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: Inosine 5'- monophosphate dehydrogenase (IMPDH) is a rate-limiting enzyme that catalyzes de novo synthesis of the guanine nucleotide and is overexpressed in both hematologic and solid tumors. FF-10501-01 is a potent new competitive IMPDH inhibitor. We investigated the anti-leukemia effect of FF-10501-01 in AML cell lines and in a Phase 1 clinical study in advanced AML and MDS, including HMA failures. Thirteen leukemia cell lines were studied, including 5 parental AML cell lines and their HMA-resistant derivatives (MOLM13, SKM1, HL60, TF1, and U937), and 3 other AML cell lines (KG1, HEL, and OCI-AML3). Cell proliferation was determined using trypan blue analysis. Flow cytometry was performed to detect drug-induced apoptosis and cell cycle analysis. High-performance liquid chromatography (HPLC) was performed to detect the intracellular concentrations of guanine nucleotides. Mycophenolic acid-treated cells were used as positive control. Effect of guanosine supplement on FF-10501-01 treatment was evaluated. Within 72 hours of treatment, FF-10501-01 inhibited proliferation of all 13 AML cell lines. The IC50 of FF-10501-01 ranged between 4.3 and 144.5 µM. MOLM13 was the most sensitive leukemia cell line, whereas the decitabine-resistant TF1 cell line was the most resistant. FF-10501-01-induced apoptosis was observed in all cell lines. Increased numbers of cells in G1 phase and decreased numbers in S phase were observed in MOLM13, SKM1 and TF1 cell lines treated with

Description: Background: Inotuzumab ozogamicin (INO) and blinatumomab both improve survival in relapsed or refractory acute lymphoblastic leukemia (ALL) compared to conventional chemotherapy. The combination of INO with reduced-intensity mini-hyper-CVD chemotherapy in older adults with newly diagnosed ALL is safe and highly effective (Kantarjian H et al, Lancet Oncol 2018;19(2):240-8). The addition of blinatumomab to this regimen may further improve outcomes. Methods: Patients (pts) ≥60 years of age with newly diagnosed Philadelphia chromosome (Ph)-negative pre-B-cell ALL were eligible. Pts were required to have a performance status of ≤3, total bilirubin ≤1.5 mg/dl, AST/ALT ≤3x ULN and creatinine ≤2 mg/dl. Pts received mini-hyper-CVD (cyclophosphamide and dexamethasone at 50% dose reduction, no anthracycline, methotrexate at 75% dose reduction, cytarabine at 0.5 g/m2 x 4 doses) for up to 8 cycles. INO was given at a dose of 1.3-1.8mg/m2 on day 3 of cycle 1 and 0.8-1.3mg/m2 on day 3 of cycles 2-4. Rituximab (if CD20+) and prophylactic IT chemotherapy were given for the first 4 cycles. Responding pts received POMP maintenance for up to 3 years. In order to decrease the risk of veno-occlusive disease (VOD), the protocol was amended in 3/2017 (pts 50+) to give INO in fractionated doses each cycle (0.6 mg/m2 on day 2 and 0.3 mg/m2 on day 8 of cycle 1; 0.3 mg/m2 on day 2 and 8 of cycles 2-4) and to administer 4 cycles of blinatumomab following 4 cycles of hyper-CVD plus INO, followed by maintenance with 12 cycles of POMP and 4 cycles of blinatumomab (1 cycle of blinatumomab after every 3 cycles of POMP). Results: 64 pts have been treated, 5 of whom were in complete remission (CR) at enrollment. Pt characteristics are summarized in Table 1. Median age was 68 years (range, 60-81 years); 27 pts (42%) were ≥70 years. 28% were positive for TP53 mutation, 19% were CRLF2 positive, and 27% had adverse-risk karyotype. 33/58 pts (57%) were CD20+ and received rituximab. Among 59 pts evaluable for morphologic response, 58 (98%) responded (CR, n=51; CRp, n=6; CRi, n=1). MRD negativity by 6-color flow cytometry was achieved in 48/62 pts (77%) after 1 cycle and 59/63 pts (94%) overall. There were no early deaths, and the 30-day and 60-day mortality rates were 0% and 3%, respectively. Among 63 pts who achieved remission, 9 (14%) relapsed, 3 (5%) underwent allogeneic SCT in first remission, 30 (48%) remain on treatment or have completed maintenance, and 21 (33%) died in CR/CRp. The rate of death in CR/CRp was higher in pts ≥70 years of age vs. 60-69 years (50% vs. 22%; P=0.02). Causes of death for pts in CR/CRp included: sepsis (n=7; all in pts 70 years and older), VOD (n=3), gunshot wound (n=1), dementia and deconditioning (n=1), end stage renal disease (n=1), MDS/AML (n=4; 3 in pts 70 years and older) and unknown causes (n=4). 6 pts (9%) developed VOD, 1 after subsequent allogeneic SCT. The rate of VOD was 6/64 (9%) with no difference in VOD in pts who did or did not receive blinatumomab. With a median follow-up of 37 months (range, 2-85 months), 34 pts (53%) were alive, 30 of whom (47%) were in CR and MRD negative status. The 3-year continuous remission and OS rates were 76% and 54%, respectively (Figure 1A). The 3-year continuous remission rate was 69% and 87% for pts age 60-69 and ≥70 years, respectively (P=0.25), and the 3-year OS rate was 63% and 42%, respectively (P=0.13; Figure 1B). The trend for worse survival in the pts ≥70 years was driven predominantly by the increased rate of death in CR/CRp in this older group. The outcomes of pts who did or did not receive blinatumomab were similar. Compared to a similar historical cohort of older pts treated with hyper-CVAD ± rituximab (n=77), mini-hyper-CVD + INO ± blinatumomab resulted in significantly higher 3-year OS (54% vs 32%; P=0.007). Conclusion: Reduced-intensity chemotherapy with hyper-CVD plus INO, with or without blinatumomab, is safe and effective in older adults with newly diagnosed Ph-negative ALL, with an overall response rate of 98% and 3-year OS rate of 54%. Further optimization of this regimen with less chemotherapy in patients 70 years and older is warranted to further decrease the rate of death in remission. Disclosures Short: Takeda Oncology: Consultancy, Research Funding; AstraZeneca: Consultancy; Amgen: Honoraria. Kantarjian:Actinium: Honoraria, Membership on an entity's Board of Directors or advisory committees; Jazz Pharma: Research Funding; Cyclacel: Research Funding; Pfizer: Honoraria, Research Funding; AbbVie: Honoraria, Research Funding; Immunogen: Research Funding; Amgen: Honoraria, Research Funding; Novartis: Research Funding; Takeda: Honoraria; Ariad: Research Funding; Agios: Honoraria, Research Funding; Astex: Research Funding; BMS: Research Funding; Daiichi-Sankyo: Research Funding. Ravandi:Xencor: Consultancy, Research Funding; Menarini Ricerche: Research Funding; Selvita: Research Funding; Cyclacel LTD: Research Funding; Macrogenix: Consultancy, Research Funding; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Jain: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; 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; 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; 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; BMS: Research Funding; Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Incyte: Research Funding; AstraZeneca: 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. Sasaki:Otsuka: Honoraria; Pfizer: Consultancy. Daver:Otsuka: Consultancy; Astellas: Consultancy; NOHLA: Research Funding; Jazz: Consultancy; Forty-Seven: Consultancy; Agios: Consultancy; Immunogen: Consultancy, Research Funding; Celgene: Consultancy; Genentech: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Abbvie: Consultancy, Research Funding; Karyopharm: Consultancy, Research Funding; Incyte: Consultancy, Research Funding; Servier: Research Funding; Pfizer: Consultancy, Research Funding; Sunesis: Consultancy, Research Funding; Hanmi Pharm Co., Ltd.: Research Funding; Glycomimetics: Research Funding; BMS: Consultancy, Research Funding; Daiichi Sankyo: Consultancy, Research Funding. Pemmaraju:sagerstrong: Research Funding; affymetrix: Research Funding; mustangbio: Consultancy, Research Funding; abbvie: Consultancy, Honoraria, Research Funding; samus: Research Funding; celgene: Consultancy, Honoraria; Daiichi-Sankyo: Research Funding; plexxikon: Research Funding; novartis: Consultancy, Research Funding; Stemline Therapeutics: Consultancy, Honoraria, Research Funding; cellectis: Research Funding; incyte: Consultancy, Research Funding. Khoury:Stemline Therapeutics: Research Funding; Angle: Research Funding; Kiromic: Research Funding. Alvarado:Jazz Pharmaceuticals: Research Funding; Abbott: Honoraria. Konopleva:Ablynx: Research Funding; Calithera: Research Funding; Stemline Therapeutics: Consultancy, Honoraria, Research Funding; Forty-Seven: Consultancy, Honoraria; 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; Astra Zeneca: Research Funding; Agios: 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. Kadia: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; 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; AbbVie: Consultancy, Research Funding. Borthakur:Merck: Research Funding; Polaris: Research Funding; BioLine Rx: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Tetralogic Pharmaceuticals: Research Funding; Cantargia AB: Research Funding; Eisai: Research Funding; Oncoceutics, Inc.: Research Funding; AbbVie: Research Funding; Agensys: Research Funding; Oncoceutics: Research Funding; NKarta: Consultancy; Bayer Healthcare AG: Research Funding; BMS: Research Funding; AstraZeneca: Research Funding; Cyclacel: Research Funding; Strategia Therapeutics: Research Funding; Incyte: Research Funding; Eli Lilly and Co.: Research Funding; Janssen: Research Funding; Novartis: Research Funding; Xbiotech USA: Research Funding; FTC Therapeutics: Membership on an entity's Board of Directors or advisory committees; Argenx: Membership on an entity's Board of Directors or advisory committees; PTC Therapeutics: Consultancy; Arvinas: Research Funding; BioTheryX: Membership on an entity's Board of Directors or advisory committees; GSK: Research Funding. Burger:BeiGene: Research Funding; Pharmacyclics, an AbbVie company: Research Funding; Gilead Sciences: Research Funding; Janssen Pharmaceuticals: Consultancy, Honoraria; Aptose Biosciences, Inc: Research Funding; AstraZeneca: Honoraria. Wierda:Genentech: Research Funding; Juno Therapeutics: Research Funding; KITE pharma: Research Funding; Sunesis: Research Funding; Miragen: Research Funding; Oncternal Therapeutics Inc.: Research Funding; Cyclcel: Research Funding; Loxo Oncology Inc.: Research Funding; Janssen: Research Funding; Xencor: Research Funding; GSK/Novartis: Research Funding; Pharmacyclics LLC: Research Funding; Acerta Pharma Inc: Research Funding; AbbVie: Research Funding; Gilead Sciences: Research Funding. DiNardo:syros: Honoraria; abbvie: Consultancy, Honoraria; daiichi sankyo: Honoraria; jazz: Honoraria; medimmune: Honoraria; notable labs: Membership on an entity's Board of Directors or advisory committees; celgene: Consultancy, Honoraria; agios: Consultancy, Honoraria. O'Brien:Astellas: Consultancy; Alexion: Consultancy; Gilead: Consultancy, Research Funding; Janssen: Consultancy, Honoraria; Pharmacyclics LLC, an AbbVie Company: Consultancy, Research Funding; Celgene: Consultancy; Sunesis: Consultancy, Research Funding; Kite: Research Funding; Aptose Biosciences, Inc: Consultancy; Acerta: Research Funding; Verastem: Consultancy; GlaxoSmithKline: Consultancy; Eisai: Consultancy; Vaniam Group LLC: Consultancy; TG Therapeutics: Consultancy, Research Funding; Regeneron: Research Funding; Pfizer: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Honoraria; Amgen: Consultancy. Jabbour:AbbVie: Consultancy, Research Funding; Cyclacel LTD: Research Funding; Pfizer: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Adaptive: Consultancy, Research Funding; Amgen: Consultancy, Research Funding. OffLabel Disclosure: The use of inotuzumab ozogamicin and blinatumomab as frontline therapy for older patients with ALL

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 combination of low intensity therapy with InO improved survival compared to intensive chemotherapy and to single agent InO in Salvage 1 (Jabbour et al. Cancer. 2018). The sequential addition of blinatumomab (blina) may allow the administration of weekly lower dose of InO and distancing allogeneic stem cell transplant (ASCT) from the last dose of InO, while deepening the minimal residual disease response. This will lead to less veno-occlusive disease (VOD) and better long-term efficacy. The aim of this study is to evaluate the outcome of pts in first relapse treated with this combination. Methods: The mini-hyper-CVD (cycles 1, 3, 5, 7) comprised cyclophosphamide (150 mg/m2 every 12 h on days 1-3), vincristine (2 mg flat dose on days 1 and 8), and dexamethasone (20 mg on days 1-4 and days 11-14) without anthracycline. Even cycles (cycles 2, 4, 6, 8) comprised methotrexate (250 mg/m2 on day 1) and cytarabine (0.5 g/m2 given every 12 h on days 2 and 3). Rituximab and intrathecal chemotherapy were given for first 4 courses. InO was originally given on day 3 of the first four cycles at the dose of 1.3-1.8 mg/m2 at cycle 1, followed by 1.0-1.3 mg/m2 in subsequent cycles. After 38 pts were treated, an amendment was made to incorporate 4 cycles of blina after 4 cycles of mini-hyper-CVD + InO. InO was given on days 2 and 8 at the dose of 0.6 and 0.3 mg/m2 at cycle 1, respectively, followed by days 2 and 8 at the dose of 0.3 and 0.3 mg/m2 at subsequent cycles; blina was continuously infused over 28 days every 42-day cycle for 4 cycles. The decision to proceed with ASCT was based on the discretion of the treating physician after discussion with the pt. After amendment, all pts were placed on prophylactic ursodiol. Inverse probability of treatment weighting (IPTW) was performed after propensity score calculations using covariates at diagnosis. Results: From 2/2013 to 3/2019, 62 pts were treated with mini-hyper-CVD + InO with (n=38, 55%) and without blina (n=24, 45%) as the first salvage therapy. Pt characteristics and outcome are summarized in Table 1. The median age at diagnosis was 39 years (range, 19-87). Among 62 pts, 8 (13%) pts had primary refractory disease; 24 (38%), CR1 duration less than 12 months. 7 (11%) pts had prior history of ASCT. MLL rearrangement by FISH was observed in 11 (18%) pts; CRLF2 rearrangement was observed in 6 (10%). Overall, 57 (92%) pts achieved response including CR in 43 (69%), and CRp/CRi in 14 (23%). MRD negativity by 6-color flow cytometry was achieved in 31/52 pts (60%) after 1 cycle and 47/55 pts (85%) overall. Three pts with detectable MRD before blina achieved negative MRD after blina therapy. The 30-day and 60-day mortality rates were 2% and 3%, respectively. Among 57 who achieved remission, 11 (19%) relapsed, 31 (54%) underwent allogeneic SCT in CR2, and 4 (6%) died in CR/CRp. Causes of death for pts in CR/CRp included: unknown (n=1), VOD (n=1), sepsis (n=1), and pneumonia (n=1). Overall, 6 pts (10%) developed VOD; 5 after subsequent ASCT. The rate of VOD was 5/42 (12%) in pts who did not receive blina; all 5 had ASCT-related; 1 received 2 ASCT, 1 in CR1 and 1 in CR2; 1 received ASCT in CR1; and 3 received ASCT in CR2. In contrast, only 1 case of VOD was observed among the 20 pts (5%) who received the weekly lower dose of InO and sequential addition of blina; this pt had VOD post ASCT in CR2. With a median follow-up of 34 months (range, 2-75 months), 29 pts (47%) were alive, 21 of whom (34%) were in CR and MRD negative status. The 3-year EFS and OS rates were 31% and 42%, respectively (Figure 1). The median EFS and OS were 10 and 17 months, respectively. With the landmark analysis at the median time to ASCT of 4 months (range, 1.9-9.5), the median EFS was 13 months and 15 months in pts with and without ASCT, respectively (Figure 2A; P=0.92); the median OS was 38 months and 31 months, respectively (Figure 2B; P=0.910). Using the IPTW analysis, compared to a similar historical cohort of pts treated with standard salvage chemotherapy (n=39) or Ino monotherapy (n=29), mini-hyper-CVD + InO ± blina (n=62) resulted in significantly improved survival (P

Description: Inosine 5'- monophosphate dehydrogenase (IMPDH) is a rate-limiting enzyme that catalyzes de novo synthesis of the guanine nucleotide and is overexpressed in both hematologic and solid tumors. FF-10501-01 is a potent new competitive IMPDH inhibitor. We investigated the anti-leukemia effect of FF-10501-01 in a Phase 1 clinical study in advanced AML and MDS, including HMA failures. Previous preclinical studies demonstrated potent anti-proliferative and apoptotic effects of FF-10501-01 on AML cell lines, including HMA-resistant derivatives, through inhibition of de novo guanine nucleotide synthesis. Therefore, we performed a standard 3+3 dose-escalation Phase 1 trial to access the safety and clinical activity of FF-10501-01 in patients with advanced AML, MDS and chronic myelomonocytic leukemia (CMML). Eligibility criteria: age ≥ 18 years, high risk MDS/CMML, AML with documented PD following previous therapy, AML ≥ 60 years of age and not a candidate for other therapy, adequate renal and hepatic function, and no known history of significant cardiac disease. A total of 29 patients, 15M and 14F (23 AML, 6 MDS) have been treated in 7 dose cohorts (50 - 500 mg/m2 PO BID) for 14 days on and 14 days off, and 400 mg/m2 for 21 days on and 7 days off, each 28-day cycle. Median (range) values: age 75 yrs (59 - 88); baseline bone marrow blast counts for AML 34% (12 - 82), for MDS 10% (5 - 16), and overall 30% (5 - 82); and prior treatment regimens 2 (1 - 7). All patients relapsed from, or progressed on, prior HMAs. At baseline, mutations in FLT3, NPM1, GATA2, TET2, ASXL1, DNMT3A, NOTCH1, JAK2, IDH2, PTPN11, KRA, TP53, RUNX1, EZH2 and/or MDM2 were present in 13 of 29 (45%) of patients. Atrial fibrillation (Gr 2) was reported in 2 subjects at a dose of 500 mg/m2 BID. This met the definition of dose-limiting toxicity (DLT) and no further enrollment was made at this dose level. The maximally tolerated dose (MTD) was declared at 1 dose level lower, 400 mg/m2 BID, and this cohort was expanded to 6 subjects. No DLTs have been observed in N=7 total subjects treated at 400 mg/m2 BID x 14 days. FF-10501-01 has been very well tolerated through 24 cycles. The most frequent drug-related AEs have been Gr 1-2 nausea, diarrhea and fatigue. Drug-related thrombocytopenia, neutropenia and bone marrow aplasia (all Gr 4) were reported in 1 patient at 200 mg/m2 BID. The median number of FF-10501-01 cycles received to date is 2 (range 1 - 24). Partial remissions have occurred in 2 AML patients (50 and 100 mg/m2 BID) after 3 cycles, lasting for 5 and 24 cycles, respectively, with the higher dose patient still on study after 24 cycles. A total of 8/23 (34.8%) AML patients, including the 2 PRs, have attained stable disease (SD) control with no disease progression over 3 - 24 cycles. Three AML patients remain on study through 3, 23 and 24 cycles, respectively. A bone marrow complete response was achieved in 1 MDS patient treated at 400 mg/m2 BID after 1 cycle. Although the bone marrow blast counts have increased since, this patient remains stable and is still on therapy through 14 cycles. Three of 6 MDS patients (50%), including the marrow CR, attained SD control with no disease progression over 3, 14 and 14 cycles, and 2 remain on study through 3 and 14 cycles, respectively. FF-10501-01 was rapidly absorbed with mean Tmax of 2.74 hours and mean t1/2 of 4.05 hours. Drug exposure (AUC0-24 and AUCcourse) increased with dose in a near linear manner. Potent suppression of circulating xanthine monophosphate (XMP), a marker of IMPDH activity, has been observed following FF-10501-01 administration on Day 1 of Cycles 1 and 2 at dose levels of 50 mg/m2 BID and above. FF-10501-01 is a promising new agent for the treatment of advanced AML and MDS in patients who have failed or progressed on HMAs and with one or more baseline mutations in pathways known to be affected in AML and MDS. Preclinical activity was seen in multiple leukemia cell lines, including HMA-resistant derivatives. In a Phase 1 trial, clinical activity with a marrow CR, PRs, long-term disease stabilization (≥ 5 cycles) and a highly tolerable safety profile were observed. The Phase 2a expansion phase of the study is soon to begin. Disclosures DiNardo: Agios: Research Funding; Daiichi Sankyo: Research Funding; Celgene: Research Funding; Novartis: Research Funding; Abbvie: Research Funding. Jabbour:ARIAD: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Novartis: Research Funding; BMS: Consultancy. Daver:BMS: Research Funding; Kiromic: Research Funding; Pfizer: Consultancy, Research Funding; Otsuka: Consultancy, Honoraria; Ariad: Research Funding; Karyopharm: Honoraria, Research Funding; Sunesis: Consultancy, Research Funding. Denton:Westat Corporation: Employment. Smith:Westat Corporation: Employment. Tiefenwerth:Westat Corporation: Employment. Iwamura:FUJIFILM Corporation: Employment. Gipson:Strategia Therapeutics, Inc.: Employment. Rosner:Strategia Therapeutics, Inc.: Employment. Myers:Strategia Therapeutics, Inc.: Employment. Paradiso:Strategia Therapeutics, Inc.: Employment.

Description: Background: Ponatinib is a potent, third-generation inhibitor of BCR-ABL that is active against T315I mutations of the ABL1 gene; these mutations are a common mechanism of resistance to earlier-generation BCR-ABL tyrosine kinase inhibitors (TKIs). Promising early efficacy of the combination of chemotherapy plus ponatinib has been reported in adults with Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL), although long-term safety and durability of responses is less well-established. Methods: Adults with newly diagnosed Ph+ ALL and those who had received ≤2 courses of prior chemotherapy with or without TKIs were eligible. Patients (pts) received 8 cycles of hyper-CVAD alternating with high-dose methotrexate/cytarabine approximately every 21 days. Initially, ponatinib was given at 45 mg daily for the first 14 days of cycle 1 then continuously for the subsequent cycles. Rituximab was administered during the first 4 cycles in pts with CD20 expression ≥ 20%; pts also received 12 doses of prophylactic intrathecal chemotherapy with alternating methotrexate and cytarabine. Pts in complete remission (CR) received maintenance with ponatinib daily with vincristine/prednisone monthly for 2 years, followed by ponatinib indefinitely. Due to concern for vascular toxicity with long-term use of high-dose ponatinib, the protocol was amended after 37 pts were treated; this amendment reduced ponatinib to 30 mg starting at cycle 2 with further reduction to 15 mg once a complete molecular response (CMR) was achieved. The primary endpoint for the study was event-free survival (EFS); secondary endpoints included response rates, overall survival (OS), and safety. Results: The baseline characteristics of the 86 treated pts are shown in Table 1. The median age was 46 years (range, 21-80). Twenty pts (23%) were ≥60 years of age. Thirty-nine pts (45%) had at least one baseline cardiovascular risk factors (hypertension, diabetes, dyslipidemia, coronary artery disease, and/or peripheral arterial disease). Of 68 pts with active disease at enrollment, all pts achieved CR. The 3-month CMR rate was 74%, and overall CMR rate was 84%. There were no early deaths. Eighteen pts (21%) underwent hematopoietic stem cell transplantation (HSCT) in first remission. With a median follow-up of 43 months (range, 2-92 months), 61 pts (71%) remain alive in remission. The 3-year continuous CR, EFS and OS rates were 84%, 70%, and 78%, respectively, and estimated 5-year continuous CR, EFS and OS rates were 84%, 68%, and 73%, respectively (Figure 1A-B). Eleven pts (13%) relapsed after a median of 20 months in remission (range, 5 to 64 months). Six pts relapsed while on another TKI, 2 pts while not on a TKI, and 3 pts while still on ponatinib. Of the 3 relapses on ponatinib, 2 pts were found to have an E255K ABL1 kinase domain mutation and 1 pt had no mutation identified. A 6-month landmark analysis showed a trend for better OS in pts who did not undergo HSCT in first remission. The 3-year OS rate was 66% for pts who underwent HSCT (n=18) and 90% for pts who did not undergo HSCT (n=57; P=0.07). The treatment was overall well-tolerated with most adverse events being Grade 1-2. Overall, 37% of pts required dose reductions of ponatinib due to adverse events; the most common causes included rash (n=7), liver function test abnormalities (n=5), pancreatitis (n=3), deep vein thrombosis (n=2), and thrombocytopenia (n=2). Nine pts (10%) died in CR. Two ponatinib-related deaths from myocardial infarction were observed in pts treated before the protocol amendment to use lower doses of ponatinib; no further ponatinib-related deaths occurred after this amendment. Conclusions: In pts with newly diagnosed Ph+ ALL, the combination of hyper-CVAD plus ponatinib resulted in sustained responses with a CMR rate of 84% and an estimated 5-year OS rate of 73%. Among pts who did not undergo HSCT in first remission, the 3-year OS rate was 90%. Future studies are needed to determine whether the incorporation of effective novel agents such as blinatumomab into frontline regimens will allow for reduction of chemotherapy while also deepening responses and increasing the proportion of pts with Ph+ ALL who are cured without need for HSCT. Disclosures Short: AstraZeneca: Consultancy; Amgen: Honoraria; Takeda Oncology: Consultancy, Research Funding. Kantarjian:Novartis: Research Funding; Actinium: Honoraria, Membership on an entity's Board of Directors or advisory committees; Jazz Pharma: Research Funding; Immunogen: Research Funding; Amgen: Honoraria, Research Funding; Takeda: Honoraria; AbbVie: Honoraria, Research Funding; Agios: Honoraria, Research Funding; Ariad: Research Funding; Astex: Research Funding; Cyclacel: Research Funding; BMS: Research Funding; Daiichi-Sankyo: Research Funding; Pfizer: Honoraria, Research Funding. Ravandi:Selvita: 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; Xencor: Consultancy, Research Funding. Daver:Abbvie: Consultancy, Research Funding; Celgene: Consultancy; Genentech: Consultancy, Research Funding; Incyte: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Karyopharm: Consultancy, Research Funding; NOHLA: Research Funding; BMS: Consultancy, Research Funding; Immunogen: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Agios: Consultancy; Servier: Research Funding; Otsuka: Consultancy; Astellas: Consultancy; Forty-Seven: Consultancy; Daiichi Sankyo: Consultancy, Research Funding; Hanmi Pharm Co., Ltd.: Research Funding; Jazz: Consultancy; Sunesis: Consultancy, Research Funding; Glycomimetics: Research Funding. DiNardo:medimmune: Honoraria; abbvie: Consultancy, Honoraria; syros: Honoraria; daiichi sankyo: Honoraria; jazz: Honoraria; notable labs: Membership on an entity's Board of Directors or advisory committees; celgene: Consultancy, Honoraria; agios: Consultancy, Honoraria. Konopleva:Agios: Research Funding; Calithera: Research Funding; Stemline Therapeutics: Consultancy, Honoraria, Research Funding; Forty-Seven: Consultancy, Honoraria; 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. Pemmaraju:mustangbio: Consultancy, Research Funding; abbvie: Consultancy, Honoraria, Research Funding; samus: Research Funding; celgene: Consultancy, Honoraria; cellectis: Research Funding; Stemline Therapeutics: Consultancy, Honoraria, Research Funding; novartis: Consultancy, Research Funding; plexxikon: Research Funding; Daiichi-Sankyo: Research Funding; sagerstrong: Research Funding; affymetrix: Research Funding; incyte: Consultancy, Research Funding. Wierda:Juno Therapeutics: Research Funding; Acerta Pharma Inc: Research Funding; Gilead Sciences: Research Funding; Pharmacyclics LLC: Research Funding; Genentech: Research Funding; AbbVie: Research Funding; GSK/Novartis: Research Funding; Oncternal Therapeutics Inc.: Research Funding; Cyclcel: Research Funding; Loxo Oncology Inc.: Research Funding; Janssen: Research Funding; Xencor: Research Funding; KITE pharma: Research Funding; Sunesis: Research Funding; Miragen: 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. Sasaki:Otsuka: Honoraria; Pfizer: Consultancy. Cortes:Jazz Pharmaceuticals: Consultancy, Research Funding; Sun Pharma: Research Funding; Immunogen: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Research Funding; BiolineRx: Consultancy; Forma Therapeutics: Consultancy, Honoraria, Research Funding; Merus: Consultancy, Honoraria, Research Funding; Biopath Holdings: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Research Funding; Daiichi Sankyo: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Astellas Pharma: Consultancy, Honoraria, Research Funding. Khoury:Stemline Therapeutics: Research Funding; Angle: Research Funding; Kiromic: Research Funding. Jain: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; Servier: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Incyte: Research Funding; Pharmacyclics, an AbbVie company: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Cellectis: Research Funding; Janssen Pharmaceuticals, Inc.: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Genentech: 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; Adaptive Biotechnologies: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Research Funding; AstraZeneca: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. O'Brien:Pfizer: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Honoraria; Acerta: Research Funding; Alexion: Consultancy; Amgen: Consultancy; Aptose Biosciences, Inc: Consultancy; Astellas: Consultancy; Celgene: Consultancy; Eisai: Consultancy; Gilead: Consultancy, Research Funding; GlaxoSmithKline: Consultancy; Kite: Research Funding; Janssen: Consultancy, Honoraria; Pharmacyclics LLC, an AbbVie Company: Consultancy, Research Funding; Regeneron: Research Funding; Sunesis: Consultancy, Research Funding; TG Therapeutics: Consultancy, Research Funding; Vaniam Group LLC: Consultancy; Verastem: Consultancy. Jabbour:Cyclacel LTD: Research Funding; Amgen: Consultancy, Research Funding; AbbVie: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Adaptive: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Takeda: Consultancy, Research Funding. OffLabel Disclosure: The use of ponatinib as frontline therapy for patients with Ph+ ALL.

Description: Background: For patients (pts) with Philadelphia chromosome (Ph)-negative B-cell acute lymphoblastic leukemia (ALL), combination chemotherapy achieves complete remission rates of 80-90%; however, many pts ultimately relapse, leading to a cure rate of only 40-50%. Blinatumomab is highly effective in both the relapsed/refractory setting and for eradication of measurable residual disease (MRD). We hypothesized that early incorporation of blinatumomab in pts with newly diagnosed Ph-negative B-cell ALL would decrease the need for intensive chemotherapy, lead to deeper and more durable responses, and improve survival. Methods: Pts 14-59 years of age with newly diagnosed Ph-negative pre-B-cell ALL, including pts who had received no more than 1 prior cycle of chemotherapy, were eligible. Pts were required to have a performance status of ≤3, total bilirubin ≤2 mg/dl and creatinine ≤2 mg/dl. Pts received hyper-CVAD alternating with high-dose methotrexate and cytarabine for up to 4 cycles, followed by 4 cycles of blinatumomab at standard doses. Pts with CD20+ disease (≥1% cells) received 8 doses of ofatumumab (2000 mg) or rituximab (375 mg/m2). Eight administrations of prophylactic IT chemotherapy were given in the first 4 cycles. Maintenance was with alternating blocks of POMP (given in maintenance cycles 1-3, 5-7, 9-11, and 13-15) and blinatumomab (given in maintenance cycles 4, 8, and 12). After 2 pts with high-risk features experienced early relapse prior to blinatumomab administration, for pts #10+ the protocol was amended so that pts with high-risk disease features (e.g. CRLF2+ by flow cytometry, complex karyotype, KMT2A rearranged, low-hypodiploidy/near triploidy, TP53 mutation, or persistent MRD) started blinatumomab after 2 cycles of hyper-CVAD. Results: 39 pts have been treated, 34 of whom are evaluable for efficacy (5 too early for assessment). 6 pts were in complete remission (CR) at enrollment and unevaluable for morphologic response. Pt characteristics of the 34 evaluable pts are summarized in Table 1. Median age was 36 years (range, 17-59 years). At least one high-risk feature was present in 19 pts (56%), including TP53 mutation in 27%, CRLF2+ in 20%, and an adverse-risk karyotype in 26%. 82% of pts received ofatumumab or rituximab. Among 28 pts with active disease at study entry, 100% achieved CR, with 82% achieving CR after the first cycle. MRD negativity by 6-color flow cytometry was achieved in 20/23 responding pts (87%) after 1 cycle and 33/34 pts (97%) overall. There were no early deaths, and the 60-day mortality rate was 0%. With a median follow-up of 22 months (range, 1-40 months), the 2-year continuous remission and OS rates were 79% and 86%, respectively (Figure 1). Overall, 5 pts (15%) relapsed, 12 (35%) underwent allogeneic SCT in first remission (including 1 additional pt who relapsed post-SCT), and 17 (50%) remain in continuous remission and are currently on treatment or have completed maintenance. All relapses occurred in pts with established poor-risk features, including 2 pts with KMT2A rearrangement, 2 pts with TP53 mutation (1 of whom was low hypodiploid), and 1 pt with baseline WBC count of 32 x 109/L. Two of these relapses occurred during hyper-CVAD cycles before the amendment allowing for earlier integration of blinatumomab for pts with high-risk disease features. Treatment was overall well-tolerated. Four pts developed grade 2-3 cytokine release syndrome (grade 2, n=3; grade 3, n=1) which resolved with corticosteroids and interruption of blinatumomab. Overall, 14 (41%) pts had a neurological AE of any grade due to blinatumomab. Only one pt discontinued blinatumomab due to blinatumomab-related adverse event (grade 2 encephalopathy and dysphasia). Conclusion: Sequential combination of hyper-CVAD and blinatumomab is highly effective as frontline treatment of Ph-negative B-cell ALL, with a CR rate of 100% and 97% of pts achieving MRD negativity. Survival data are promising with an estimated 2-year OS of 86%, which compares favorably to historical controls. This study continues to accrue pts. Disclosures Short: Astellas: Research Funding; Amgen: Honoraria; AstraZeneca: Consultancy; Takeda Oncology: Consultancy, Honoraria, Research Funding. Kantarjian:Jazz: Research Funding; Novartis: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding; Daiichi-Sankyo: Honoraria, Research Funding; Oxford Biomedical: Honoraria; Aptitute Health: Honoraria; BioAscend: Honoraria; Delta Fly: Honoraria; Janssen: Honoraria; Actinium: Honoraria, Membership on an entity's Board of Directors or advisory committees; Immunogen: Research Funding; BMS: Research Funding; Adaptive biotechnologies: Honoraria; Abbvie: Honoraria, Research Funding; Sanofi: Research Funding; Amgen: Honoraria, Research Funding; Ascentage: Research Funding. Ravandi:Astellas: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding; Macrogenics: Research Funding; AstraZeneca: Consultancy, Honoraria; Jazz Pharmaceuticals: Consultancy, Honoraria, Research Funding; Xencor: Consultancy, Honoraria, Research Funding; Orsenix: Consultancy, Honoraria, Research Funding; Abbvie: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria; BMS: Consultancy, Honoraria, Research Funding. Kadia:Abbvie: Honoraria, Research Funding; BMS: Honoraria, Research Funding; Cyclacel: Research Funding; Astellas: Research Funding; Cellenkos: Research Funding; Pfizer: Honoraria, Research Funding; Celgene: Research Funding; Pulmotec: Research Funding; Amgen: Research Funding; Genentech: Honoraria, Research Funding; Ascentage: Research Funding; Incyte: Research Funding; JAZZ: Honoraria, Research Funding; Novartis: Honoraria; Astra Zeneca: Research Funding. Thompson:Pharmacyclics: Research Funding; Adaptive Biotechnologies: Consultancy, Research Funding; Genentech: Consultancy; Janssen-Cilag: Honoraria; AbbVie: Research Funding. Alvarado:Tolero Pharmaceuticals: Research Funding; Daiichi-Sankyo: Research Funding; Astex Pharmaceuticals: Research Funding; Jazz Pharmaceuticals: Research Funding; Sun Pharma: Research Funding; BerGenBio ASA: Research Funding; MEI Pharma: Research Funding; FibroGen: Research Funding. Jain:Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Precision Bioscienes: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Fate Therapeutics: Research Funding; AstraZeneca: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pharmacyclics: 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; Genentech: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Research Funding; Pfizer: Research Funding; ADC Therapeutics: Research Funding; Incyte: Research Funding; Servier: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Cellectis: Research Funding; Verastem: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Adaptive Biotechnologies: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; TG Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees; BeiGene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Aprea Therapeutics: Research Funding. Yilmaz:Pint Pharma: Honoraria; Pfizer: Research Funding; Daicho Sankyo: Research Funding. Konopleva:Calithera: Research Funding; Genentech: Consultancy, Research Funding; Amgen: Consultancy; 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; Agios: Research Funding; AstraZeneca: Research Funding; Cellectis: Research Funding; Stemline Therapeutics: Consultancy, Research Funding; Forty-Seven: Consultancy, Research Funding; Rafael Pharmaceutical: Research Funding; Eli Lilly: Research Funding; AbbVie: Consultancy, Research Funding; Ascentage: Research Funding; F. Hoffmann La-Roche: Consultancy, Research Funding; Kisoji: Consultancy; Sanofi: Research Funding; Ablynx: Research Funding. Garcia-Manero:AbbVie: Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Astex Pharmaceuticals: Consultancy, Honoraria, Research Funding; Acceleron Pharmaceuticals: Consultancy, Honoraria; Amphivena Therapeutics: Research Funding; Jazz Pharmaceuticals: Consultancy; Merck: Research Funding; H3 Biomedicine: Research Funding; Helsinn Therapeutics: Consultancy, Honoraria, Research Funding; Novartis: Research Funding; Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Onconova: Research Funding. O'Brien:Amgen, Astellas, Celgene, GlaxoSmithKline, Janssen Oncology, Aptose Biosciences Inc. Vaniam Group, AbbVie, Alexion, Verastem, Eisai, Juno Therapeutics, Vida Ventures: Consultancy; Kite, Regeneron, Acerta: Research Funding; Gilead, Pharmacyclics, TG Therapeutics, Pfizer, Sunesis: Consultancy, Research Funding. Jabbour:Takeda: Other: Advisory role, Research Funding; AbbVie: Other: Advisory role, Research Funding; Pfizer: Other: Advisory role, Research Funding; Genentech: Other: Advisory role, Research Funding; BMS: Other: Advisory role, Research Funding; Adaptive Biotechnologies: Other: Advisory role, Research Funding; Amgen: Other: Advisory role, Research Funding. OffLabel Disclosure: Blinatumomab - frontline therapy for ALL

Description: Background: Inotuzumab ozogamicin (INO) and blinatumomab both improve overall survival (OS) in relapsed or refractory B-cell acute lymphoblastic leukemia (ALL). Use of these effective monoclonal antibodies in the frontline setting may lead to deep and durable remissions in older adults with newly diagnosed Philadelphia chromosome (Ph)-negative B-cell ALL. Methods: Patients (pts) ≥60 years of age with newly diagnosed Ph-negative pre-B-cell ALL, including pts who had received no more than 1 prior cycle of chemotherapy, were eligible. Pts were required to have a performance status of ≤3, total bilirubin ≤1.5 mg/dl, AST/ALT ≤3x ULN and creatinine ≤2 mg/dl. Pts received mini-hyper-CVD (cyclophosphamide and dexamethasone at 50% dose reduction, no anthracycline, methotrexate at 75% dose reduction, cytarabine at 0.5 g/m2 x 4 doses) for up to 8 cycles. INO was initially given at a dose of 1.3-1.8mg/m2 on day 3 of cycle 1 and 0.8-1.3mg/m2 on day 3 of cycles 2-4. Rituximab (if CD20+) and prophylactic IT chemotherapy were given for the first 4 cycles. Responding pts received POMP maintenance for up to 3 years. In order to decrease the risk of veno-occlusive disease (VOD), the protocol was amended in 3/2017 (pts 50+) to give INO in fractionated doses each cycle (0.6 mg/m2 on day 2 and 0.3 mg/m2 on day 8 of cycle 1; 0.3 mg/m2 on day 2 and 8 of cycles 2-4) and to administer 4 cycles of blinatumomab following 4 cycles of hyper-CVD plus INO, followed by maintenance with 12 cycles of POMP and 4 cycles of blinatumomab (1 cycle of blinatumomab after every 3 cycles of POMP). The cumulative dose of INO given before and after this most recent amendment was 4.3 mg/m2 and 2.7 mg/m2, respectively. Results: 73 pts have been treated, 70 of whom are evaluable for efficacy (3 pts too early for response assessment). 6 pts were in complete remission (CR) at enrollment and unevaluable for morphological response. Pt characteristics of the 70 evaluable pts are summarized in Table 1. Median age was 68 years (range, 60-81 years); 29 pts (41%) were ≥70 years. 41% were positive for TP53 mutation, 18% were CRLF2 positive by flow cytometry, and 27% had adverse-risk karyotype. 38/64 pts (59%) were CD20+ and received rituximab. Among 64 pts evaluable for morphologic response, 63 (98%) responded (CR, n=56; CRp, n=6; CRi, n=1). MRD negativity by flow cytometry was achieved in 53/66 pts (80%) after 1 cycle and 65/68 pts (96%) overall. There were no early deaths, and the 30-day and 60-day mortality rates were 0% and 3%, respectively. Among 69 pts who achieved remission, 9 (13%) relapsed, 3 (4%) underwent allogeneic SCT in first remission (1 of whom subsequently relapsed), 35 (51%) remain on treatment or have completed therapy, and 21 (32%) died in CR/CRp. Notably, 6 pts (9%) developed VOD, 1 after subsequent allogeneic SCT. The rate of VOD was 6/70 (9%) with no difference in rate of VOD in pts who did or did not receive fractionated INO and blinatumomab. With a median follow-up of 45 months (range, 2-98 months), the 4-year continuous remission and OS rates were 78% and 50%, respectively (Figure 1A). Age and cytogenetic risk were the primary factors associated with OS. The 4-year OS rate was 61% in pts 60-69 years vs. 34% in pts ≥70 years (P=0.06), driven by higher rates of death in remission in the older pts (13/29 [45%] vs. 8/41 [20%] in pts 60-69 years of age; P=0.03). These remission deaths in pts ≥70 years were primarily due to infection (n=7) or development of MDS/AML (n=3). Pts with high-risk cytogenetic features (e.g. KMT2A rearranged, low hypodiploidy/near triploidy, complex cytogenetics) had a 4-year OS rate of 22% vs. 57% for patients without high-risk cytogenetic features (Figure 1B; P=0.009). Neither CRLF2 positivity by flow cytometry nor the presence of a TP53 mutation significantly impacted OS. Conclusion: Reduced-intensity chemotherapy with hyper-CVD plus INO, with or without blinatumomab, is safe and effective in older adults with newly diagnosed Ph-negative ALL, with an overall response rate of 98% and 4-year OS rate of 50%. This novel regimen leads to durable remissions and apparent cure in the majority of pts age 60-69 years of age and in those without poor-risk cytogenetic features. To decrease treatment-related mortality, the protocol has been amended to eliminate chemotherapy for pts ≥70 years of age. Disclosures Short: Amgen: Honoraria; Takeda Oncology: Consultancy, Honoraria, Research Funding; Astellas: Research Funding; AstraZeneca: Consultancy. Kantarjian:Janssen: Honoraria; Abbvie: Honoraria, Research Funding; Immunogen: Research Funding; Oxford Biomedical: Honoraria; Delta Fly: Honoraria; Adaptive biotechnologies: Honoraria; Aptitute Health: Honoraria; Daiichi-Sankyo: Honoraria, Research Funding; BioAscend: Honoraria; Actinium: Honoraria, Membership on an entity's Board of Directors or advisory committees; Ascentage: Research Funding; Amgen: Honoraria, Research Funding; Jazz: Research Funding; Sanofi: Research Funding; Pfizer: Honoraria, Research Funding; BMS: Research Funding; Novartis: Honoraria, Research Funding. Ravandi:Celgene: Consultancy, Honoraria; Orsenix: Consultancy, Honoraria, Research Funding; Astellas: Consultancy, Honoraria, Research Funding; AstraZeneca: Consultancy, Honoraria; Jazz Pharmaceuticals: Consultancy, Honoraria, Research Funding; Xencor: Consultancy, Honoraria, Research Funding; Macrogenics: Research Funding; Amgen: Consultancy, Honoraria, Research Funding; BMS: Consultancy, Honoraria, Research Funding; Abbvie: Consultancy, Honoraria, Research Funding. Jain:Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Fate Therapeutics: Research Funding; Aprea Therapeutics: Research Funding; Servier: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Cellectis: Research Funding; Verastem: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Adaptive Biotechnologies: 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; Pfizer: Research Funding; BMS: Research Funding; AstraZeneca: 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; ADC Therapeutics: Research Funding; Incyte: Research Funding; Pharmacyclics: 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; TG Therapeutics: 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, Research Funding. Kadia:JAZZ: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding; BMS: Honoraria, Research Funding; Abbvie: Honoraria, Research Funding; Novartis: Honoraria; Astra Zeneca: Research Funding; Cyclacel: Research Funding; Ascentage: Research Funding; Genentech: Honoraria, Research Funding; Amgen: Research Funding; Cellenkos: Research Funding; Celgene: Research Funding; Astellas: Research Funding; Incyte: Research Funding; Pulmotec: Research Funding. Alvarado:FibroGen: Research Funding; Astex Pharmaceuticals: Research Funding; Daiichi-Sankyo: Research Funding; Sun Pharma: Research Funding; MEI Pharma: Research Funding; Tolero Pharmaceuticals: Research Funding; BerGenBio ASA: Research Funding; Jazz Pharmaceuticals: Research Funding. Burger:Janssen Pharmaceuticals: Consultancy, Speakers Bureau; TG Therapeutics: Research Funding, Speakers Bureau; AstraZeneca: Consultancy; Pharmacyclics, an AbbVie company: Consultancy, Research Funding, Speakers Bureau; Beigene: Research Funding, Speakers Bureau; Gilead Sciences: Consultancy, Research Funding. Daver: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; 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; Daiichi Sankyo: 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; 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; 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. Borthakur:Abbvie: Research Funding; Jannsen: Research Funding; Xbiotech USA: Research Funding; Polaris: Research Funding; BMS: Research Funding; Oncoceutics: Research Funding; Curio Science LLC: Consultancy; AstraZeneca: Research Funding; Novartis: Research Funding; Incyte: Research Funding; PTC Therapeutics: Consultancy; Argenx: Consultancy; BioTherix: Consultancy; Nkarta Therapeutics: Consultancy; Treadwell Therapeutics: Consultancy; PTC Therapeutics: Research Funding; GSK: Research Funding; FTC Therapeutics: Consultancy; Cyclacel: Research Funding; BioLine Rx: Consultancy; BioLine Rx: Research Funding. DiNardo:Novartis: Consultancy; ImmuneOnc: Honoraria; Syros: Honoraria; Daiichi Sankyo: Consultancy, Honoraria, Research Funding; MedImmune: Honoraria; Celgene: Consultancy, Honoraria, Research Funding; Calithera: Research Funding; Notable Labs: Membership on an entity's Board of Directors or advisory committees; Agios: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Honoraria, Research Funding; Takeda: Honoraria; Jazz: Honoraria. Konopleva:Forty-Seven: Consultancy, Research Funding; AbbVie: Consultancy, Research Funding; Cellectis: Research Funding; Stemline Therapeutics: Consultancy, Research Funding; AstraZeneca: Research Funding; Amgen: Consultancy; Ablynx: Research Funding; Agios: Research Funding; Ascentage: Research Funding; Eli Lilly: Research Funding; Calithera: Research Funding; Sanofi: Research Funding; Genentech: Consultancy, Research Funding; Kisoji: Consultancy; Rafael Pharmaceutical: 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; F. Hoffmann La-Roche: Consultancy, Research Funding. Pemmaraju:Plexxikon: Research Funding; Cellectis: Research Funding; Daiichi Sankyo: Research Funding; Samus Therapeutics: Research Funding; Incyte Corporation: Honoraria; Pacylex Pharmaceuticals: Consultancy; Celgene: Honoraria; AbbVie: Honoraria, Research Funding; Blueprint Medicines: Honoraria; Affymetrix: Other: Grant Support, Research Funding; SagerStrong Foundation: Other: Grant Support; Stemline Therapeutics: Honoraria, Research Funding; LFB Biotechnologies: Honoraria; DAVA Oncology: Honoraria; Novartis: Honoraria, Research Funding; Roche Diagnostics: Honoraria; MustangBio: Honoraria. Garcia-Manero:Jazz Pharmaceuticals: Consultancy; Bristol-Myers Squibb: Consultancy, Research Funding; Acceleron Pharmaceuticals: Consultancy, Honoraria; Helsinn Therapeutics: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Amphivena Therapeutics: Research Funding; Merck: Research Funding; Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Honoraria, Research Funding; Astex Pharmaceuticals: Consultancy, Honoraria, Research Funding; Novartis: Research Funding; H3 Biomedicine: Research Funding; Onconova: Research Funding. O'Brien: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; Kite, Regeneron, Acerta: Research Funding. Jabbour:Amgen: Other: Advisory role, Research Funding; BMS: Other: Advisory role, Research Funding; Genentech: Other: Advisory role, Research Funding; AbbVie: Other: Advisory role, Research Funding; Adaptive Biotechnologies: Other: Advisory role, Research Funding; Takeda: Other: Advisory role, Research Funding; Pfizer: Other: Advisory role, Research Funding. OffLabel Disclosure: Inotuzumab ozogamicin and blinatumomab - frontline treatment of ALL