ALBERT

Description: 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.

Description: Background Multi-agent combination chemotherapy regimens for the treatment of ALL are considered a cancer success story in the pediatric setting. For adults, the same magnitude of success has not been realized using similar strategies. These regimens produce high complete remission (CR) rates of 80-90% but the cure rates are 40-50%. The incorporation of targeted agents (tyrosine kinase inhibitors and monoclonal antibodies) has improved survival and cure rates in adult ALL subsets. Blinatumomab, a bispecific T-cell engaging (BiTE) CD19-CD3 antibody, is effective in patients with relapsed/refractory disease and in patients with measurable residual disease (MRD). Better outcomes were obtained when blinatumomab was administered earlier in the course of the disease. We hypothesized that incorporating blinatumomab in sequential combination with Hyper-CVAD in previously untreated patients with ALL would improve the eradication of MRD, decrease the need for intensive chemotherapy, and improve survival. Methods Patients were eligible to participate in this phase 2 single-arm study if they were at least 14 years old, had newly diagnosed untreated Philadelphia-negative B-ALL or B-cell lymphoblastic lymphoma, had ECOG performance status (PS) of 0-3, and normal liver, kidney and cardiac function. Patients in CR after one prior course of chemotherapy were also eligible. Therapeutic regimen consisted of 4 alternating cycles of Hyper-CVAD (cyclophosphamide, vincristine, doxorubicin and dexamethasone, cycles 1 & 3) and high-dose methotrexate/cytarabine (cycles 2 & 4) followed by 4 consecutive cycles of blinatumomab (4 weeks every 6 week-cycle). All patients received 8 prophylactic intrathecal injections with methotrexate and cytarabine during the first 4 cycles of treatment. Additionally, patients with CD20+ ALL (≥ 1% cells) received a total of 8 doses of rituximab (375 mg/m2) or ofatumumab (2000 mg) during the hyper-CVAD cycles. Maintenance phase consisted of POMP (6-mercaptopurine, vincristine, methotrexate, prednisone) on cycles 1-3, 5-7, 9-11 and 13-15 alternating with blinatumomab on cycles 4, 8 and 12. The primary outcome was relapse-free survival (RFS) and secondary outcomes were overall survival (OS), overall response rate and MRD negativity rate. Results To date, 17 patients were treated, three of them enrolled in CR after 1 cycle of Hyper-CVAD. Patient's characteristics are summarized in Table 1. Median age is 43 years (range, 20-59). All but one patient had CD20 expression. Six patients (35%) had TP53 mutations. Four patients (24%) had low hypodiploidy-near triploidy. One patient (6%) had CRLF2 overexpression. All 14 evaluable patients achieved CR for an overall response rate of 100%. Minimal residual disease (MRD) negativity, assessed by 6-color multicolor flow, was achieved in 93% of the patients after one cycle of therapy. No early death within 6 weeks was reported. Patients have received a median of 4 cycles (1-4) of chemotherapy and 4 cycles (0-4) of blinatumomab. Two patients had early relapse during the Hyper-CVAD cycles after 2 and 4 cycles, respectively. Three patients underwent allogeneic stem cell transplantation (HSCT) (1 with histiocytic proliferation in the bone marrow, 1 with t(4;11) and 1 with CRLF2+ ALL). A total of 14 patients have initiated the blinatumomab phase. Nine patients received the total 8 courses of hyper-CVAD and blinatumomab and are currently receiving maintenance in CR. The treatment was well tolerated. Grade 3-4 adverse events attributed to blinatumomab occurred in 2 patients (12%) and were manageable and reversible. One patient developed transient Grade 3 cytokine release syndrome and one had Grade 3 ataxia. Both recovered after holding blinatumomab therapy and dexamethasone administration. Treatment was resumed thereafter with no recurrence. With a median follow up of 14 months (range, 3-20 months), 16 patients (94%) are alive (14 of them in first CR); one patient died after HSCT of a transplant-related complication. The 1-year RFS rate was 77% (95% CI 42-93%) (Figure 1A) and the 1-year OS rate was 90% (95% CI 47-99%) (Figure 1B). Conclusion The sequential combination of Hyper-CVAD and blinatumomab in newly diagnosed adult patients with B-ALL is safe and highly effective. These early results are favorable. The study continues to accrue patients. Disclosures Short: Takeda Oncology: Consultancy. Ravandi:Abbvie: Research Funding; Seattle Genetics: Research Funding; Macrogenix: Honoraria, Research Funding; Orsenix: Honoraria; Orsenix: Honoraria; Amgen: Honoraria, Research Funding, Speakers Bureau; Jazz: Honoraria; Xencor: Research Funding; Macrogenix: Honoraria, Research Funding; Jazz: Honoraria; Sunesis: Honoraria; Astellas Pharmaceuticals: Consultancy, Honoraria; Seattle Genetics: Research Funding; Abbvie: Research Funding; Amgen: Honoraria, Research Funding, Speakers Bureau; Bristol-Myers Squibb: Research Funding; Xencor: Research Funding; Astellas Pharmaceuticals: Consultancy, Honoraria; Bristol-Myers Squibb: Research Funding; Sunesis: Honoraria. Cortes:Astellas Pharma: Consultancy, Research Funding; Daiichi Sankyo: Consultancy, Research Funding; Arog: Research Funding; Novartis: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding. Jain:BMS: Research Funding; ADC Therapeutics: Research Funding; BMS: Research Funding; Genentech: Research Funding; ADC Therapeutics: Research Funding; Servier: Research Funding; Astra Zeneca: Research Funding; Genentech: Research Funding; Verastem: Research Funding; Abbvie: Research Funding; Incyte: Research Funding; Pfizer: Research Funding; Seattle Genetics: Research Funding; Pharmacyclics: Research Funding; Celgene: Research Funding; Pfizer: Research Funding; Infinity: Research Funding; Abbvie: Research Funding; Infinity: Research Funding; Pharmacyclics: Research Funding; Seattle Genetics: Research Funding; Cellectis: Research Funding; Incyte: Research Funding; Adaptive Biotechnologioes: Research Funding; Celgene: Research Funding; Pharmacyclics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Astra Zeneca: Research Funding; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Servier: Research Funding; Astra Zeneca: Honoraria, Membership on an entity's Board of Directors or advisory committees; Verastem: Research Funding; Verastem: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Cellectis: Research Funding; ADC Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Adaptive Biotechnologioes: Research Funding; Servier: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novimmune: 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; Adaptive Biotechnologies: Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: 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; Astra Zeneca: Honoraria, Membership on an entity's Board of Directors or advisory committees; Verastem: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; ADC Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Servier: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novimmune: Honoraria, Membership on an entity's Board of Directors or advisory committees; Adaptive Biotechnologies: 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. Konopleva:Stemline Therapeutics: Research Funding. Sasaki:Otsuka Pharmaceutical: Honoraria. Jabbour:Abbvie: Research Funding; Pfizer: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; Novartis: Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding.

Description: 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

Description: 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

Description: Background: Neutropenic patients with hematologic malignancies are at high risk of infectious related-deaths. Granulocyte transfusions (GTX) are used in neutropenic patients to treat severe refractory infections. These blood products are usually irradiated to eliminate T-cells that can cause transfusion-associated graft-versus-host disease (TA-GVHD) in severely immunocompromised patients. We adopted a strategy of rapid utilization of non-irradiated GTX in neutropenic patients with severe abdominal infection to accelerate recovery and prevent infectious-related deaths. We report here the safety and efficacy data of 119 transfusions administered in 22 patients with abdominal infections. Methods: We retrospectively analyzed the safety and efficacy data of patients with abdominal infections who received non-irradiated GTX in our institution between January 1st 2015 and December 31st 2017. Patients with hematological malignancies, severe neutropenia ( 1.0 x 109/L or significant clinical improvement. Granulocyte donors were mobilized using subcutaneous G-CSF 480 mcg and 8 mg of oral dexamethasone regardless of ABO and HLA compatibility. ABO incompatible GTX were drained of red cells prior to transfusion. We collected increments of absolute neutrophil counts (ANC) after each GTX, number of days with ANC 〉 1.0 x 109/L and transfusion-related complications. Controlled infection was defined as significant clinical improvement or antibiotic de-escalation or end. Results: A total of 119 non-irradiated GTX were administered in 22 patients for 25 different infectious episodes. Baseline characteristics of patients are summarized in table 1. Median age of patients was 53.5 year-old (range 21 to 73) and 12 patients (54.5%) were male. Most patients had acute myeloid leukemia (14/22 patients, 63.6%) and relapsed disease (13 patients). GTX were administered in 11 patients (44%) for neutropenic enterocolitis, 6 (24%) for small bowel obstruction and/or perforation, 5 (20%) for clostridium difficile colitis, 2 (8%) for abdominal abscesses and 1 (4%) for appendicitis. Patients received a median of 3 GTX during their infectious episode (range 1 to 17). The median ANC before first GTX was 0.1 x 109/L (range 0.0 to 4.5). After GTX, there was a median increase in ANC of 0.3 x 109/L (range -0.8 to 26.1), with the peak of ANC occurring at a median of 24 hours after first GTX and returning to baseline at a median of 2 days after the last GTX. In 15 patients (68%), ANC was above 1 x 109/L for 3 days or more. GTX contributed to control infection in 19 infectious episodes (76%) after a median of 5 days following first transfusion (range 2 to 32 days). There was no significant association between sex, infectious diagnosis, initial ANC, number of GTX, mean ANC increment per patient or ANC 〉 0.1 x 109/L for 3 days and the rate of controlled infection 7 days after first GTX. Twelve patients (54.5%) were able to pursue their treatments without significant delays (〉 7 days) after their infectious episode. Five patients (22.3%) died with the active infection for which they had received a GTX; all these patients also had active refractory disease and severe comorbidities. The median overall survival (OS) from first GTX was 7.7 months (95% CI; 2.7 to 17.4). Patients who had a controlled infection within 7 days of first GTX had significantly better OS (median OS 12.4 months vs. 1.6 months, log-rank p 〈 0.001) (Figure 1). Pulmonary events leading to death were reported in 2 patients; one had acute respiratory distress syndrome and cardiac arrest the day after the first GTX, but had pneumonia before transfusion, and one had worsening of pre-existing lung infiltrates 3 days after GTX and eventually died of respiratory failure. Importantly, no TA-HSCT were reported in the medical notes, neither suspected by the review of the patients' charts. Conclusion: Non-irradiated GTX are safe and effective to control severe abdominal infection. Noteworthy, no TA-GVHD occurred in this cohort of severely immunocompromised patients. Pulmonary complications after GTX are rare but can be serious, mostly seen in patients with pre-existing pulmonary infiltrates. GTX in such instances may pose higher risks. Further studies are needed to evaluate the comparative safety and efficacy of non-irradiated GTX with irradiated GTX. Disclosures Ravandi: Xencor: Research Funding; Sunesis: Honoraria; Macrogenix: Honoraria, Research Funding; Jazz: Honoraria; Astellas Pharmaceuticals: Consultancy, Honoraria; Xencor: Research Funding; Seattle Genetics: Research Funding; Seattle Genetics: Research Funding; Amgen: Honoraria, Research Funding, Speakers Bureau; Jazz: Honoraria; Orsenix: Honoraria; Bristol-Myers Squibb: Research Funding; Sunesis: Honoraria; Orsenix: Honoraria; Amgen: Honoraria, Research Funding, Speakers Bureau; Abbvie: Research Funding; Bristol-Myers Squibb: Research Funding; Macrogenix: Honoraria, Research Funding; Abbvie: Research Funding; Astellas Pharmaceuticals: Consultancy, Honoraria. Kadia:Takeda: Consultancy; BMS: Research Funding; Abbvie: Consultancy; Novartis: Consultancy; Jazz: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; Jazz: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Novartis: Consultancy; BMS: Research Funding; Abbvie: Consultancy; Amgen: Consultancy, Research Funding; Celgene: Research Funding; Pfizer: Consultancy, Research Funding; Takeda: Consultancy; Celgene: Research Funding. DiNardo:Bayer: Honoraria; Karyopharm: Honoraria; Celgene: Honoraria; Abbvie: Honoraria; Agios: Consultancy; Medimmune: Honoraria. Wierda:AbbVie, Inc: Research Funding; Genentech: Research Funding. Daver:ImmunoGen: Consultancy; Incyte: Consultancy; Karyopharm: Research Funding; Otsuka: Consultancy; Novartis: Research Funding; Novartis: Consultancy; ARIAD: Research Funding; Kiromic: Research Funding; Alexion: Consultancy; BMS: Research Funding; Daiichi-Sankyo: Research Funding; Karyopharm: Consultancy; Pfizer: Research Funding; Incyte: Research Funding; Pfizer: Consultancy; Sunesis: Consultancy; Sunesis: Research Funding. Pemmaraju:abbvie: Research Funding; samus: Research Funding; daiichi sankyo: Research Funding; plexxikon: Research Funding; stemline: Consultancy, Honoraria, Research Funding; celgene: Consultancy, Honoraria; Affymetrix: Research Funding; cellectis: Research Funding; novartis: Research Funding; SagerStrong Foundation: Research Funding. Bose:Incyte Corporation: Honoraria, Research Funding; Astellas Pharmaceuticals: Research Funding; Constellation Pharmaceuticals: Research Funding; CTI BioPharma: Research Funding; Pfizer, Inc.: Research Funding; Celgene Corporation: Honoraria, Research Funding; Blueprint Medicines Corporation: Research Funding. Konopleva:cellectis: Research Funding; Immunogen: Research Funding; abbvie: Research Funding; Stemline Therapeutics: Research Funding. Andreeff:Celgene: Consultancy; Amgen: Consultancy, Research Funding; SentiBio: Equity Ownership; Oncolyze: Equity Ownership; Jazz Pharma: Consultancy; Aptose: Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Oncoceutics: Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Reata: Equity Ownership; United Therapeutics: Patents & Royalties: GD2 inhibition in breast cancer ; Eutropics: Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Daiichi-Sankyo: Consultancy, Patents & Royalties: MDM2 inhibitor activity patent, Research Funding; Astra Zeneca: Research Funding. Verstovsek:Italfarmaco: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees; Incyte: Consultancy. Cortes:novartis: Research Funding.

Description: 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.

Description: Background: Therapy-related acute myeloid leukemia (t-AML) is associated with higher risk cytogenetics and disease biology, which partly account for poorer outcomes compared with de novo AML. Normal karyotype (NK) among patients (pts) with t-AML is rare, and the relative contribution of prior chemotherapy or radiotherapy exposure to outcomes of pts with AML with NK is uncertain. Methods: We reviewed all pts with newly diagnosed AML treated at MD Anderson Cancer Center between 2007 and 2019. Patients were separated into two groups (t-AML and de novo AML) based on their prior administration of chemotherapy or radiotherapy for an antecedent neoplasm. We analyzed patients' characteristics and outcomes including remission rates, relapse rates and survival. Survival curves were estimated by Kaplan-Meier method. Gray's method was used for cumulative incidence of relapse (CIR) analysis. Multivariate analyses for relapse-free survival (RFS) and overall survival (OS) were conducted using Cox proportional hazards regression model including age, t-AML (vs. de novo AML), European LeukemiaNet (ELN) 2017 risk classification, and type of therapy (intensive chemotherapy vs. low intensity/hypomethylating agent-based therapy) as covariates. Results: A total of 1977 pts with AML who had complete cytogenetic information available were identified. Among 742 pts (38%) with NK, 61 pts (8%) had t-AML and 681 pts (92%) had de novo AML. NK was present in 18% of all t-AML (61/340 pts). Prior therapy in pts with NK t-AML was chemotherapy (24 pts, 39%), radiation (21 pts, 34%), or both (16 pts, 26%). Characteristics of pts with NK AML are summarized in Table 1. Median age was higher for t-AML vs. de novo AML (71 years [range, 48-89] vs. 64 years [range, 18-92], p 〈 0.01). No statistically significant difference was noted by mutational status or ELN 2017 risk category. Pts with t-AML were less likely to receive intensive induction chemotherapy (26% vs. 52%, p 〈 0.01). However, rates of allogeneic stem cell transplant were similar (15% and 22% in t-AML and de novo AML, respectively, p = 0.17). Response rates by type of treatment are shown in Table 2. In pts who received low-intensity therapy, no significant difference was seen in CR/CRi rates between t-AML and de novo AML (60% vs. 61%, p=0.92). However, in pts who received intensive chemotherapy, there was a trend for higher CR/CRi rates in pts with de novo AML compared with t-AML (86% vs. 69%, p=0.05). With a median follow-up of 54 months, median OS was significantly shorter for pts with t-AML compared with de novo AML: 10.2 months vs. 20.6 months (hazard ratio [HR] 2.07, 95% confidence interval [CI], 1.54-2.78, p 〈 0.01, Figure 1A). Similarly, RFS was significantly worse for t-AML with a median of 12.0 months compared to 14.8 months for de novo AML (HR 1.55, 95% CI 1.06-2.26, p = 0.02, Figure 1B). Although pts with t-AML had worse OS and RFS, interestingly, this was not driven by higher relapse rates. The 5-year CIR rate was similar for pts with t-AML and de novo AML (42% vs. 56%, p = 0.21, Figure 1C). In contrast, the 5-year cumulative incidence of death in CR/CRi was significantly higher in patients with t-AML compared to patients with de novo AML (51% vs 16%, p 〈 0.01, Figure 1D), suggesting that non-relapse death is the main driver of worse outcomes for pts with t-AML. In multivariate analysis, age ≥60 was independently associated with shorter OS (HR 1.79, 95% CI 1.06-3.01, p=0.03) whereas favorable ELN 2017 risk category was prognostic of longer OS (HR 0.62, 95% CI 0.40-0.96, p=0.03). Additionally, there was a trend toward poor OS for adverse ELN 2017 risk category (HR 1.35, 95% CI 0.99-1.86, p=0.06) and better OS with intensive chemotherapy (HR 0.64, 95% CI 0.40-1.01, p=0.06). However, t-AML was not independently associated with OS (HR 1.34, 95% CI 0.83-2.17, p = 0.24) or RFS (HR 1.02, 95% CI 0.53-1.98, p = 0.95). Conclusions: t-AML with NK is rare entity that comprises

Description: 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.

Description: Background: The majority of adult patients (pts) with B-ALL achieve complete remission (CR) with contemporary multi-agent chemotherapy regimens. Persistence or recurrence of measurable residual disease (MRD+) in CR is associated with an increased risk of relapse and lower overall survival (OS) rates. Blinatumomab (blina) is a CD19-CD3 bispecific T-cell engager (BiTE) monoclonal antibody effective in the treatment of relapsed/refractory B-ALL and for the eradication of MRD+. In the BLAST trial, 78% of patients achieved complete MRD response (MRD-) with blina and responders had an improved 4-year OS of 52%. Uncertainty remain whether pts MRD- after blina should undergo allogeneic hematopoietic stem cell transplant (HSCT). In pts with Philadelphia-chromosome positive (Ph+) B-ALL, blina in combination with tyrosine kinase inhibitors (TKI) has not been evaluated for eradication of MRD. The objective of this trial was to evaluate the safety and efficacy of blina in pts with B-ALL and MRD+. Methods: This is an open-label, single-arm, Phase II trial including pts with B-ALL in CR with persistent or recurrent MRD+. Pts in first CR (CR1) or in second CR or beyond (CR2+) were eligible. MRD+ was defined as ≥ 0.01% B-ALL cells by 6-color multiparameter flow cytometry for Ph- B-ALL pts and BCR-ABL1 to ABL1 transcripts ratio of ≥ 0.01% International Scale (IS) by RT-qPCR for pts with Ph+ ALL. Pts received continuous IV infusion of blina 28 µg/day over 4 weeks followed by a 2-week treatment-free interval. For the first cycle, blina was initiated at 9 µg/day for 1 week and then escalated to 28 µg/day, if tolerated. A TKI of treating physician's choice was added for pts with Ph+ ALL. Responders could receive up to 4 additional consolidation cycles (for a total of 5), and pts could proceed to HSCT at any time. The primary endpoint was relapse-free survival (RFS). Secondary endpoints included the MRD negativity rate, OS, and the safety profile. Results: Between December 2015 and June 2019, 25 patients with B-ALL in CR with MRD+ were enrolled. Baseline characteristics of the patients are shown in Table 1. Ten (40%) pts had Ph+ B-ALL. Eighteen (72%) pts were in CR1 and 7 (28%) were in CR2+. Sixteen (64%) pts had persistent MRD+, and 9 (36%) had MRD+ recurrence after being negative for a median or 20 months (range, 2-36). Pts received a median of 2 cycles (range, 1-5) of blina. For pts with Ph+ B-ALL, blina was combined with ponatinib in 8 pts, bosutinib in 1 pt and dasatinib in 1 pt. The rate of MRD- with blina was 78% (18/23 pts). MRD- was achieved in 6/8 (75%) pts with Ph+ ALL and 12/15 (80%) pts with Ph- ALL (p = 1.00); 11/16 (69%) pts in CR1 vs 7/7 (100%) pts in CR2+ (p = 0.27); and 9/14 (64%) pts with persistent MRD+ vs 9/9 (100%) with recurrent MRD+ (p = 0.12) (Table 2). The median time to MRD- was 1.3 month (range, 1.0 - 5.6); 16/18 (89%) responders achieved MRD- after one cycle. One Ph- ALL pt achieved MRD- after 2 cycles and one Ph+ ALL pt achieved MRD- after 4 cycles. Six of 18 (33%) responding pts proceeded to HSCT after blina (3/11 in CR1 and 3/7 in CR2+), with a median time from treatment start to HSCT of 3.1 months (range, 2.1 - 6.4). Post-HSCT, 1 pt died of transplant-related complications and 5 remain alive in CR. Among 12 responding pts who did not proceed to HSCT, 4 relapsed and 8 are alive in remission. With a median follow-up of 25 months (range, 2 - 43), the median RFS and OS have not been reached. The 2-year RFS and OS were 58% [95% CI, 39 - 85%] and 68% [95% CI, 49 - 93%], respectively (Figure 1A-1B). There was no difference in RFS and OS according of Ph+ status or between pts in CR1 and in CR2+ (Table 2). The 2-year RFS and OS rates for complete MRD responders were 62% [95% CI, 41 - 95%] and 76% [95% CI, 56 - 100%], versus 40% [95% CI, 14 - 100%] and 40% [95% CI, 56 - 100%) for non-responders, respectively (Figure 2A-2B). The 2-year RFS and OS for pts who proceeded to HSCT were both 78% [95% CI, 55 - 100%], versus 37% [95% CI, 15 - 88%] and 56% [95% CI, 31 - 100%) for pts who were not transplanted, respectively. Blinatumomab-related adverse events of any grade were observed in 8/25 pts (32%). Cytokine release syndrome was reported in 3 pts (12%; grade 2, n=2; grade 3, n=1) and neurological adverse events in 4 pts (16%; grade 2; n=3, grade 3, n=1). All events resolved with supportive management and blina could be restarted. Conclusion: Blinatumomab is highly effective for eradication of MRD+ in pts with B-ALL. Pts who achieve MRD- with blina have an excellent outcome. The study continues to accrue patients. Disclosures Kantarjian: Pfizer: Honoraria, Research Funding; Jazz Pharma: Research Funding; Novartis: Research Funding; Daiichi-Sankyo: Research Funding; Astex: Research Funding; AbbVie: Honoraria, Research Funding; Agios: Honoraria, Research Funding; Immunogen: Research Funding; Cyclacel: Research Funding; Takeda: Honoraria; Amgen: Honoraria, Research Funding; Ariad: Research Funding; Actinium: Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Research Funding. Khoury:Angle: Research Funding; Stemline Therapeutics: Research Funding; Kiromic: Research Funding. Ravandi:Cyclacel LTD: Research Funding; Menarini Ricerche: Research Funding; Macrogenix: Consultancy, Research Funding; Selvita: Research Funding; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Xencor: Consultancy, Research Funding. Short:AstraZeneca: Consultancy; Amgen: Honoraria; Takeda Oncology: Consultancy, Research Funding. Takahashi:Symbio Pharmaceuticals: Consultancy. Borthakur:AbbVie: Research Funding; PTC Therapeutics: Consultancy; GSK: Research Funding; Incyte: Research Funding; Bayer Healthcare AG: Research Funding; Eisai: Research Funding; Tetralogic Pharmaceuticals: Research Funding; Merck: Research Funding; Argenx: Membership on an entity's Board of Directors or advisory committees; Arvinas: Research Funding; Cantargia AB: Research Funding; Xbiotech USA: Research Funding; Agensys: Research Funding; BioTheryX: Membership on an entity's Board of Directors or advisory committees; FTC Therapeutics: Membership on an entity's Board of Directors or advisory committees; Strategia Therapeutics: Research Funding; AstraZeneca: Research Funding; Janssen: Research Funding; BioLine Rx: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Research Funding; Eli Lilly and Co.: Research Funding; BMS: Research Funding; Cyclacel: Research Funding; Oncoceutics: Research Funding; Oncoceutics, Inc.: Research Funding; NKarta: Consultancy; Polaris: Research Funding. Konopleva: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; Cellectis: Research Funding; AbbVie: Consultancy, Honoraria, Research Funding; Eli Lilly: Research Funding; Forty-Seven: Consultancy, Honoraria; Stemline Therapeutics: Consultancy, Honoraria, Research Funding; Calithera: Research Funding. Alvarado:Jazz Pharmaceuticals: Research Funding; Abbott: Honoraria. Jain:Adaptive Biotechnologies: 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; Precision Biosciences: 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; 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. Kadia:Amgen: Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Consultancy, Research Funding; Pfizer: Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Research Funding; Celgene: Research Funding; Genentech: Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; Bioline RX: Research Funding; Jazz: Membership on an entity's Board of Directors or advisory committees, 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. Jabbour:Amgen: Consultancy, Research Funding; AbbVie: Consultancy, Research Funding; Cyclacel LTD: Research Funding; Pfizer: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Adaptive: Consultancy, Research Funding.

Description: 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.