ALBERT

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: 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: Abstract 4552 Background: Myeloablative total body irradiation (TBI) may be incorporated in the condition regimen prior to hematopoietic cell transplant (HCT) for a variety of hematologic malignancies. Recent studies suggest improved patient tolerance and similar overall outcomes when TBI is administered prior to chemotherapy versus after systemic therapy. Patients and Methods: We retrospectively reviewed outcomes of adult patients (〉18yrs old) who received myeloablative TBI as part of their conditioning regimen at the Massachusetts General Hospital between 1993 and 2012. All patients received TBI prior to chemotherapy; a median dose 13 Gy (range 12–16 Gy) was delivered. Patient characteristics including presenting disease, treatment course, treatment outcome and late-effects of therapy were analyzed. Results: The study cohort consisted of 116 patients; 55 patients received TBI for non-Hodgkin lymphoma (NHL), 25 for acute lymphoblastic leukemia (ALL), 16 for acute myelogenous leukemia (AML), 5 for chronic myelogenous leukemia (CML), 9 for Hodgkin lymphoma (HL), and 6 for other hematologic disease including MDS, MM, and CLL. Ten patients died of transplant-related mortality. Sixty-three patients underwent allogeneic HCT with a matched-related donor, 53 patients underwent autologous HCT, 5 patients had a tandem HCT, and the remaining patients were divided evenly among umbilical cord, haploidentical, and matched unrelated donor HCT. Twice daily TBI was administered for most patients; 56 cases received TBI three times daily. Cyclophosphamide + TBI (Cy/TBI) was the most commonly used regimen (n=100). At the time of this report, 56 patients were still alive, with a median followup of 84.7 months (range 0.5–220 months). Median survival for all 116 cases was 67 months; stratified by diagnosis: 112 months NHL, 50 months HL, 69 months ALL, 20 months AML, 17 months CML, and 36 months for other malignancies. Overall survival for the entire cohort was 53% (95% CI = 43 to 62%) and 43% (95% CI = 32 to 53%) at 5- and 10-years, respectively. Progression free or relapse-free survival (P/RFS) was 44% (95% CI = 34 to 54%) and 33% (95% CI = 23 to 43%) at 5- and 10-years, respectively. Patients with ALL had the longest P/RFS (69 months) followed by NHL (42 months). Thirteen patients developed second malignancies; 9 patients developed skin cancer, 2 were diagnosed with other solid tumors, and 2 patients had both skin cancer and another malignancy. Endocrine dysfunction such as hypothyroidism and hypogonadism was documented in 11 patients, 23 patients developed late ocular toxicity. Other late toxicities include pulmonary (14 patients), cardiac (4 patients), and 11 cases of neuropathy. None of these late toxicities were seen in patients with less than 2.5 years of survivorship after transplant. Conclusion: Similar to other reports, our results show that conditioning regimens that include the use of TBI prior to high-dose chemotherapy have OS and P/RFS that are comparable to other conditioning regimens. Appropriate screening for late toxicities of therapy should begin in the 3rd year of survivorship. Disclosures: No relevant conflicts of interest to declare.

Description: BACKGROUND: Ivosidenib, a potent mutant isocitrate dehydrogenase 1 (mIDH1) inhibitor, is being assessed in a phase 1 study of mIDH1 advanced hematologic malignancies (NCT02074839). We characterized the pharmacokinetics (PK) of ivosidenib in this population, and the effects of patient/disease characteristics and concomitant medications. METHODS: Ivosidenib was given in continuous 28-day cycles at 100 mg twice daily and 300 mg, 500 mg, 800 mg, and 1200 mg once daily (QD). Enrollment is complete; 258 patients received ≥1 ivosidenib dose (78 in escalation, 180 in expansion); samples were available from 253 patients (223 received ivosidenib 500 mg QD). Ivosidenib concentrations were determined using validated liquid chromatography with tandem mass spectrometry (LC-MS/MS)-based methods. Population PK modeling was conducted using NONMEM software. The impact of demographics, renal and hepatic function, disease type, Eastern Cooperative Oncology Group (ECOG) performance status, and concomitant cytochrome P450 3A4 (CYP3A4) inhibitors/inducers and gastric acid reducers on ivosidenib PK was explored. RESULTS: Ivosidenib PK were best described using a 2-compartment model with first-order absorption, dose-dependent bioavailability, and a time-dependent change in relative bioavailability and clearance between Day 1 and steady state. Mean steady-state apparent clearance (CL/F) was 5.39 L/h (between-patient variability ~35%) and mean central volume of distribution (Vc/F) was 234 L (~47%). Less than dose-proportional bioavailability was observed, with a dose doubling translating to a ~40% increase in exposure. The moderate/strong CYP3A4 inhibitors voriconazole, fluconazole, and posaconazole were associated with 36%, 41%, and 35% reductions in CL/F, and hence 57%, 69%, and 53% increases in area under the plasma ivosidenib concentration-time curve (AUC), respectively (Figure 1). Baseline body weight had a significant impact on Vc/F. Low albumin at baseline and during treatment correlated with decreased CL/F and Vc/F. However, the effects of body weight and albumin did not appear to be clinically relevant. No effects of creatinine clearance or measures of liver function (alanine aminotransferase, aspartate aminotransferase, bilirubin, within the range studied) on ivosidenib CL/F were detected. Concomitant use of pantoprazole or famotidine did not affect ivosidenib CL/F. CONCLUSION: This population PK model of ivosidenib suggests that no dose adjustments are needed based on the range of patient and disease characteristics analyzed. Disclosures Le: Millennium: Patents & Royalties; Agios: Employment, Equity Ownership. Wada:Certara: Employment; Agios: Consultancy. Dai:Agios: Employment, Equity Ownership. Fan:Agios: Employment, Equity Ownership. Liu:Agios: Employment, Equity Ownership. Liu:Agios: Employment, Equity Ownership. Attar:Agios: Employment, Equity Ownership. Agresta:Agios: Employment, Equity Ownership. Yang:Agios: Employment, Equity Ownership.

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: Reduced intensity conditioning (RIC) double cord blood transplantation is an effective strategy in adults to provide allogeneic donors for patients with uncommon HLA types. However, the risk of second cancers has not been established. We treated 53 patients with hematologic malignancies using a RIC regimen of fludarabine 30 mg/m2/day Days −8 through −3 (total dose 180 mg/m2), melphalan 100 mg/m2 Day −2 and rabbit antithymocyte globulin 1.5 mg/kg Days −7, -5, -3, -1 (total dose 6 mg/kg). Cord blood units were a 4/6 or higher HLA A, B, DR allele match with the patient and each other and achieved a minimum precryopreservation cell dose of 3.7 x 107 NC/kg. Twenty-one patients received GVHD prophylaxis with cyclosporine and mycophenolate mofetil and 32 patients received tacrolimus and sirolimus. Median age was 49 (range 19–67) years and the majority of patients had acute leukemia or relapsed lymphoma. Median follow-up was 27 months among the 29 patients still alive. Nine patients developed a second malignancy. Seven patients had lymphoma and two had MDS/MPD. The second cancers occurred at a median of 141 days (range 39 days-26 months) after transplant. Five second cancers (both MDS/MPD and 3 of 7 lymphomas) were donor derived; the origin of the others was not determined. Patients with Epstein Barr Virus lymphoproliferative disorder (EBV-LPD) had a median EBV viral load of 445,000 copies/ml (range 3300–5.4 million). Six of seven patients with lymphoma had wide spread organ involvement; 6 patients were treated with Rituxan but only one of them had a sustained response; the rest died of EBV-LPD. Both cases of MDS/MPD were donor derived and fatal. One occurred in a patient transplanted for CLL; the other patient was transplanted for AML. The overall survival for the entire cohort of 53 patients was 55% at two years. The actuarial rate of second malignancy was 19% at 26 months post-transplant (2 year rate of 16%). The rate of donor-derived myeloid disease was 6%. Second malignancy was the leading cause of death, with relapse the second leading cause of death. Neither age, GVHD prophylaxis, HLA matching, nor total nucleated cell dose predicted for a higher rate of second malignancy. There was a trend to a higher risk of second cancer in patients who received an infused CD34+ cell dose of ≤ 1.9 x 105 cells/kg)—(30% vs. 7%, P=0.070). In summary, 1) Second malignancies occur at a high rate after RIC cord blood transplantation; 2) A low infused CD34+ cell dose/kg may be associated with a higher risk of second cancer; 3) Strategies to reduce thymoglobulin dose may be important to reduce the incidence of EBV-LPD; 4) It is important to assess the genetic origin of post-transplant myeloid diseases to establish the risk of donor-derived leukemia. 723: Recurrence, Secondary Neoplasia, and Late Complications

Description: Abstract 3555 Introduction: Cytogenetic status represents a major prognostic factor for individuals with AML. However, approximately 50% of individuals have CN-AML and, within this cohort, genetic features have important prognostic and therapeutic implications. Mutations in the FLT3 receptor are found in 30–40% of patients with CN-AML. While the FLT3-internal tandem duplication (ITD) is associated with a poor DFS and OS when compared to CN-AML patients with a wtFLT3R, the prognostic significance of the FLT3-tyrosine kinase domain (TKD) mutation is less clear. There is considerable debate over the best postremission treatment for CN-AML patients who have a FLT3ITD. Our primary objective was to determine the relationship between different postremission therapies and outcome in CN-AML patients with FLT3 mutations. Methods: We retrospectively reviewed the outcomes of newly diagnosed AML patients at the Massachusetts General Hospital and Dana-Farber Cancer Institute/Brigham and Women Hospital between 2002–2008 who were younger than 60 years of age, had a normal karyotype, and had a FLT3ITD and/or TKD mutation at diagnosis. The method of Kaplan and Meier was used to estimate DFS and OS; groups were compared using the log-rank test. A p-value less than .05 was interpreted as statistically significant. Results: At diagnosis, there were 37 patients with an ITD mutation (7 also had a TKD mutation) and 19 patients with an isolated TKD mutation at diagnosis. Patients who received an allogeneic SCT were not included in the analysis. ITD positive patients with an allelic ratio (AR) of mutant to wt FLT3 〉.2 had a significantly worse DFS and OS than those with an AR

Description: Abstract 1484 Introduction: Acute Myeloid Leukemia (AML) is more common among patients over the age of 60, who also historically have a poorer prognosis. It is unclear which patients will benefit most from intensive chemotherapy; prognostic factors have been identified to risk-stratify these patients, but tend to consider characteristics specific to the disease such as cytogenetics [Lancet 2010; 376: 2000–08], and may not account for patient comorbidities that preceded the diagnosis of AML. Increased body mass index (BMI) has been associated with an increased incidence of various malignancies, including AML [The Oncologist 2010; 15: 1083–1101], and is increasingly prevalent among the general population. We sought to determine whether patient BMI at time of AML diagnosis is related to overall survival among patients older than age 60. Methods: We performed a retrospective chart review of all patients diagnosed at Massachusetts General Hospital with records available in the electronic medical record between January 1, 1992 and May 1, 2011. Patients were identified using billing codes and pathology records and underwent chart review to confirm a diagnosis of AML. Patients were included in this review if they had a pathologically-confirmed new diagnosis of AML, were older than age 60 at the time of diagnosis, and were given cytarabine-based induction chemotherapy. We collected past medical history, presenting labs, patient cytopathology, weight, and height at diagnosis. Overall survival (OS) was estimated using the Kaplan-Meier method, with 95% confidence intervals calculated using Greenwood's formula. We then performed a stepwise multivariable Cox regression analysis, pre-specifying that a variable had to be significant at the 0.3 level before it could be entered into the model, while a variable in the model had to be significant at the 0.05 level for it to remain in the model. Results: We identified 152 patients with AML diagnosed after the age of 60. The median age was 68 years (range 60–87); 54% of patients were male, and 86% were white. Patient disease was identified as de novo in 50%, and secondary in 50%. Cytogenetics, when available (86.2% of patients), were most commonly normal (37.5%) or poor risk (34.2%); only 1.3% of patients were good risk. The median OS for all patients was 269 days (95% CI 217–323). The 60 day OS for all patients was 83% (95% CI 77–89%). Using the log-rank test to perform a univariate analysis, worsened OS was associated with increased age (P=0.024); body mass index (BMI) 〈 27, the median BMI in our cohort, (P=0.011); presence of coronary artery disease (CAD) (P=0.042); and with cytogenetics (P=0.013). The multivariable analysis of the Cox proportional-hazards model found that the hazard rate for death was increased with older age (HR 1.53, P=0.027, 95% CI 1.05–2.24), lower BMI 〈 27 (HR 1.93, P=0.002, 95% CI 1.28–2.92) and cytogenetics (P

Description: Abstract 2689 Introduction: Acute promyelocytic leukemia (APL) is a distinct subtype of acute myeloid leukemia (AML) characterized by promyelocytes in the blood and bone marrow, coagulopathy, and characteristic translocation between chromosomes 15q22 and 17q21. Internal tandem duplication (ITD) mutations within the FMS-like tyrosine kinase receptor (FLT3) are found in approximately 30% of patients with APL. While cytogenetically normal AML patients with ITD mutations (especially with high ratio of mutant: WT allele) have a poorer prognosis due to high relapse rate, the prognostic value of ITD in APL is debated. We analyzed the clinical outcome of patients with APL to determine the relationship between FLT3 receptor status and prognosis. Materials and Methods: We conducted a retrospective analysis of all adult APL patients 〈 age 60 who were newly diagnosed and tested for FLT3R mutations at Massachusetts General Hospital and Dana-Farber Cancer Institute/Brigham and Women's Hospital between 2002 and 2008. Patient characteristics, complete remission (CR) rates, disease free survival (DFS), and overall survival (OS) were assessed by medical record review under an IRB-approved protocol. CR, DFS and OS were defined according to standard criteria. Kaplan-Meier method was used to estimate median DFS and OS and log-rank p-values were presented. We assessed the associations of clinical characteristics and the type of mutation patients had using Kruskal-Wallis tests. A p-value less than 0.05 was interpreted as statistically significant. Results and Discussion: We identified a total of 26 patients with APL for whom FLT3 mutation status was known. There were 13 patients with wtFLT3, 9 with ITD (1 also had TKD), and the remaining 4 had an isolated TKD mutation. Of the 13 patients with wt FLT3APL, 4 had prior chemotherapy and/or radiation. No patients in the FLT3ITD APL or FLT3TKD APL groups had prior chemotherapy or radiation. As we had only 4 patients had an isolated FLT3TKD mutation, we restricted our analyses to patients who had either wt FLT3 or FLT3ITD+/− TKD. Of the wtFLT3 APL patients, 9/13 were enrolled and treated on CALGB 9710. Of the remaining 4 patients, two were treated according to the PETHEMA regimen, one with a history of breast cancer and significant anthracycline exposure was treated with ATRA and AsO3, and the last patient died before therapy could be initiated. Of the 9 patients with FLT3ITD APL, 5 were treated on CALGB 9710, 2 were treated according to 9710 but off protocol, and 2 with the PETHEMA regimen. Baseline clinical characteristics were similar between the two groups including CR rates [92 (12/13) versus 100% (9/9) for wt and ITD, respectively]. Patients with the ITD had a lower fibrinogen at presentation than those with wt (103 vs. 235 mg/dl, p=.04). While patients with ITD appeared to have a higher WBC, it was not statistically significant (p=.1). However, patients with ITD had an inferior DFS compared to wt (Figure 1) (p=.01) while there was no significant difference in OS between the two groups (p=.39). Of the 5 patients with ITD who relapsed, 3 received AsO3 reinduction and autologous SCT, 1 with CNS recurrence received myeloablative allogeneic SCT, and the fifth died in relapse without treatment. The observation that FLT3ITD APL patients have a reduced DFS raises the possibility that APL therapy may be improved for this group of patients, possibly by incorporating FLT3 inhibitors. Disclosures: DeAngelo: Deminimus: Consultancy. Stone:Novartis: Consultancy.

Description: Background: There is an unmet need fortreatments (Tx) for myeloid malignancies, particularly relapsed/refractory (RR) AML, that provide durable remissions without worsening existing cytopenias that place patients (pts) at risk for serious infections or bleeding. Oral AG-221 is a selective, potent inhibitor of the mutant isocitrate dehydrogenase 2 (mIDH2) enzyme associated with hematologic malignancies. A phase 1/2 dose-escalation and expansion study of AG-221 [NCT01915498] is ongoing in pts with advanced hematologic malignancies. Reported here are AG-221 safety and efficacy results with a focus on pts with RR-AML, and the first AG-221 data to show changes in absolute neutrophil count (ANC) in early Tx and associated adverse events (AEs), response by mIDH2 type (R140Q or R172K), and mIDH2 variant allele frequency (VAF) on Tx over time. Objectives: Assess AG-221 safety and efficacy in pts with advanced myeloid malignancies; and in responding RR-AML pts, evaluate response by mIDH2 mutation type, associations between ANC improvement and AEs, and mIDH2 VAF over time. Methods: Pts ≥18 years with mIDH2-positive myeloid malignancies are eligible. AG-221 is administered QD or BID in continuous 28-day cycles. Dosing began at 50 mg QD or 30 mg BID and increased in subsequent cohorts. Response is measured from peripheral blood (PB) and bone marrow (BM) samples on days 15, 29, 57, and every 56 days thereafter, and by objective investigator report. Evaluable pts had a response assessment at Cycle 2 Day 1 or later, or discontinued before assessment. Stable disease (SD) is failure to achieve at least partial remission (PR) but no progressive disease (PD). ANC improvement in this analysis is defined as ≥1.0x109/L increase from baseline (BL). Next-generation sequencing was used to assess mIDH2 VAF longitudinally in a subset of responders, using the FoundationOne Heme test on purified mononuclear cells from BM or PB. Results: At data cut-off (1 July 2015), 198 pts had received AG-221 and 83 (42%) remained on Tx. Median age was 69 yrs (19-100). 70% of pts had an R140Q and 25% had an R172K mutation (5% unknown). Most pts had RR-AML (n=138, 70% [untreated AML 17%, MDS 7%, other 6%]). Among RR-AML pts, 88 (64%) had received ≥2 prior Tx regimens (2 n=46, 3 n=24, ≥4 n=18), including intensive therapy, HMAs, or BM transplant. Median Tx durations overall and for RR-AML pts were 4.5 (95%CI 3.6-5.9) and 5.2 (3.6-6.1) months (mos), respectively. The highest daily AG-221 dose was 450 mg; maximum tolerated dose has not been reached. The most common Tx-related AEs were indirect hyperbilirubinemia (19%) and nausea (18%). Serious AEs (SAEs) were mainly disease-related; 35 pts (18%) had Tx-related SAEs, notably, leukocytosis (n=7). In all, 181 pts (91%), including 128 RR-AML pts, were efficacy evaluable. Objective responses were seen in 74 pts (41%), including 52 RR-AML pts (41%) (Table). Median response durations overall and in RR-AML pts were 6.9 (95%CI 3.7-9.2) and 6.0 (3.7-9.2) mos, respectively. Response rates were consistent in RR-AML pts, regardless of number of prior Tx regimens or mIDH2 type (R140Q 36%, R172K 39%). Eight pts went to transplant, including 5 RR-AML pts (Fig 1). Improvement from BL ANC (median 0.4 x109/L [0-15.5]) occurred in 72 RR-AML pts (56%), including 43 responders, and 23pts (40%) with SD. Among RR-AML responders, ANC increases occurred in cycle 1 (median 0.6 mos; 0.1-9.3), were durable through cycle 6 (Fig 2), and were associated with lower rates of infections and febrile neutropenia at cycles 1, 3, and 6 vs pts without ANC improvement. mIDH2 VAF did not decrease on-Tx in RR-AML pts who achieved a CR, CRp, or PR (Fig 3). Conclusions: AG-221 was well-tolerated and induced responses in pts with advanced myeloid malignancies, including heavily pretreated RR-AML. Response rates in RR-AML were consistent regardless of number of prior Tx regimens or mIDH2 type. mIDH2 VAF did not change from BL in responding pts; however, rapid ANC improvements suggest that despite the persisting mutant clone, differentiation into mature myeloid cells (eg, neutrophils) occurred. These data give insight into the putative mechanism of AG-221 as a differentiation agent associated with early ANC improvement and clinical benefits. Table. All(N=181) RR-AML(N=128) n (%) Overall Response (CR, PR, CRp, CRi, mCR) 74 (41) 52 (41) CR 30 (17) 23 (18) CRp 3 (2) 1 (1) CRi 1 (1) 1 (1) mCR 15 (8) 8 (6) PR 25 (14) 19 (15) SD 81 (45) 57 (45) PD 9 (5) 7 (6) Not evaluable 17 (9) 12 (9) Disclosures Stein: Seattle Genetics: Consultancy; Agios Pharmaceuticals: Consultancy. DiNardo:Novartis: Research Funding. Altman:BMS: Consultancy; Spectrum: Consultancy; Astellas: Consultancy; Seattle Genetics: Consultancy; Ariad: Consultancy; Novartis: Consultancy. DeAngelo:Incyte: Consultancy; Pfizer: Consultancy; Bristol Myers Squibb: Consultancy; Agios: Consultancy; Amgen: Consultancy; Novartis: Consultancy; Ariad: Consultancy; Celgene: Consultancy. Kantarjian:ARAID: Research Funding; Amgen: Research Funding; Pfizer: Research Funding; BMS: Research Funding; Novartis: Research Funding. Sekeres:Celgene Corporation: Membership on an entity's Board of Directors or advisory committees. Fathi:Agios Pharmaceuticals: Other: Advisory Board participation; Seattle Genetics: Other: Advisory Board participation, Research Funding; Merck: Other: Advisory Board participation. Flinn:Celgene Corporation: Research Funding. Frankel:Stemline: Consultancy, Patents & Royalties, Research Funding. Levine:Loxo Oncology: Membership on an entity's Board of Directors or advisory committees; CTI BioPharma: Membership on an entity's Board of Directors or advisory committees; Foundation Medicine: Consultancy. Medeiros:Agios Pharmaceuticals: Honoraria; Celgene: Honoraria, Research Funding. Pollyea:Ariad: Consultancy; Pfizer: Consultancy; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Karyopharm: Consultancy; Agios: Consultancy, Membership on an entity's Board of Directors or advisory committees; GlycoMimetics: Other: Member of data safety monitoring board. Stone:Abbvie: Consultancy; Sunesis: Consultancy, Other: DSMB for clinical trial; Celator: Consultancy; Celgene: Consultancy; Juno: Consultancy; AROG: Consultancy; Merck: Consultancy; Agios: Consultancy; Pfizer: Consultancy; Roche/Genetech: Consultancy; Amgen: Consultancy; Novartis: Research Funding; Karyopharm: Consultancy. Yen:Agios Pharmaceuticals: Employment, Equity Ownership. Attar:Agios Pharmaceuticals: Employment, Equity Ownership. Xu:Celgene Corporation: Employment, Equity Ownership. Tosolini:Celgene Corporation: Employment, Equity Ownership. Mei:Celgene Corporation: Employment, Equity Ownership. Thakurta:Celgene Corporation: Employment, Equity Ownership. Knight:Celgene Corporation: Employment, Equity Ownership. De Botton:Agios Pharmaceuticals: Research Funding.