: Research Funding; BMS: Honoraria, Research Funding; Abbvie: Honoraria, Research Funding; Incyte: Research Funding; Ascentage: Research Funding; Cellenkos: Research Funding; Pfizer: Honoraria, Research Funding; Astra Zeneca: Research Funding. Alvarado:FibroGen: Research Funding; Daiichi-Sankyo: Research Funding; Jazz Pharmaceuticals: Research Funding; Sun Pharma: Research Funding; BerGenBio ASA: Research Funding; MEI Pharma: Research Funding; Tolero Pharmaceuticals: Research Funding; Astex Pharmaceuticals: Research Funding. DiNardo:Agios: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Honoraria, Research Funding; Syros: Honoraria; Calithera: Research Funding; ImmuneOnc: Honoraria; Daiichi Sankyo: Consultancy, Honoraria, Research Funding; Novartis: Consultancy; Takeda: Honoraria; Notable Labs: Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Honoraria, Research Funding; MedImmune: Honoraria; Jazz: Honoraria. Issa:Novartis: Membership on an entity's Board of Directors or advisory committees; Syndax: Research Funding; Celegene: Research Funding. Pemmaraju:MustangBio: Honoraria; AbbVie: Honoraria, Research Funding; Pacylex Pharmaceuticals: Consultancy; LFB Biotechnologies: Honoraria; Daiichi Sankyo: Research Funding; Incyte Corporation: Honoraria; Stemline Therapeutics: Honoraria, Research Funding; SagerStrong Foundation: Other: Grant Support; Novartis: Honoraria, Research Funding; Affymetrix: Other: Grant Support, Research Funding; Plexxikon: Research Funding; Celgene: Honoraria; DAVA Oncology: Honoraria; Roche Diagnostics: Honoraria; Cellectis: Research Funding; Blueprint Medicines: Honoraria; Samus Therapeutics: Research Funding. Garcia-Manero:Astex Pharmaceuticals: Consultancy, Honoraria, Research Funding; Amphivena Therapeutics: Research Funding; Onconova: Research Funding; H3 Biomedicine: Research Funding; AbbVie: Honoraria, Research Funding; Novartis: Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Acceleron Pharmaceuticals: Consultancy, Honoraria; Merck: Research Funding; Helsinn Therapeutics: Consultancy, Honoraria, Research Funding; Jazz Pharmaceuticals: Consultancy. Verstovsek:Incyte Corporation: Consultancy, Research Funding; Roche: Research Funding; NS Pharma: Research Funding; Gilead: Research Funding; Genentech: Research Funding; Novartis: Consultancy, Research Funding; ItalPharma: Research Funding; AstraZeneca: Research Funding; PharmaEssentia: Research Funding; CTI Biopharma Corp: Research Funding; Sierra Oncology: Consultancy, Research Funding; Promedior: Research Funding; Blueprint Medicines Corp: Research Funding; Protagonist Therapeutics: Research Funding; Celgene: Consultancy, Research Funding. Champlin:Johnson and Johnson: Consultancy; Actinium: Consultancy; DKMS America: Membership on an entity's Board of Directors or advisory committees; Genzyme: Speakers Bureau; Omeros: Consultancy; Takeda: Patents & Royalties; Cytonus: Consultancy. Khouri:Bristol Myers Squibb: Research Funding; Pfizer: Research Funding. Kebriaei:Novartis: Other: Served on advisory board; Pfizer: Other: Served on advisory board; Amgen: Other: Research Support; Ziopharm: Other: Research Support; Kite: Other: Served on advisory board; Jazz: Consultancy. O'Brien:Kite, Regeneron, Acerta: Research Funding; Gilead, Pharmacyclics, TG Therapeutics, Pfizer, Sunesis: Consultancy, Research Funding; Amgen, Astellas, Celgene, GlaxoSmithKline, Janssen Oncology, Aptose Biosciences Inc. Vaniam Group, AbbVie, Alexion, Verastem, Eisai, Juno Therapeutics, Vida Ventures: Consultancy. Kantarjian:Daiichi-Sankyo: Research Funding; Immunogen: Research Funding; Ariad: Research Funding; Novartis: Research Funding; BMS: Research Funding; Cyclacel: Research Funding; Agios: Honoraria, Research Funding; Jazz Pharma: Research Funding; Takeda: Honoraria; AbbVie: Honoraria, Research Funding; Actinium: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Research Funding; Astex: Research Funding; Pfizer: Honoraria, Research Funding. Jabbour:Pfizer: Other: Advisory role, Research Funding; Adaptive Biotechnologies: Other: Advisory role, Research Funding; BMS: Other: Advisory role, Research Funding; Genentech: Other: Advisory role, Research Funding; Takeda: Other: Advisory role, Research Funding; Amgen: Other: Advisory role, Research Funding; AbbVie: Other: Advisory role, Research Funding.

Background Unplanned 30-day readmissions are a frequent complication of acute myeloid leukemia (AML) therapy, with rates of 30-60% from published studies, including a 30% readmission rate (RaR) for induction and 40-50% RaR during consolidation. However, the data is still limited regarding predictors for readmissions. Methods We retrospectively reviewed hospitalizations for AML for adult patients >/= 18 years at our institution between January 2018 and December 2018. Unplanned readmissions were defined as any hospitalization within 30-days after discharge from the index admission, excluding all elective re-admissions for scheduled chemotherapy. Patients >/= 60 years of age receiving their initial induction therapy remained hospitalized for at least 21 days until bone marrow analysis and neutrophil count above 500/mm3. The primary objective was to identify the 30-day unplanned readmission rates, cause of readmissions, and predicted factors for readmissions. The secondary outcome included 30-day readmission mortality rate and inpatient mortality rate. Results There were a total of 1681 AML hospitalizations, 393 admissions for 273 pts (average 1.44 re-admit/pt) during frontline induction, 364 for 179 pts (average 2.03) during consolidation and 924 for 298 pts (average 3.1) with relapsed/refractory AML (R/R AML). The median age was 68 years for the frontline induction and consolidation groups and 60 years for R/R AML patients. Baseline characteristics are listed in Table 1. The median length of index admission was 21 days for induction, 4 days during consolidation, and 7 days for R/R AML. The 30-day unplanned RaR was 27% for induction, 30% for consolidation, and 46% for R/R AML, with a median time to readmission of 7 days, 11 days, and 7 days, respectively. The most common causes of readmissions were infections (80%, 75% and 75% during induction, consolidation and R/R AML respectively), including 39% neutropenic fever of unknown origin (NF), 13% pneumonia, and 8% bacteremia for induction; 24% NF, 20% pneumonia and 11% gastrointestinal infections during consolidation; and 18% NF, 20% pneumonia and 14% bacteremia for R/R AML. (Figure 1) The median length of readmission was 6 days for frontline pts and 8 days for R/R AML. The rate of ICU stay was 9% for induction, and 22% for consolidation, and 18% for R/R AML. (Figure 2). There was a significant increase of ICU stay for readmissions during consolidation (22% vs 5%, p=0.010) and R/R AML (18% vs 10% p= We confirmed hypoalbuminemia (OR 3.42; p= 0.006), thrombocytopenia (OR 2.10; p= 0.015) and history of diabetes (OR 1.93; p= 0.020) as an independent predictor for readmissions during induction by multivariate analysis, while history of diabetes was significantly associated with increased risk of readmission for consolidation (OR 1.69; p=0.04) and neutropenia (OR 1.32, p= The 30-day mortality rate and inpatient mortality rate was 6% for unplanned induction readmissions, 11% for consolidation, and 18% for R/R AML. With the exception of induction, there was a higher incidence of 30-mortality for unplanned re-admissions during consolidation and R/R AML. The most common causes of death after readmission were infections with 57% for induction, 70% for consolidation, and 73% for R/R AML pts. Conclusions Unplanned 30-day readmissions, most commonly due to infection, were common among patients with AML, with rates increasing with each sequential line of therapy. While the 30-day mortality and ICU admissions remain low for induction pts, those receiving consolidation or with R/R AML had significantly higher rates. We identified several factors, including hypoalbuminemia, thrombocytopenia, neutropenia and diabetes, as independent predictors for readmission. Implementing more frequent monitoring or trading increased length-of-stay for RaR in high-risk pts could help reduce mortality in AML. Disclosures Pemmaraju: Plexxikon: Research Funding; Incyte Corporation: Honoraria; Stemline Therapeutics: Honoraria, Research Funding; Cellectis: Research Funding; AbbVie: Honoraria, Research Funding; MustangBio: Honoraria; Celgene: Honoraria; Pacylex Pharmaceuticals: Consultancy; Affymetrix: Other: Grant Support, Research Funding; Samus Therapeutics: Research Funding; Daiichi Sankyo: Research Funding; DAVA Oncology: Honoraria; Roche Diagnostics: Honoraria; SagerStrong Foundation: Other: Grant Support; Blueprint Medicines: Honoraria; LFB Biotechnologies: Honoraria; Novartis: Honoraria, Research Funding. DiNardo:Takeda: Honoraria; Celgene: Consultancy, Honoraria, Research Funding; MedImmune: Honoraria; ImmuneOnc: Honoraria; AbbVie: Consultancy, Honoraria, Research Funding; Agios: Consultancy, Honoraria, Research Funding; Syros: Honoraria; Daiichi Sankyo: Consultancy, Honoraria, Research Funding; Jazz: Honoraria; Novartis: Consultancy; Calithera: Research Funding; Notable Labs: Membership on an entity's Board of Directors or advisory committees. Daver:Daiichi Sankyo: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol-Myers Squibb: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Karyopharm: Research Funding; Servier: Research Funding; Genentech: Research Funding; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Astellas: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novimmune: Research Funding; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Trovagene: Research Funding; Fate Therapeutics: Research Funding; ImmunoGen: Research Funding; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Jazz: Consultancy, Membership on an entity's Board of Directors or advisory committees; Trillium: Consultancy, Membership on an entity's Board of Directors or advisory committees; Syndax: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; KITE: Consultancy, Membership on an entity's Board of Directors or advisory committees; Agios: Consultancy, Membership on an entity's Board of Directors or advisory committees. Borthakur:Oncoceutics: Research Funding; Nkarta Therapeutics: Consultancy; Treadwell Therapeutics: Consultancy; BioTherix: Consultancy; Novartis: Research Funding; AstraZeneca: Research Funding; Incyte: Research Funding; Abbvie: Research Funding; Jannsen: Research Funding; GSK: Research Funding; Cyclacel: Research Funding; BioLine Rx: Research Funding; Polaris: Research Funding; Xbiotech USA: Research Funding; BioLine Rx: Consultancy; FTC Therapeutics: Consultancy; PTC Therapeutics: Research Funding; PTC Therapeutics: Consultancy; Argenx: Consultancy; Curio Science LLC: Consultancy; BMS: Research Funding. Cortes:Immunogen: Research Funding; Bristol-Myers Squibb: Research Funding; BiolineRx: Consultancy, Research Funding; Arog: Research Funding; Amphivena Therapeutics: Research Funding; Astellas: Research Funding; Telios: Research Funding; Pfizer: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Merus: Research Funding; Jazz Pharmaceuticals: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; Sun Pharma: Research Funding; BioPath Holdings: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Daiichi Sankyo: Consultancy, Research Funding. Ravandi:Amgen: Consultancy, Honoraria, Research Funding; Jazz Pharmaceuticals: Consultancy, Honoraria, Research Funding; Xencor: Consultancy, Honoraria, Research Funding; Macrogenics: Research Funding; Orsenix: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria, Research Funding; BMS: Consultancy, Honoraria, Research Funding; Astellas: Consultancy, Honoraria, Research Funding; AstraZeneca: Consultancy, Honoraria. Kantarjian:Astex: Research Funding; Daiichi-Sankyo: Research Funding; Immunogen: Research Funding; Cyclacel: Research Funding; Actinium: Honoraria, Membership on an entity's Board of Directors or advisory committees; Jazz Pharma: Research Funding; Novartis: Research Funding; Agios: Honoraria, Research Funding; Ariad: Research Funding; Amgen: Honoraria, Research Funding; Takeda: Honoraria; AbbVie: Honoraria, Research Funding; BMS: Research Funding; Pfizer: Honoraria, Research Funding. Garcia-Manero:Novartis: Research Funding; Helsinn Therapeutics: Consultancy, Honoraria, Research Funding; Acceleron Pharmaceuticals: Consultancy, Honoraria; Amphivena Therapeutics: Research Funding; H3 Biomedicine: Research Funding; Jazz Pharmaceuticals: Consultancy; Astex Pharmaceuticals: Consultancy, Honoraria, Research Funding; Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Honoraria, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Merck: Research Funding; Onconova: Research Funding; Celgene: Consultancy, Honoraria, Research Funding. Kadia:Ascentage: Research Funding; Astra Zeneca: Research Funding; Novartis: Honoraria; Amgen: Research Funding; Pulmotec: Research Funding; Astellas: Research Funding; Cyclacel: Research Funding; JAZZ: Honoraria, Research Funding; BMS: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding; Genentech: Honoraria, Research Funding; Abbvie: Honoraria, Research Funding; Incyte: Research Funding; Celgene: Research Funding; Cellenkos: Research Funding.

Context BL and HGBCL have a propensity for CNS involvement, which confers poor prognosis. Standard of care includes dose-intense chemoimmunotherapy (Hyper-CVAD or CODOX/MVAC with rituximab [R]). Despite favorable efficacy and tolerability of DA-EPOCH-R, outcomes are poor in patients with bone marrow (BM)/CNS disease with high rates of CNS relapse due to the lack of systemic directed CNS therapy (13%; Zayac ASH 2019). Objective To report the long-term outcomes with Hyper-CVAD-R in adults with BL and HGBCL. Main outcomes measured We evaluated complete remission (CR) rates, relapse- free survival (RFS), overall survival (OS), and cumulative incidence of relapse (CIR). Results Seventy-nine patients treated between 2000 and 2018 met WHO 2017 criteria (BL 54, HGBCL 25). Median age was 44 years (18–77 years); 25% were older than 60 years old. Most patients had high-risk disease; 73% BM involvement, 28% CNS involvement, and 63% had LDH > 3 times the normal level. Among the 25 patients with HGBCL, 7 (28%) had double-hit lymphomas (BCL-2 rearrangement), and the median international prognostic index was 3.5 (range 2–5). The CR rate was 91% (BL 96%; HGBCL 79%; P=0.16), and the 30-day mortality was 3%. The 5-year OS and RFS rates were 52% (BL 55%; HGBCL 44%; P=0.86) and 58% (BL 59%; HGBCL 57%; P=0.62), respectively. The CIR was 21% (BL 14%; HGBCL 37%, P=0.06); associated with BM involvement (27% vs 0%; P=0.02) and CNS involvement (42% vs 12%; P Conclusion Our data support the efficacy of Hyper-CVAD-R in preventing CNS relapse, especially among high-risk patients with BM or CNS involvement.

Patients with relapsed or refractory (R/R) T-cell acute lymphoblastic leukemia/lymphoma (T-ALL) have dismal outcomes. Preclinical studies have suggested that T-ALL cells are sensitive to BCL2 inhibition. The clinical activity of venetoclax, a selective BCL2 inhibitor, in T-ALL is unknown.We retrospectively reviewed the efficacy and safety of venetoclax combined with chemotherapy for patients with R/R T-ALL treated at our institution.Thirteen patients with R/R T-ALL with a median age of 46 years (range, 20-75 years) were treated with venetoclax plus chemotherapy. Five patients (38%) had early T-cell precursor ALL. The patients had received a median of 2 previous lines of therapy (range, 1-11). Venetoclax at a median dose of 200 mg/d for 21 days, generally with a concomitant azole antifungal, was combined with various agents, including hyper-CVAD (hyperfractionated cyclophosphamide, vincristine, doxorubicin, dexamethasone), asparaginase, nelarabine, decitabine, or other intensive chemotherapy. Of the 10 patients evaluable for bone marrow response, 6 (60%) achieved a remission with bone marrow blasts 5%, including 3 with complete hematologic recovery. The median overall survival and relapse-free survival were 7.7 and 4.0 months, respectively. No early death or clinically significant tumor lysis syndrome were reported. The median interval to neutrophil recovery and platelet recovery were 15 days and 44 days, respectively, with prolonged cytopenias observed with venetoclax 400 mg/d or when given for14 days per cycle.Combination therapy with venetoclax showed promising clinical efficacy in R/R T-ALL. Further studies are warranted to evaluate the clinical benefit of BCL2 inhibitors in T-ALL.

This article reviews the recent advances in the pathophysiology and management of acute lymphoblastic leukemia (ALL) in adults. Addition of rituximab to standard chemotherapy improves survival in the frontline treatment of B cell ALL, and measurable residual disease (MRD) is the most important prognostic factor. Tyrosine kinase inhibitors (TKI), particularly ponatinib, in combination with Hyper-CVAD significantly improve outcomes in Ph + ALL challenging the benefit of allogeneic stem cell transplant in first line for these patients. Blinatumomab, inotuzumab ozogamicin, and chimeric antigen receptor (CAR) T cells are better options than chemotherapy alone for the treatment of relapsed or refractory ALL. Combination of these agents with chemotherapy and their incorporation in the frontline setting show promises to improve cure rates of ALL. Development of monoclonal antibodies, CAR T, and potent TKI has improved the outcome of ALL. Advances in our understanding of ALL biology are expected to bring new therapeutic strategies in the upcoming years.

Background: In adults with B-ALL, multi-agent combination chemotherapy produce high complete remission (CR) rates of 80-90%, but a significant proportion of patients relapse and the long-term cure rate is 40-50%. Monoclonal antibodies have improved survival in B-ALL both in the frontline and relapsed/refractory (R/R) setting. Blinatumomab (Blina) is a bispecific T-cell engaging (BiTE) CD19-CD3 antibody effective in the treatment of R/R B-ALL and for eradication of measurable residual disease (MRD). Better outcomes are observed when Blina is administered earlier in the course of the disease. We hypothesized that early incorporation of Blina in sequential combination with the Hyper-CVAD regimen in newly diagnosed B-ALL would improve the rates of MRD eradication, decrease the need for intensive chemotherapy, and improve survival. Methods: This is a single-arm phase 2 clinical trial for patients (pts) ≥ 14 year-old with newly diagnosed B-ALL. Untreated pts or pts who had received ≤ 1 course of chemotherapy with PS of 0-3 and normal organ function are eligible. The treatment protocol consists of 4 alternating cycles of Hyper-CVAD and high-dose methotrexate (MTX) / cytarabine (AraC) followed by 4 consecutive cycles of Blina. Pts with CD20+ B-ALL (≥ 1% cells) receive 8 doses of rituximab (375 mg/m2) or ofatumumab (2000 mg); all pts receive 8 prophylactic intrathecal injections of MTX and AraC during the Hyper-CVAD cycles. The maintenance phase consists of 12 cycles of POMP. Blina is administered as a maintenance in all pts after every 3 cycles of POMP for 3 cycles. Allogeneic hematopoietic stem cell transplant (HSCT) is offered for high-risk pts. On June 5th 2017 after treating 10 patients, the protocol was amended: pts with high-risk features (i.e. Ph-like ALL, complex karyotype, t(4;11), low-hypodiploidy / near triploidy [Ho-Tr] or persistent MRD+) start Blina earlier after 2 cycles of Hyper-CVAD. The primary outcome is relapse-free survival (RFS) and secondary outcomes include CR rates, MRD negativity (MRD-) rates and overall survival (OS). MRD is assessed by 6-color multiparameter flow cytometry with a sensitivity of 10-4. Safety is evaluated by frequency and grading of adverse events according to the CTCAE v4.0. Results: As of July 3rd 2019, 27 pts were enrolled and treated, including 5 pts who were already in CR at study entry. The baseline characteristics of the pts are summarized in Table 1. The median age was 38 years (range, 18-59). Twenty (74%) pts had CD20+ expression. Fifteen (56%) pts had high-risk features at baseline: 9 (33%) with TP53 mutation, 4 (15%) with Ph-like, 5 (19%) with Ho-Tr, 1 (4%) with t(4;11) and 1 (4%) with complex karyotype. The overall CR rate was 100% with 18/22 (82%) achieved CR after 1 cycle of Hyper-CVAD. The median time to CR was 23 days (range, 16-100). MRD negativity was achieved in 26/27 (96%) pts, of them 16/22 (73%) pts after 1 cycle of Hyper-CVAD. The only patient who did not achieve MRD- has not received Blina on protocol because of relapse after 4 cycles of Hyper-CVAD. Pts have received a median of 3 cycles (range, 2-4) of Hyper-CVAD and 2 cycles (range, 0-4) of Blina. Eight (30%) pts have undergone HSCT for high-risk features. With a median follow-up of 17 months (range, 2-30), 4 relapses and 2 deaths were reported. One patient died from pulmonary complications after HSCT and one patient died of sepsis during re-induction chemotherapy after relapse. The 12-month estimated RFS was 76% (95% CI, 60-97%) (Figure 1) and the 12-month estimated OS was 89% (95% CI, 76-100%) (Figure 2). The 60-day mortality rate was 0% and no death has been reported during Hyper-CVAD + Blina treatment. Grade 3-4 neurological adverse events related to Blina were reported in 4/23 (17%) pts and one grade 3 cytokine release syndrome was reported. These events were all manageable and reversible with dexamethasone and Blina interruption. Treatment has been resumed without recurrence in all but one patient with recurring grade 2 dysphasia and confusion who required discontinuation of Blina therapy. Reduction in the number of Hyper-CVAD cycles allowed to decrease the incidence of myelosuppression and febrile neutropenia. Conclusion: The sequential combination of Hyper-CVAD and Blina in newly diagnosed B-ALL is safe and highly effective. This regimen produced CR in all pts and MRD eradication in 96% of pts. The preliminary survival outcomes are favorable. The study continues to accrue patients. Disclosures Kantarjian: Pfizer: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Novartis: Research Funding; Ariad: Research Funding; Daiichi-Sankyo: Research Funding; Takeda: Honoraria; Agios: Honoraria, Research Funding; Astex: Research Funding; Cyclacel: Research Funding; BMS: Research Funding; Actinium: Honoraria, Membership on an entity's Board of Directors or advisory committees; Immunogen: Research Funding; Jazz Pharma: Research Funding; AbbVie: Honoraria, Research Funding. Short:Takeda Oncology: Consultancy, Research Funding; AstraZeneca: Consultancy; Amgen: Honoraria. Ravandi:Macrogenix: Consultancy, Research Funding; Selvita: Research Funding; Cyclacel LTD: Research Funding; Menarini Ricerche: Research Funding; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Xencor: Consultancy, Research Funding. Garcia-Manero:Astex: Consultancy, Research Funding; Onconova: Research Funding; H3 Biomedicine: Research Funding; Merck: Research Funding; Amphivena: Consultancy, Research Funding; Helsinn: Research Funding; Novartis: Research Funding; AbbVie: Research Funding; Celgene: Consultancy, Research Funding. Cortes:Merus: Consultancy, Honoraria, Research Funding; Astellas Pharma: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria, Research Funding; Forma Therapeutics: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Research Funding; Biopath Holdings: Consultancy, Honoraria; Immunogen: Consultancy, Honoraria, Research Funding; Sun Pharma: Research Funding; Jazz Pharmaceuticals: Consultancy, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; BiolineRx: Consultancy; Daiichi Sankyo: Consultancy, Honoraria, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding. Jain:AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Adaptive Biotechnologies: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Precision Biosciences: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Verastem: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Cellectis: Research Funding; Servier: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; AstraZeneca: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Incyte: Research Funding; ADC Therapeutics: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Research Funding; Genentech: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen Pharmaceuticals, Inc.: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Pharmacyclics, an AbbVie company: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Konopleva:Eli Lilly: Research Funding; AbbVie: Consultancy, Honoraria, Research Funding; Cellectis: Research Funding; Amgen: Consultancy, Honoraria; F. Hoffman La-Roche: Consultancy, Honoraria, Research Funding; Genentech: Honoraria, Research Funding; Ascentage: Research Funding; Kisoji: Consultancy, Honoraria; Reata Pharmaceuticals: Equity Ownership, Patents & Royalties; Ablynx: Research Funding; Astra Zeneca: Research Funding; Agios: Research Funding; Forty-Seven: Consultancy, Honoraria; Stemline Therapeutics: Consultancy, Honoraria, Research Funding; Calithera: Research Funding. Takahashi:Symbio Pharmaceuticals: Consultancy. Sasaki:Otsuka: Honoraria; Pfizer: Consultancy. Wierda:Genentech: Research Funding; GSK/Novartis: Research Funding; Pharmacyclics LLC: Research Funding; Acerta Pharma Inc: Research Funding; Gilead Sciences: Research Funding; Oncternal Therapeutics Inc.: Research Funding; AbbVie: Research Funding; Miragen: Research Funding; Xencor: Research Funding; Juno Therapeutics: Research Funding; Janssen: Research Funding; Loxo Oncology Inc.: Research Funding; KITE pharma: Research Funding; Sunesis: Research Funding; Cyclcel: Research Funding. Jabbour:Adaptive: Consultancy, Research Funding; AbbVie: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Cyclacel LTD: Research Funding; Takeda: Consultancy, Research Funding; BMS: Consultancy, Research Funding. OffLabel Disclosure: Blinatumomab is not approved for the treatment of newly diagnosed untreated acute lymphoblastic leukemia.

Background: Isocitrate dehydrogenase 2 (IDH2) mutations occur in 5-10% of patients (pts) with myelodysplastic syndrome (MDS) and are frequently associated with intermediate-risk cytogenetics, excess bone marrow blasts, neutropenia and sustained platelets. Enasidenib (ENA) is a selective oral inhibitor of the mutant IDH2 enzyme with single-agent activity in relapsed/refractory acute myeloid leukemia (AML). This study was designed to evaluate the efficacy and tolerability of ENA alone and in combination with azacitidine (AZA) in pts with high-risk IDH2-mutated MDS. Methods: This is a multicenter Phase II trial for pts with IDH2-mutated MDS, AML with 20-30% marrow blasts, or chronic myelomonocytic leukemia. The study includes two cohorts: HMA-naïve pts with high-risk MDS (IPSS int-2 or high-risk; IPSS-R high-risk or very high risk; or high-risk molecular features including TP53, ASXL1, EZH2 and/or RUNX1 mutations) (Arm A) receive AZA + ENA; pts relapsed/refractory with prior HMA therapy (Arm B) receive ENA alone. All pts receive ENA at a dose of 100 mg orally daily, on days 1-28 of each 28-day cycle. In Arm A, ENA is given in combination with AZA 75 mg/m2 IV or SC on days 1-7 of each cycle. The primary efficacy endpoint is overall response rate (ORR), including complete remission (CR), marrow CR (mCR), partial remission (PR) and hematologic improvement (HI) based on the Modified International Working group (IWG) Response Criteria for MDS. The primary safety endpoint is the incidence and severity of adverse events using the Common Toxicity Criteria for Adverse Events v4.0. Results: Using a pre-specified data cutoff of July 1st 2019, 25 pts have been enrolled with a median follow-up of 6.4 months (range, 2.4 - 17.1); 10 HMA-naïve pts (Arm A) and 15 HMA-failure pts (Arm B). The median age was 71 years (range, 46-83) (Table 1). Sixteen pts (64%) had neutropenia (absolute neutrophil count < 1.0 x 109/L) and 20 pts (80%) had anemia (hemoglobin < 11 g/dL), including 12 (48%) red blood cell (RBC) transfusion-dependent (TD) pts at baseline. Seventeen pts (68%) had high or very high risk IPSS-R. Nineteen pts (76%) had diploid or +8 cytogenetics, and 5 pts (20%) had -7 or complex karyotype. High-risk co-occurring mutations included ASXL1 (46%), RUNX1 (17%), EZH2 (8%) and TP53 (8%). Among 18 evaluable pts (7 too early for response assessment), the ORR was 67% (12/18) (Table 2). In HMA-naïve pts, 6/6 (100%) responded to therapy, including 2 CRs and 4 mCRs (1 with HI for neutrophils [HI-N]). In HMA-failure pts, 6/12 (50%) responded, including 2 CRs, 1 PR, 1 mCR (with HI-N) and 2 with stable disease with HI (1 with HI-N, 1 with HI erythroid). Interestingly, 3 pts who achieved CR also had clearance of the IDH2 mutation (1 in Arm A; 2 in Arm B). Two of 5 pts (40%) and 3/7 pts (43%) with neutropenia at baseline achieved HI-N in Arm A and B, respectively. Median time to first and best response were both 1.3 months (range, 0.9-2.1) in Arm A and 1.8 months (range, 0.9-3.7) and 2.7 months (0.9-4.6), respectively in Arm B. Among evaluable pts with RBC TD at baseline, 0/2 pt and 3/8 (38%) pts achieved transfusion independence, in Arm A and B, respectively. At last follow-up, 16 pts remain on treatment (7 with ongoing response) and 9 pts stopped treatment: 4 due to progression, 1 pt decision, 1 underwent allogeneic transplant and 3 responding pts with mCR died from pneumonia or other infectious complications while on study (Figure 1). Adverse events (AEs) of any grade were reported in 17/25 pts (68%) and grade 3-4 AEs were reported in 11/25 pts (44%). Most AEs were manageable without dose interruption. The most common non-hematological AEs were unconjugated hyperbilirubinemia (39%), nausea (33%), fatigue (33%), pneumonia (22%) and diarrhea (17%). Possible differentiation syndrome (DS) was reported in 3 pts on days 31, 38 and 42 of treatment; 2 pts received dexamethasone with resolution, and 1 pt required hydrea and was ultimately determined to have progression to AML. Four pts developed leukocytosis (white blood cell count of 15.3, 28.3, 35.7, 56.6 x 109/L), with 3 at the time of possible DS and 1 at day 119 considered unrelated to DS. Conclusion: Enasidenib is well tolerated and shows promising efficacy in IDH2-mutated high-risk MDS. The ORR was 67%, including 100% in newly diagnosed pts receiving the combination of azacitidine plus enasidenib and 50% ORR in HMA-failure pts receiving enasidenib alone. The study continues to accrue and updated results will be presented at ASH. Disclosures DeZern: Celgene: Consultancy; Astex Pharmaceuticals, Inc.: Consultancy. Takahashi:Symbio Pharmaceuticals: Consultancy. Konopleva:Astra Zeneca: Research Funding; Calithera: Research Funding; Ablynx: Research Funding; Reata Pharmaceuticals: Equity Ownership, Patents & Royalties; Kisoji: Consultancy, Honoraria; Stemline Therapeutics: Consultancy, Honoraria, Research Funding; Ascentage: Research Funding; Genentech: Honoraria, Research Funding; F. Hoffman La-Roche: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria; Forty-Seven: Consultancy, Honoraria; Eli Lilly: Research Funding; AbbVie: Consultancy, Honoraria, Research Funding; Cellectis: Research Funding; Agios: Research Funding. Loghavi:MDACC: Employment; GLG Consultants: Consultancy; AlphaSights: Consultancy. Alvarado:Jazz Pharmaceuticals: Research Funding; Abbott: Honoraria. Ravandi:Selvita: Research Funding; Xencor: Consultancy, Research Funding; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Cyclacel LTD: Research Funding; Macrogenix: Consultancy, Research Funding; Menarini Ricerche: Research Funding. Sasaki:Otsuka: Honoraria; Pfizer: Consultancy. Sekeres:Celgene: Membership on an entity's Board of Directors or advisory committees; Syros: Membership on an entity's Board of Directors or advisory committees; Millenium: Membership on an entity's Board of Directors or advisory committees. Nazha:Abbvie: Consultancy; Incyte: Speakers Bureau; Daiichi Sankyo: Consultancy; MEI: Other: Data monitoring Committee; Novartis: Speakers Bureau; Jazz Pharmacutical: Research Funding; Tolero, Karyopharma: Honoraria. Roboz:Trovagene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Actinium: Consultancy, Membership on an entity's Board of Directors or advisory committees; Agios: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amphivena: Consultancy, Membership on an entity's Board of Directors or advisory committees; Argenx: Consultancy, Membership on an entity's Board of Directors or advisory committees; Astex: Consultancy, Membership on an entity's Board of Directors or advisory committees; Astellas: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bayer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celltrion: Consultancy, Membership on an entity's Board of Directors or advisory committees; Daiichi Sankyo: Consultancy, Membership on an entity's Board of Directors or advisory committees; Eisai: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Jazz: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; MEI Pharma: 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; Otsuka: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Roche/Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees; Sandoz: Consultancy, Membership on an entity's Board of Directors or advisory committees. Kantarjian:Immunogen: Research Funding; Cyclacel: Research Funding; Actinium: Honoraria, Membership on an entity's Board of Directors or advisory committees; AbbVie: Honoraria, Research Funding; Jazz Pharma: Research Funding; Astex: Research Funding; Ariad: Research Funding; Amgen: Honoraria, Research Funding; BMS: Research Funding; Takeda: Honoraria; Agios: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding; Novartis: Research Funding; Daiichi-Sankyo: Research Funding. Garcia-Manero:Amphivena: Consultancy, Research Funding; Helsinn: Research Funding; Novartis: Research Funding; AbbVie: Research Funding; Celgene: Consultancy, Research Funding; Astex: Consultancy, Research Funding; Onconova: Research Funding; H3 Biomedicine: Research Funding; Merck: Research Funding. DiNardo:medimmune: Honoraria; abbvie: Consultancy, Honoraria; jazz: Honoraria; syros: Honoraria; notable labs: Membership on an entity's Board of Directors or advisory committees; agios: Consultancy, Honoraria; celgene: Consultancy, Honoraria; daiichi sankyo: Honoraria. OffLabel Disclosure: Enasidenib is not approved for the treatment of myelodysplastic syndrome

Background: Cytogenetic abnormalities have prognostic implications in acute lymphoblastic leukemia (ALL). High risk cytogenetics include complex karyotype (≥ 5 anomalies), low-hypodiploidy / near-triploidy, 14q32/IGH rearrangements and 11q23/KMT2A rearrangements. The most frequent gene partner involved in KMT2A-rearranged ALL is AFF1 located on chromosome 4q21. ALL with t(4;11)(q21;q23) - KMT2A-AFF1 has a very poor outcome and patients (pts) with this translocation are offered allogeneic stem cell transplantation (HSCT) in first complete remission (CR1). More than 130 gene partners have been described in KMT2A rearrangements. The frequency and prognostic signification of these various gene partners in KMT2A-rearranged ALL is unknown and it is uncertain whether pts harboring these translocations should be offered HSCT in CR1. Methods: We retrospectively reviewed 1102 pts with newly diagnosed ALL treated at our institution between 1984 and 2019 to identify pts with KMT2A rearrangement. Presence of t(11;v)(q23;v) was assessed by conventional cytogenetics with G-banding and/or by fluorescence in situ hybridization (FISH). Clinical and laboratory data were collected retrospectively. We analyzed the pts characteristics at baseline and evaluated remission rates, overall survival (OS) and relapse-free survival (RFS). The survival curves were estimated using the Kaplan-Meier method and differences between groups were evaluated with the log-rank test. Univariate Cox proportional hazard ratio were used for estimation of hazard ratios (HR). HSCT in CR1 was considered as a time-dependent covariate. Results: We identified 51 cases (5%) of ALL with KMT2A rearrangement or amplification. Two cases (4%) were cryptic KMT2A rearrangements identified by FISH, but with a normal karyotype. The most common KMT2A rearrangement was t(4;11)(q21;q23) in 42/51 (82%) pts. Four (8%) pts had t(11;19)(q23;p13) in which KMT2A can be partnered with MLLT1 or ELL, 1 (2%) pt had t(9;11)(p21;q23) - KMT2A-MLLT3, 1 (2%) pt had t(11;15)(q32;q26) with unknown gene partner, 1 (2%) pt had hsr(11)(q23) with KMT2A amplification, and 2 (4%) pts had an unknown gene partner (identification by FISH). Sixteen (31%) pts had additional chromosomal abnormalities, with i(7q) (3/51, 6%) and + X (2/51, 4%) the only identified in more than one case. The pts' clinical characteristics are summarized in table 1. All but one were B-cell ALL. The median age at diagnosis was 45 year-old (range, 18 - 78). The median white blood cell count (WBC) at diagnosis was 107.0 x 109/L (range, 0.5 - 1573.0) and 29/51 (57%) pts had hyperleukocytosis with WBC ≥ 100 x 109/L. None of the cases of B-ALL had CD20 expression, but 32/41 (78%) had CD22 expression (median of 59%; range 0 - 99%). Pts were treated with various regimens, with most pts receiving the Hyper-CVAD regimen (n=35), or one of its variation including addition of anti-CD20 monoclonal antibody (n=2), blinatumomab (n=1), nelarabine for T-cell ALL (n = 1) or dose adjusted regimen with omission of doxorubicin (mini-Hyper-CVD, n = 4). The complete remission rate was 88% (45/51) with 5 (10%) deaths during induction and 1 (2%) refractory disease. The measurable residual disease (MRD) negativity rate was 57% (17/30 evaluable pts). With a median follow-up of 63 months, the median OS and RFS were 14 months (95% confidence interval [CI], 10 - 39] and 10 months (95% CI, 6 - 17), respectively. The 5-year OS and RFS rates were 17% (95% CI, 9 - 35%) and 15% (95% CI, 7 - 33%), respectively. Comparing the 42 pts with t(4;11) and the 9 pts with other KMT2A abnormalities, no difference in OS (HR 0.94, p = 0.89) and RFS (HR 1.00, p = 0.99) were observed (Figure 1A-1B). HSCT in CR1 was associated with a better outcome in terms of OS (HR 0.49, 95% CI 0.24 - 0.99, p = 0.049) and RFS (HR 0.44, 95% CI 0.22 - 0.92). In the 17 (33%) pts who underwent HSCT in CR1 (16 with t(4;11) and 1 with other KMT2A rearrangement), the 5-year OS and RFS rates were 30% (95% CI, 14 - 68%) and 24% (95% CI, 9 - 62%), respectively, versus 10% (95% CI, 3 - 35%) and 9% (95% CI, 3 - 34%), respectively, in the 34 (67%) pts who did not undergo HSCT. The only 2 pts with KMT2A rearrangements other than t(4;11) who remain alive are the only 2 who have undergone HSCT: 1 in CR1 and 1 in CR2. Conclusion: Patients with KMT2A-rearranged ALL have a poor prognosis, which do not differ based on the gene partner involved. These patients benefit from HSCT in CR1. Disclosures Kantarjian: BMS: Research Funding; Astex: Research Funding; Pfizer: Honoraria, Research Funding; Ariad: Research Funding; Agios: Honoraria, Research Funding; AbbVie: Honoraria, Research Funding; Immunogen: Research Funding; Jazz Pharma: Research Funding; Actinium: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Research Funding; Cyclacel: Research Funding; Novartis: Research Funding; Daiichi-Sankyo: Research Funding; Takeda: Honoraria. Khoury:Kiromic: Research Funding; Angle: Research Funding; Stemline Therapeutics: Research Funding. Jain:Incyte: Research Funding; Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; ADC Therapeutics: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Adaptive Biotechnologies: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Precision Biosciences: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; AstraZeneca: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Cellectis: Research Funding; Verastem: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Servier: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen Pharmaceuticals, Inc.: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Research Funding; Genentech: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pharmacyclics, an AbbVie company: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Ravandi:Xencor: Consultancy, Research Funding; Macrogenix: Consultancy, Research Funding; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Menarini Ricerche: Research Funding; Selvita: Research Funding; Cyclacel LTD: Research Funding. Short:Takeda Oncology: Consultancy, Research Funding; Amgen: Honoraria; AstraZeneca: Consultancy. DiNardo:medimmune: Honoraria; notable labs: Membership on an entity's Board of Directors or advisory committees; jazz: Honoraria; daiichi sankyo: Honoraria; celgene: Consultancy, Honoraria; agios: Consultancy, Honoraria; abbvie: Consultancy, Honoraria; syros: Honoraria. Takahashi:Symbio Pharmaceuticals: Consultancy. Borthakur:Xbiotech USA: Research Funding; Eisai: Research Funding; AstraZeneca: Research Funding; Cantargia AB: Research Funding; BioTheryX: Membership on an entity's Board of Directors or advisory committees; BMS: Research Funding; Eli Lilly and Co.: Research Funding; Oncoceutics, Inc.: Research Funding; PTC Therapeutics: Consultancy; NKarta: Consultancy; BioLine Rx: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Cyclacel: Research Funding; GSK: Research Funding; Janssen: Research Funding; Incyte: Research Funding; AbbVie: Research Funding; Merck: Research Funding; Tetralogic Pharmaceuticals: Research Funding; Strategia Therapeutics: Research Funding; Polaris: Research Funding; Argenx: Membership on an entity's Board of Directors or advisory committees; Arvinas: Research Funding; FTC Therapeutics: Membership on an entity's Board of Directors or advisory committees; Bayer Healthcare AG: Research Funding; Agensys: Research Funding; Oncoceutics: Research Funding; Novartis: Research Funding. Konopleva:Ablynx: Research Funding; Reata Pharmaceuticals: Equity Ownership, Patents & Royalties; Agios: Research Funding; Astra Zeneca: Research Funding; Kisoji: Consultancy, Honoraria; Ascentage: Research Funding; Genentech: Honoraria, Research Funding; F. Hoffman La-Roche: Consultancy, Honoraria, Research Funding; Calithera: Research Funding; Amgen: Consultancy, Honoraria; Cellectis: Research Funding; AbbVie: Consultancy, Honoraria, Research Funding; Stemline Therapeutics: Consultancy, Honoraria, Research Funding; Eli Lilly: Research Funding; Forty-Seven: Consultancy, Honoraria. Alvarado:Jazz Pharmaceuticals: Research Funding; Abbott: Honoraria. Kadia:Takeda: Membership on an entity's Board of Directors or advisory committees; Genentech: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees, Research Funding; Jazz: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Research Funding; Bioline RX: Research Funding; BMS: Research Funding; Amgen: Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Consultancy, Research Funding; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees. Garcia-Manero:H3 Biomedicine: Research Funding; Astex: Consultancy, Research Funding; Onconova: Research Funding; Amphivena: Consultancy, Research Funding; Helsinn: Research Funding; Novartis: Research Funding; AbbVie: Research Funding; Celgene: Consultancy, Research Funding; Merck: Research Funding. Verstovsek:Incyte: Research Funding; Roche: Research Funding; NS Pharma: Research Funding; Celgene: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Blueprint Medicines Corp: Research Funding; Genetech: Research Funding; CTI BioPharma Corp: Research Funding; Promedior: Research Funding; Gilead: Research Funding; Pragmatist: Consultancy; Constellation: Consultancy; Protaganist Therapeutics: Research Funding; Sierra Oncology: Research Funding; Pharma Essentia: Research Funding; Astrazeneca: Research Funding; Ital Pharma: Research Funding. Cortes:Bristol-Myers Squibb: Consultancy, Research Funding; Sun Pharma: Research Funding; Biopath Holdings: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Research Funding; Forma Therapeutics: Consultancy, Honoraria, Research Funding; BiolineRx: Consultancy; Takeda: Consultancy, Research Funding; Daiichi Sankyo: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria, Research Funding; Astellas Pharma: Consultancy, Honoraria, Research Funding; Jazz Pharmaceuticals: Consultancy, Research Funding; Merus: Consultancy, Honoraria, Research Funding; Immunogen: Consultancy, Honoraria, Research Funding. Jabbour:AbbVie: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; Adaptive: Consultancy, Research Funding; Cyclacel LTD: Research Funding; Pfizer: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Takeda: Consultancy, Research Funding.

Background: The Hyper-CVAD regimen is safe and effective in the frontline treatment of B-ALL. The addition of rituximab to the Hyper-CVAD regimen (HCVAD-R) improved the 3-year overall survival (OS) to 60% in pts with B-ALL. Ofatumumab is an anti-CD20 monoclonal antibody that binds to the small extracellular loop of the CD20 molecule and has greater in vitro potency and increased complement-mediated cell lysis compared to rituximab. We hypothesized that ofatumumab plus Hyper-CVAD may increase the rates of complete remission (CR) and measurable residual disease negativity (MRD-) and improve survival by decreasing relapse rates. Methods: Pts were eligible if they had newly diagnosed untreated or minimally treated (≤ 1 cycle) Philadelphia chromosome (Ph)-negative CD20+ B-ALL. CD20 positivity was defined as ≥ 1% positive B-ALL cells. Pts received 8 alternating cycles of Hyper-CVAD and high-dose methotrexate/cytarabine (MTX/AraC). Ofatumumab was administered on days 1 and 11 of cycles 1 and 3; and days 1 and 8 of cycles 2 and 4. Pts then received POMP maintenance on cycles 1-5, 8-17 and 20-30 and late intensifications on cycles 6-7 and 18-19 (Hyper-CVAD + ofatumumab followed by MTX + peg-asparaginase). Pts received a total of 8 intrathecal injections of MTX and AraC for CNS prophylaxis. The primary endpoint was relapse-free survival (RFS) and secondary endpoints include CR rates, MRD negativity rates and OS. On a subset of 27 patient samples, transcriptome sequencing (RNA-seq) was performed to identify translocations and RNA expression signature for Ph-like ALL. We also performed a comprehensive detection of fusions and mutations reported in Ph-like ALL on RNA from these 27 samples using a multiplex fusion and mutation detection assay (Archer® FusionPlex® ALL). Results: Between August 2011 and May 2017, 69 pts were enrolled, including 4 already in CR at baseline after receiving 1 cycle of chemotherapy. Pts characteristics are summarized in Table 1. The median age was 41 years (18-71) and 48% pts were in the adolescent and young adult (AYA) age category (18-39 year-old). 7 of the 27 pts (26%) who had RNA-seq had Ph-like ALL gene expression signature. Among the 7 pts; 5 had Ph-like ALL fusions identified by Archer and/or RNA-seq-based fusion detection, including 2 P2RY8-CRLF2, 1 IGH-CRLF2, 1 BCR-FGFR1, and 1 ATF71P-PDGFRB. One patient had high CRLF2 expression with an unknown fusion partner. The remaining case lacked a fusion by either platform. Pts with Ph-like ALL had a higher median WBC of 41 x 109/L (range, 2 - 184). 43 pts (62%) had CD20 expression on ≥20% of the leukemic cells. 10/44 tested pts (23%) had TP53 mutation and 10/37 (27%) had CRLF2 overexpression by flow cytometry (4/5 CRLF2 rearrangement confirmed by Archer). 4 pts (6%) had low-hypodiploidy / near triploidy (Ho-Tr) and 2 (3%) pts had complex karyotype (CK). All but 1 pt (98%) achieved CR (2 after 2 cycles); only 1 pt (2%) died during induction. The MRD- rate was 65% after cycle 1 and 93% overall. These rates were 14% and 71%, respectively for pts with Ph-like ALL. The median time to MRD- was 0.7 month (range, 0.4-8 months) overall and 3 months (range, 0.7-6.5 months) for pts with Ph-like ALL. A total of 13 pts (19%) underwent allogeneic stem cell transplantation for adverse-risk cytogenetics (CK or Ho-Tr), Ph-like ALL (n=1/7), or persistent MRD+. The most common non-hematologic grade 3-4 toxicity was infection which occurred in 56% and 81% of pts, during induction and consolidation, respectively. With a median follow-up of 44 months, 46 pts (64%) are alive, including 37 pts (54%) in CR1. The median RFS and OS were 52 months (95% CI, 43 - NR) and not reached (95% CI, 65 - NR), respectively. The estimated 4-yr RFS and OS rates were 60% (95% CI, 49 - 73%) and 68% (95% CI, 58 - 81%), respectively (Figure 1A-1B). For AYA pts, the 4-yr OS rate was 74% (95% CI, 60 - 91%) (Figure 2A). The 4-yr OS rates were 54% (95%, 26 - 100%) for pts with Ph-like ALL compared to 74% (95% CI, 57 - 97%) for pts without Ph-like ALL (Figure 2B). There was no difference in OS according to the CD20 expression level (20% cut-off; p = 0.31). Using historical control pts, there was a trend towards improved OS with HCVAD-O versus HCVAD-R for pts with CD20 ≥ 20% (4-yr OS rate 63% vs 49%, p = 0.16) and HCVAD-O versus HCVAD alone for pts with CD20 1-19% (4-yr OS rate 73% vs 62%, p = 0.46). Conclusion: HCVAD-O is a safe and highly effective regimen in pts with CD20+ Ph-negative B-ALL. This regimen achieves excellent outcomes in the AYA population. Disclosures Kantarjian: BMS: Research Funding; AbbVie: Honoraria, Research Funding; Takeda: Honoraria; Daiichi-Sankyo: Research Funding; Amgen: Honoraria, Research Funding; Jazz Pharma: Research Funding; Immunogen: Research Funding; Cyclacel: Research Funding; Pfizer: Honoraria, Research Funding; Ariad: Research Funding; Astex: Research Funding; Novartis: Research Funding; Agios: Honoraria, Research Funding; Actinium: Honoraria, Membership on an entity's Board of Directors or advisory committees. Konopleva:Agios: Research Funding; AbbVie: Consultancy, Honoraria, Research Funding; Astra Zeneca: Research Funding; Ablynx: Research Funding; Calithera: Research Funding; Kisoji: Consultancy, Honoraria; Cellectis: Research Funding; Amgen: Consultancy, Honoraria; Ascentage: Research Funding; Genentech: Honoraria, Research Funding; F. Hoffman La-Roche: Consultancy, Honoraria, Research Funding; Reata Pharmaceuticals: Equity Ownership, Patents & Royalties; Stemline Therapeutics: Consultancy, Honoraria, Research Funding; Eli Lilly: Research Funding; Forty-Seven: Consultancy, Honoraria. Ravandi:Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Cyclacel LTD: Research Funding; Menarini Ricerche: Research Funding; Xencor: Consultancy, Research Funding; Macrogenix: Consultancy, Research Funding; Selvita: Research Funding. Jain:AstraZeneca: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Servier: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Cellectis: Research Funding; Verastem: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Precision Biosciences: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Adaptive Biotechnologies: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pharmacyclics, an AbbVie company: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen Pharmaceuticals, Inc.: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Incyte: Research Funding; ADC Therapeutics: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Research Funding; Genentech: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Short:AstraZeneca: Consultancy; Amgen: Honoraria; Takeda Oncology: Consultancy, Research Funding. Garcia-Manero:Amphivena: Consultancy, Research Funding; Helsinn: Research Funding; Novartis: Research Funding; AbbVie: Research Funding; Celgene: Consultancy, Research Funding; Astex: Consultancy, Research Funding; Onconova: Research Funding; H3 Biomedicine: Research Funding; Merck: Research Funding. Cortes:Daiichi Sankyo: Consultancy, Honoraria, Research Funding; Merus: Consultancy, Honoraria, Research Funding; Biopath Holdings: Consultancy, Honoraria; Immunogen: Consultancy, Honoraria, Research Funding; Forma Therapeutics: Consultancy, Honoraria, Research Funding; Sun Pharma: Research Funding; Jazz Pharmaceuticals: Consultancy, Research Funding; Astellas Pharma: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; BiolineRx: Consultancy. Sasaki:Otsuka: Honoraria; Pfizer: Consultancy. Kadia:Celgene: Research Funding; Bioline RX: Research Funding; BMS: Research Funding; Jazz: Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Membership on an entity's Board of Directors or advisory committees, Research Funding; Genentech: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy, Research Funding. DiNardo:celgene: Consultancy, Honoraria; medimmune: Honoraria; abbvie: Consultancy, Honoraria; jazz: Honoraria; syros: Honoraria; agios: Consultancy, Honoraria; daiichi sankyo: Honoraria; notable labs: Membership on an entity's Board of Directors or advisory committees. Verstovsek:Astrazeneca: Research Funding; Ital Pharma: Research Funding; Protaganist Therapeutics: Research Funding; Constellation: Consultancy; Pragmatist: Consultancy; Incyte: Research Funding; Roche: Research Funding; NS Pharma: Research Funding; Celgene: Consultancy, Research Funding; Gilead: Research Funding; Promedior: Research Funding; CTI BioPharma Corp: Research Funding; Genetech: Research Funding; Blueprint Medicines Corp: Research Funding; Novartis: Consultancy, Research Funding; Sierra Oncology: Research Funding; Pharma Essentia: Research Funding. Mullighan:Loxo Oncology: Research Funding; AbbVie: Research Funding; Pfizer: Honoraria, Other: speaker, sponsored travel, Research Funding; Illumina: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: sponsored travel; Amgen: Honoraria, Other: speaker, sponsored travel. O'Brien:AbbVie: Consultancy, Honoraria; Acerta: Research Funding; Alexion: Consultancy; Amgen: Consultancy; Astellas: Consultancy; Aptose Biosciences, Inc: Consultancy; Celgene: Consultancy; Kite: Research Funding; GlaxoSmithKline: Consultancy; Eisai: Consultancy; Gilead: Consultancy, Research Funding; Janssen: Consultancy, Honoraria; Pharmacyclics LLC, an AbbVie Company: Consultancy, Research Funding; TG Therapeutics: Consultancy, Research Funding; Sunesis: Consultancy, Research Funding; Regeneron: Research Funding; Vaniam Group LLC: Consultancy; Verastem: Consultancy; Pfizer: Consultancy, Honoraria, Research Funding. Jabbour:Takeda: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Adaptive: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; AbbVie: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Cyclacel LTD: Research Funding. OffLabel Disclosure: Ofatumumab is not approved by the FDA for treatment of B-cell acute lymphoblastic leukemia.

INTRODUCTION: Myelodysplastic syndromes (MDS) are characterized by ineffective hematopoiesis and cytopenias due to uncontrolled programmed cell death. The presence of pro-inflammatory cytokines and constitutive activation of innate immunity signals in MDS cells suggest inflammatory cell death, such as necroptosis, may be responsible for disease phenotype. There is no data evaluating the association of RIPK1, RIPK3 and MLKL with response and prognosis in MDS. METHODS: We evaluated 64 bone marrow samples from 55 patients with MDS or chronic myelomonocytic leukemia (CMML) obtained prior to (n=46) or after (n=18) therapy with hypomethylating agents (HMAs). RNA from sorted bone marrow CD34+ cells was isolated and subject to amplification and RNA-seq. Gene co-expression was evaluated using Spearman correlation. Pathway enrichment analysis was performed using gene set enrichment analysis, with the fgsea library in R. Sequencing data was obtained by use of a 81-gene targeted PCR-based next generation sequencing (NGS) platform. Previously described somatic mutations registered at the Catalogue of Somatic Mutations in Cancer (COSMIC: http://cancer.sanger.ac.uk/cosmic) were considered as potential driver mutations. RESULTS: Compared to healthy controls, MLKL (CMML vs controls: 2.09 log2FC, p=0.0013; MDS vs control: 1.89 log2FC, p=0.003), but not RIPK1 or RIPK3, were significantly upregulated in patients with MDS and CMML (Figure 1A-C). No differences in the level of expression of RIPK1, MLKL or RIPK3 were observed based on the mutation context or burden. No significant difference in RIPK1, RIPK3 or MLKL expression levels was observed based on presence of cytogenetic abnormalities (RIPK1: 0.10 log2FC, p=0.6; RIPK3: -0.39 log2FC, p=0.40; MLKL: 0.34 log2FC, p=0.30). Higher expression levels of MLKL were associated with lower hemoglobin levels at the time of diagnosis (-0.19 log2FC per 1g/dL increase of Hgb, p=0.03) (Figure 1D). Exposure to HMA therapy was associated with a trend to decreased expression of MLKL (-0.52 log2FC, p=0.08) when all post-HMA therapy samples were evaluated. Among patient matched samples, significant reduction in MLKL levels was observed after HMA therapy (-1.06 log2FC, p=0.05). The degree of reduction in expression levels was greater among non-responders (-2.89 log2FC, p=0.06) compared to responders (-0.78, log2FC, p=0.06). Expression levels of RIPK1 at the time of diagnosis predicted for shorter survival for patients with high RIPK1 levels, defined as a log expression higher than median mRNA expression values, (median OS 10.7 vs 24.2 months, HR 1.92, 95% CI 1.00-3.67, p=0.049 by Cox proportional hazards) (Figure 1E). A multivariate analysis for overall survival using both IPSS-R risk and RIPK1 expression levels demonstrated that high RIPK1 expression was an independent adverse prognostic factor in MDS patients (HR 6.83, 95% CI 1.74-26.8, p=0.006). A total of 359 genes were significantly correlated with RIPK1 levels in MDS CD34+ cells (Spearman's method q CONCLUSIONS: This data provides further support for a role of necroptosis in MDS, and potentially response to HMAs and prognosis. This data also indicates that RIPK1/RIPK3/MLKL are potential therapeutic targets in MDS. Figure 1 Disclosures Sasaki: Otsuka: Honoraria; Pfizer: Consultancy. Bueso-Ramos:Incyte: Consultancy. Kantarjian:Cyclacel: Research Funding; Jazz Pharma: Research Funding; AbbVie: Honoraria, Research Funding; Astex: Research Funding; Amgen: Honoraria, Research Funding; Actinium: Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Research Funding; Immunogen: Research Funding; Daiichi-Sankyo: Research Funding; Pfizer: Honoraria, Research Funding; Novartis: Research Funding; Ariad: Research Funding; Agios: Honoraria, Research Funding; Takeda: Honoraria. Garcia-Manero:Amphivena: Consultancy, Research Funding; Helsinn: Research Funding; Novartis: Research Funding; AbbVie: Research Funding; Celgene: Consultancy, Research Funding; Astex: Consultancy, Research Funding; Onconova: Research Funding; H3 Biomedicine: Research Funding; Merck: Research Funding.

Acute myeloid leukemia (AML) is an aggressive hematological malignancy with a globally poor outcome, especially in patients ineligible for intensive chemotherapy. Until recently, therapeutic options for these patients included low-dose cytarabine (LDAC) or the hypomethylating agents (HMA) azacitidine and decitabine, which have historically provided only short-lived and modest benefits. The oral B-cell lymphoma 2 inhibitor, venetoclax, Venetoclax, an oral B-cell lymphoma 2 (BCL2) inhibitor, is now approved by the USA Food and Drug Administration (FDA) in combination with LDAC or HMA in older AML patients ineligible for intensive chemotherapy. Is now approved by the US Food and Drug Administration for this indication. In the pivotal clinical trials evaluating venetoclax either in combination with LDAC or with HMA, the rates of complete remission (CR) plus CR with incomplete hematological recovery were 54% and 67%, respectively and the median overall survival (OS) was 10.4 months and 17.5 months, respectively, comparing favorably with outcomes in clinical trials evaluating single-agent LDAC or HMA. The most common adverse events with venetoclax combinations are gastrointestinal symptoms, which are primarily low grade and easily manageable, and myelosuppression, which may require delays between cycles, granulocyte colony-stimulating factor (G-CSF) administration, or decreased duration of venetoclax administration per cycle. A bone marrow assessment after the first cycle of treatment is critical to determine dosing and timing of subsequent cycles, as most patients will achieve their best response after one cycle. Appropriate prophylactic measures can reduce the risk of venetoclax-induced tumor lysis syndrome. In this review, we present clinical data from the pivotal trials evaluating venetoclax-based combinations in older patients ineligible for intensive chemotherapy, and provide practical recommendations for the prevention and management of adverse events associated with venetoclax.

Prognostic markers that capture leukemia stem cell (LSC) activity can be useful for the risk stratification of acute myeloid leukemia (AML) patients. In a recent issue of Nature, Ng et al. (2016) develop a prognostic score based on a 17-gene expression signature of LSCs to predict outcome in AML patients.

Introduction: Acute myeloid leukemia (AML) is a heterogeneous disease with variable responses to therapy and clinical outcomes. Cytogenetics and molecular analyses help to stratify patients and to select therapy, especially regarding indication of hematopoietic stem cell transplant (HSCT) after achieving complete remission (CR). Patients in the intermediate cytogenetic risk category (~40%) represent a clinical dilemma regarding consolidation because of the high rate of relapse with chemotherapy alone and high rate of morbidity/mortality with HSCT. Consequently, we aimed to identify new prognostic markers to refine the risk stratification of this patients' subgroup and to identify which patients are most likely to benefit from HSCT. Methods: We analyzed RNA sequencing data of 263 specimens from patients with de novo AML treated with curative intent including 165 patients with intermediate risk cytogenetics. Data from 24 586 genes were normalized as RPKM values with logarithmic transformation and standardization. Cox proportional hazard models were used to assess the prognostic impact of gene expression (GE) on overall survival (OS) and relapse-free survival (RFS). We performed univariate analyses (UVA) and multivariate analyses (MVA) adjusted for age and white blood cell count (WBC) at diagnosis, mutations in NPM1, FLT3, CEBPA, RUNX1, ASXL1, TP53 and DNMT3A and HSCT as a time-dependent (TD) covariate. Interaction between GE and TD-HSCT was tested in MVA for OS and RFS. Genes with a significant interaction between GE and TD-HSCT (p < 0.10) were retained for further analyses. GE of candidate markers were dichotomized using a bioinformatic method assessing hazard ratios (HR) and p values for all potential cut-offs to identify the most optimal threshold. The markers were finally reassessed as dichotomic variables for association with covariates, CR rates, RFS and OS. All statistical tests were two-sided with p values < 0.05 considered significant. Results: We identified SPAG1 (Sperm Associated Antigen 1) as the gene with the highest HR for OS and RFS in the intermediate cytogenetic risk group. SPAG1 expression was dichotomized on the median RPKM value in the global cohort of 263 de novo AML specimens (RPKM cut-off 2.06). Using this cut-off, 79 patients had low expression of SPAG1 and 86 patients had high expression of SPAG1 in the intermediate cytogenetic risk cohort. Median age, sex, WBC at diagnosis and HSCT in CR1 rates were similar between the two groups. Patients with high expression of SPAG1 had a higher frequency of FLT3-ITD (51.2% vs 32.9%, p = 0.02) and DNMT3A mutations (51.2% vs 32.9%, p = 0.02). SPAG1-high patients were enriched in the NPM1/FLT3-ITD/DNMT3A triple positive mutation population (SPAG1-high 24/33 vs SPAG1-low 9/33, OR 3.00, p = 0.01). The frequencies of all other analyzed mutations were similar between both groups. CR rates did not differ between the two groups (SPAG1-high 77.9% vs SPAG1-low 79.7%, p = 0.77). In UVA with censorship at time of HSCT, SPAG1-high patients had worse OS (5-year estimates 14.2% vs 28.1%, HR 1.75, 95% CI 1.16-2.63, p < 0.01) and RFS (5-year estimates 9.3% vs 27.1%, HR 1.90, 95% CI 1.20-3.01, p < 0.01) (Figure 1). In MVA with censorship at time of HSCT, high expression of SPAG1 remained significantly associated with OS (HR 1.78, 95% CI 1.12-2.83, p = 0.01) and RFS (HR 2.34, 95% CI 1.38-3.96, p < 0.01). Furthermore, there was a significant interaction between SPAG1 GE and TD-HSCT (p = 0.09) in the RFS model. Importantly, SPAG1 had a lower prognostic impact for RFS in the model including TD-HSCT (HR 1.65, 95% CI 1.07-2.55, p = 0.02) compared with the model in which survival was censored at time of HSCT (HR 2.34, p < 0.01). High SPAG1 expression was also associated with worse OS in the TCGA AML dataset which is enriched in intermediate cytogenetic risk samples (p < 0.001). Conclusion: In patients with intermediate cytogenetic risk AML, high expression of SPAG1 is independently associated with worse OS and RFS. The prognostic impact of SPAG1 expression on RFS is lower when adjusted for TD-HSCT indicating that the adverse prognosis conferred by high expression of this gene may be partially overcome by HSCT in CR1. Consequently, SPAG1 expression might help identify AML patients with intermediate cytogenetic risk who are most likely to benefit from HSCT in CR1. These results need to be validated in other independent cohorts and prospective studies before implementation into clinics. Disclosures Sauvageau: ExCellThera: Employment, Equity Ownership.

7002 Background: Smoking increases the relative risk of AML by 40% and 25% in active and former smokers, respectively, compared with non-smokers (Fircanis et al., 2014). While the relationship of smoking with AML development is recognized, whether smoking impacts underling AML biology and clinical outcome remains ill-defined. Methods: Newly diagnosed, treatment naïve AML pts seen at MDACC between 2012 and 2017 with available smoking history were evaluated, along with baseline parameters, co-occurring mutations, cytogenetics and clinical outcome. Results: We identified 858 pts [486 (57%) male; median age 67 yrs (14-97)], representing 535 (62%) treatment naïve and 323 (38%) salvage pts. Smoking status was recorded as smokers (active = 39 pt, former = 380 pt), versus never smoker (439 pt). In tx naïve group, smoking is associated with lower remission rates (OR 0.63, 95% CI 0.43-0.94, p = 0.02) and inferior OS (HR = 1.6, 95% CI 1.27-2.02, p < 0.001). Smoking status was not significant in multivariate analysis including AML biologic characteristics and ELN 2017 risk stratification. Therefore we postulated that worse OS may be driven by smoking associated AML biology rather than smoking associated comorbidities. Indeed, in univariate analysis smoking was associated with poor ELN risk (p = 0.015), complex karyotype (p = 0.0002), and TP53 mutation (p = 0.0235) while negatively associated with NPM1 (p = 0.018), FLT3-ITD (p = 0.032) and GATA2 (p = 0.0497). Age was a significant cofounder between smokers vs non-smoker ( < 0.0001). After controlling for age, significance was retained for ELN risk, complex karyotype and GATA2 at p = 0.0454, p = 0.0006, p = 0.048 respectively, while significance was lost for NPM1 (p = 0.079), FLT3-ITD (p = 0.1) and TP53 (p = 0.084). In analysis of young pts ( < 60 yr), smoking is positively associated with complex karyotype (p = 0.0042) and TP53 (p = 0.0289), and negatively associated with RUNX1 (p = 0.0143) and IDH2 (p = 0.0357). Conclusions: We report the largest analysis of smoking status and impact on molecular, cytogenetics, and AML clinical outcomes. Smoking history is associated with poorer risk molecular and cytogenetics, lower response rate and shorter survival in treatment naïve patients.