ALBERT

Description: Key Points Infiltrating FLT3-ITD neutrophils identified in skin confirms terminal differentiation of FLT3-ITD blasts after FLT3 inhibitor therapy. Neutrophilic dermatosis after FLT3 inhibition may be a manifestation of a differentiation syndrome associated with this treatment.

Description: Key Points AE induces hematopoietic self-renewal through a COX/prostaglandin E2/β-catenin signaling pathway. Clinically available COX inhibitors may target AML stem cells and suppress AML of various karyotypes.

Description: 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.

Description: Background Post-remission therapies for patients with AML such as high-dose cytarabine (HiDAC) and allogeneic stem cell transplant (alloSCT) have led to improved outcomes for younger patients, but disease recurrence remains prevalent with ~40% 5-year OS. CD33 is a cell surface receptor expressed in ~90% of AML, representing a promising target for therapy. Vadastuximab talirine (33A) is a CD33-directed antibody conjugated to 2 molecules of a pyrrolobenzodiazepine (PBD) dimer. Methods This phase 1b dose-escalation study (NCT02326584) evaluates the safety and anti-leukemic activity of 33A in combination with consolidation therapy (HiDAC) or as a single agent for maintenance therapy. AML patients (ECOG status 0-1) must be in 1st remission (CR or CRi) after standard induction therapy and be able to receive HiDAC (consolidation cohort) or be in 1st remission and have completed planned post-remission therapies, either chemotherapy and/or alloSCT (maintenance cohort). For maintenance post-alloSCT, patients were between Day 60 and 100 post-transplant without significant GVHD. Prior to HiDAC administration (3 gm/m2 q12h Day 1, 3, 5), 33A is given on Day 1 for up to 4 cycles (28-day cycle). For maintenance therapy, 33A is given as a single agent on Day 1 for up to 8 cycles (6-wk cycle). Results Consolidation cohort: 21 patients (57% male) with a median age of 52 years (range, 21-64) were treated with 5, 10, or 20 mcg/kg of 33A with HiDAC. Patients received a median of 2 cycles (range, 1-4). As anticipated, all patients experienced Grade 4 myelosuppression. At 20 mcg/kg, 1 DLT (lack of recovery of platelets [25K] and/or ANC [500] by Day 42) occurred in Cycle 1. At 10 mcg/kg, no DLTs were observed but delay of subsequent cycles of treatment occurred in 4 of 10 patients, primarily due to thrombocytopenia. No DLTs were observed in the 8 patients treated at 5 mcg/kg and 1 non-hematologic-related dose delay was reported (otitis externa). Non-hematologic treatment-emergent adverse events (AE) in ≥25% of patients regardless of relationship included nausea (38%) and fatigue (33%). No infusion-related reactions (IRRs) or events of veno-occlusive disease were reported. The 30- and 60-day mortality rates were 0%. Of the 19 efficacy evaluable patients, 15 (79%) have maintained remission, 18 patients are alive and 3 patients (14%) remain on treatment. Reasons for treatment discontinuation were completion of planned consolidation therapy (38%), AE (thrombocytopenia, 14%), leukemic relapse (5%), and other non-AE (29%). Nine patients (43%) went on to receive an alloSCT. Maintenance cohort: 22 patients (41% male) with a median age of 45.5 years (range, 23-71) have been treated with 5 mcg/kg of 33A. Patients were a median of 6.2 months from diagnosis (range, 3.4-21.5); 12 patients completed chemotherapy-based treatment alone and 10 patients completed standard chemotherapy with an alloSCT in 1st remission. Patients received a median of 3 cycles (range, 1-6); no DLTs were reported. AEs reported in ≥15% of patients were fatigue (41%), neutropenia (41% [36% ≥G3]), nausea (36%), thrombocytopenia (36% [27% ≥G3]), diarrhea, dyspnea, headache, and vomiting (18% each); no IRRs were observed. Of the 20 efficacy evaluable patients, 15 (75%) have maintained remission. Reasons for treatment discontinuation were AEs (41%, primarily myelosuppression), leukemic relapse (14%), completion of planned therapy (9%), and other non-AE reasons (19%); 4 patients (18%) remain on treatment. Median OS is not yet reached and 19 patients are alive. Pharmacokinetic data in patients receiving post-remission therapy with 33A demonstrate that exposure appears to be greater than in patients with active disease, possibly due to a decrease in target-mediated disposition. Conclusions 33A can be safely administered in combination with HiDAC and as monotherapy in the post-remission setting. In combination with HiDAC, non-hematologic toxicities of 33A were consistent with effects reported with HiDAC alone. As a single agent, 33A administered as maintenance post-chemotherapy and/or alloSCT results in predictable on-target myelosuppression, with mild non-hematologic adverse effects. Disclosures Yang: Seattle Genetics: Research Funding. Ravandi:Seattle Genetics: Consultancy, Honoraria, Research Funding; BMS: Research Funding. Advani:Seattle Genetics: Consultancy, Research Funding. Walter:Emergent Biosolutions: Consultancy; Seattle Genetics: Research Funding; CSL Behring: Research Funding; Celator Pharmaceuticals: Research Funding; Amgen: Research Funding; Abbvie: Research Funding; Pfizer: Consultancy; Amphivena Therapeutics, Inc.: Consultancy, Research Funding; Astra-Zeneca: Consultancy; Covagen AG: Consultancy; Agios: Consultancy; Arog: Research Funding. Faderl:Seattle Genetics: Research Funding; Pfizer: Research Funding; Astellas: Research Funding; Celator Pharmaceuticals: Research Funding; BMS: Research Funding; Ambit Bioscience: Research Funding; Karyopharm: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; JW Pharma: Consultancy; Amgen: Speakers Bureau. Stein:Seattle Genetics: Research Funding; Amgen: Consultancy, Research Funding, Speakers Bureau; Stemline Therapeutics: Consultancy, Research Funding; Argios: Research Funding; Celgene: Research Funding. Erba:Celgene: Consultancy, Speakers Bureau; Amgen: Consultancy, Research Funding; Agios: Research Funding; Pfizer: Consultancy; Novartis: Consultancy, Speakers Bureau; Juno: Research Funding; Jannsen: Consultancy, Research Funding; Ariad: Consultancy; Millennium Pharmaceuticals, Inc.: Research Funding; Astellas: Research Funding; Incyte: Consultancy, DSMB, Speakers Bureau; Seattle Genetics: Consultancy, Research Funding; Gylcomimetics: Other: DSMB; Daiichi Sankyo: Consultancy; Sunesis: Consultancy; Celator: Research Funding. Fathi:Agios Pharmaceuticals: Other: Advisory Board participation; Seattle Genetics: Consultancy, Other: Advisory Board participation, Research Funding; Merck: Other: Advisory Board participation; Celgene: Consultancy, Research Funding; Bexalata: Other: Advisory Board participation. Levy:Amgen: Speakers Bureau; Jansen: Speakers Bureau; Millennium: Speakers Bureau; Seattle Genetics: Research Funding. Wood:Pfizer: Honoraria, Other: Laboratory Services Agreement; Amgen: Honoraria, Other: Laboratory Services Agreement; Juno: Other: Laboratory Services Agreement; Seattle Genetics: Honoraria, Other: Laboratory Services Agreement. Feldman:Seattle Genetics: Employment, Equity Ownership. Voellinger:Seattle Genetics: Employment, Equity Ownership.

Description: Unlike the significant advances seen with intensive chemotherapy for pediatric acute lymphoblastic leukemia (ALL) over the last two decades, long-term outcomes among patients over age 50 remain poor, with median survival less than one year. This contrast has been attributed to high-risk chromosomal features, decreased compliance with and tolerance of effective therapies, and exposure to less intensive multi-agent regimens among adults with ALL. In recent years, more intensive chemotherapeutic paradigms, derived from pediatric protocols, have been studied in adult ALL. The purpose of the current study was to determine the efficacy of an intensified multi-agent approach, derived from a completed DFCI consortium pediatric regimen used in younger adults, in an older (age 〉50) population of patients with ALL. For this study, modifications of the pediatric regimen included incorporation of clofarabine in consolidation, adjustment to dose and scheduling of PEG asparaginase and steroids, as well as inclusion of stem cell transplant (SCT) for eligible patients. The primary endpoint was survival rate at 1 year, with the goal of improving from the 33% historical control to 53%. Adults, aged 51-75 years, with newly diagnosed ALL or lymphoblastic lymphoma, were eligible. During induction, patients received multi-agent chemotherapy with vincristine, prednisone, doxorubicin, and PEG asparaginase. Imatinib was instituted if cytogenetics confirmed the presence of the Philadelphia chromosome. Patients received prophylactic intrathecal therapy with induction, and those with CNS involvement underwent additional IT therapy. Prednisone was administered for 21 days for those aged less than 60 and for 7 days for those aged 60 and above. Following induction, cycle one of consolidation included treatment with clofarabine, prednisone, and PEG asparaginase. After induction and first consolidation course, eligible patients proceeded to allogeneic SCT. Patients without matched sibling donors could receive unrelated donor or cord blood transplants. While those eligible under age 60 could undergo ablative conditioning regimens, those 60 and older received reduced intensity regimens. Those not eligible for SCT, went on to receive CNS, consolidation and continuation phases of treatment, as per protocol, which incorporated treatment with cycles of vincristine, doxorubicin, 6-mercaptopurine, and dexamethasone. PEG asparaginase was incorporated into the induction, consolidation I, CNS phase, and consolidation II phases of therapy. As of the most current analysis, 30 patients have been enrolled. A total of 19 of 29 evaluable patients (66%) have achieved a complete remission (CR). Three patients were refractory to induction therapy, four discontinued treatment during induction due to toxicity, of which three died, and nine patients have experienced relapse following remission. Nine patients have undergone SCT. A total of 15 patients have died on study out of 27 evaluated, and the overall survival, calculated by the method of Kaplan and Meier, at one year was 62% [95% CI, 41%-77%] (Figure 1), while disease-free survival for the 18 patients who achieved a CR following induction therapy at one year was 77% [95% CI, 49%-90%]. In total, for evaluable patients with at least one year of follow-up, the proportion surviving at one year was 61% [two-sided 80% CI, 47-75%] (16/26), significantly higher than the historical rate (33% used for this analysis, one-sided 90% exact CI) among such patients. Overall survival is also shown for Ph+ and Ph- groups (Figure 2). The most common grade 3/4 toxicities included transaminitis and hyperbilirubinemia, cytopenias, hypophosphatemia, hyperglycemia, and neutropenic fever. The major toxicity of liver injury, thought related to PEG asparaginase, prompted an amendment to the protocol to reduce the dose. Additionally, PEG asparaginase administration was limited to only those with Philadelphia chromosome-negative disease, to decrease risk of severe hepatotoxcity in patients receiving concurrent imatinib and PEG asparaginase. These data suggest that intensive multi-agent chemotherapy is tolerable in older patients with ALL, and can result in improved outcomes when compared to historical data. Additional study of similarly intensive regimens, incorporating novel therapies and alternative formulations of asparaginase, are warranted in older populations of ALL. Disclosures Fathi: Seattle Genetics: Research Funding; Seattle Genetics: Advisory Board, Advisory Board Other. Stone:Novartis: Research Funding.

Description: Background: Many older adults (≥60) with AML have a poor prognosis and spend a high portion of their life from diagnosis until death in the hospital. Using a large cohort, we examined the reasons for hospitalizations and identified those which are potentially avoidable. Methods: We conducted a retrospective analysis of 329 consecutive patients (≥60) diagnosed with AML between 5/1/2005 and 12/31/2011 at two major tertiary care hospitals to examine the reasons for hospitalizations during treatment. Practicing physicians used a consensus-driven medical record review process to identify primary reason for each hospitalization and categorize it as "potentially avoidable" or "not avoidable" based on a novel adaptation of the Graham's criteria for potentially avoidable hospital admissions. We compared the rate of potentially avoidable hospitalizations between older patients receiving intensive chemotherapy (n=197) versus non-intensive chemotherapy (n=132) using multivariate logistic regression analysis controlling for age, gender, marital status, disease risk, comorbidities, and the receipt of stem cell transplantation. Results: We evaluated 1040 hospitalizations after the diagnosis of AML in 329 unique patients. The median age was 69.9 years [range 60-90] and the median number of hospitalizations was 4.2 [range 0-18]. 33.1% (109/329) of patients underwent stem cell transplantation. The most common primary reasons for hospitalizations were: fever/infection (38.0%), planned hospitalizations for chemotherapy or transplantation (37.7%), and uncontrolled symptoms (9.8%). We identified 180/1040 hospitalizations (17.4%) as potentially avoidable; among these, 47.8% were due to premature hospital discharge, 18.9% could have been managed in the outpatient setting, and 16.1% were due to failure of timely outpatient follow-up. Potentially avoidable hospitalizations represented 12.9% (76/589) and 23.1% (10/451) of hospitalizations among patients who received intensive chemotherapy and non-intensive chemotherapy, respectively. In multivariate logistic regression analysis, the receipt of non-intensive chemotherapy was associated with higher risk of potentially avoidable hospitalization [OR 2.01, 95% CI 1.27-3.20, P = 0.003]. Conclusions: Although many hospitalizations in older patients with AML are unavoidable and driven by the illness course and its treatment, a substantial proportion are potentially avoidable. Patients with AML undergoing non-intensive chemotherapy are at higher risk of having potentially avoidable hospitalization. Future interventions to reduce health care utilization in this population are needed, especially among those who are treated with non-intensive chemotherapy. Disclosures Steensma: Incyte: Consultancy; Amgen: Consultancy; Celgene: Consultancy; Onconova: Consultancy. LeBlanc:Boehringer Ingelheim: Membership on an entity's Board of Directors or advisory committees; Epi-Q: Consultancy; Flatiron: Consultancy; Helsinn Therapeutics: Honoraria, Research Funding. Fathi:Agios Pharmaceuticals: Other: Advisory Board participation; Merck: Other: Advisory Board participation; Seattle Genetics: Other: Advisory Board participation, Research Funding. DeAngelo:Amgen: Consultancy; Celgene: Consultancy; Pfizer: Consultancy; Incyte: Consultancy; Novartis: Consultancy; Ariad: Consultancy; Agios: Consultancy; Bristol Myers Squibb: Consultancy. Stone:Merck: Consultancy; Sunesis: Consultancy, Other: DSMB for clinical trial; Novartis: Research Funding; Agios: Consultancy; Amgen: Consultancy; Abbvie: Consultancy; Celgene: Consultancy; Karyopharm: Consultancy; Roche/Genetech: Consultancy; AROG: Consultancy; Pfizer: Consultancy; Juno: Consultancy; Celator: Consultancy. Chen:Bayer: Consultancy, Research Funding.

Description: Background: Aurora kinases play essential roles in regulating cell division, and increased expression has been noted in myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML). We previously conducted a phase I study of alisertib combined with "7+3" induction chemotherapy in untreated patients with AML, and found the combination to have an adverse event profile similar to 7+3 alone, with promising efficacy, particularly for patients with high-risk disease, such as those who were older, with high-risk molecular features, or with secondary AML. These patients collectively have a historically grim prognosis, with an approximate rate of remission, in trials, of 45%. CPX-351, a liposomal daunorubicin-cytarabine product, was recently approved for use in secondary AML after it was demonstrated to be superior to 7+3 induction, with a median survival of 9.6 months versus 5.9 months among older patients, in a phase 3 trial. We recently completed accrual to a phase II study of alisertib plus induction chemotherapy in patients with untreated, high-risk AML. Methods: Patients were eligible if they had AML defined by WHO 2016 and either an adverse-risk karyotype (European Leukemia Net Guidelines), secondary (post-MDS/MPN) AML, therapy-related AML, or age ≥ 65 vears. We used a Simon two-stage design, assuming a null composite remission rate (complete remission [CR] and CR with incomplete count recovery [CRi]) of 45%. Patients could be enrolled prior to cytogenetic classification, but those without adverse-risk karyotype who lacked other eligibility criteria were removed before day 8 and replaced. All patients received continuous infusion cytarabine 100mg/m2 on days 1-7 [D1-7] and idarubicin 12mg/m2 [or daunorubicin 60mg/m2] D1-3 (7+3). On D8 through D15, alisertib at 30mg BID orally (PO) was administered. All underwent a mid-induction marrow biopsy to assess for residual disease, which if present, was treated with 5+2 re-induction without alisertib. Following remission, patients could receive up to 4 consolidation cycles with cytarabine (3g/m2 BID D1,3,5 for age

Description: Background Treatment of AML among the elderly is challenging due to intolerance of intensive therapy and greater prevalence of therapy-resistant biology. Hypomethylating agents (HMAs) are commonly used in this setting, but yield suboptimal remission rates and modest survival (Dombret 2015, Kantarjian 2012). Vadastuximab talirine (33A) is a CD33-directed antibody conjugated to 2 molecules of a pyrrolobenzodiazepine (PBD) dimer. Upon binding, 33A is internalized and transported to the lysosomes where PBD dimer is released via proteolytic cleavage of the linker, crosslinking DNA, and leading to cell death. In preclinical studies, HMA priming followed by 33A resulted in upregulated CD33 expression, increased DNA incorporation of the PBD dimer, and enhanced cytotoxicity. Methods A combination cohort in a phase 1 study (NCT01902329) was designed to evaluate the safety, tolerability, pharmacokinetics, and antileukemic activity of 33Ain combination with an HMA. Eligible patients (ECOG status 0-1) must have had previously untreated CD33-positive AML andhad declined intensive therapy. A single dose level of 33A, 10 mcg/kg,was administered outpatient IV every 4 weeks on the last day of HMA (azacitidine or decitabine [5-day regimen], standard dosing). Investigator assessment of response was per IWG criteria; CRi required either platelet count of ≥100,000/µL or neutrophils of ≥1,000/µL (Cheson 2003). Results Fifty-three patients (median age 75 years; range, 60-87) have been treated with 33A+HMA. All patients had adverse (38%) or intermediate (62%) cytogenetic risk by MRC criteria; 40 patients (75%) were considered unfit for intensive therapy and 13 patients (25%) declined intensive therapy.Of the patients with secondary AML (23/53, 43%), median age was 77 years (range 60-87) with most of the patients ≥75 years (70%). The median treatment duration is currently 19.3 weeks (range, 2-86) with 13 patients remaining on treatment; no DLTs or infusion reactions were reported. G3 or higher AEs reported in ≥15% of patients were thrombocytopenia (55%), anemia (43%), febrile neutropenia (43%), neutropenia (38%), pneumonia (19%), and leukopenia (17%); no G4 or 5 bleeding events were observed. Other non-hematologic treatment-emergent AEs regardless of relationship to study treatment and reported in ˃25% of patients were fatigue (58%), nausea (47%), constipation (43%), decreased appetite, peripheral edema (40% each), pyrexia (32%), dyspnea (28%), diarrhea (26%), and dizziness (25%). 30- and 60-day mortality rates were 2% and 8% with no treatment-related deaths reported. A total of 37% (90/246) of doses were delayed due to AEs primarily related to myelosuppression (neutropenia 16%, thrombocytopenia 6%, febrile neutropenia 4%).Thirty-six of the 49 efficacy evaluable patients (73%)achieved CR (21, 43%) or CRi (15, 31%); an additional 4 patients were not efficacy evaluable by protocol definition, due to death (n=2) or withdrawal of consent (n=2) before a response assessment marrow could be obtained. Remissions were achieved after a median of 2 cycles (range, 1-4) and were observed in most of the patients with adverse risk disease including antecedent myelodysplasia (16/22, 73%), adverse cytogenetics (15/18, 83%), FLT3/ITD (5/5, 100%), and patients≥75 years (17/26, 65%). Seventeen of 22 efficacy-evaluable patients with secondary AML (77%) achieved CR (11, 50%) or CRi (6, 27%). Of all responding patients, 17 of 36 (47%) achieved MRD negativity by flow cytometry. The median relapse-free survival was 9.1 months (range, 0.1-16.5+) andOS continues to evolve with22 patients (42%) alive with a median follow-up of 10 months. Conclusions The combination of 33A+HMA is well tolerated with no identified pattern of off-target toxicity. Activity with the combination appears markedly improved when compared to the historical experience of HMA monotherapy in this patient population (Table 1). The CR+CRi rate of 73% in older AML patients with poor risk factors in the setting of low early mortality is particularly encouraging. Activity was maintained even in the highest risk patient groups (adverse risk cytogenetics, underlying myelodysplasia, secondary AML, FLT3/ITD). Survival data are evolving and compare favorably to historical controls. CASCADE, a phase 3 trial investigating 33A+HMA v. HMA alone in older AML patients is now enrolling (NCT02785900). Disclosures Fathi: Merck: Other: Advisory Board participation; Agios Pharmaceuticals: Other: Advisory Board participation; Bexalata: Other: Advisory Board participation; Seattle Genetics: Consultancy, Other: Advisory Board participation, Research Funding; Celgene: Consultancy, Research Funding. Erba:Gylcomimetics: Other: DSMB; Millennium Pharmaceuticals, Inc.: Research Funding; Jannsen: Consultancy, Research Funding; Ariad: Consultancy; Sunesis: Consultancy; Pfizer: Consultancy; Celator: Research Funding; Juno: Research Funding; Seattle Genetics: Consultancy, Research Funding; Agios: Research Funding; Astellas: Research Funding; Novartis: Consultancy, Speakers Bureau; Incyte: Consultancy, DSMB, Speakers Bureau; Celgene: Consultancy, Speakers Bureau; Amgen: Consultancy, Research Funding; Daiichi Sankyo: Consultancy. Stein:Celgene: Other: Advisory Board, Research Funding; Agios Pharmaceuticals: Other: Advisory Board, Research Funding; Seattle Genetics: Research Funding; Novartis: Consultancy. Ravandi:Seattle Genetics: Consultancy, Honoraria, Research Funding; BMS: Research Funding. Faderl:JW Pharma: Consultancy; Amgen: Speakers Bureau; Karyopharm: Consultancy, Research Funding; Ambit Bioscience: Research Funding; BMS: Research Funding; Celator Pharmaceuticals: Research Funding; Astellas: Research Funding; Pfizer: Research Funding; Seattle Genetics: Research Funding; Celgene: Consultancy, Research Funding. Advani:Seattle Genetics: Consultancy, Research Funding. DeAngelo:Baxter: Consultancy; Pfizer: Consultancy; Amgen: Consultancy; Celgene: Consultancy; Ariad: Consultancy; Incyte: Consultancy; Novartis: Consultancy. Kovacsovics:Seattle Genetics: Research Funding. Jillella:Seattle Genetics: Research Funding. Levy:Seattle Genetics: Research Funding; Jansen: Speakers Bureau; Amgen: Speakers Bureau; Millennium: Speakers Bureau. O'Meara:Seattle Genetics: Employment, Equity Ownership. Ho:Seattle Genetics: Employment, Equity Ownership. Stein:Seattle Genetics: Research Funding; Amgen: Consultancy, Research Funding, Speakers Bureau; Stemline Therapeutics: Consultancy, Research Funding; Argios: Research Funding; Celgene: Research Funding.

Description: Introduction: IDH2 mutations (mIDH2) are recurrent in ~5% of patients (pts) with MDS and ~15% of pts with acute myeloid leukemia (AML). mIDH2 proteins have neomorphic enzymatic activity and are associated with DNA and histone hypermethylation, altered gene expression, and blocked differentiation of hematopoietic progenitor cells. Enasidenib (AG-221/CC-90007) is a small-molecule allosteric inhibitor of mIDH2 protein that induces hematological responses in pts with mIDH2 AML, including relapsed or refractory (R/R) AML (Stein, Clin Cancer Res, 2016). The current analysis is the first to evaluate the safety and clinical efficacy of enasidenib monotherapy in pts with mIDH2-positive MDS. Methods: This analysis includes pts ages ≥18 years with MDS and mIDH2 who participated in a phase 1 study with a dose-finding period followed by an expansion phase in which all pts received daily oral enasidenib 100 mg QD in 28-day cycles. Pts had R/R MDS or were not candidates for standard therapies. Response was measured using peripheral blood (PB) and bone marrow (BM) samples from days 15, 29, 57, and every 56 days thereafter, and by objective investigator report. Overall response rate (ORR) reflects the best response achieved by pts, and includes complete remission (CR), partial remission (PR), marrow CR (mCR), and any hematologic improvement (HI) (IWG 2006 MDS criteria). Evaluable pts required a response assessment at Cycle 2 Day 1 or later, or discontinued before assessment. Overall survival (OS) was estimated using Kaplan-Meier methods. Next-generation sequencing identified pre-existing co-occurring genomic alterations using the FoundationOne® Heme test on purified mononuclear cells from BM or PB, to assess relationships between co-mutational status and clinical response. Results: Of 16 pts with MDS in this study, 12 pts had discontinued and 4 pts continued to receive enasidenib at interim database lock (15 April 2016). Reasons for discontinuation included disease progression (n=1), adverse event (AE; n=1), death (n=4), investigator decision (n=2), and other (n=1); 3 pts proceeded to transplant. Median age was 67 years (range 45-78) (Table 1). R140 mutations were more common than R172 mutations (88% vs 12%). At entry, 3 pts (19%) had relapsed following allogeneic stem cell transplant and 11 (69%) had failed prior treatment (Tx) with a hypomethylating agent (HMA). Six pts (38%) had received ≥2 prior anticancer Tx for MDS. MDS pts in the dose-finding phase received daily enasidenib doses of 60 mg (n=1), 150 mg (1), 200 mg (3), or 300 mg (1); 10 pts received enasidenib 100 mg QD. Median number of Tx cycles was 3 (range 1-25); 5 pts (31%) received ≥6 enasidenib cycles and 4 pts (25%) received ≥12 cycles. Grade 3-4 Tx-emergent AEs (TEAEs) were reported for 13 pts (81%); the most frequent were hyperbilirubinemia (n=5, unconjugated), pneumonia (n=4), thrombocytopenia (n=3) and hypokalemia (n=3). Seven pts (44%) had a grade 3-4 drug-related TEAE. One pt was not evaluable for response. ORR was 53% (8/15), including 1 pt who achieved CR (Figure 1). Of 10 evaluable pts who had received prior HMA Tx, 5 (50%) had a response with enasidenib, including the pt in CR. Of the 4 pts with no prior MDS Tx, 2 responded (1 PR, 1 mCR). Median time to CR, PR, or mCR (sustained ≥4 weeks) was 24 days (range 17-87) from beginning enasidenib Tx, and to HI (sustained ≥8 weeks) was 11 days (11-60). Two pts experienced disease progression. Median OS was not reached after a median follow-up of 4.7 months. FoundationOne® data were available for 12 pts; the most frequently observed known somatic co-occurring mutations were ASXL1 and SRSF2 (Figure 2). Although trends between response and co-occurring ASXL1 and/or SRSF2 mutations were observed, the small number of pts tested prevents definitive conclusions. Discussion: Daily Tx with oral enasidenib monotherapy was well tolerated and induced responses in more than one-half of these MDS pts with mIDH2, 50% of whom had higher-risk disease, and two-thirds of whom had failed prior HMA Tx. Notably, one-half of evaluable MDS pts who had failed prior HMA Tx had a response, including a CR, with enasidenib monotherapy. Only 2 pts experienced disease progression during Tx. Mutational testing is rapidly becoming essential to diagnosis and prognostication in MDS, and assessment of IDH2 mutations can identify MDS pts who may benefit from targeted Tx with enasidenib. Disclosures Stein: Seattle Genetics: Research Funding; Agios Pharmaceuticals: Other: Advisory Board, Research Funding; Celgene: Other: Advisory Board, Research Funding; Novartis: Consultancy. Fathi:Merck: Other: Advisory Board participation; Agios Pharmaceuticals: Other: Advisory Board participation; Seattle Genetics: Consultancy, Other: Advisory Board participation, Research Funding; Celgene: Consultancy, Research Funding; Bexalata: Other: Advisory Board participation. DiNardo:Novartis: Other: advisory board, Research Funding; Agios: Other: advisory board, Research Funding; Celgene: Research Funding; Daiichi Sankyo: Other: advisory board, Research Funding; Abbvie: Research Funding. Pollyea:Celgene: Other: advisory board, Research Funding; Ariad: Other: advisory board; Glycomimetics: Other: DSMB member; Alexion: Other: advisory board; Pfizer: Other: advisory board, Research Funding. Roboz:Celgene: Consultancy; Astex: Consultancy; Agios: Consultancy; Pfizer: Consultancy; Juno: Consultancy; Genoptix: Consultancy; Amgen: Consultancy; MEI Pharma: Consultancy; Janssen: Consultancy; AstraZeneca: Consultancy; Onconova: Consultancy; Sunesis: Consultancy; Novartis: Consultancy; Roche/Genentech: Consultancy; MedImmune: Consultancy; Celator: Consultancy; Amphivena: Consultancy. Sekeres:Amgen Inc.: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Millenium/Takeda: Membership on an entity's Board of Directors or advisory committees. Stone:Pfizer: Consultancy; Sunesis Pharmaceuticals: Consultancy; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Agios: Consultancy; Amgen: Consultancy; Celator: Consultancy; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Karyopharm: Consultancy; Novartis: Consultancy; Jansen: Consultancy; Juno Therapeutics: Consultancy; ONO: Consultancy; Seattle Genetics: Consultancy; Merck: Consultancy; Roche: Consultancy; Xenetic Biosciences: Consultancy. Attar:Agios Pharmaceuticals, Inc.: Employment, Equity Ownership. Tosolini:Celgene: Employment, Equity Ownership. Xu:Celgene: Employment, Equity Ownership. Amatangelo:Celgene: Employment, Equity Ownership. Gupta:Celgene: Employment, Equity Ownership. Knight:Celgene: Employment, Equity Ownership. De Botton:Agios, Celgene, Pfizer, Novartis, Pierre Fabre, Servier: Consultancy, Honoraria, Research Funding. Kantarjian:Amgen: Research Funding; ARIAD: Research Funding; Bristol-Myers Squibb: Research Funding; Pfizer Inc: Research Funding; Delta-Fly Pharma: Research Funding; Novartis: Research Funding.

Description: The hematopoietic cell transplantation comorbidity index (HCT-CI) was specifically developed to assign weighted scores to comorbidities existing prior to allogeneic HCT; thus stratifying post-HCT mortality risks. The utility of comorbidities assessed prior to treatment for AML is unknown. Here, we a) investigated the impact of each comorbidity on 1-year overall mortality of patients (pts) with newly diagnosed AML, b) designed and validated a new comorbidity score (AML-CI) comparing its performance to that of the HCT-CI, and c) identified other relevant risk factors for AML outcomes. We retrospectively collected comorbidities and laboratorydata from 1079 pts with newly diagnosed AML who received therapy at 5 institutions from 2008- 2012. Pts were aged ≤49 (29%), 50-59 (25%), 60-69 (26%), and ≥70 (20%) years old. Cytogenetic-risks were favorable (21%), intermediate (36%), or unfavorable (43%). Regimen intensity was low in 18%, intermediate in 63%, and high in 19%. HCT-CI comorbidities were evaluated per HCT-CI standard comorbidity definitions with the exception that renal comorbidity was defined per serum creatinine and/or creatinine clearance. Newly evaluated comorbiditiesincluded including hyperlipidemia, hypertension, deep venous thrombosis, gastroesophageal reflux disease, hypothyroidism, hypoalbuminemia, thrombocytopenia, neutropenia, anemia, elevated lactate dehydrogenase (LDH), smoking, and alcohol intake. Pts were randomly divided into a training (n=710) and a testing set (n=369). In the training set, the unadjusted hazard ratios (HRs) for 1-year overall mortality were calculated for each comorbidity as well as all adjustment factors: gender, age, race, cytogenetic-risks, regimen intensity, WBC, blast count, and marrow blast percentages. Only factors that were associated with overall mortality at a significance level of P