ALBERT

Description: Introduction: Outcomes for acute myeloid leukemia (AML) among older patients has remained largely unchanged for decades. Long-term survival for patients aged 〉60 years is poor (median survival 10.5 months). Targeting the proteasome in AML is attractive, since leukemia stem cells have demonstrated sensitivity to proteasome inhibition in preclinical models, perhaps through down regulation of nuclear NF-KB (Guzman, Blood 2001). AML cell lines are susceptible to synergistic cytotoxicity when bortezomib, a proteasome inhibitor, is combined with daunorubicin and cytarabine. We have shown that adding bortezomib to standard treatment in AML results in a high remission rate, although grade 2 sensory neurotoxicity was noted in approximately 12% of treated patients. A newer generation proteasome inhibitor, ixazomib, is less frequently associated with neurotoxicity, and, therefore, was selected for combination with conventional chemotherapy in this phase I trial. The primary objective of this study was to determine the maximum tolerated dose (MTD) of ixazomib in combination with conventional induction and consolidation chemotherapy for AML. Herein are the initial results of this trial. Methods: Adults 〉60 years of age with newly diagnosed AML were screened for eligibility. Patients with secondary AML were eligible, including those with prior hypomethylating agent therapy for myelodysplastic syndromes (MDS). We excluded those with promyelocytic leukemia. There were 2 phases in this study. In the first phase (A), the induction treatment consisted of the following: cytarabine 100 mg/m2/day by continuous IV infusion, Days 1-7; daunorubicin 60 mg/m2/day IV, Days 1, 2, 3, and ixazomib was provided orally at the cohort dose, Days 2, 5, 9, and 12. Consolidaton or transplant was at the discretion of the treating physician in phase A. In the second phase (B), induction was the same as that with the determined MTD of ixazomib. All patients were to be treated with the following consolidation: cytarabine at 2 g/m2/day, days 1-5 with ixazomib on days 2, 5, 9, and 12 at the cohort dose for consolidation. A standard 3 + 3 patient cohort dose escalation design was used to determine whether the dose of ixazomib could be safely escalated in 3 cohorts (1.5 mg/day, 2.3 mg/day, 3.0 mg/day), initially in induction (phase A) and subsequently in consolidation (phase B). The determined MTD of ixazomib in the first portion (A) of the trial was used during induction in the second portion (B), which sought to determine the MTD for ixazomib during consolidation. Secondary objectives included rate of complete remission, disease-free survival, and overall survival (OS). Results: Thirty-six patients have been enrolled on study, and 28 have completed dose levels A-1 through A-3 and B1 through B-2. Full information on cohort B-3 has not yet been obtained, hence, this report covers the experience with the initial 28 patients, cohorts A-1 through B-2. There were 12 (43%) patients among the 28 with secondary AML, either with prior hematologic malignancy or therapy-related AML. Nineteen patients (68%) were male, and the median age was 68 years (range 61-80 years). There have been no grade 5 toxicities due to study drug. Three patients died early due to leukemia, 2 of which were replaced for assessment of the MTD. Nearly all the grade 3 and 4 toxicities were hematologic (Table). There was 1 DLT (grade 4 platelet count decrease extending beyond Day 42). There has been no grade 3 or 4 neurotoxicity with ixazomib to date. Among the 28 patients in the first 5 cohorts, 22 achieved complete remissions (CR) and 2 achieved CRi, for a composite remission rate (CCR) of 86%. Among the 12 patients with secondary AML 8 achieved CR and 2 achieved CRi, for a CCR of 83%. The median OS for the 28 patients has not been reached (graph). The 18-month OS estimate was 65% [90% CI, 50-85%]. Conclusions: The highest dose level (3 mg) of ixazomib planned for induction in this trial has been reached safely. For consolidation there have been no serious safety issues in the first 2 cohorts with a dose up to 2.3 mg, apart from 1 DLT in the form of delayed platelet count recovery. The recommended phase 2 dose of ixazomib for induction is 3 mg. Accrual to cohort B-3 is ongoing. Notably, to date, no grade 3 or 4 neurotoxicity has been encountered. The remission rate in this older adult population with the addition of ixazomib to standard chemotherapy appears favorable. Figure Disclosures Amrein: Amgen: Research Funding; AstraZeneca: Consultancy, Research Funding; Takeda: Research Funding. Attar:Aprea Therapeutics: Current Employment. Brunner:Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Forty-Seven Inc: Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Research Funding; Takeda: Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Research Funding. Hobbs:Constellation: Honoraria, Research Funding; Novartis: Honoraria; Incyte: Research Funding; Merck: Research Funding; Bayer: Research Funding; Jazz: Honoraria; Celgene/BMS: Honoraria. Neuberg:Celgene: Research Funding; Madrigak Pharmaceuticals: Current equity holder in publicly-traded company; Pharmacyclics: Research Funding. Fathi:Blueprint: Consultancy; Boston Biomedical: Consultancy; BMS/Celgene: Consultancy, Research Funding; Novartis: Consultancy; Kura Oncology: Consultancy; Trillium: Consultancy; Amgen: Consultancy; Seattle Genetics: Consultancy, Research Funding; Abbvie: Consultancy; Pfizer: Consultancy; Newlink Genetics: Consultancy; Forty Seven: Consultancy; Trovagene: Consultancy; Kite: Consultancy; Daiichi Sankyo: Consultancy; Astellas: Consultancy; Amphivena: Consultancy; PTC Therapeutics: Consultancy; Agios: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; Jazz: Consultancy. OffLabel Disclosure: Ixazomib is FDA approved for multiple myeloma. We are using it in this trial for acute myeloid leukemia.

Description: Characterization of molecular alterations in acute myeloid leukemia (AML) has led to development of targeted therapies, including FLT3 and IDH1/2 inhibitors. Maintenance therapy following hematopoietic cell transplantation (HCT) has shown substantial promise. Enasidenib (ENA), a selective IDH2 inhibitor, was associated with impressive rates of response in relapsed/refractory (R/R) AML and is now FDA-approved for this indication. We sought to assess the tolerability and define the maximum tolerated dose (MTD) of ENA as maintenance following HCT for IDH2-mutated myeloid malignancy. HCT-eligible patients (pts) ≥ 18 years with AML in remission, or myelodysplastic syndrome (MDS) with 1000/µL and platelets 〉 50000/µL). Those with prior HCT, active disease, QTc ≥450ms, and active infections were excluded. ENA was initiated between day 30 and 90 after HCT, at which time the following were required: chimerism ≥70% of donor origin among blood/marrow cells, no acute graft versus host disease (aGVHD) requiring ≥0.5mg/kg/day prednisone or equivalent, and no relapse. ENA was taken orally (po) daily (qd) in 28-day cycles. The period for dose-limiting toxicity (DLT) evaluation was the first cycle, escalation to successive levels was guided by DLT incidence, and 2 levels (50mg,100mg) were studied. Following establishment of MTD or recommended phase 2 dose (RP2D), 10 pts would be enrolled in an expansion cohort. Pts were monitored for relapse and toxicity and continued until disease progression, intolerable toxicity, or receipt of 12 cycles. Nineteen pts have been registered prior to HCT at 3 sites, Massachusetts General Hospital, Dana Farber Cancer Institute, and Johns Hopkins Hospital. Three pts could not initiate ENA following HCT; 2 due to logistic challenges of the COVID pandemic and 1 due to relapse. The remaining 16 pts initiated ENA treatment. The median age was 61 years (range 31-76); 12 (75%) were male, and 13 (81%) were Caucasian. Fourteen (88%) had AML, of which 6 were AML with MDS related changes and 2 had antecedent myeloproliferative neoplasm. Two pts (13%) had MDS. Among these 16 pts, 9 (56%) had IDH2 R140, and 5 (25%) had IDH2 R172 mutations. IDH2 subtype data was unavailable for 2 pts. Of 15 pts with available data from time of diagnosis, 11 (73%) had intermediate-risk and 4 (27%) had adverse-risk cytogenetics. Among these 15 pts, common concurrent mutations were DNMT3A (47%), SRSF2 (33%), and RUNX1 (33%). Eleven AML pts (85%) received intensive versus non-intensive therapies (15%) prior to HCT, and among all pts, 7 (44%) had received ENA prior to HCT. HCT data was available for all 16 pts; 4 pts (25%) received myeloablative, and 12 (75%) received reduced-intensity conditioning. Nine pts (56%) had a matched unrelated, 6 (38%) had haploidentical, and 1 (6%) had a matched related donor HCT. Three pts were enrolled at the 50mg dose level, 6 pts at 100mg, and after no DLTs were detected, the remaining were enrolled in an expansion cohort at 100mg qd. Median follow-up (F/U) for surviving patients is currently 11.7 months (range 1.5-18.9). 2 pts (13%) have relapsed during F/U, at 96 and 364 days post HCT. Additional ≥grade (G) 3 toxicities detected during treatment, possibly or probably related to ENA, included neutropenia, anemia, and bilirubinemia. Six pts (38%) required dose interruptions lasting a median 19 days (range 7-25), 4 required a dose reduction to 50mg, and 1 stopped treatment due to G3 bilirubinemia. In total, 3 pts (18%) discontinued study treatment, 1 for aforementioned G3 bilirubinemia, 1 to pursue a GVHD trial, and 1 for relapse. Six pts have completed the 12-month f/u without relapse, and 7 remain on study. 15 of 16 pts remain alive. Thus far, 3 pts have experienced ≥ G2 aGVHD, and 4 had moderate chronic GVHD. Serial measurement of 2HG is being conducted on samples, and these will be reported. Enasidenib is well-tolerated as post-HCT maintenance therapy for myeloid malignancy at the RP2D of 100mg qd. No DLTs have been detected, and a low rate of post-HCT relapse has been identified to date, although longer f/u is needed. Larger, randomized studies of ENA in the post-SCT setting would determine the true efficacy of this agent as maintenance therapy. Disclosures Fathi: Blueprint: Consultancy; Jazz: Consultancy; Amgen: Consultancy; Newlink Genetics: Consultancy; Pfizer: Consultancy; Abbvie: Consultancy; Seattle Genetics: Consultancy, Research Funding; Agios: Consultancy, Research Funding; PTC Therapeutics: Consultancy; Takeda: Consultancy, Research Funding; Boston Biomedical: Consultancy; Amphivena: Consultancy; BMS/Celgene: Consultancy, Research Funding; Kite: Consultancy; Trovagene: Consultancy; Forty Seven: Consultancy; Novartis: Consultancy; Daiichi Sankyo: Consultancy; Astellas: Consultancy; Trillium: Consultancy; Kura Oncology: Consultancy. Soiffer:Gilead: Consultancy; Novartis: Consultancy; Juno: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; VOR Biopharma: Consultancy; alexion: Consultancy; Rheos Therapeutics: Consultancy; Cugene: Consultancy; Precision Bioscience: Consultancy; Be the Match/ National Marrow Donor Program: Membership on an entity's Board of Directors or advisory committees; Kiadis: Membership on an entity's Board of Directors or advisory committees; Mana Therapeutics: Consultancy. Levis:Menarini: Honoraria; Amgen: Honoraria; FujiFilm: Honoraria, Research Funding; Astellas: Honoraria, Research Funding; Daiichi-Sankyo: Honoraria. Mims:Novartis: Speakers Bureau; Kura Oncology: Membership on an entity's Board of Directors or advisory committees; Leukemia and Lymphoma Society: Other: Senior Medical Director for Beat AML Study; Agios: Consultancy; Syndax Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceuticals: Other: Data Safety Monitoring Board; Abbvie: Membership on an entity's Board of Directors or advisory committees. Devine:Magenta Therapeutics: Consultancy. Defilipp:Incyte: Research Funding; Regimmune: Research Funding; Syndax Pharmaceuticals: Consultancy. Spitzer:Jazz Pharmaceuticals, Inc.: Membership on an entity's Board of Directors or advisory committees; Bluebird Bio: Membership on an entity's Board of Directors or advisory committees. Frigault:Celgene: Consultancy; Arcellx: Consultancy; Novartis: Consultancy, Research Funding; Gilead/Kite: Consultancy, Research Funding. Amrein:Amgen: Research Funding; AstraZeneca: Consultancy, Research Funding; Takeda: Research Funding. Hobbs:Incyte: Research Funding; Merck: Research Funding; Bayer: Research Funding; Constellation: Honoraria, Research Funding; Jazz: Honoraria; Celgene/BMS: Honoraria; Novartis: Honoraria. Brunner:Janssen: Research Funding; Acceleron Pharma Inc.: Consultancy; GSK: Research Funding; Xcenda: Consultancy; Takeda: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Jazz Pharma: Consultancy; Forty Seven, Inc: Consultancy; Celgene/BMS: Consultancy, Research Funding; Biogen: Consultancy; Astra Zeneca: Research Funding. Narayan:Genentech: Other: Prior Spouse employment within 24 months and prior spouse equity divested within past 24 months; Takeda: Other: Prior Spouse employment within 24 months; Sanofi-Genzyme: Other: Current Spouse employment . Chen:AbbVie: Other: Data and Safety Monitoring Board Member; Incyte Corporation: Consultancy; Takeda: Consultancy; Actinium: Other: Data and Safety Monitoring Board Member; Equillium: Other: Data and Safety Monitoring Board Member; Magenta: Consultancy; Kiadis: Consultancy. OffLabel Disclosure: Enasidenib as post-transplant maintenance therapy

Description: BACKGROUND: Angiogenesis is increasingly known to play a role in pathogenesis of hematologic malignancies, including myeloid neoplasms. Regorafenib is a multikinase inhibitor that targets angiogenic, stromal and oncogenic kinases including VEGF- 1, 2, 3, TIE-2, PDGFR-β,c-KIT, rRET, RAF-1, FGFR-1, BRAF and p38 MAP kinase. As a result of regorafenib's broad inhibition of kinases and its effects on angiogenesis, this drug has the potential to overcome the limitations of more selective kinase inhibitors and may be associated with efficacy in various myeloid neoplasms, including acute myeloid leukemia (AML), myelodysplastic syndrome (MDS), and myeloproliferative neoplasms (MPN). METHODS: We conducted a single-center, open-label, dose-escalation and expansion phase I trial in patients with relapsed/refractory AML, MPN, or MDS to assess the safety, tolerability, and preliminary efficacy of regorafenib and identify the recommended phase 2 dose (RP2D). A 3+3 dose escalation design was used with 2 planned dose levels (120 mg or 160 mg daily in 28-day cycles), as well as 1 de-escalation level (80 mg daily). An additional 10 patients were treated on an expansion cohort. RESULTS: Six patients were enrolled during the dose escalation phase (3 at 120 mg daily followed by 3 at 160 mg daily), with no DLTs, as defined by a Grade 〉3 toxicity occurring within the first 28 days after initiation of treatment, and unrelated to the myeloid neoplasm. Therefore, the RP2D of regorafenib was identified as 160 mg daily. Ten additional patients were enrolled on this dose during the expansion phase. The median age was 74 (range 36-84), and 13 (81%) patients were male. Diagnoses included 7 AML, 6 MDS, and 3 MPN patients (Table 1). Dose modifications and delays occurred in 5 and 4 patients, respectively. The median duration of treatment was 56 days or 2.5 cycles (range: 5-410 days, 1-15 cycles). Of the 16 patients, the best overall disease response as measured by IWG criteria included partial remission (in 1 patient with AML), stable disease in 12 (2 de novo AML, 2 secondary AML, 3 MPN, and 5 MDS) patients, and progressive disease in 3 (1 MDS and 2 secondary AML) patients. An initial improvement in absolute neutrophil count and/or hemoglobin was observed in the 6 MDS patients, although this did not meet criteria for hematologic improvement by IWG criteria. All patients have discontinued off treatment. The most frequent Grade 3-4 adverse effects (AEs) included liver function test abnormalities (5.1%), fatigue (4.3%), thrombocytopenia (3.4%), and neutropenia (3.4%) (Table 2). The majority of AEs were grades 1-2. CONCLUSIONS: Regorafenib demonstrates an acceptable safety profile in relapsed/refractory myeloid malignancy patients, a population where few treatment options exist. The majority of patients achieved stable disease. Modest improvements in cell counts were observed in MDS patients, and we are performing correlative studies to clarify regorafenib's mechanism of action and identify populations which may benefit from treatment. Disclosures Amrein: AstraZeneca: Consultancy, Research Funding; Takeda: Research Funding; Amgen: Research Funding. Brunner:Novartis: Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Research Funding; AstraZeneca: Research Funding; Forty-Seven Inc: Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees. Fathi:Kura Oncology: Consultancy; Trillium: Consultancy; Boston Biomedical: Consultancy; Pfizer: Consultancy; Daiichi Sankyo: Consultancy; Jazz: Consultancy; Agios: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; PTC Therapeutics: Consultancy; Amphivena: Consultancy; Astellas: Consultancy; Amgen: Consultancy; Seattle Genetics: Consultancy, Research Funding; Abbvie: Consultancy; Blueprint: Consultancy; Kite: Consultancy; Trovagene: Consultancy; Forty Seven: Consultancy; Newlink Genetics: Consultancy; Novartis: Consultancy; BMS/Celgene: Consultancy, Research Funding. Narayan:Sanofi-Genzyme: Other: Current Spouse employment ; Takeda: Other: Prior Spouse employment within 24 months; Genentech: Other: Prior Spouse employment within 24 months and prior spouse equity divested within past 24 months. Neuberg:Pharmacyclics: Research Funding; Madrigak Pharmaceuticals: Current equity holder in publicly-traded company; Celgene: Research Funding. Chen:Takeda: Consultancy; Magenta: Consultancy; Equillium: Other: Data and Safety Monitoring Board Member; AbbVie: Other: Data and Safety Monitoring Board Member; Incyte Corporation: Consultancy; Actinium: Other: Data and Safety Monitoring Board Member; Kiadis: Consultancy. Hobbs:Merck: Research Funding; Constellation: Honoraria, Research Funding; Incyte: Research Funding; Jazz: Honoraria; Novartis: Honoraria; Celgene/BMS: Honoraria; Bayer: Research Funding. OffLabel Disclosure: Regorafenib was used to assess safety and preliminary efficacy in advanced myeloid malignancies

Description: Characterization of pathogenic alterations in acute myeloid leukemia (AML) has led to development of promising targeted therapies, including FLT3 (FLT3i) and IDH1/2 inhibitors (IDHi), with several approved for use; midostaurin (MIDO), gilteritinib, enasidenib (ENA), and ivosidenib (IVO). A proportion of patients (pts) have concurrentFLT3andIDHmutations at diagnosis or develop a second mutation during therapy.FLT3mutations, in particular, are associated with poor response rates to IDHi therapy, and treatment-emergentFLT3mutations also appear to confer therapeutic resistance to these agents. There is therefore growing interest to study combined therapies that target multiple pathways, but the clinical experience with combined IDHi and FLT3i therapy has not yet been reported. We performed a retrospective data collection and analysis at 5 institutions (Massachusetts General Hospital, University of Pennsylvania, Johns Hopkins University, University of California San Francisco, and MD Anderson). Using de-identified information from institutional databases, pts treated with concurrent IDHi and FLT3i were identified. Collected data included demographic data, date of initial diagnosis, number of prior therapies, prior hematopoietic cell transplant (HCT), prior targeted therapy, type ofIDHandFLT3mutation, concurrent mutations and cytogenetics, duration of concurrent therapy, therapy-related toxicity, best response, toxicities, and vital status. We identified 12 pts who received concurrent IDHi and FLT3i therapy, 11 of which had relapsed/refractory (R/R) AML. Median age was 57 (range 31-84) and 9 (75%) were male. 7 (58%) were Caucasian, 3 (25%) African American, and 2 (17%) Asian. All pts had intermediate-risk cytogenetics.IDH1R132 mutations were detected in 3 (25%), andIDH2R140 mutations in 9 (75%) pts. OneIDH2mutation arose at relapse. All pts hadFLT3-ITDmutations, and for 3 (38%), this mutation was known to have emerged at relapse. Common concurrent mutations includedDNMT3A(75%) andNPM1(58%). Median number of prior lines of therapy was 2 (range 0-6), and 4 pts (33%) had underwent prior HCT. Six pts (50%) had received FLT3i monotherapy in a prior line of treatment; 4 sorafenib, 1 gilteritinib, 1 MIDO, and 1 with FF-10101 (one pt had 2 prior lines of FLT3i). Six pts were initiated on concurrent therapy in simultaneous fashion, and the remainder were sequential; 2 pts (17%) were on IDHi therapy to which the FLT3i was added, and 4 (33%) had been on FLT3i with subsequent IDHi addition. Four pts (33%) received concurrent gilteritinib and ENA, 3 (25%) received gilteritinib and IVO, 3 (25%) received sorafenib and ENA, and 2 (17%) MIDO and ENA. Three pts received hypomethylating therapy concurrent with combined FLT3i/IDHi therapy; 2 received azacitidine (AZA) with ENA/MIDO, and 1 received AZA with ENA/gilteritinib. Pts were on concurrent therapy for a median of 75 days (range 9-343). Two pts had rash attributable to sorafenib, leading to temporary treatment pause in one and discontinuation in the other. No other toxicities were thought to be related to concurrent treatment. Four pts (33%) achieved CR or CRi (2 CR, 2 CRi), all with persistence of molecular residual disease (MRD). The median duration of remission for these pts was 310 days (range 85-326), and 3 have since relapsed. One pt experienced MLFS, 1 had peripheral blast reduction and 1 had improvement in platelets. An additional pt had MRD(+) CR (byNPM1PCR) on gilteritinib prior to addition of ENA, and then achieved MRD(-) CR with dual therapy. The 4 remaining pts did not respond to concurrent treatment. Two pts (17%) were effectively bridged to HCT following dual therapy. Five pts (42%) remain alive. In this retrospective analysis, a notable proportion of pts benefitted from concurrent FLT3i and IDHi therapy. Composite remission rate was 33%, and overall response rate (CR+CRi+MLFS) was 42% among a largely R/R patient cohort, the majority of whom had received IDHi or FLT3i monotherapy in a prior line of treatment. An additional pt in MRD(+) CR cleared MRD following concurrent treatment. Concurrent therapy appeared to be largely well-tolerated. These response rates are particularly intriguing, given the presence ofFLT3/ITDmutations, alterations thought to confer resistance to IDHi monotherapy. Larger, prospective studies are needed to fully assess the promise of concurrent FLT3i and IDHi therapy in co-mutated pts with AML. Disclosures Fathi: Amphivena:Consultancy;Astellas:Consultancy;Trillium:Consultancy;Amgen:Consultancy;Seattle Genetics:Consultancy, Research Funding;Abbvie:Consultancy;Pfizer:Consultancy;Newlink Genetics:Consultancy;Forty Seven:Consultancy;Trovagene:Consultancy;Kite:Consultancy;BMS/Celgene:Consultancy, Research Funding;Novartis:Consultancy;Daiichi Sankyo:Consultancy;Kura Oncology:Consultancy;Blueprint:Consultancy;PTC Therapeutics:Consultancy;Agios:Consultancy, Research Funding;Takeda:Consultancy, Research Funding;Jazz:Consultancy;Boston Biomedical:Consultancy.Perl:Arog Pharmaceuticals Inc:Other: uncompensated consulting, travel costs for meetings;Astellas:Consultancy, Honoraria, Other: writing/editorial support, travel costs for meeting presentations related to study, Research Funding;AbbVie Inc:Consultancy, Honoraria, Other, Research Funding;Syndax:Consultancy, Honoraria;Takeda:Honoraria, Other: Travel costs for meeting;Leukemia & Lymphoma Society, Beat AML:Consultancy;Novartis:Honoraria, Other, Research Funding;Actinium Pharmaceuticals Inc:Consultancy, Honoraria, Research Funding;Daiichi Sankyo:Consultancy, Honoraria, Other: Writing/editorial support, travel costs for meetings, Research Funding;FUJIFILM Pharmaceuticals USA, Inc:Research Funding;New Link Genetics:Honoraria, Other;Bayer HealthCare Pharmaceuticals:Research Funding;Biomed Valley Discoveries:Research Funding;Loxo Oncology Inc, a wholly owned subsidiary of Eli Lilly & Company:Consultancy, Honoraria, Other;Jazz:Honoraria, Other;Agios:Consultancy, Honoraria, Other;FORMA Therapeutics:Consultancy, Honoraria, Other.Levis:Menarini:Honoraria;Amgen:Honoraria;FujiFilm:Honoraria, Research Funding;Daiichi-Sankyo:Honoraria;Astellas:Honoraria, Research Funding.Smith:Daiichi Sanyko:Consultancy, Honoraria;Abbvie:Other: Research Support, Research Funding;FujiFilm:Other: Research support, Research Funding;Astellas Pharma:Honoraria, Other: Research Support, Research Funding;Revolution Medicines:Other: Research Support, Research Funding;Sanofi:Honoraria.Brunner:Forty-Seven Inc:Membership on an entity's Board of Directors or advisory committees;AstraZeneca:Research Funding;Takeda:Research Funding;Celgene:Membership on an entity's Board of Directors or advisory committees, Research Funding;Novartis:Research Funding;Jazz Pharmaceuticals:Membership on an entity's Board of Directors or advisory committees.Amrein:Amgen:Research Funding;AstraZeneca:Consultancy, Research Funding;Takeda:Research Funding.Hobbs:Merck:Research Funding;Constellation:Honoraria, Research Funding;Incyte:Research Funding;Bayer:Research Funding;Celgene/BMS:Honoraria;Novartis:Honoraria;Jazz:Honoraria.Narayan:Sanofi-Genzyme:Other: Current Spouse employment ;Takeda:Other: Prior Spouse employment within 24 months;Genentech:Other: Prior Spouse employment within 24 months and prior spouse equity divested within past 24 months.Daver:Pfizer:Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding;Karyopharm:Research Funding;Servier:Research Funding;Daiichi Sankyo:Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding;Genentech:Research Funding;AbbVie:Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding;Astellas:Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding;Novimmune:Research Funding;Gilead:Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding;Amgen:Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding;Trovagene:Research Funding;Fate Therapeutics:Research Funding;ImmunoGen:Research Funding;Novartis:Consultancy, Membership on an entity's Board of Directors or advisory committees;Celgene:Consultancy, Membership on an entity's Board of Directors or advisory committees;Jazz:Consultancy, Membership on an entity's Board of Directors or advisory committees;Trillium:Consultancy, Membership on an entity's Board of Directors or advisory committees;Syndax:Consultancy, Membership on an entity's Board of Directors or advisory committees;Amgen:Consultancy, Membership on an entity's Board of Directors or advisory committees;KITE:Consultancy, Membership on an entity's Board of Directors or advisory committees;Agios:Consultancy, Membership on an entity's Board of Directors or advisory committees;Bristol-Myers Squibb:Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding.DiNardo:Calithera:Research Funding;Celgene:Consultancy, Honoraria, Research Funding;Agios:Consultancy, Honoraria, Research Funding;Syros:Honoraria;Daiichi Sankyo:Consultancy, Honoraria, Research Funding;Notable Labs:Membership on an entity's Board of Directors or advisory committees;Jazz:Honoraria;ImmuneOnc:Honoraria;Takeda:Honoraria;MedImmune:Honoraria;Novartis:Consultancy;AbbVie:Consultancy, Honoraria, Research Funding. OffLabel Disclosure: Midostaurin for relapsed/refractory AML Sorafenib for relapsed/refractory AML

Description: Background: Sabatolimab (MBG453) is a high-affinity, humanized, IgG4 (S228P) antibody targeting TIM-3, an inhibitory receptor expressed on multiple immune cells and on leukemic stem/progenitor cells and blasts, but not on normal hematopoietic stem cells. Sabatolimab is being evaluated for treatment of patients (pts) with intermediate to very high risk MDS or AML in the STIMULUS clinical trial program. Here we report PK and clinical data supporting sabatolimab doses being evaluated in the STIMULUS program. Methods: PK analyses were done in a ph 1-1b/2 study in pts with adv solid tumors (NCT02608268) and a ph 1b study in pts with high/very high risk MDS (HR-MDS) or AML who were ineligible for intensive chemotherapy (NCT03066648). Pts with solid tumors received IV sabatolimab 80-1200 mg Q2W/Q4W or sabatolimab 20-800 mg Q2W/80-1200 mg Q4W + spartalizumab (PD-1 inhibitor). Based on findings in solid tumors, pts with HR-MDS/AML received IV sabatolimab 160-1200 mg Q2W/800 mg Q4W in treatment arms including sabatolimab monotherapy, + hypomethylating agent (HMA; decitabine [Dec] or azacitidine), and + spartalizumab (± Dec). Total sabatolimab serum concentration was used in population PK (popPK) modeling to simulate average (Cavg), maximal (Cmax), and trough (Ctrough) concentrations at steady state. Total serum soluble TIM-3 was measured and simulation was used to predict membrane-bound TIM-3 occupancy in the bone marrow (BM). PK exposure-response analysis (data cutoff 27 Nov 2019) and assessment of clinical safety/efficacy by dose (data cutoff 25 Jun 2020) were conducted in pts with HR-MDS/AML who received sabatolimab (dosed at 240 or 400 mg Q2W or 800 mg Q4W) + HMA. Results: Sabatolimab PK was similar for pts with solid tumors (n=252), HR-MDS, and AML (n=155 HR-MDS + AML); no drug-drug interactions were seen for any combinations. The estimated half-life of sabatolimab was ~16.7 days at linear PK dose levels and moderate accumulation was seen after multiple dosing. At lower doses (≤80 mg Q2W or ≤240 mg Q4W), sabatolimab exhibited nonlinear elimination indicative of target-mediated drug disposition, potentially related to internalization of the membrane-bound antibody-TIM-3 complex. At doses ≥240 mg Q2W and ≥800 mg Q4W, a plateau in the accumulated total soluble TIM-3 level was reached and PK approached a proportional dose-exposure relationship. Based on popPK modeling, among sabatolimab + HMA regimens 400 mg Q2W had the highest Ctrough at steady state, and 800 mg was predicted to be an equivalent Q4W dosing regimen. Both doses had similar steady state Cavg and similarly high occupancy rates for membrane-bound TIM-3 in the BM (〉95% in ≥95% of pts with HR-MDS/AML), suggesting similarly high levels of TIM-3 engagement. PK exposure-safety analysis included 102 pts with HR-MDS/AML who received sabatolimab + HMA and were categorized into 4 exposure quartiles based on steady state Cmax and Cavg. There was no relationship between steady state Cmax or Cavg quartiles and incidence of treatment-related AEs. Similarly, exposure-efficacy analysis (n=92) showed no clear relationship between steady state Ctrough or Cavg and percent BM blast reduction or clinical benefit (CR/mCR/CRi/PR). The effect of sabatolimab dose on safety/efficacy was also evaluated in an updated clinical analysis in pts with HR-MDS/AML treated with sabatolimab + HMA. Overall, sabatolimab + HMA was safe and well tolerated with a low rate of study discontinuation due to AE (3.4% [4/116]). Rates of most common gr ≥3 treatment-emergent AEs and rates of gr ≥3 possible immune-mediated AEs related to study treatment did not appear to be dose dependent (Table). Among 35 evaluable pts with HR-MDS, CR/mCR/PR rates were 50.0%, 33.3% and 54.5% at sabatolimab doses of 240 mg Q2W, 400 mg Q2W and 800 mg Q4W. Among 60 evaluable pts with AML, CR/CRi/PR rates were 35.3%, 37.5% and 31.6%, respectively. There were no notable differences in responses across the 3 doses (Table). Conclusion: Sabatolimab 400 mg Q2W was predicted to have the highest steady state Ctrough and TIM-3 occupancy rate when combined with HMA, and 800 mg was predicted to be an equivalent Q4W dosing regimen. No clear relationship was seen between sabatolimab dose or steady state exposure and safety/efficacy at the doses tested. These results support clinical development of the sabatolimab 400 mg Q2W and 800 mg Q4W dosing regimens. Co-senior authors Andrew Brunner and Uma Borate contributed equally to the work. Table Disclosures Wei: AbbVie: Honoraria, Research Funding, Speakers Bureau; Pfizer: Honoraria; BMS: Consultancy, Honoraria, Research Funding, Speakers Bureau; Janssen: Honoraria; Amgen: Honoraria, Research Funding; Walter and Eliza Hall Institute of Medical Research: Patents & Royalties; Novartis: Honoraria, Research Funding, Speakers Bureau; Genetech: 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, Research Funding; AstraZeneca: Honoraria, Research Funding; Astellas: Honoraria, Membership on an entity's Board of Directors or advisory committees; Servier: Consultancy, Honoraria, Research Funding. Porkka:BMS/Celgene: Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding. Knapper:Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Garcia-Manero:Helsinn Therapeutics: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Acceleron Pharmaceuticals: Consultancy, Honoraria; Onconova: Research Funding; Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Merck: Research Funding; H3 Biomedicine: Research Funding; AbbVie: Honoraria, Research Funding; Astex Pharmaceuticals: Consultancy, Honoraria, Research Funding; Novartis: Research Funding; Jazz Pharmaceuticals: Consultancy; Bristol-Myers Squibb: Consultancy, Research Funding; Amphivena Therapeutics: Research Funding. Wermke:MacroGenics: Honoraria. Janssen:MSD: Other: Founder of the HematologyApp which is supported by Janssen, BMS, Incyte, MSD, Pfizer, Daiichi-Sankyo, Roche and Takeda; Roche: Other: Founder of the HematologyApp which is supported by Janssen, BMS, Incyte, MSD, Pfizer, Daiichi-Sankyo, Roche and Takeda; Daiichi-Sankyo: Other: Founder of the HematologyApp which is supported by Janssen, BMS, Incyte, MSD, Pfizer, Daiichi-Sankyo, Roche and Takeda; Takeda: Other: Founder of the HematologyApp which is supported by Janssen, BMS, Incyte, MSD, Pfizer, Daiichi-Sankyo, Roche and Takeda; Janssen: Other: Founder of the HematologyApp which is supported by Janssen, BMS, Incyte, MSD, Pfizer, Daiichi-Sankyo, Roche and Takeda; Abbvie: Membership on an entity's Board of Directors or advisory committees; Incyte: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Founder of the HematologyApp which is supported by Janssen, BMS, Incyte, MSD, Pfizer, Daiichi-Sankyo, Roche and Takeda; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Founder of the HematologyApp which is supported by Janssen, BMS, Incyte, MSD, Pfizer, Daiichi-Sankyo, Roche and Takeda; BMS: Other: Founder of the HematologyApp which is supported by Janssen, BMS, Incyte, MSD, Pfizer, Daiichi-Sankyo, Roche and Takeda, Research Funding; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Traer:Notable Labs: Consultancy, Current equity holder in private company; Genentech: Membership on an entity's Board of Directors or advisory committees; Agios: Membership on an entity's Board of Directors or advisory committees; Daiichi Sankyo: Membership on an entity's Board of Directors or advisory committees; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Incyte: Research Funding; Astellas: Membership on an entity's Board of Directors or advisory committees. Narayan:Sanofi-Genzyme: Other: Current Spouse employment ; Takeda: Other: Prior Spouse employment within 24 months; Genentech: Other: Prior Spouse employment within 24 months and prior spouse equity divested within past 24 months. Kontro:Abbvie: Research Funding; Jazz Pharma: Membership on an entity's Board of Directors or advisory committees; Astellas: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Ottmann:Amgen: Honoraria, Research Funding; Novartis: Honoraria; Celgene: Honoraria, Research Funding; Fusion Pharma: Honoraria; Incyte: Honoraria, Research Funding. Liao:Novartis: Current Employment. Stein:Novartis: Current Employment, Divested equity in a private or publicly-traded company in the past 24 months, Ended employment in the past 24 months. Khanshan:Novartis: Current Employment. Naidu:Novartis Pharmaceuticals: Current Employment. Zhang:Novartis: Current Employment. Rinne:Novartis: Current Employment; Qiagen: Consultancy. Sun:Novartis: Current Employment, Current equity holder in publicly-traded company, Divested equity in a private or publicly-traded company in the past 24 months. Brunner:Biogen: Consultancy; Acceleron Pharma Inc.: Consultancy; Celgene/BMS: Consultancy, Research Funding; Forty Seven, Inc: Consultancy; Jazz Pharma: Consultancy; Novartis: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; Xcenda: Consultancy; GSK: Research Funding; Janssen: Research Funding; Astra Zeneca: Research Funding. Borate:Genentech: Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceuticals: Research Funding; AbbVie: Other: Investigator in AbbVie-funded clinical trials; Pfizer: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; Daiichi Sankyo: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding.

Description: Background: Idiopathic hypereosinophilia and hypereosinophilic syndrome (HES) comprise a rare, heterogeneous group of hematologic disorders characterized by the overproduction of eosinophils leading to tissue eosinophilic infiltration and damage. Hypereosinophilia can be primary - due to a clonal or malignant process - or secondary to a non-clonal process. Primary eosinophilia can be accompanied by clonal markers, such as in myeloid/lymphoid neoplasms with eosinophilia and rearrangement of PDGFRA/B, FGFR1 or PCM1-JAK2, genetic mutations or chromosomal abnormalities leading to a diagnosis of chronic eosinophilic leukemia. Without easily identifiable clonal markers, a diagnosis of idiopathic HES is made after secondary causes are excluded. Thrombotic complications in clonal eosinophilic disorders have been described in case reports but the prevalence of thrombosis has not been extensively studied. We hypothesized that HES is associated with an increased thrombotic risk compared to the general population. Additionally, given the known increased thrombotic risk in patients with clonal hematopoiesis of indeterminate potential, we also hypothesized that the risk of thrombosis is greatest in HES patients with evidence of an underlying clonal process. Methods: Using an institutional database, we retrospectively analyzed 44 patients with HES who had undergone molecular testing with a DNA based next generation sequencing (NGS) assay (Heme SnapShot) and an RNA based NGS assay (Heme fusion) as part of their work up for HES at Massachusetts General Hospital from 2016 to 2020. Patients with secondary eosinophilia were excluded. We used Fisher's exact test to compare rates of thrombotic events or death between patients with and without molecular aberration. Relative risk and corresponding 95% CI was estimated by fitting a log-binomial regression model. Results: Among the 44 patients analyzed, 16 (36.4%) had a molecular aberration detected on NGS. Of the patients with molecular aberrations detected, 4 (25%) had PGFRA, PGFRB, or FGFR1 fusions. Other pathogenic mutations were as follows - 1 (6.3%) JAK2 mutation, 3 (18.8%) TET2, 1 (6.3%) DNMT3A and 9 (56.4%) had mutations in other genes. White blood cell count, absolute eosinophil count, hematocrit, platelet count, tryptase and vitamin B12 levels at diagnosis of HES were similar between the two groups. After a median follow-up time of 29 months (IQR 19.3, 52), 9 (20.5%) of all HES patients had a thrombotic event after diagnosis of HES (4 venous and 5 arterial) with a median time to first thrombotic event of 14.0 months (IQR 3.5, 28.0). HES patients with a molecular aberration had increased number of thrombotic events compared to HES patients with no molecular aberrations, 37.5% versus 10.7% respectively (p = 0.053, risk ratio 3.5, 95% CI 1.01 - 12.12). Three patients with molecular aberrations died versus 1 patient with no molecular aberrations (p = 0.129, risk ratio 5.25, 95% CI 0.59 - 46.36). Among patients with at least 12 months of follow-up (n = 40, 14 with and 26 without molecular aberrations), the one-year cumulative incidence of thrombotic events was 42.9% in patients with molecular aberrations vs 11.5% without (p = 0.044, RR 3.7 95% CI 1.2-12.0). HES patients who had thrombotic events had an increased risk of death compared to those without thrombotic events (p = 0.0226, RR 11.7, 95% CI 1.8 - 75.2). Conclusions: Thrombotic complications are common in the current study of patients with HES and are associated with an increased risk of death. Although our patient cohort was small, presence of molecular aberrations had increased rates of thrombotic events and mortality, suggesting an area of further study including possible therapeutic trials. Figure 1 Disclosures Brunner: Takeda: Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Research Funding; AstraZeneca: Research Funding; Forty-Seven Inc: Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees. Al-Samkari:Argenx: Consultancy; Amgen: Research Funding; Dova: Consultancy, Research Funding; Agios: Consultancy, Research Funding; Rigel: Consultancy. Rosovsky:Bristol-Myers Squibb, Janssen: Research Funding; Bristol-Myers Squibb, Dova, Janssen, Portola: Consultancy. Fathi:PTC Therapeutics: Consultancy; Takeda: Consultancy; TrovaGene: Consultancy; Amgen: Consultancy; Bristol-Myers Squibb: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Astellas: Consultancy; Novartis: Consultancy; NewLink Genetics: Consultancy, Honoraria; Daiichi Sankyo: Consultancy; Forty Seven: Consultancy; Jazz: Consultancy, Honoraria; Kite: Consultancy, Honoraria; Trillium: Consultancy; Seattle Genetics: Consultancy, Research Funding; Pfizer: Consultancy; Kura: Consultancy; Boston Biomedical: Consultancy; Blue Print Oncology: Consultancy; AbbVie: Consultancy; Agios: Consultancy, Research Funding; Amphivena: Consultancy, Honoraria. Weitzman:Abbvie: Consultancy. Hobbs:Incyte: Research Funding; Bayer: Research Funding; Novartis: Honoraria; Celgene/BMS: Honoraria; Merck: Research Funding; Constellation: Honoraria, Research Funding; Jazz: Honoraria.

Description: Background: CTLA-4 blockade with ipilimumab (IPI) has modest activity in hematologic malignancies relapsed post allogeneic hematopoietic cell transplantation (allo-HCT) (Davids M, NEJM). Adding decitabine (DAC) to IPI may increase efficacy of this approach in myelodysplastic syndromes (MDS)/acute myeloid leukemia (AML), and we further asked the extent to which alloreactivity contributed to this activity. Here, we present safety (Table 1) and clinical activity (Figure 1) from a phase I, multicenter, investigator-initiated study (CTEP 10026) of DAC plus IPI in pts with R/R MDS/AML with (Arm A) and without (Arm B) prior HCT. Methods: Pts ≥ 18 y with R/R MDS (≥ 5% blasts), R/R AML or untreated secondary AML were eligible. Prior HMA was permitted but trial was later amended to exclude those with disease progression on HMA therapy within 12 weeks of study entry. Pts post allo-HCT (Arm A) were required to be 〉 3 mo from donor cell infusion, have no prior acute GVHD Gr III or higher, be 〉 2 weeks off of immunosuppression and have donor T-cell chimerism ≥ 20%. Treatment was given in 28-day cycles with a lead-in single agent DAC (cycle 0) followed by combination DAC + IPI for up to a year. DAC infusion was given at 20 mg/m2 days 1-5. IPI infusion was given at 3 mg/kg (DL0), 5 mg/kg (DL1) or 10 mg/kg (DL2) on day 1 of cycles 1-4, 5, 7, 9 and 11. DLT was defined as ≥ Gr 3 non-hematologic adverse event (AE), acute GVHD, and steroid-refractory immune-related AE within 8 weeks of first IPI dose. Results: At data cut-off, 32 of 39 enrolled pts received at least 1 dose of DAC+IPI; 4 of 7 did not move on to C1D1 due to AML-related complications. Median age was 72 y (range 29-85); 25 had AML and 7 had MDS. Median number of prior regimens was 2 (range, 0-5). Twenty of 32 pts had received prior HMA therapy. A median of 3 IPI doses were given (range, 1-8). NGS performed on screening marrows using an 88-gene panel revealed mutations most commonly in ASXL1 (n=9), RUNX1 and STAG2 (n=6 each), and DNMT3A, NRAS and TP53 (n=5 each). Arm A (Post allo-HCT): Sixteen pts received DAC+IPI across the 3 DLs (7 at DL0, 3 at DL1, 6 at DL2; dose-expansion is open at DL2). The most common treatment emergent Gr 3/4 AEs were febrile neutropenia (n=3) and AST elevation, lymphocytopenia, neutropenia, thrombocytopenia, leukopenia (n=2 each). Seven of 16 pts experienced immune-related AE, including 1 with late-onset acute GVHD Gr III (colon/liver), 4 with chronic GVHD (mild, n=2; moderate, n=1; severe n=1), and 2 with Gr 2/3 ipi-induced colitis. All immune-related AEs were reversible with steroids, except for one case of steroid refractory Gr III acute GVHD complicated by fatal septic shock (DLT at IPI 10 mg/kg). In total, 4 of 16 evaluable pts achieved response, including 3 with CR and 1 with marrow CR; 2 of 4 responders had immune-related AE. For these 16 pts, the median OS is 12.8 mo (95% CI: 7.6-NA). Arm B (transplant-naïve): Sixteen pts received DAC+IPI across the 3 DLs (4 at DL0, 3 at DL1, 6 at DL2; 3 are in dose-expansion at DL2). The most common treatment emergent Gr 3/4 AEs were lymphocytopenia, thrombocytopenia and leukopenia (n=5 each); neutropenia (n=4); and anemia, fatigue, lung infection, and febrile neutropenia (n=3 each). In 6 of 16 pts that had ≥ Gr 2 immune-related AEs, all were reversible with steroids (including Gr 3 colitis (n=1), Gr 3 dermatitis (n=2), Gr 2 pneumonitis (n=1), Gr 3 hypophysitis/Gr 2 arthritis (n=1)), except for a case of Gr 2 dermatitis (resolved)/Gr 4 immune thrombocytopenia (refractory to steroids, transfusions and IVIG) (n=1; DLT at IPI 10 mg/kg). No study treatment-related deaths were observed. Objective responses were detected in 8 of 16 evaluable pts with 3 CR, 2 CRi, and 3 marrow CR. Only 2 of 8 responders had immune-related AEs. For these 16 pts, the median OS is 18.3 mo (95% CI: 11.7-NA). Overall, 2 pts discontinued study treatment due to AE. Dose expansion continues at DL2 (MTD) in Arm A and Arm B to further establish safety and tolerability. Correlative science including immunophenotyping is ongoing and will be presented. Conclusion: In this ongoing phase 1 study in pts with R/R or secondary MDS/AML, DAC plus IPI had expected AE profile and exhibited encouraging clinical activity. The rate of immune-related toxicity was frequent but similar to prior observations with IPI 10 mg/kg for melanoma. Further, high clinical activity was observed amongst pts who did not receive allo-HCT, suggesting that an alloreactive environment may not be required to benefit from CTLA-4 blockade. Disclosures Garcia: Pfizer: Research Funding; Genentech: Research Funding; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Eli Lily: Research Funding. Brunner:Astra Zeneca: Research Funding; Janssen: Research Funding; Xcenda: Consultancy; GSK: Research Funding; Takeda: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Jazz Pharma: Consultancy; Forty Seven, Inc: Consultancy; Celgene/BMS: Consultancy, Research Funding; Biogen: Consultancy; Acceleron Pharma Inc.: Consultancy. Neuberg:Celgene: Research Funding; Madrigal Pharmaceuticals: Current equity holder in publicly-traded company; Pharmacyclics: Research Funding. Steensma:Takeda: Consultancy; BMS/Celgene: Consultancy; Onconova: Consultancy; Arena: Current equity holder in publicly-traded company; CRISPR: Current equity holder in publicly-traded company; Aprea Therapeutics: Research Funding; Arrowhead Pharmaceuticals: Current equity holder in publicly-traded company; Astex Pharmaceuticals, Onconova Therapeutics, Pfizer, Stemline Therapeutics, Summer Road: Consultancy; H3 Biosciences: Research Funding. Rodig:Bristol Myers Squibb: Research Funding; Merck: Research Funding; Affimed: Research Funding; KITE/Gilead: Research Funding; Immunitas: Current equity holder in private company, Membership on an entity's Board of Directors or advisory committees. Lindsley:Takeda Pharmaceuticals: Consultancy; Jazz Pharmaceuticals: Consultancy, Research Funding; Bluebird Bio: Consultancy; MedImmune: Research Funding. Davids:Research to Practice: Honoraria; Eli Lilly: Consultancy; Adaptive Biotechnologies: Consultancy; Novartis: Consultancy, Research Funding; Pharmacyclics: Consultancy, Research Funding; Merck: Consultancy; Gilead Sciences: Consultancy; Surface Oncology: Research Funding; MEI Pharma: Consultancy, Research Funding; Bristol Myers Squibb: Research Funding; Ascentage Pharma: Consultancy, Research Funding; AstraZeneca: Consultancy, Research Funding; Sunesis: Consultancy; Zentalis: Consultancy; Syros Pharmaceuticals: Consultancy; Janssen: Consultancy; BeiGene: Consultancy; Celgene: Consultancy; Genentech: Consultancy, Research Funding; AbbVie: Consultancy; TG Therapeutics: Consultancy, Research Funding; Verastem: Consultancy, Research Funding. Wu:BionTech: Current equity holder in publicly-traded company; Pharmacyclics: Research Funding. Stone:Pfizer: Consultancy; Syros: Consultancy; Stemline: Consultancy; Actinium: Consultancy, Membership on an entity's Board of Directors or advisory committees; Gemoab: Consultancy; Syndax: Consultancy, Research Funding; Macrogenics: Consultancy; Trovagene: Consultancy; Biolinerx: Consultancy; Argenix: Other; Jazz: Consultancy; Aztra-Zeneca: Consultancy; Daiichi-Sankyo: Consultancy; Astellas: Consultancy; Syntrix: Other: DSMB; Novartis: Consultancy, Research Funding; Takeda: Other: DSMB; Arog: Consultancy, Research Funding; Agios: Consultancy, Research Funding; Abbvie: Consultancy, Research Funding; Janssen: Consultancy; Celgene: Consultancy, Other. DeAngelo:Takeda: Consultancy; Blueprint Medicines Corporation: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Incyte Corporation: Consultancy; Abbvie: Research Funding; Glycomimetics: Research Funding; Shire: Consultancy; Autolos: Consultancy; Amgen: Consultancy; Agios: Consultancy; Pfizer: Consultancy; Forty-Seven: Consultancy; Jazz: Consultancy. Soiffer:Rheos Therapeutics: Consultancy; Celgene: Other; Juno: Other; Alexion: Consultancy; Novartis: Consultancy; VOR Biopharma: Consultancy; Mana Therapeutics: Consultancy; Precision Bioscience: Consultancy; Cugene: Consultancy; Gilead: Consultancy; Be The Match/National Marrow Donor Program: Membership on an entity's Board of Directors or advisory committees; Kiadis: Membership on an entity's Board of Directors or advisory committees. OffLabel Disclosure: Decitabine plus Ipilimumab to be given in the context of a clinical trial

Description: Introduction: While progress has been made in the treatment of childhood leukemia, the outlook for patients 〉60 years of age with acute lymphoblastic leukemia (ALL) is poor with complete remission rates (CR) of approximately 60% and 3-year survivals (OS) of less than 15%. Intensified treatment in a later CALGB trial showed little improvement with a CR=61% and 5-year OS=6% (Stock, Cancer 2013). Ixazomib is an oral proteasome inhibitor, which has shown single agent activity and promising combination activity in pediatric ALL patients (Messinger, Blood 2012). We sought to assess the safety and tolerability, as well as early efficacy of adding ixazomib to a current MGH-DFCI/HCC multi-agent regimen for older adults with ALL. Methods: Patients aged 51 to 75 years of age with newly diagnosed B-ALL and T-ALL were screened for eligibility. Patients with mature ALL (including Burkitt's) were excluded. Patients with Philadelphia chromosome positive ALL (BCR-ABL1+) were eligible, and dasatinib was added to the chemotherapy on Day 10 for these patients. The chemotherapy treatment schedule from induction through maintenance is outlined in Table 1. A standard 3 + 3 patient cohort dose escalation design was used to determine the maximum tolerated dose (MTD) of ixazomib during induction for these patients, the primary objective of the trial. After consolidation I, patients in complete remission (CR) with a suitable donor were offered a hematopoietic stem cell transplantation (HSCT) as per institutional guidelines. Those not going to HSCT continued therapy as noted in the table. Results: There were 19 patients with B-ALL enrolled, none with T-ALL. Among these patients, 7 harbored BCR-ABL1 rearrangements. The median age was 65 years, 74% were male, and 90% had a performance status 0 or 1. The MTD was 2.3 mg of ixazomib, as 2 patients at 3.0 mg developed DLT's: a grade 3 peripheral neuropathy and a grade 5 acute kidney injury (Table 2). Grade 3 and 4 toxicities encountered at any time consisted mainly of grade 4 neutropenia in 13 patients and grade 4 thrombocytopenia in 12 patients. One patient experienced grade 3 neutropenia and 5 patients experienced grade 3 thrombocytopenia. Two patients with grade 2 neuropathy did not meet the definition of DLT. Among the 19 patients, 15 (79%, [95% confidence interval (CI), 54-94%]) achieved CR (14) or CRi (1), and 5 patients went on to HSCT. The median follow-up time was 2 years (range, 1-5) for 8 patients remaining alive. The 1-year overall survival estimate was 53% [95% CI, 29-72%], while the 2-year overall survival estimate was 47% [95% CI, 24-67%]. Conclusions: A dose of 2.3 mg of ixazomib in combination with induction chemotherapy among older patients with ALL was well-tolerated and associated with a promising rate of complete remission. Disclosures Amrein: Takeda: Research Funding; AstraZeneca: Consultancy, Research Funding; Amgen: Research Funding. Brunner:Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Research Funding; AstraZeneca: Research Funding; Forty-Seven Inc: Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Novartis: Research Funding. Hobbs:Novartis: Honoraria; Celgene/BMS: Honoraria; Jazz: Honoraria; Constellation: Honoraria, Research Funding; Incyte: Research Funding; Merck: Research Funding; Bayer: Research Funding. Neuberg:Celgene: Research Funding; Pharmacyclics: Research Funding; Madrigak Pharmaceuticals: Current equity holder in publicly-traded company. Fathi:Takeda: Consultancy, Research Funding; Agios: Consultancy, Research Funding; PTC Therapeutics: Consultancy; Amphivena: Consultancy; Astellas: Consultancy; Daiichi Sankyo: Consultancy; Novartis: Consultancy; Newlink Genetics: Consultancy; Pfizer: Consultancy; Blueprint: Consultancy; Trillium: Consultancy; Kura Oncology: Consultancy; Forty Seven: Consultancy; Jazz: Consultancy; Boston Biomedical: Consultancy; BMS/Celgene: Consultancy, Research Funding; Kite: Consultancy; Trovagene: Consultancy; Amgen: Consultancy; Seattle Genetics: Consultancy, Research Funding; Abbvie: Consultancy. OffLabel Disclosure: MLN 9708, ixazomib is FDA approved for multiple myeloma. In this trial it is used to treat acute lymphoblastic leukemia.

Description: INTRODUCTION: High rates of healthcare utilization at the EOL have been shown to negatively impact patients' quality-of-life (QOL), psychological distress, and caregivers' bereavement outcomes. Older patients (〉 60 years) with acute myeloid leukemia (AML) often experience high healthcare utilization at the EOL, including hospitalizations and chemotherapy close to death. Yet, factors associated with healthcare utilization at the EOL in this population are unknown. METHODS: We conducted a secondary analysis of two supportive care studies including 168 deceased older patients with AML. We assessed patients' demographics, QOL [Functional Assessment Cancer Therapy-Leukemia], and psychological distress [Hospital Anxiety and Depression Scale (HADS); Patient Health Questionnaire (PHQ-9)] at diagnosis. We used multivariate logistic regression models to examine the associations between demographic factors, patient-reported outcomes, and the following EOL care outcomes abstracted from the electronic health record: 1) hospitalizations in the last 7 days of life; 2) receipt of chemotherapy in the last 30 days of life; and 3) hospice utilization. RESULTS: The median age of the cohort was 67 (range 20-100), and the majority identified as male (63.7% - 107/168) and white (88.1% - 148/168). Overall, 66.7% (110/165) of patients were hospitalized in the last 7 days of life, 51.8% (71/137) received chemotherapy in the last 30 days of life, 59.5% (100/168) died in the hospital, while 40.7% (70/168) utilized hospice services. In multivariate models, higher education (OR = 1.54, SE=0.24, P=0.006), and elevated depression symptoms (PHQ-9: OR=1.09, SE=0.04, P=0.028) at the time of diagnosis were associated with higher odds of being hospitalized in the last 7 days of life. In contrast, higher QOL at diagnosis (OR=0.98, SE=0.01, P=0.009) was associated with lower odds of being hospitalized in the last 7 days of life. Depression symptoms at the time of diagnosis as measured by the HADS was the only factor associated with the receipt of chemotherapy in the last 30 days of life (HADS-Depression: OR=1.10, SE=0.05, P=0.042). Patient-reported factors, including demographics, QOL, and psychological distress, were not associated with hospice utilization. CONCLUSIONS: Older patients with AML who reported higher levels of education, elevated depression symptoms, and lower QOL at the time of diagnosis were more likely to experience intense healthcare utilization at the EOL. These findings identify an AML population who are at higher risk for hospitalizations and additional chemotherapy at the EOL, and who may benefit from targeted interventions to optimize their EOL care. Disclosures Fathi: Seattle Genetics: Consultancy, Research Funding; Boston Biomedical: Consultancy; Kura: Consultancy; Pfizer: Consultancy; Jazz: Consultancy, Honoraria; Kite: Consultancy, Honoraria; NewLink Genetics: Consultancy, Honoraria; Novartis: Consultancy; PTC Therapeutics: Consultancy; Takeda: Consultancy; Trillium: Consultancy; TrovaGene: Consultancy; Amgen: Consultancy; Bristol-Myers Squibb: Consultancy, Research Funding; AbbVie: Consultancy; Agios: Consultancy, Research Funding; Amphivena: Consultancy, Honoraria; Forty Seven: Consultancy; Daiichi Sankyo: Consultancy; Celgene: Consultancy, Research Funding; Astellas: Consultancy; Blue Print Oncology: Consultancy. Hobbs:Celgene/BMS: Honoraria; Novartis: Honoraria; Merck: Research Funding; Jazz: Honoraria; Incyte: Research Funding; Constellation: Honoraria, Research Funding; Bayer: Research Funding. Brunner:Janssen: Research Funding; GSK: Research Funding; Takeda: Consultancy, Research Funding; Xcenda: Consultancy; Novartis: Consultancy, Research Funding; Jazz Pharma: Consultancy; Forty Seven, Inc: Consultancy; Celgene/BMS: Consultancy, Research Funding; Biogen: Consultancy; Acceleron Pharma Inc.: Consultancy; Astra Zeneca: Research Funding. Luger:Daiichi-Sankyo: Honoraria; Hoffman La Roche: Research Funding; Acceleron: Honoraria; Bristol-Myers Squibb: Honoraria; Ariad: Research Funding; Kura: Research Funding; Biosight: Research Funding; Loxo Oncology: Honoraria; Agios: Honoraria; Pfizer: Honoraria; Onconova: Research Funding. Bhatnagar:KaryoPharm Therapuetics: Research Funding; Cell Therapeutics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees; Astellas: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; KITE: Membership on an entity's Board of Directors or advisory committees. LeBlanc:UpToDate: Patents & Royalties; AstraZeneca: Research Funding; American Cancer Society, BMS, Duke University, NINR/NIH, Jazz Pharmaceuticals, Seattle Genetics: Research Funding; AbbVie, Agios, Amgen, AstraZeneca, CareVive, BMS/Celgene, Daiichi-Sankyo, Flatiron, Helsinn, Heron, Otsuka, Medtronic, Pfizer, Seattle Genetics, Welvie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Agios, AbbVie, and Bristol Myers Squibb/Celgene: Speakers Bureau.