Citations

Background: Mutations in isocitrate dehydrogenase 1 (IDH1) occur in ~3% of individuals with myelodysplastic syndrome (MDS) and have been associated with increased transformation to acute myeloid leukemia (AML). Ivosidenib (AG-120) is an oral, potent, targeted inhibitor of the mutant isocitrate dehydrogenase 1 enzyme (mIDH1) and is approved in the US for the treatment of newly diagnosed AML with a susceptible IDH1 mutation in patients ≥75 years of age or who have comorbidities that preclude the use of intensive induction chemotherapy, and in adult patients with relapsed or refractory (R/R) AML. The first-in-human, phase 1 dose escalation and expansion study of ivosidenib (NCT02074839) enrolled adults with mIDH1 advanced hematologic malignancies, including R/R MDS, and the study is ongoing. In the initial phase of the study (DiNardo et al. N Engl J Med 2018), the 12 patients with R/R MDS received 500 mg ivosidenib once daily and were characterized as follows: 75% were male, median age was 72.5 years (range 52-78), and 42% were ≥75 years of age; median number of prior therapies was 1 (range 1-3). Adverse events (AEs) of any grade, irrespective of causality, occurring in ≥20% of the 12 patients were diarrhea, fatigue, back pain, rash (n=4 each, 33.3%), anemia, urinary tract infection, decreased appetite, hypokalemia, arthralgia, dyspnea, pruritus, and hypotension (n=3 each, 25.0%). No AEs led to permanent discontinuation of treatment. Response was assessed according to International Working Group 2006 criteria for MDS. According to investigators, five of 12 patients achieved complete remission (CR) (41.7%; 95% CI 15.2%, 72.3%); median duration of CR was not estimable for these patients (95% CI 2.8 months, not estimable). Nine of 12 patients were transfusion independent for at least 56 days during study treatment. Mutation clearance was observed in one of the 5 CR patients. Here we report the design of a new sub-study of this trial, which is being undertaken to further assess the safety, tolerability, and clinical activity of treatment with ivosidenib in patients with R/R MDS. Methods: This sub-study is evaluating the safety, tolerability, pharmacokinetics, pharmacodynamics, and clinical activity of ivosidenib. Adults with R/R MDS with an IDH1 mutation will be enrolled in the MDS sub-study. These individuals must have R/R disease after treatment with standard agents indicated for MDS. Eligible patients must have a platelet count of ≥20,000/μL, and adequate hepatic function (total bilirubin ≤1.5 × upper limit of normal [ULN]; aspartate aminotransferase, alanine aminotransferase, and alkaline phosphatase ≤3.0 × ULN) and renal function (serum creatinine ≤2.0 × ULN or creatinine clearance >40 mL/min). Additional key inclusion criteria are bone marrow blasts >5% and/or transfusion dependence. Ivosidenib is to be administered at a dose of 500 mg once daily orally on Days 1 to 28 of 28-day cycles. The addition of the MDS sub-study to this phase 1 clinical study in patients with hematological malignancies will provide additional insights into the use of ivosidenib for the treatment of mIDH1 R/R MDS. Disclosures Foran: Agios: Honoraria, Research Funding. DiNardo:notable labs: Membership on an entity's Board of Directors or advisory committees; medimmune: Honoraria; daiichi sankyo: Honoraria; abbvie: Consultancy, Honoraria; agios: Consultancy, Honoraria; jazz: Honoraria; celgene: Consultancy, Honoraria; syros: Honoraria. Watts:Takeda: Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Stein:Agios: Consultancy, Membership on an entity's Board of Directors or advisory committees; Astellas Pharma US, Inc: Membership on an entity's Board of Directors or advisory committees; Celgene Corporation: Membership on an entity's Board of Directors or advisory committees; Daiichi Sankyo, Inc.: Membership on an entity's Board of Directors or advisory committees; Bioline: Membership on an entity's Board of Directors or advisory committees; Genentech: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; PTC Therapeutics: Membership on an entity's Board of Directors or advisory committees; Syros: Membership on an entity's Board of Directors or advisory committees. De Botton:Daiichi Sankyo: Consultancy; Astellas: Consultancy; Bayer: Consultancy; AbbVie: Consultancy; Syros: Consultancy; Forma: Consultancy, Research Funding; Janssen: Consultancy; Novartis: Consultancy; Pfizer: Consultancy; Servier: Consultancy; Pierre Fabre: Consultancy; Celgene: Consultancy, Speakers Bureau; Agios: Consultancy, Research Funding. Fathi:Amphivena, Kite, Jazz, NewLink Genetics,: Honoraria; Agios, Astellas, Celgene, Daiichi Sankyo, Novartis, Takeda, Amphivena, Kite, Forty Seven,Trovagene, NewLink genetics, Jazz, Abbvie, and PTC Therapeutics: Consultancy. Stein:Stemline: Speakers Bureau; Amgen: Consultancy, Speakers Bureau; Celgene: Speakers Bureau. Stone:AbbVie, Actinium, Agios, Argenx, Arog, Astellas, AstraZeneca, Biolinerx, Celgene, Cornerstone Biopharma, Fujifilm, Jazz Pharmaceuticals, Amgen, Ono, Orsenix, Otsuka, Merck, Novartis, Pfizer, Sumitomo, Trovagene: Consultancy; Argenx, Celgene, Takeda Oncology: Other: Data and Safety Monitoring Board/Committee: ; Novartis, Agios, Arog: Research Funding. Patel:France Foundation: Honoraria; Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Dava Oncology: Honoraria. Tallman:UpToDate: Patents & Royalties; Daiichi-Sankyo: Consultancy, Membership on an entity's Board of Directors or advisory committees; BioLineRx: Consultancy, Membership on an entity's Board of Directors or advisory committees; Rigel: Consultancy, Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; Cellerant: Research Funding; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Delta Fly Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees; Nohla: Consultancy, Membership on an entity's Board of Directors or advisory committees; ADC Therapeutics: Research Funding; Tetraphase: 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, Research Funding; Biosight: Research Funding; Oncolyze: Consultancy, Membership on an entity's Board of Directors or advisory committees; KAHR: Consultancy, Membership on an entity's Board of Directors or advisory committees. Choe:Agios: Employment, Equity Ownership; Agios: Employment, Equity Ownership. Wang:Agios: Employment, Equity Ownership. Zhang:Agios: Employment, Equity Ownership; Agios: Employment, Equity Ownership. Fan:Agios: Employment, Equity Ownership. Yen:Agios: Employment, Equity Ownership. Oluyadi:Agios: Employment, Equity Ownership. Winkler:Agios: Employment. Hickman:Agios: Employment, Equity Ownership. Agresta:Agios: Employment, Equity Ownership. Liu:Agios: Employment, Equity Ownership. Wu:Agios: Employment, Equity Ownership. Attar:Aprea Therapeutics: Employment; Agios: Employment, Equity Ownership. Kantarjian:Astex: Research Funding; Takeda: Honoraria; Actinium: Honoraria, Membership on an entity's Board of Directors or advisory committees; Immunogen: Research Funding; AbbVie: Honoraria, Research Funding; Jazz Pharma: Research Funding; Agios: Honoraria, Research Funding; Ariad: Research Funding; Amgen: Honoraria, Research Funding; Cyclacel: Research Funding; BMS: Research Funding; Daiichi-Sankyo: Research Funding; Novartis: Research Funding; Pfizer: Honoraria, Research Funding. OffLabel Disclosure: Ivosidenib (AG-120) is an IDH1 inhibitor indicated for the treatment of AML with a susceptible IDH1 mutation as detected by an FDA-approved test in: 1) adult patients with newly-diagnosed AML who are more than 75 years old or who have comorbidities that preclude use of intensive induction chemotherapy and 2) adult patients with relapsed or refractory AML. It is being evaluated in clinical trials for mutant IDH1 advanced hematologic malignancies.

Background : CD47 is a transmembrane protein ubiquitously expressed in human cells. CD47 is overexpressed in various malignancies and is correlated with negative prognosis in AML and MDS (Chao et al. Curr Opin Immunol.2012; Majeti et al. Cell.2009). Interaction of CD47 with signal-regulatory protein alpha (SIRPα) expressed on macrophages inhibits phagocytosis (Kim et al. Leukemia.2012). CC-90002, a humanized anti-CD47 monoclonal antibody, blocks CD47/SIRPα interactions, thereby enabling macrophage-mediated killing of tumor cells. In preclinical studies, CC-90002 demonstrated antibody-mediated phagocytosis of several hematologic cancer cell lines, including AML cells. CC-90002 also demonstrated a rapid and substantial reduction in tumor burden in AML xenograft models. Herein, we report results from CC-90002-AML-001 evaluating CC-90002 in patients (pts) with R/R AML and high-risk MDS. Methods : In this phase I multicenter study (NCT02641002), CC-90002 was administered intravenously once/week for 4 weeks of each 42-day cycle during cycles 1−4 then once every 4 weeks during a maintenance phase of 28-day cycles. Pts were enrolled in cohorts of escalating dose levels using a modified 3+3 design. The primary objectives were to determine preliminary safety and tolerability, non-tolerated dose (NTD), maximum tolerated dose (MTD), and/or recommended phase 2 dose. Secondary objectives were to measure preliminary efficacy, pharmacokinetics, and the presence and frequency of anti-drug antibodies (ADAs). Results: As of July 18, 2018, 24 pts with R/R AML and 4 pts with high-risk R/R MDS were enrolled. Pts received CC-90002 at 0.1 mg/kg (n=6), 0.3 mg/kg (n=6), 1 mg/kg (n=6), 2 mg/kg (n=4), and 4 mg/kg (n=6). Median age was 70 years (range, 28-85) and 16 (57%) were male. The most common AML subtypes were AML with myelodysplasia-related changes (n=9) and AML not otherwise specified (n=9). All 4 pts with MDS were classified as having refractory anemia with excess blasts-2 and high- or very high-risk disease per the Revised International Prognostic Index Scoring System. The median number of prior systemic anticancer regimens was 3 (range, 1-10), and 29% of pts had prior stem cell transplants. The median treatment duration was 6.9 weeks (range, 2-44). Four pts experienced a dose-limiting toxicity, consisting of grade 4 disseminated intravascular coagulation and grade 4 cerebral hemorrhage in 1 pt (0.1 mg/kg), grade 3 purpura in 1 pt (0.3 mg/kg), grade 4 congestive cardiac failure and grade 4 acute respiratory failure in 1 pt (1 mg/kg), and grade 4 sepsis in 1 pt (4 mg/kg). The most common (≥30%) any-grade treatment-emergent adverse events (TEAEs) were diarrhea (46%); thrombocytopenia (39%); febrile neutropenia and aspartate aminotransferase increased (36% each); and anemia, alanine aminotransferase increased, and cough (32% each). A total of 23 pts (82%) had serious TEAEs with febrile neutropenia (n=10), bacteremia (n=4), pneumonia (n=4), and general physical health deterioration (n=3) occurring in>2 pts. No TEAEs led to dose reductions; however, 7 pts (25%) discontinued due to TEAEs. Overall, 82% of pts were dependent on red blood cell (RBC) transfusions and CC-90002 treatment did not interfere with continued RBC transfusion in pts on study. No pts experienced hemolysis, tumor lysis syndrome, or macrophage activation/cytokine release syndrome. Sixteen pts died during the study. The best overall response observed was stable disease in 2 pts with MDS. CC-90002 serum exposures appeared to increase with doses above 0.3−4.0 mg/kg and the terminal half-life ranged from 4.6−17.0 hours. Development of ADAs targeting CC-90002 occurred at all dose levels tested and the proportion of pts testing positive for ADAs in cycle 1 increased over time (4/27 pts at day 8, 6/25 pts at day 15, and 8/22 pts at day 22). ADAs continued to be present across different doses with increases in median serum ADA titers after cycle 1. No apparent dose-ADA relationship was observed. Conclusion: CC-90002 showed a lack of objective responses in pts with R/R AML and high-risk MDS. The MTD and NTD were not established. The CC-90002-AML-001 study was discontinued in dose escalation for lack of preliminary monotherapy activity and evidence of ADAs in most pts. CC-90002 in combination with rituximab is being explored in CD20+ NHL to enhance efficacy of CD47 blockade while reducing ADAs (CC-90002-ST-001; NCT02367196). Disclosures Zeidan: BeyondSpring: Honoraria; Seattle Genetics: Honoraria; Acceleron Pharma: Consultancy, Honoraria, Research Funding; Celgene Corporation: Consultancy, Honoraria, Research Funding; Abbvie: Consultancy, Honoraria, Research Funding; Otsuka: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria, Research Funding; Medimmune/AstraZeneca: Research Funding; Boehringer-Ingelheim: Consultancy, Honoraria, Research Funding; Trovagene: Consultancy, Honoraria, Research Funding; Incyte: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Research Funding; ADC Therapeutics: Research Funding; Jazz: Honoraria; Ariad: Honoraria; Agios: Honoraria; Novartis: Honoraria; Astellas: Honoraria; Daiichi Sankyo: Honoraria; Cardinal Health: Honoraria. DeAngelo:Novartis: Consultancy, Research Funding; Jazz Pharmaceuticals Inc: Consultancy; Shire: Consultancy; Incyte: Consultancy; Blueprint: Consultancy, Research Funding; Pfizer: Consultancy; Amgen: Consultancy; GlycoMimetics: Research Funding; Celgene: Consultancy; Abbvie: Research Funding; Takeda Pharmaceuticals: Consultancy. Seet:University of California, Los Angeles: Employment. Tallman:Rigel: Consultancy, Membership on an entity's Board of Directors or advisory committees; Nohla: Consultancy, Membership on an entity's Board of Directors or advisory committees; BioLineRx: Consultancy, Membership on an entity's Board of Directors or advisory committees; Nohla: Consultancy, Membership on an entity's Board of Directors or advisory committees; Rigel: 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; ADC Therapeutics: Research Funding; Cellerant: Research Funding; Delta Fly Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees; Tetraphase: Consultancy, Membership on an entity's Board of Directors or advisory committees; ADC Therapeutics: Research Funding; Rigel: Consultancy, Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; UpToDate: Patents & Royalties; Oncolyze: Consultancy, Membership on an entity's Board of Directors or advisory committees; Delta Fly Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees; Cellerant: Research Funding; Nohla: Consultancy, Membership on an entity's Board of Directors or advisory committees; ADC Therapeutics: Research Funding; Delta Fly Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees; Oncolyze: Consultancy, Membership on an entity's Board of Directors or advisory committees; Delta Fly Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees; Cellerant: Research Funding; Delta Fly Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees; Biosight: Research Funding; Orsenix: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Biosight: Research Funding; Biosight: Research Funding; Daiichi-Sankyo: Consultancy, Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceuticals: 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; Jazz Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; KAHR: Consultancy, Membership on an entity's Board of Directors or advisory committees; UpToDate: Patents & Royalties; KAHR: Consultancy, Membership on an entity's Board of Directors or advisory committees; Oncolyze: Consultancy, Membership on an entity's Board of Directors or advisory committees; BioLineRx: Consultancy, Membership on an entity's Board of Directors or advisory committees; BioLineRx: Consultancy, Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; Oncolyze: 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; Tetraphase: Consultancy, Membership on an entity's Board of Directors or advisory committees; Rigel: Consultancy, Membership on an entity's Board of Directors or advisory committees; Biosight: Research Funding; Daiichi-Sankyo: 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; KAHR: Consultancy, Membership on an entity's Board of Directors or advisory committees; Rigel: 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, Research Funding; Jazz Pharmaceuticals: 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, Research Funding; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Tetraphase: Consultancy, Membership on an entity's Board of Directors or advisory committees; ADC Therapeutics: Research Funding; Rigel: Consultancy, Membership on an entity's Board of Directors or advisory committees; Nohla: Consultancy, Membership on an entity's Board of Directors or advisory committees; Tetraphase: Consultancy, Membership on an entity's Board of Directors or advisory committees; UpToDate: Patents & Royalties; Delta Fly Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees; Tetraphase: Consultancy, Membership on an entity's Board of Directors or advisory committees; ADC Therapeutics: Research Funding; UpToDate: Patents & Royalties; BioLineRx: Consultancy, Membership on an entity's Board of Directors or advisory committees; Biosight: Research Funding; Jazz Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; UpToDate: Patents & Royalties; Tetraphase: Consultancy, Membership on an entity's Board of Directors or advisory committees; Nohla: 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, Research Funding; Oncolyze: Consultancy, Membership on an entity's Board of Directors or advisory committees; UpToDate: Patents & Royalties; KAHR: 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, Research Funding; BioLineRx: Consultancy, Membership on an entity's Board of Directors or advisory committees; BioLineRx: Consultancy, Membership on an entity's Board of Directors or advisory committees; Nohla: Consultancy, Membership on an entity's Board of Directors or advisory committees; KAHR: Consultancy, Membership on an entity's Board of Directors or advisory committees; KAHR: Consultancy, Membership on an entity's Board of Directors or advisory committees; Oncolyze: Consultancy, Membership on an entity's Board of Directors or advisory committees; Biosight: Research Funding. Wei:Celgene Corp.: Employment, Equity Ownership. Li:Celgene Corp.: Employment, Equity Ownership. Hock:Celgene Corp.: Employment, Equity Ownership. Burgess:Celgene Corporation: Employment, Equity Ownership, Patents & Royalties: Patent - CD47 antibodies and methods of use thereof; University of California: Other: Volunteer clinical faculty, without salary, Patents & Royalties: Patent - T315A and F317I mutations of BCR-ABL kinase domain. Hege:Celgene Corporation: Employment, Equity Ownership, Patents & Royalties; Mersana Therapuetics: Membership on an entity's Board of Directors or advisory committees; Arcus Biosciences: Membership on an entity's Board of Directors or advisory committees; Society for Immunotherapy of Cancer: Membership on an entity's Board of Directors or advisory committees. Stock:Agios: Membership on an entity's Board of Directors or advisory committees; Research to Practice: Honoraria; UpToDate: Honoraria; Daiichi: Membership on an entity's Board of Directors or advisory committees; Astellas: Membership on an entity's Board of Directors or advisory committees; Kite, a Gilead Company: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees.

Background: The use of midostaurin in combination with standard induction chemotherapy has been shown to improve the outcomes in patients with newly diagnosed FLT3 mutated (FLT3m) AML (Stone et al) and allogeneic transplant is often recommended in first remission. While likely to achieve remission with standard induction, the majority of these patients will relapse and die of their disease. Gilteritinib, a potent FLT3 inhibitor, has been approved for use in patients with relapsed or refractory FLT3 mutated AML. In Phase I/II studies, when used as part of induction therapy, gilteritinib has shown promising CR rates. We have designed a trial comparing the outcomes of induction therapy with gilteritinib to those with midostaurin. The hypothesis is that gilteritinib, when added to induction chemotherapy, will produce more FLT3m negative composite complete remission (CRc). The Ratify trial combined midostaurin with daunorubicin 60 mg/m2/d X 3 days and cytarabine X 7 days Daunorubicin 90 mg/m2/d has however been shown to be superior during induction in patients with newly diagnosed FLT3 ITD mutated AML (Luskin et al, Burnett et al) While improved survival is the ultimate goal of any leukemia regimen, it is known that AML patients who proceed to allogeneic transplant with measurable residual disease (MRD) positive disease fare worse than those with MRD negative disease. As such, our goal is to increase the likelihood of an MRD negative state after induction. Study Design This is a randomized, open-label, multicenter phase II study comparing gilteritinib to midostaurin in combination with cytarabine 100 mg/m2 and daunorubicin 90 mg/m2 in newly diagnosed FLT3 mutated AML patients ages 18-65. Central confirmation of FLT3 mutation and other pretreatment studies are required. In order to identify patients without delay, all patients with suspected AML will be able to be prescreened without enrollment to the randomized treatment trial. Patients will be stratified according to TKD vs. ITD FLT3 mutation. Patients with FLT3-ITD mutation will undergo further stratification with NPM1 mutation status (positive vs. negative) and FLT3 ITD to FLT3 wild type signal ratio (high [≥ 0.5] vs. low [<0.5]). Patients will be randomized to receive standard induction treatment (cytarabine and daunorubicin) with either gilteritinib or midostaurin. Mandatory bone marrow samples are required after Induction and Consolidation. Patients who achieve CR or complete remission with incomplete hematologic recovery (CRi) will be assessed for MRD and be eligible at count recovery to go on to receive standard consolidation treatment of high-dose cytarabine with the study drug received during induction (gilteritinib or midostaurin). Patients may proceed to allogeneic transplant after induction or after 0-4 cycles of chemotherapy consolidation and may participate in BMT CTN 1506. Key Eligibility: Newly diagnosed FLT3m AML Primary Objective To evaluate the FLT3m negative (evaluated by polymerase chain reaction [PCR] and capillary electrophoresis) composite complete response (CRc) (includes CR or CRi)rate of patients with FLT3 mutated AML who receive gilteritinib compared to those who receive midostaurin in addition to standard therapy with cytarabine and daunorubicin during induction. Sample Size and Statistical design The accrual goal of this study will be 179 patients. Patients who achieve remission will be followed for survival and relapse. With an allocation ratio of 1:1 to the two arms, the study will have 80% power to detect an improvement of 20% in the FLT3 mutation negative CRc rate in the gilteritinib arm (i.e. from 40% to 60%) at the one-sided significance level of 0.05 based on Fisher's exact test. This study is conducted through PrECOG and is funded by Astellas Pharma. The study is slated to open in the summer of 2019 at 30 US sites. References: Stone R.M., Mandrekar S.J., Sanford B.L., et al. N Engl J Med 2017; 377:454-464 Luskin MR, Lee JW, Fernandez HF et al. Blood 2016 :blood-2015-07-657403; doi: https://doi.org/10.1182/blood-2015-07-657403 Burnett AK, Russell NH, Hills RK et al. Blood 2016; Blood 2016 128:449-452; doi: https://doi.org/10.1182/blood-2016-04-712091 Figure Disclosures Luger: Genetech: Research Funding; Jazz: Honoraria; Celgene: Research Funding; Pfizer: Honoraria; Kura: Research Funding; Onconova: Research Funding; Agios: Honoraria; Ariad: Research Funding; Biosight: Research Funding; Seattle Genetics: Research Funding; Cyslacel: Research Funding; Daichi Sankyo: Honoraria. Loghavi:MDACC: Employment; GLG Consultants: Consultancy; AlphaSights: Consultancy. Lazarus:Genentech: Speakers Bureau; Pluristem Therapeutics, Inc: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Adaptive Biotechnologies: Consultancy, Honoraria; CSL Behring: Consultancy; Jazz Pharmaceuticals: Consultancy, Honoraria, Speakers Bureau; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; AstraZeneca: Honoraria, Speakers Bureau; Actinium Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Honoraria, Speakers Bureau; Seattle Genetics: Consultancy, Honoraria, Speakers Bureau; Biosight: Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Speakers Bureau; Teva Pharmaceuticals: Speakers Bureau. Rowe:BioSight: Consultancy. Tallman:Jazz Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; Rigel: Consultancy, Membership on an entity's Board of Directors or advisory committees; Biosight: Research Funding; ADC Therapeutics: Research Funding; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; KAHR: Consultancy, Membership on an entity's Board of Directors or advisory committees; Nohla: Consultancy, Membership on an entity's Board of Directors or advisory committees; Oncolyze: Consultancy, Membership on an entity's Board of Directors or advisory committees; BioLineRx: 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; Delta Fly 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, Research Funding; Cellerant: Research Funding; Tetraphase: Consultancy, Membership on an entity's Board of Directors or advisory committees; UpToDate: Patents & Royalties. Pratz:Astellas Pharma: Consultancy, Research Funding; AbbVie: Consultancy, Research Funding; Agios: Consultancy, Research Funding; Millenium/Takeda: Research Funding; Boston Biomedical: Consultancy. OffLabel Disclosure: In this study gilteritinib is being studies in newly diagnosed AML.

AbstractBackgroundPatients with acute myeloid leukemia (AML) are surviving longer. There are no data on changes in myocardial mechanics from standard of care low‐dose anthracycline‐based induction chemotherapy in older patients with AML. The aim of this study was to demonstrate the potential utility of strain imaging in detecting early changes in left ventricular function in this patient population after induction chemotherapy.MethodsThirty two patients enrolled in the ECOG‐ACRIN E2906 study (cytarabine and daunorubicin vs clofarabine [Genzyme/Sanofi]) from 2011 to 2014 were evaluated retrospectively. Two‐dimensional transthoracic echocardiography (TTE) imaging with Doppler and two‐dimensional speckle‐tracking echocardiography (2DSTE) using EchoInsight software (Epsilon imaging) were performed before and after induction chemotherapy.ResultsEighteen patients received cytarabine and daunorubicin (7 + 3) and 14 received clofarabine. The clofarabine group was older than the 7 + 3 cohort (67.8 ± 4.0 vs 63.7 ± 3.8, P = .007). There were no other significant differences in cardiac risk factors between groups. The 7 + 3 group had a decrease in average peak systolic global longitudinal (−19.1 ± 2.8 to −17.2 ± 3.0, P = .01) and circumferential strain (−29.4 ± 6.3 to −23.9 ± 4.3, P = .011). These changes were not demonstrated in the clofarabine group and were not associated with a decline in left ventricular ejection fraction (LVEF).ConclusionsIn older AML patients, standard cytarabine and daunorubicin chemotherapy causes early changes in global longitudinal and circumferential strain not seen with clofarabine therapy. These findings demonstrate subclinical left ventricular dysfunction after exposure to low cumulative doses of anthracycline‐based induction chemotherapy and may help us better identify those patients at risk for adverse long‐term cardiovascular outcomes.

Abstract Background: The persistence of detectable MRD in complete remission (CR/CRi - CR with incomplete CBC recovery) has been reported to contribute to inferior outcome in younger AML patients (pts) in retrospective studies, however MRD has not been studied prospectively in older adults (age ≥60 yrs) receiving intensive therapy with curative intent. We performed a planned prospective study of MRD status after AML induction therapy in older adults, integrated into the large multicenter ECOG-ACRIN (E-A) E2906 Phase III trial. Methods Eligible patients age ≥60 yrs with AML were randomized 1:1 to receive either 'Standard' 7&3 (Dauno 60mg/m2) induction, with 2 cycles of intermediate dose Ara-C (1.5g/m2 x 12 doses; 6 doses if age ≥70) consolidation (Arm A); or single agent clofarabine (CLO) induction and consolidation (2 cycles) (Arm B). The design and primary clinical results for E2906 (n=727) have been reported previously (Foran et al, ASH #217a, 2015), demonstrating superior overall survival (OS) with standard therapy despite similar CR/CRi rates using stringent criteria, and similar 30-day induction mortality rates. Submission of diagnostic & remission bone marrow or peripheral blood samples was protocol mandated for prospective MRD assessment, and analysis was performed in the central E-A Leukemia Translational Research Lab (LTL) using 6-color multiparameter flow cytometry. MRD-positive (MRD+) was defined as ≥0.1%. LTL flow cytometric analysis was done blinded to treatment arm and outcome of patients. Only pt samples collected within +/-6 days of CR/CRi confirmation were included in this analysis. Statistical analysis was performed using X2 (categories) and Wilcoxon rank sum (continuous) tests to compare baseline patient and disease characteristics. Log-rank tests and multivariate Cox models stratified by treatment arm and adjusted for patient and disease variable (including WBC, cytogenetics, sex, performance status, secondary AML) were used to examine the MRD effect on OS and disease-free survival (DFS, relapse or death). Results The median follow-up is 47.8 months, and 297 of 685 evaluable patients (43.4%) achieved CR/CRi (Standard 44.6%; CLO 42.0%, p=ns). Remission MRD samples were only available for 147 CR/CRi patients (49.5%), owing to variability in sample viability and AML involvement, collection practices and timing of sample collection at individual sites, and patient/physician decision. 58/147 evaluable CR/CRi patients achieved MRD-negative (MRD-) status (Standard 40.7%, CLO 47.9%, p=0.74). Women (56.9% vs. men 43.1%, p=0.003) were more likely to be MRD-, but there was no other significant difference in MRD status stratified by clinical or disease features. MRD+ status at CR/CRi was associated with significantly inferior OS (p=0.031, Figure 1) and also inferior overall DFS (p=0.02); this was most pronounced for DFS after CLO (Arm B, Figure 2) (p=0.005), but not Standard (Arm A) therapy (p=0.41). The impact of MRD+ was confirmed on multivariate analysis using Cox Model Fitting, for OS: OS for All MRD+ pts, HR 1.64 (95% CI 1.00-2.68) (p=0.05); OS for Standard (Arm A) MRD+ pts, HR 1.06 (95% CI 0.51-2.21) (p=0.87); and OS for CLO (Arm B) MRD+ pts, HR 2.30 (95% CI 1.05-5.06) (p=0.04). There was a similar impact for DFS on multivariate analysis using Cox Model Fitting: DFS for All MRD+ pts, HR 1.86 (95% CI 1.16-2.98) (p=0.01); DFS for Standard (Arm A) MRD+ pts, HR 1.15 (95% CI 0.60-2.19) (p=0.67); and DFS for CLO (Arm B) MRD+ pts, HR 3.45 (95% CI 1.47-8.09) (p=0.004). Post-remission therapy was not stratified by MRD in E2906, and 33% of MRD-evaluable pts underwent allogeneic transplantation (no difference in transplant rate for MRD+ vs. MRD-). Conclusions MRD+ ≥0.1% is common (60.5%) after induction therapy in older adults & is significantly associated with inferior OS and DFS in 1st CR/CRi. However we observed excellent outcomes for MRD- pts in first CR/CRi regardless of induction regimen or post-remission therapy used. MRD+ pts in CR/CRi who went on to receive CLO consolidation had significantly poorer outcomes than those who went on to receive intermediate dose Ara-C consolidation. This observation differs strikingly from younger AML, and suggests that intensified Ara-C may abrogate the adverse impact of MRD in older pts in CR. These results strongly support incorporation of centralized MRD at the time of remission into future studies to guide optimal post-remission strategies in older pts with AML. Disclosures Foran: Agios: Research Funding; Xencor, Inc.: Research Funding. Lazarus:Pluristem Ltd.: Consultancy. Altman:Bayer: Other: payment to the institution to conduct clinical trial work; Pfizer: Other: payment to the institution to conduct clinical trial work; Boeringer Ingelheim: Other: payment to the institution to conduct clinical trial work; Epizyme: Other: payment to the institution to conduct clinical trial work; Janssen Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Immune Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Cyclacel: Other: payment to the institution to conduct clinical trial work; Incyte: Other: payment to the institution to conduct clinical trial work; GSK: Other: payment to the institution to conduct clinical trial work; Agios: Other: Payment to the institution to conduct the trial ; Astellas Pharma: Other; Celgene: Membership on an entity's Board of Directors or advisory committees, Other: payment to the institution to conduct clinical trial work; BMS: Membership on an entity's Board of Directors or advisory committees; Syros: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Ariad: Other: payment to the institution to conduct clinical trial work; FujiFilm: Other: payment to the institution to conduct clinical trial work; Genetech: Other: Payment to the institution to conduct clinical trial work; Celator: Other: payment to the institution to conduct clinical trial work. Al-Kali:Novartis: Research Funding. Pratz:Millenium/Takeda: Research Funding; Agios: Research Funding; AbbVie: Consultancy, Research Funding; Astellas: Consultancy, Research Funding; Boston Scientific: Consultancy. Powell:Rafael Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees. Tallman:ADC Therapeutics: Research Funding; BioSight: Other: Advisory board; Daiichi-Sankyo: Other: Advisory board; Orsenix: Other: Advisory board; AROG: Research Funding; AbbVie: Research Funding; Cellerant: Research Funding.

Abstract Introduction: Mutations localized in the tyrosine kinase domain activation loop of FLT3 (FLT3-TKD), representing point mutations in codon D835/I836 and rarely deletions of codon I836, induce constitutive tyrosine phosphorylation and activation of the receptor tyrosine kinase similarly to FLT3 internal tandem duplication (ITD) mutations. However, the prognostic role of FLT3-TKD in AML, particularly in the presence of NPM1 mutations, is not well established. The phase 3 RATIFY trial [NCT00651261; Stone et al. N Engl J Med. 2017] showed that in combination with standard chemotherapy, midostaurin (PKC412) improved survival outcomes across all 3 FLT3 stratification subgroups (ITD high allelic ratio [≥ 0.7], ITD low allelic ratio [< 0.7], and TKD) vs placebo in patients with newly diagnosed FLT3-mutated AML. Here, we evaluated the prognostic impact of FLT3-TKD and NPM1 mutations in a post hoc analysis from the RATIFY trial. Methods: In RATIFY, newly diagnosed patients with AML 18-60 years old were randomly assigned to receive midostaurin or placebo together with standard induction and consolidation therapy followed by 12 28-day cycles of maintenance therapy with midostaurin or placebo. FLT3-TKD mutation was detected by PCR and capillary electrophoresis at 9 reference laboratories. Patients were categorized as NPM1 mutated (mut) or NPM1 wild-type (WT) using PCR. Efficacy outcomes included complete remission (CR), overall survival (OS), event-free survival (EFS) and disease-free survival (DFS). EFS and DFS analyses were performed considering CR within a 60-day window. P values presented have not been adjusted for multiplicity. Results: Of the total randomized 162 FLT3-TKD patients, 134 with available NPM1 data had consented for exploratory analysis and thus were included in this study (see Table for subgroup distribution). Overall, 47.8% of patients were male, and the median age was 49 years (95% CI, 45.5-51.1 years). The median white blood cell (WBC) count was higher in patients with NPM1-mut than in patients with NPM1-WT (34.1 vs 15.5 × 109/L, P = .0011). CR rates (during the first 60 days) were higher in patients with FLT3-TKD/NPM1-mut vs FLT3-TKD/NPM1-WT (66% vs 53%); however, this was driven by the higher rate of CR in the midostaurin arm (76% NPM1-mut vs 44% NPM1-WT) rather than the placebo arm (53% NPM1-mut vs 60% NPM1-WT). The overall CR rate (regardless of NPM1 genotype) was 64% for midostaurin and 56% for placebo in FLT3-TKD patients. The prognostic effect of the NPM1 mutation concurrent with FLT3-TKD was seen for all endpoints consistently with hazard ratios (HRs) around 0.50 or lower (Figures 1 and 2 and Table). Overall (regardless of treatment) OS, EFS, and DFS estimates at 3 years were 73% vs 52%, 48% vs 25%, and 74% vs 47%, respectively, in patients with FLT3-TKD/NPM1-mut vs FLT3-TKD/NPM1-WT. Whereas the HRs for midostaurin vs placebo were 0.73 for both OS and EFS, the impact of treatment on outcomes varied between the individual NPM1/TKD subgroups and was not consistently observed when endpoints were censored at stem cell transplant (SCT) (Table). It should be noted that the number of patients in each subgroup was small and therefore the HRs with 95% CIs should be interpreted with caution. Multivariate analyses in these FLT3-TKD patients revealed that NPM1 genotype was an independent prognostic factor for OS, EFS and DFS (2-sided P < .05), whereas study drug, age, sex, WBC at baseline and SCT (no/yes) did not reach this level of significance in the Cox model. Conclusions: This post hoc analysis of the FLT3-TKD patient subset in the RATIFY trial showed the high prognostic value of NPM1 mutational status. Whereas midostaurin showed an overall benefit in the FLT3-TKD patients for OS, EFS, CR and DFS, the impact of treatment on outcome varied between the individual NPM1 subgroups within these FLT3-TKD patients and was not consistently observed.Further analyses using additional endpoints and additional multivariate analyses are planned. Support: U10CA180821, U10CA180882, U10CA180820, U10CA180791, U10CA180888, U10CA180863, (CCSRI) #704970, U24CA196171; ClinicalTrials.gov Identifier: NCT00651261 Disclosures Voso: Celgene: Research Funding, Speakers Bureau. Larson:Ariad/Takeda: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; BristolMyers Squibb: Consultancy, Research Funding. Heuser:Janssen: Consultancy; Pfizer: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; StemLine Therapeutics: Consultancy; Astellas: Research Funding; BergenBio: Research Funding; Karyopharm: Research Funding; Bayer Pharma AG: Consultancy, Research Funding; Tetralogic: Research Funding; Sunesis: Research Funding; Daiichi Sankyo: Research Funding. Wei:Novartis: Honoraria, Other: Advisory committee, Research Funding, Speakers Bureau; Pfizer: Honoraria, Other: Advisory committee; Amgen: Honoraria, Other: Advisory committee, Research Funding; Abbvie: Honoraria, Other: Advisory board, Research Funding, Speakers Bureau; Servier: Consultancy, Honoraria, Other: Advisory committee, Research Funding; Celgene: Honoraria, Other: Advisory committee, Research Funding. Brandwein:Lundbeck: Consultancy; Celgene: Consultancy; Pfizer: Consultancy; Novartis: Consultancy; Boehringer Ingelheim: Consultancy, Research Funding. de Witte:Novartis: Research Funding; Amgen: Consultancy, Research Funding; Celgene: Honoraria, Research Funding. Medeiros:Celgene: Consultancy, Research Funding; Genentech: Employment. Tallman:Cellerant: Research Funding; Orsenix: Other: Advisory board; BioSight: Other: Advisory board; ADC Therapeutics: Research Funding; AROG: Research Funding; AbbVie: Research Funding; Daiichi-Sankyo: Other: Advisory board. Schlenk:Pfizer: Research Funding, Speakers Bureau. Ganser:Novartis: Membership on an entity's Board of Directors or advisory committees. Cheng:Novartis: Employment. Gathmann:Novartis: Employment. Tiecke:Novartis: Employment. Thiede:AgenDix: Other: Ownership; Novartis: Honoraria, Research Funding. Döhner:AbbVie: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Research Funding; Seattle Genetics: Consultancy, Honoraria; Celator: Consultancy, Honoraria; Sunesis: Consultancy, Honoraria, Research Funding; Bristol Myers Squibb: Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Seattle Genetics: Consultancy, Honoraria; AROG Pharmaceuticals: Research Funding; Sunesis: Consultancy, Honoraria, Research Funding; Astellas: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria; AROG Pharmaceuticals: Research Funding; Celator: Consultancy, Honoraria; Astex Pharmaceuticals: Consultancy, Honoraria; Bristol Myers Squibb: Research Funding; Agios: Consultancy, Honoraria; Agios: Consultancy, Honoraria; Astellas: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Astex Pharmaceuticals: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Research Funding; Jazz: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Jazz: Consultancy, Honoraria; Pfizer: Research Funding; Pfizer: Research Funding; Novartis: Consultancy, Honoraria, Research Funding. Stone:Otsuka: Consultancy; Argenx: Other: Data and Safety Monitoring Board; Amgen: Consultancy; Agios: Consultancy, Research Funding; Orsenix: Consultancy; Ono: Consultancy; Novartis: Consultancy, Research Funding; Astellas: Consultancy; Arog: Consultancy, Research Funding; Merck: Consultancy; Cornerstone: Consultancy; Fujifilm: Consultancy; Jazz: Consultancy; Celgene: Consultancy, Other: Data and Safety Monitoring Board, Steering Committee; Pfizer: Consultancy; Sumitomo: Consultancy; AbbVie: Consultancy.

Abstract BACKGROUND: Recurrent mutations in isocitrate dehydrogenase 1 (IDH1) are observed in approximately 4% of patients with myelodysplastic syndrome (MDS) and have been linked with increased transformation to acute myeloid leukemia. Ivosidenib (AG-120), an oral, potent, targeted, small-molecule inhibitor of the mutant IDH1 protein (mIDH1), is a therapeutic candidate for the treatment of patients with mIDH1 MDS. Through inhibition of mIDH1, ivosidenib suppresses the production of the oncometabolite 2-hydroxyglutarate (2-HG), leading to clinical responses via differentiation of malignant cells. AIM: To report safety and efficacy data from patients with relapsed or refractory (R/R) MDS enrolled in the first-in-human, phase 1, dose escalation and expansion study of ivosidenib in patients with mIDH1 advanced hematologic malignancies (NCT02074839). METHODS: This ongoing study is evaluating the safety, maximum tolerated dose (MTD), pharmacokinetics, pharmacodynamics, and clinical activity of ivosidenib. Trial enrollment was completed on 08May2017. In dose escalation, patients received single-agent ivosidenib orally once daily (QD) or twice daily in 28-day cycles. The MTD was not reached and 500 mg QD was selected as the dose to be tested in expansion. Expansion Arm 3 enrolled patients with mIDH1 advanced hematologic malignancies, including MDS. The overall response rate (ORR) for MDS was defined as complete remission (CR) + partial remission + marrow CR. Exploratory biomarker assessments included baseline co-occurring mutations (next-generation sequencing panel for hematologic malignancies) and mIDH1 variant allele frequency (VAF) in bone marrow mononuclear cells (BEAMing Digital PCR; lower limit of detection for mIDH1, 0.02-0.04%). Here, we present safety and efficacy data for patients with MDS in expansion Arm 3 and in dose escalation whose starting dose was 500 mg QD. RESULTS: In all, 258 patients (78 in dose escalation, 180 in expansion) received ivosidenib, including 12 patients with MDS (9 from expansion and 3 from escalation) whose starting dose was 500 mg QD. Baseline characteristics for these 12 patients were: 9 men/3 women; median age, 72.5 years (range, 52-78) and 42% were ≥75 years of age; median number of prior therapies, 1 (range, 1-3). As of 10Nov2017, 7 of 12 (58.3%) patients remained on treatment and 5 (41.7%) had discontinued (one for allogeneic stem cell transplantation). The median duration of exposure to ivosidenib was 11.0 months (range, 3.3-31.1). The most common adverse events (AEs) of any grade, irrespective of causality, occurring in ≥20% of the 12 patients were back pain (n=4, 33.3%) and anemia, decreased appetite, diarrhea, dyspnea, fatigue, hypokalemia, pruritus, and rash (n=3, 25.0% each). The majority of these AEs were grade 1-2 and reported as unrelated to treatment. No AEs led to permanent discontinuation of treatment. IDH differentiation syndrome (IDH-DS) was observed in 2 of 12 (16.7%) patients; the events were grade 1 and 2, respectively. Of the 12 patients with MDS receiving ivosidenib 500 mg QD, 5 achieved CR (41.7%; 95% CI 15.2%, 72.3%) and 6 achieved marrow CR (50.0%), resulting in an ORR of 91.7% (95% CI 61.5%, 99.8%). The median durations of CR and overall response were not estimable at the time of the data cutoff. The percentages of patients who remained in CR and response at 12 months were 60.0% and 61.4%, respectively. Among 5 patients who were transfusion dependent at baseline, 4 became transfusion independent for at least 56 days on treatment. Baseline co-occurring mutations and changes in mIDH1 VAF levels on ivosidenib therapy will be presented. CONCLUSION: In patients with mIDH1 R/R MDS, ivosidenib monotherapy was well tolerated and induced durable remissions and transfusion independence. These findings support the role of ivosidenib as an effective, oral, targeted treatment for patients with mIDH1 R/R MDS. Disclosures DiNardo: Karyopharm: Other: Advisory role; Medimmune: Other: Advisory role; Celgene: Other: Advisory role; Bayer: Other: Advisory role; Agios: Consultancy, Other: Advisory role; AbbVie: Consultancy, Other: Advisory role. Watts:Jazz Pharma: Consultancy, Speakers Bureau; Takeda: Research Funding. Stein:Celgene: Consultancy; Daiichi Sankyo: Consultancy; Agios: Consultancy; Pfizer: Consultancy; Novartis: Consultancy; Bayer: Consultancy. de Botton:Agios: Research Funding; Celgene: Honoraria, Research Funding. Fathi:Takeda: Consultancy, Honoraria; Jazz: Honoraria; Celgene: Consultancy, Honoraria, Research Funding; Boston Biomedical: Consultancy, Honoraria; Astellas: Honoraria; Seattle Genetics: Consultancy, Honoraria; Agios: Honoraria, Research Funding. Stein:Amgen: Speakers Bureau; Celgene: Speakers Bureau. Foran:Agios: Research Funding; Xencor, Inc.: Research Funding. Stone:AbbVie: Consultancy; Agios: Consultancy, Research Funding; Cornerstone: Consultancy; Orsenix: Consultancy; Fujifilm: Consultancy; Sumitomo: Consultancy; Pfizer: Consultancy; Celgene: Consultancy, Other: Data and Safety Monitoring Board, Steering Committee; Ono: Consultancy; Novartis: Consultancy, Research Funding; Otsuka: Consultancy; Jazz: Consultancy; Merck: Consultancy; Astellas: Consultancy; Arog: Consultancy, Research Funding; Argenx: Other: Data and Safety Monitoring Board; Amgen: Consultancy. Patel:France Foundation: Honoraria; Dava Oncology: Honoraria; Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Tallman:Cellerant: Research Funding; BioSight: Other: Advisory board; ADC Therapeutics: Research Funding; AbbVie: Research Funding; Daiichi-Sankyo: Other: Advisory board; AROG: Research Funding; Orsenix: Other: Advisory board. Choe:Agios: Employment, Equity Ownership. Wang:Agios: Employment, Equity Ownership. Zhang:Agios: Employment, Equity Ownership. Dai:Agios: Employment, Equity Ownership. Fan:Agios: Employment, Equity Ownership. Yen:Agios: Employment, Equity Ownership. Kapsalis:Agios: Employment, Equity Ownership. Hickman:Agios: Employment, Equity Ownership. Agresta:Agios: Employment, Equity Ownership. Liu:Agios: Employment, Equity Ownership. Wu:Agios: Employment, Equity Ownership, Patents & Royalties. Attar:Agios: Employment, Equity Ownership.

Abstract Background Therapy-related myeloid neoplasm (tMN) includes t-myelodysplasia (tMDS) and t-acute myeloid leukemia (tAML) and are serious late effects of the treatment of cancer. Prognosis of tMN is poor, related to the increased frequency of adverse cytogenetics and other clinical features which predict poor response to conventional treatment. Over the last years, azacitidine (AZA) has become the standard of treatment for high risk MDS (Silverman, JCO 2002; Fenaux, Lancet Oncol 2009) and has shown efficacy in AML. AZA represents an interesting option for patients with tMN considering its safety profile and its efficacy in poor prognosis subgroups of apparently de novo MDS patients including those with monosomy 7. Most prospective trials of AZA have excluded patients with tMN. Most tMN data are retrospective or registry studies (Bally, Leuk Res 2013). This abstract presents the results of 47 t-MN patients prospectively enrolled as a specific cohort in the E1905 study. Methods E1905 study is a randomized phase 2 study from the North American Leukemia Intergroup (NCT00313586, Prebet , ASH 2010) testing 10 days of AZA (50mg/m2/d s.c.) vs. 10 days of AZA + the histone deacetylase inhibitor entinostat (4 mg/m2/d PO days 3 and day 10). 6 cycles of treatment were planned; responding patients could receive up to 24 cycles. MDS, CMML, and AML with myelodysplasia-related changes were included. Patients with tMN were subsequently accrued as a separate cohort after amendment of the protocol. Response was assessed using IWG 2000 criteria (Cheson et al, Blood 2000); the primary endpoint of the overall trial was achievement of a normal hemogram in 25% of treated patients in either treatment arm. Results A total of 47 patients were included. Median age was 70 years (39y-83y), 45% male, and 94% of patients had ECOG PS 0-1. 29 patients could be subclassified as t-MDS and 18 as t-AML. At inclusion, median peripheral blood counts were: neutrophils 1.0 G/l, Platelets 35 G/L, Hemoglobin 9.2 g/l, peripheral blood blasts 0%, marrow blasts 14.0%. 68% of patients were RBC transfusion dependent and 40% platelet transfusion dependent. As expected, the cytogenetic evaluation showed a high frequency of unfavorable risk cytogenetics (74%) as compared to normal or intermediate risk cytogenetics (26%). Baseline characteristics were not statistically different between the 2 arms. 24 patients were treated with AZA monotherapy and 23 with AZA+entinostat. The median number of administered cycles was 4 and was significantly higher in patients treated with AZA monotherapy (6 cycles vs.3 cycles, p=0.008). 8 patients in the combination arm and 1 patient in the AZA monotherapy arm died of infection or hemorrhage before cycle 3. In an intent to treat analysis, overall response rates (CR, PR, or trilineage Hematologic improvement) were 11/24 (46%) in AZA monotherapy (95% CI 26 – 67%) and 4/23 (17%) in the combination arm (95% CI 5 – 39%, p=0.06 comparing the two arms). Median overall survival in the two arms were 12.8 months and 5.7 months (p=0.008). Conclusions In this group of very high risk patients with therapy-related myeloid neoplasms, the use of the novel 50 * 10 schedule of azacitidine monotherapy appears effective, with response rates comparable to those for patients with de novo MDS/AML treated on the same protocol (74 pts, 40% with unfavorable cytogenetics, ORR=32%, median OS=18 months). Because there are no prospective data examining the approved dose schedule of AZA (75 mg/m2/day * 7 days), it is not clear if this surprisingly high response rate derives from the current extended schedule of lower dose AZA, or would be true with standard dose AZA as well. This high response may enable many of these patients to proceed to allogeneic stem cell transplant. Entinostat combined with azacitidine at the dose and schedule applied in E1905 does not appear to be effective and tolerable as compared to azacitidine alone. Disclosures: Prebet: CELGENE: Honoraria. Off Label Use: Use of azacitidine in acute myeloid leukemia. Gore:CELGENE: Equity Ownership, Research Funding.

Abstract Background Activating mutations in FLT3 - and in particular FLT3-ITD (internal tandem duplication) - are common in younger patients with AML, and are associated with relapse and with inferior overall survival (OS), however their prevalence and impact in older adults remains uncertain. We performed an analysis of FLT3-ITD mutations in patients age ≥60 yrs in the large prospective multicenter ECOG-ACRIN (E-A) E2906 Phase III trial. Methods Eligible patients (pts) age ≥60 yrs (n=727) were randomized to 'Standard' therapy with 7&3 (Dauno 60mg/m2) induction, and 2 cycles of intermediate dose Ara-C (1.5g/m2 x 12 doses; 6 doses if age ≥70yrs) consolidation (Arm A); or single agent clofarabine (CLO) induction and consolidation (2 cycles) (Arm B). As previously reported (Foran et al, ASH #217a, 2015), there was superior overall survival (OS) with standard therapy. AML diagnostic samples collected prospectively in the central E-A Leukemia Translational Research Lab (LTL) were used to detect mutations in the FLT3 gene by PCR using cDNA from total RNA. LTL investigators were blinded to treatment assignment. Patients with no RNA available or blast count <10% (threshold of sensitivity for the PCR assay) on the submitted sample were excluded. Statistical analysis was performed using X2 (categories) and Wilcoxon rank sum (continuous) tests to compare baseline patient and disease characteristics. Log-rank tests and multivariate Cox models stratified by treatment arm and adjusted for patient and disease variable (including WBC, cytogenetics, sex, performance status, secondary AML) were used to examine FLT3-ITD effect on OS and disease-free survival [DFS; relapse or death after complete remission (CR)/CRi (CR with incomplete CBC recovery)]. Results In the first 231 pts tested, FLT3-ITD mutations were identified in 43 (18.6%) pts, and the remainder were FLT3-ITD-negative (i.e. non-ITD). The proportion with FLT3-ITD was the same for patients age 60-69 yrs (18.8%) vs. ≥70 yrs (18.3%). In comparison to non-ITD, FLT3-ITD+ pts had significantly higher WBC (median 18.1 vs. 6.3, p=0.002) and BM blasts (80% vs. 51.5%, p=0.0004) at AML diagnosis, and were more likely to have intermediate risk (79.1% vs. 59%) vs. unfavorable risk (7.0 % vs. 31.4%) cytogenetics (p=0.002). There was no difference in CR/CRi rate overall (p=0.40), however standard (Arm A) pts with FLT3-ITD had a significantly higher CR/CRi rate (78.9% vs. non-ITD 51.5%, p=0.04). With median follow-up 53.5 months, FLT3-ITD patients tended to have worse OS (HR 1.24, 95%CI 0.85-1.81) but this was not statistically significant (Figure 1, p=0.26), and results were similar for both Arms A/B. DFS similarly tended to be worse overall for FLT3-ITD (HR 1.44, 95%CI 0.65-2.43) (p=0.17), and DFS was significantly worse for FLT3-ITD+ Arm A/Standard pts (Figure 2, p=0.033), while Arm B/CLO pts had a worse DFS regardless of FLT3 mutation status (Arm B, FLT3-ITD vs. non-ITD, p=0.93). More patients with FLT3-ITD underwent allogeneic transplantation (25.6% vs. non-ITD 19.7%), although this was not significant (p=0.41). Conclusions FLT3-ITD mutations are prevalent in older and elderly (age ≥70 yrs) patients with AML, and while they occur at somewhat lower rates than reported for younger adults, FLT3-ITD+ AML in this population has a leukemia phenotype similar to that reported in younger patients. Despite significantly higher CR/CRi rates with Standard therapy, older pts with FLT3-ITD also have significantly worse DFS following intensified Ara-C consolidation therapy than non-ITD pts. These results support routine assessment of FLT3-ITD status in older AML patients, and the incorporation of novel post-remission treatment strategies to improve outcome in FLT3-ITD+ pts ≥60 yrs. Disclosures Foran: Agios: Research Funding; Xencor, Inc.: Research Funding. Lazarus:Pluristem Ltd.: Consultancy. Tallman:BioSight: Other: Advisory board; AbbVie: Research Funding; Daiichi-Sankyo: Other: Advisory board; Cellerant: Research Funding; Orsenix: Other: Advisory board; ADC Therapeutics: Research Funding; AROG: Research Funding.

Abstract Introduction B progenitor acute lymphoblastic leukemia (B-ALL) is a leading cause of childhood cancer death. Many chimeric genes have been identified and led to a refined classification of B-ALL and tailored therapies. Still, up to 30% of B-ALL cannot be classified into established subtypes, and the outcome for many is poor. Methods To identify novel subtypes of B-ALL, we performed integrative genomic analysis including transcriptome sequencing (RNA-seq) of 1,988 cases from St. Jude, Children's Oncology Group and adult cooperative group studies and analyzed chromosomal rearrangements, gene-expression profiles (GEP), somatic mutations and chromosome-level copy-number alterations. Cases lacking known or putative subtype-defining alterations underwent whole genome sequencing. Effects on proliferation and transformation of novel lesions were assessed by retroviral expression in cell lines and point-mutation knock-in mice using CRISPR/Cas9 genome editing. Results Using integrated genetic alterations and gene expression profiling, we classified 23 B-ALL subtypes (Table and Figure). Three groups included cases with similar GEP as canonical subtypes (ETV6-RUNX1, KMT2A-rearranged, and ZNF384-rearranged), but lacking the expected drivers (e.g., ETV6-RUNX1-like, n=42). Eighteen cases (0.9%) had rearrangements of BCL2, MYC and/or BCL6 showing a distinct GEP; they were mostly adults (n=16) with very poor outcome. These alterations, rarely seen in ALL, are identical to those observed in "double/triple hit" lymphoma, and are of pre-B immunophenotype. Eight cases with tightly clustered GEP comprised a novel subtype defined by IKZF1 N159Y missense mutation. N159Y is in the DNA-binding domain of IKZF1, and is known to perturb IKZF1 function, with distinct nuclear mislocalization and induction of aberrant intercellular adhesion. We identified two subtypes with distinct GEP characterized by PAX5 alterations. One, herein termed PAX5 altered (PAX5alt), comprised 148 (7.4%) cases, was characterized by diverse PAX5 alterations including rearrangements (n=57), sequence mutations (n=46) and/or focal intragenic amplifications (n=8). These PAX5 alterations were found in 73.6% of PAX5alt cases and different alteration types were mutually exclusive. Other PAX5 alterations, including deletions and large-scale amplifications were also assessed using SNP array, but were not enriched in the PAX5alt group. Clinically, PAX5alt pediatric and adult patients had favorable (96.8±3.2%) and intermediate (42.1±10.2%) 5-year overall survival (OS), respectively. The other GEP distinct subtype comprised 44 cases, all with PAX5 P80R missense mutations. In 30 of these cases, PAX5 P80R was homozygous due to deletion of the wild-type (WT) PAX5 allele or copy-neutral loss of heterozygosity. Of the other 14 cases with heterozygous PAX5 P80R mutations, 13 had a second frameshift (n=7), nonsense (n=2) or deleterious missense (n=4) PAX5 mutation. Four of the remaining 1,944 cases also had the PAX5 P80R mutation, but all were heterozygous with preservation of a WT PAX5 allele, consistent with the notion that homozygous or compound heterozygous PAX5 P80R mutation is the hallmark of this subtype. Adult PAX5 P80R cases (n=14) showed better 5-year OS (61.9±13.4%) than those in PAX5alt subtype (42.1±10.2%). To examine the effects of PAX5 P80R on B-cell maturation, WT PAX5, PAX5 P80R, V26G and P34Q were expressed in Pax5-/- lineage-depleted bone marrow cells. Expression of WT PAX5, PAX5 V26G and P34Q resulted in near complete rescue of B cell differentiation; however, expression of PAX5 P80R blocked the differentiation at the pre-pro-B stage of B-cell maturation. Further, Pax5 P80R heterozygous or homozygous mice developed pre-B-ALL with a median latency of 166 and 87 days, respectively, with heterozygous mice acquiring alterations on the second allele. In contrast, Pax5+/- mice, and those harboring G183S mutation observed in familial leukemia, do not spontaneously develop B-ALL. Conclusions These results show the utility of transcriptome sequencing in defining subtypes and founding genetic alterations in B-ALL, provide a revised taxonomy of the disease across the age spectrum, and reinforce the central role of PAX5 as a checkpoint in B lymphoid maturation and leukemogenesis. Disclosures McKay: ImmunoGen Inc.: Employment. Tallman:Orsenix: Other: Advisory board; AROG: Research Funding; BioSight: Other: Advisory board; Cellerant: Research Funding; AbbVie: Research Funding; Daiichi-Sankyo: Other: Advisory board; ADC Therapeutics: Research Funding. Stock:Jazz Pharmaceuticals: Consultancy. Konopleva:Stemline Therapeutics: Research Funding. Relling:Shire Pharmaceuticals: Research Funding. Mullighan:Cancer Prevention and Research Institute of Texas: Consultancy; Amgen: Honoraria, Speakers Bureau; Abbvie: Research Funding; Loxo Oncology: Research Funding; Pfizer: Honoraria, Research Funding, Speakers Bureau.