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Introduction: CPX-351 (Vyxeos®; daunorubicin and cytarabine liposome for injection), a dual-drug liposomal encapsulation of daunorubicin and cytarabine in a synergistic 1:5 molar drug ratio, has been approved by the US FDA and EMA for the treatment of adults with newly diagnosed therapy-related AML or AML with myelodysplasia-related changes. A randomized phase 3 study that evaluated patients 60 to 75 years of age with newly diagnosed high-risk/secondary AML provided the basis for approval and demonstrated that induction followed by consolidation with CPX-351 significantly improved overall survival and remission rates versus conventional 7+3, with a comparable safety profile. Several targeted therapies have demonstrated efficacy when added to cytotoxic therapy for the treatment of patients with previously untreated AML, including venetoclax (Venclexta®/Venclyxto®; a B-cell leukemia/lymphoma-2 [BCL-2] inhibitor), midostaurin (Rydapt®; a FMS-related tyrosine kinase 3 [FLT3] inhibitor), and enasidenib (Idhifa®; an isocitrate dehydrogenase 2 [IDH2] inhibitor). Preclinical data indicate synergistic activity may be achieved with CPX-351 in combination with venetoclax or midostaurin. Results of these studies suggest a rationale for the combination of targeted therapies using CPX-351 as a chemotherapy backbone. Study Design and Methods: V-FAST (Vyxeos - First Phase Assessment with Targeted Agents) is an open-label, multicenter, multi-arm, nonrandomized, phase 1b master trial (ClinicalTrials.gov #NCT04075747) to evaluate CPX-351 in combination with targeted agents (venetoclax, midostaurin, or enasidenib) in adults with previously untreated AML who are considered fit for intensive chemotherapy. As V-FAST is a master trial, it is designed to permit the expedited incorporation of CPX-351 combinations with other targeted agents into the study as it proceeds, thus ensuring a timely investigation of novel combinations moving forward. Key eligibility criteria are shown in Table 1. The primary study endpoints are to establish the recommended phase 2 dose (RP2D) and safety of each combination regimen. Secondary endpoints include remission rates (via morphologic assessment), bone marrow measurable residual disease status, and pharmacokinetics. Exploratory endpoints include duration of remission, overall survival, event-free survival, and the proportion of patients proceeding to hematopoietic cell transplantation. Patients will be monitored for safety until 1 month following the end of treatment and survival for up to 2 years following the first administration of treatment. Cytogenetic and/or molecular testing will determine which treatment arm each patient is assigned to (ie, no FLT3 or IDH2 mutations: CPX-351 plus venetoclax; FLT3 mutation: CPX-351 plus midostaurin; IDH2 mutation: CPX-351 plus enasidenib). For each combination, a dose-exploration phase (standard 3+3 design; up to 12 patients/combination) will employ dose de-escalation or escalation of CPX-351 and/or the targeted agent based on the occurrence of dose-limiting toxicities to determine a RP2D and evaluate the safety of the combination. The initial cohort for each arm will be treated with the dosing described in Table 2. In the subsequent expansion phase for each combination, an additional 20 patients will be treated to confirm the RP2D, further evaluate safety, and provide an initial assessment of efficacy. In both study phases, CPX-351 will be administered intravenously by 90-minute infusion on Days 1, 3, and 5; targeted therapies will be administered per a standard route for each agent. Patients may receive 1 to 2 induction cycles of combination therapy. Those achieving remission may receive up to 2 consolidation cycles with CPX-351 plus the targeted agent received during induction; hematopoietic stem cell transplantation is permitted in place of or following chemotherapy consolidation at the discretion of the treating physician. This study is ongoing and actively enrolling patients. Disclosures Lin: Celgene: Research Funding; Aptevo: Research Funding; Abbvie: Research Funding; Astellas Pharma: Research Funding; Ono Pharmaceutical: Research Funding; Mateon Therapeutics: Research Funding; Prescient Therapeutics: Research Funding; Pfizer: Research Funding; Celyad: Research Funding; Genetech-Roche: Research Funding; Gilead Sciences: Research Funding; Incyte: Research Funding; Trovagene: Research Funding; Tolero Pharmaceuticals: Research Funding; Seattle Genetics: Research Funding; Bio-Path Holdings: Research Funding; Jazz: Research Funding. Mannis:AbbVie, Agios, Bristol-Myers Squibb, Genentech: Consultancy; Glycomimetics, Forty Seven, Inc, Jazz Pharmaceuticals: Research Funding. Erba:Glycomimetics: Other: member of Scientific Steering Committee; AbbVie, Daiichi Sankyo, Forma, ImmunoGen, Jazz Pharmaceuticals, MacroGenics, Novartis, PTC: Research Funding; AbbVie, Agios, Celgene, Incyte, Jazz Pharmaceuticals, and Novartis: Speakers Bureau; AbbVie, Agios, Amgen, Astellas, Celgene, Daiichi Sankyo, Glycomimetics, ImmunoGen, Incyte, Jazz Pharmaceuticals, MacroGenics, Novartis, and Pfizer: Consultancy; Celgene: Other: chair of the Scientific Steering Committee; Covance (AbbVie): Other: chair of the Independent Review Committee. Levis:Daiichi-Sankyo: Honoraria; FujiFilm: Honoraria, Research Funding; Astellas: Honoraria, Research Funding; Amgen: Honoraria; Menarini: Honoraria. Zou:Jazz Pharmaceuticals: Current Employment, Current equity holder in publicly-traded company. Faderl:Jazz Pharmaceuticals: Current Employment, Current equity holder in publicly-traded company. Cheung:Jazz Pharmaceuticals: Current Employment, Current equity holder in publicly-traded company. Pullarkat:Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; AbbVie, Inc.: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Genetech: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Pfizer: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Dova: Consultancy, Honoraria; Servier: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. OffLabel Disclosure: This study will explore CPX-351 in combination with targeted agents for the treatment of adults with AML.

Introduction: The combination of a DNA methyltransferase inhibitor (DNMTi; parenteral azacitidine or decitabine) with the BCL2 inhibitor venetoclax is a newly established standard-of-care regimen for patients with newly diagnosed acute myeloid leukemia (AML) ineligible to receive intensive induction chemotherapy (DiNardo et al, 2020). Replacing the parenteral DNMTi with an oral DNMTi with equivalent exposure may provide the benefit of reducing patient and caregiver burden of chronic parenteral therapy, and may help responding patients stay on treatment longer. ASTX727 (a fixed-dose combination of decitabine 35 mg and cedazuridine 100 mg) is an oral DNMTi that provides equivalent exposure to its parenteral DNMTi at standard dosing (Savona et al, 2020) and is under evaluation in combination with venetoclax as an all-oral regimen. Methods: This is an ongoing Phase 1 study being conducted at 7 US medical centers (ClinicalTrials.gov NCT04657081). Newly diagnosed AML patients 75 years or older, or with comorbidities that preclude use of intensive induction chemotherapy are eligible. The primary objective is to evaluate the effect of ASTX727 on the PK of venetoclax. Key secondary objectives are to evaluate the effect of venetoclax on the PK of ASTX727, and to determine the safety and efficacy profile for the combination. For Cycle 2 and beyond, ASTX727 is administered orally daily on days 1-5 and venetoclax 400 mg is administered orally daily on days 1-28 of 28-day cycles. For Cycle 1, ASTX727 is given in the same dose schedule while venetoclax is given as a ramp-up on days 1 and 2 according to the venetoclax US prescribing information (USPI); therefore, the PK studies are conducted during Cycle 2. Delay of subsequent cycles and venetoclax dose modifications for hematologic toxicities and anti-fungal concomitant medications follow the venetoclax USPI. Response assessments are evaluated using the 2017 ELN criteria (Döhner et al, 2017) and the CRh criterion (complete response [CR] with partial hematologic recovery) defined as those patients achieving marrow CR criteria but not peripheral blood count criteria and demonstrating an absolute neutrophil count >500/μL and platelet >50,000/μL (Kantarjian et al, 2017). Results: At the data cut-off date of August 1, 2021, 15 AML patients have enrolled and received study treatment. Median age is 78 years (range 66 - 84) and 9 (60%) are males. Of the 12 patients with data, 2 (17%), 6 (50%), and 4 (33%) patients are in the favorable, intermediate, and adverse risk ELN categories, respectively. Of the 15 dosed patients, 6 (40%) are diagnosed with AML with myelodysplasia-related changes. The median duration of exposure is 2 cycles (range 1-5) and 1.7 months (range 0.8-5.6). The most common adverse events (AEs) of Grade 2 or higher occurring in ≥10% of patients include neutropenia (5, 33%), febrile neutropenia (2, 13%), anemia (2, 13%), thrombocytopenia (2, 13%), vomiting (2, 13%), pneumonia (2, 13%), peripheral edema (2, 13%), hypertension (2, 13%) and vascular access complication (2, 13%). There are 17 serious AEs experienced in 7 patients; a grade 3 pneumonia and a grade 3 dysphagia are the only serious AEs assessed as related to ASTX727 and/or venetoclax and both events occurred in the same patient. Both AEs were part of the patient's medical history. Two deaths have occurred to date: one patient due to rapidly progressive disease during Cycle 2 and one patient who achieved a best response of CRh transitioned to hospice due to progressive multiple myeloma. Of 9 patients with response assessments and evaluable data, 3 (33%) achieved CR and 4 (44%) achieved CRh as the best response for a composite CR+CRh rate of 78%. Preliminary PK data available from 9 patients show venetoclax exposures are not affected by coadministration of ASTX727and are similar to historical data. Exposures of decitabine and cedazuridine are consistent with the range seen in previous studies. Updated PK, safety, and efficacy data will be provided in December 2021. Conclusions: A preliminary analysis of ASTX727 and venetoclax combination therapy in patients with newly diagnosed AML unfit for intensive induction chemotherapy demonstrate expected PK data, and a similar safety and efficacy profile to the approved combination therapy of a DNMTi and venetoclax. These preliminary data suggest that an all-oral regimen of a DNMTi in combination with venetoclax is feasible and should be investigated further. Disclosures Mannis: AbbVie, Agios, Astellas Pharma, Bristol Myers Squibb, Genentech, MacroGenics, Pfizer, and Stemline: Consultancy; Astex, Forty Seven Inc/Gilead, Glycomimetics, and Jazz Pharmaceuticals: Research Funding. Griffiths: Novartis: Honoraria; Apellis Pharmaceuticals: Research Funding; Alexion Pharmaceuticals: Consultancy, Research Funding; Boston Biomedical: Consultancy; Genentech: Research Funding; Abbvie: Consultancy, Honoraria; Takeda Oncology: Consultancy, Honoraria; Astex Pharmaceuticals: Honoraria, Research Funding; Taiho Oncology: Consultancy, Honoraria; Celgene/Bristol-Myers Squibb: Consultancy, Honoraria, Research Funding. Savona: Geron: Consultancy, Membership on an entity's Board of Directors or advisory committees; Karyopharm: Consultancy, Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees; CTI: Consultancy, Membership on an entity's Board of Directors or advisory committees; BMS-Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; NOVARTIS: Consultancy, Membership on an entity's Board of Directors or advisory committees; Ryvu: Consultancy, Membership on an entity's Board of Directors or advisory committees; Sierra Oncology: Consultancy, Membership on an entity's Board of Directors or advisory committees; Taiho: Consultancy, Membership on an entity's Board of Directors or advisory committees; TG Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; ALX Oncology: Research Funding; Astex: Research Funding; Incyte: Research Funding. Odenike: Celgene, Incyte, AstraZeneca, Astex, NS Pharma, AbbVie, Gilead, Janssen, Oncotherapy, Agios, CTI/Baxalta, Aprea: Research Funding; AbbVie, Celgene, Impact Biomedicines, Novartis, Taiho Oncology, Takeda: Consultancy. Roboz: MEI Pharma - IDMC Chair: Consultancy; Amgen: Consultancy; Jazz: Consultancy; Celgene: Consultancy; Agios: Consultancy; Janssen: Consultancy; Astex: Consultancy; Daiichi Sankyo: Consultancy; Janssen: Research Funding; AstraZeneca: Consultancy; Blueprint Medicines: Consultancy; Bayer: Consultancy; Actinium: Consultancy; AbbVie: Consultancy; Jasper Therapeutics: Consultancy; Helsinn: Consultancy; Glaxo SmithKline: Consultancy; Mesoblast: Consultancy; Bristol Myers Squibb: Consultancy; Novartis: Consultancy; Astellas: Consultancy; Otsuka: Consultancy; Pfizer: Consultancy; Roche/Genentech: Consultancy. Dillingham: Astex Pharmaceuticals, Inc.: Current Employment. Wason: Astex Pharmaceuticals, Inc.: Current Employment. Zhu: Astex Pharmaceuticals, Inc.: Current Employment. Chan: Astex Pharmaceuticals, Inc.: Current Employment. Keer: Astex Pharmaceuticals, Inc.: Current Employment. Oganesian: Astex Pharmaceuticals, Inc.: Current Employment. Dao: Astex Pharmaceuticals, Inc.: Current Employment. DiNardo: AbbVie: Consultancy, Research Funding; Agios/Servier: Consultancy, Honoraria, Research Funding; Novartis: Honoraria; Takeda: Honoraria; Notable Labs: Current holder of stock options in a privately-held company, Membership on an entity's Board of Directors or advisory committees; ImmuneOnc: Honoraria, Research Funding; GlaxoSmithKline: Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Honoraria, Research Funding; Foghorn: Honoraria, Research Funding; Forma: Honoraria, Research Funding; Celgene, a Bristol Myers Squibb company: Honoraria, Research Funding. OffLabel Disclosure: 1. Inqovi (35 mg decitabine and 100 mg cedazuridine) is a prescription medicine approved in the United States to treat adults with myelodysplastic syndromes and chronic myelomonocytic leukemia. In this study, Inqovi is referred as ASTX727 due to the off-label investigational use in combination with venetoclax in adults with newly diagnosed acute myeloid leukemia 75 years or older, or who have comorbidities that preclude use of intensive induction chemotherapy. 2. Venclexta is a prescription medicine approved in the United States for: 1) adults with chronic lymphocytic leukemia or small lymphocytic lymphoma; 2) adults with newly diagnosed acute myeloid leukemia 75 years or older, or who have comorbidities that preclude use of intensive induction chemotherapy, in combination with azacitidine, decitabine, or low-dose cytarabine. In this study, Venclexta is referred as venetoclax due to the off-label investigational use in combination with ASTX727 in adults with newly diagnosed acute myeloid leukemia 75 years or older, or who have comorbidities that preclude use of intensive induction chemotherapy.

Introduction: CPX-351 (United States: Vyxeos ®; Europe: Vyxeos ® Liposomal), a dual-drug liposomal encapsulation of daunorubicin and cytarabine in a synergistic 1:5 molar ratio, is approved for the treatment of newly diagnosed therapy-related acute myeloid leukemia (AML) or AML with myelodysplasia-related changes in adults and pediatric patients aged ≥1 year in the United States and in adults in the European Union. In a phase 3 study in adults aged 60 to 75 years with newly diagnosed high-risk/secondary AML, after 5 years of follow-up CPX-351 significantly improved median overall survival and remission rates versus conventional 7+3 cytarabine/daunorubicin, with a comparable safety profile. Preclinical data suggest CPX-351 may have synergistic activity with targeted agents, including the BCL-2 inhibitor venetoclax (VEN). Interim results from the V-FAST (Vyxeos - First Phase Assessment with Targeted Agents) study have demonstrated the safety and preliminary efficacy of CPX-351 in combination with VEN or midostaurin. Herein, we report the preliminary results of a subgroup analysis of adults with newly diagnosed AML treated with CPX-351 + VEN, based on age, to provide insights into the tolerability of this novel combination in younger versus older adults with AML. Methods: V-FAST is an ongoing, open-label, multicenter, multi-arm, nonrandomized, phase 1b master trial (NCT04075747) to evaluate the safety and preliminary efficacy of CPX-351 combined with targeted agents (venetoclax, midostaurin, enasidenib). Each combination arm had a dose-exploration phase (3+3 design; n ≤12) and a subsequent expansion phase (n = 20) to determine the recommended phase 2 dose (RP2D), safety, and initial efficacy of that treatment combination. Eligible patients included adults aged 18 to ≤75 years with newly diagnosed AML who were deemed fit for intensive chemotherapy and had an ECOG performance status of 0 to 2. Patients assigned to treatment with CPX-351 + VEN were to have wild type FLT3 and IDH2 based on molecular testing. The RP2D of this treatment arm was determined to be dose level 1, in which patients received CPX-351 100 units/m 2 (daunorubicin 44 mg/m 2 + cytarabine 100 mg/m 2) on Days 1, 3, and 5 + VEN 400 mg on Days 1 to 14 of the first induction. At this dose level, 1 of 6 patients in the dose-exploration phase experienced 2 dose-limiting toxicities (grade 4 neutropenia [Day 16] and grade 4 thrombocytopenia [Day 18]) that extended beyond 49 days; no dose adjustments were required and the study enrolled an additional 21 patients at this dose level. For this subgroup analysis, patients were grouped by age: 18 to ≤59 years (younger) and 60 to ≤75 years (older). Results: A total of 21 patients received CPX-351 + VEN and had sufficient data to be included in the analysis, comprising 14 patients aged 18 to ≤59 years and 7 patients aged 60 to ≤75 years. Patient baseline characteristics are shown in Table 1. The most common TEAEs of any grade in younger adults were neutropenia, febrile neutropenia, and constipation; the most common TEAEs in older adults were febrile neutropenia, thrombocytopenia, and nausea (Table 2). The most common grade ≥3 TEAEs in both age groups included febrile neutropenia, thrombocytopenia, neutropenia, and leukopenia (Table 2). TEAEs categorized as serious events included febrile neutropenia (n = 3 [younger]; n = 1 [older]), sepsis (n = 2 [younger]), ischemic stroke (n = 1 [older]), skin infection (n = 1 [older]), and AML (n = 1 [younger]). Six evaluable patients in the younger age group and 1 in the older age group died during the study due to primary causes of relapse/progression (n = 4), adverse event (n = 2), and other (n = 1; sepsis and multiorgan failure after early termination from treatment). Median platelet and neutrophil recovery times were similar between age groups (Table 3) and consistent with the previously reported safety profile of CPX-351 monotherapy. Complete remission (CR) or CR with incomplete platelet or neutrophil recovery was achieved by 6/14 (43%) evaluable younger adults and 4/6 (67%) evaluable older adults, including 5/14 (36%) and 3/6 (50%) who achieved CR. Conclusions: This analysis of preliminary results by age group from the V-FAST study supports the conclusion that the combination of CPX-351 + VEN is equally feasible with a manageable safety profile in both younger and older adult patients with newly diagnosed AML. Promising remission rates were also reported for both age groups. Figure 1 Figure 1. Disclosures Pullarkat: Amgen, Dova, and Novartis: Consultancy, Honoraria; AbbVie, Amgen, Genentech, Jazz Pharmaceuticals, Novartis, Pfizer, and Servier: Membership on an entity's Board of Directors or advisory committees. Levis: Astellas and FujiFilm: Research Funding; Jazz: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Amgen, Astellas Pharma, Daiichi-Sankyo, FujiFilm, and Menarini: Honoraria; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria; BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Mannis: AbbVie, Agios, Astellas Pharma, Bristol Myers Squibb, Genentech, MacroGenics, Pfizer, and Stemline: Consultancy; Astex, Forty Seven Inc/Gilead, Glycomimetics, and Jazz Pharmaceuticals: Research Funding. Strickland: Sunesis: Research Funding; AbbVie, ArcherDx, Genentech, Incyte, Kura Oncology, Novartis, Pfizer, and Syros: Consultancy. Lin: AbbVie, Aptevo Therapeutics, Astellas Pharma, Bio-Path Holdings, Celgene, Celyad, Genentech-Roche, Gilead Sciences, Incyte, Jazz Pharmaceuticals, Novartis, Ono Pharmaceutical, Pfizer, Prescient Therapeutics, Seattle Genetics, Tolero, Trovagene: Research Funding. Faderl: Jazz Pharmaceuticals: Current Employment, Current equity holder in publicly-traded company. Chakravarthy: Jazz Pharmaceuticals: Current Employment, Current equity holder in publicly-traded company. Chandrasekaran: Jazz Pharmaceuticals: Current Employment, Current equity holder in publicly-traded company. Cheung: Jazz Pharmaceuticals: Current Employment, Current equity holder in publicly-traded company. Erba: AbbVie, Daiichi Sankyo, Forma, ImmunoGen, Jazz Pharmaceuticals, MacroGenics, Novartis, and PTC: Research Funding; AbbVie, Agios, Celgene, Incyte, Jazz Pharmaceuticals, and Novartis: Speakers Bureau; AbbVie, Agios, Amgen, Astellas Pharma, Celgene, Daiichi Sankyo, Glycomimetics, ImmunoGen, Incyte, Jazz Pharmaceuticals, MacroGenics, Novartis, and Pfizer: Consultancy; Glycomimetics: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Covance (AbbVie): Other: Independent Review Committee . OffLabel Disclosure: combination of CPX-351 [Vyxeos] and venetoclax in adults with previously untreated AML

Background: The combination of HMA and venetoclax is now standard of care for patients with AML who are not candidates for intensive chemotherapy. Elderly patients are more likely to have secondary AML (sAML), although the presence of an antecedent hematologic malignancy is often not apparent by history. Lindsley et al (Blood, 2015) showed that a somatic mutation in SRSF2, SF3B1, U2AF1, ZRSR2, ASXL1, EZH2, BCOR, or STAG2 is >95% specific for sAML and associated with worse outcomes. While outcomes with HMA/ven in patients meeting standard criteria for sAML have recently been reported (Pullarkat, ASCO 2021), we set out to conduct a real-world analysis of sAML patients receiving HMA/ven, including those with a secondary mutation profile (SMP) as described by Lindsley et al. We hypothesized that-when treated with HMA/ven-outcomes of patients with SMP may be most similar to those with de novo AML. Methods: Patients diagnosed with AML at Stanford Cancer Institute from 4/2017-3/2021 and treated with front-line HMA/ven were retrospectively reviewed. These included patients previously treated with HMA monotherapy for an antecedent hematologic malignancy and those who had previously received ≤ 3 cycles of HMA monotherapy for AML. Responses were classified per the modified International Working Group response criteria. Overall survival (OS) was assessed for all patients, and for patients who had a complete response (CR) or CR with incomplete hematologic recovery (CRi), duration of response (DoR) was also assessed. Statistical analyses were performed in R using the logrank test, with hazard ratios (HR) computed using the Cox proportional hazards model. For multivariate analyses, p-values for a specific variable were calculated using Cox proportional hazards regression. Results: 82 patients met criteria for inclusion; 78 had valid response assessments and 49 (62.8%) had achieved a CR or CRi at first response assessment. Median age was 72 years, with 3 patients younger than 60. 62 patients were male, median ECOG performance status (PS) was 1, median Charlson Comorbidity Index (CCI) was 6, median time to death or end of follow-up from the start of treatment was 366 days, and 58% of patients had adverse risk AML per ELN guidelines. Fig 1a demonstrates demographics for de novo, sAML (excluding SMP), and patients with SMP AML. 13 patients met criteria for AML-MRC, 23 patients had prior history of antecedent hematologic malignancy (18 with MDS or CMML, 5 with MDS/MPN overlap or MPN), 12 had tAML, and 20 patients possessed a SMP and did not meet criteria for the other three categories of sAML. 14 patients with de novo AML were characterized by the absence of any of the above factors. Patients with de novo AML were less likely to have adverse risk disease (29% vs. 64% in others) and had lower CCI scores (mean 5.1 vs. 6.2) but had no significant differences in age, gender, follow-up time, or PS. There was no statistically significant difference in rates of CR/CRi between the different subgroups or the different types of sAML; 69% of patients with de novo AML, 79% of SMP patients, and 57% of patients with other types of sAML achieved a CR or CRi. However, SMP patients had response durations and OS patterns similar to patients with de novo AML (Fig 1b and 1c), and when grouped with de novo patients, both DoR (HR = 3.5, p = 0.047, Fig 1d) and OS (HR = 2.1, p = 0.042, Fig 1e) were significantly longer than those of the sAML patients. Neither DoR nor OS were significantly longer when the SMP patients were grouped with sAML patients (respectively: HR = 3.3, p = 0.22, Fig 1f; HR = 1.5, p = 0.37, Fig 1g). In multivariate Cox proportional regression adjusting for age, ELN risk category, CCI, and PS, worse OS for sAML patients was maintained relative to the SMP and de novo patients (HR 2.9, p = 0.036), although the difference in DoR was no longer significant (HR 4.4, p= 0.10). Conclusions: Patients meeting standard definitions of sAML had worse outcomes than those with de novo AML when treated with HMA/ven in a retrospective, real-world analysis. Although a secondary mutation profile as described by Lindsley et al may be helpful in identifying patients with sAML, when treated with HMA/ven, patients with this profile have outcomes that align more closely with those of patients with de novo AML. Figure 1 Figure 1. Disclosures Mannis: Astex, Forty Seven Inc/Gilead, Glycomimetics, and Jazz Pharmaceuticals: Research Funding; AbbVie, Agios, Astellas Pharma, Bristol Myers Squibb, Genentech, MacroGenics, Pfizer, and Stemline: Consultancy.

Introduction: The addition of gemtuzumab ozogamicin (GO) to 7+3 chemotherapy for newly diagnosed acute myeloid leukemia (AML) has been shown to significantly improve event-free survival (EFS) for cytogenetically favorable-risk AML, with marginal benefit for intermediate-risk AML, and no benefit for cytogenetically adverse-risk AML. Of note, with the exception of mutated FLT3-ITD, little is known about the impact of GO in ELN 2017-defined genotypically adverse-risk AML, and a recent randomized trial found no EFS benefit for 7+3+GO in patients (pts) with genotypically favorable-risk, NPM1-mutated AML. Since 2017, our institution incorporated GO into 7+3-based inductions for all "non-adverse" risk AML pts, as defined by wild-type FLT3 and no abnormalities on rapid FISH analysis for del(5q)/monosomy 5, del(7q)/monosomy 7, and del(20q). We report our experience treating all pts with "non-adverse" risk AML-as defined by this algorithm-with 7+3+GO. Methods: An institutional database was queried in order to identify all pts ≥18 years old who received 7+3-based chemotherapy for newly diagnosed AML between 2017 and 2020; pts who received the FDA-approved fractionated dose of GO were included in the analysis. Data collection included demographic variables, karyotype/FISH, targeted PCR analyses, and multigene NGS panels for AML-related mutations including, but not limited to, mutations in FLT3, NPM1, CEBPA, TP53, RUNX1, and ASXL1. Outcome data included response to induction, relapse, and death, as well as hematopoietic cell transplant (HCT) rates, conditioning regimens, and post-transplant complications. Results: Between January 2017 and July 2020, 96 pts received 7+3-based induction at our institution. Of these, 29 (30%) received 7+3 in combination with GO. Median age at diagnosis was 46 years (range 23-66), with 17 (59%) males. Sixteen (55%) pts had ELN favorable-risk AML (5 [31%] by cytogenetics and 11 [69%] by genotype), 6 (21%) pts had ELN intermediate-risk AML, and 7 (24%) pts had ELN adverse-risk AML (4 [57%] by cytogenetics and 3 [43%] by genotype). Median time from diagnosis to start of induction was 4 days (range 0-43). For cytogenetically adverse-risk pts, median time from diagnostic bone marrow biopsy to receipt of adverse karyotype results was 8 days (7-14). Median time from start of induction to receipt of multigene NGS results for all pts was 15 days (3-32). Overall, 22 (76%) pts achieved remission. All genotypically adverse-risk pts (1 with mutated TP53 and 2 with mutated RUNX1) were refractory to induction, while 3 of 4 (75%) cytogenetically adverse-risk pts (1 with t(6;9), 1 with monosomy 7, and 2 with 11q23 abnormalities) achieved remission. Eight of the 29 (28%) pts proceeded to HCT, including 4 adverse-risk pts. Of the adverse-risk pts, all received myeloablative conditioning prior to HCT and 3 (75%) developed veno-occlusive disease (VOD), with 2 (50%) requiring defibrotide therapy. In favorable/intermediate-risk pts, 4 (18%) proceeded to HCT (2 intermediate-risk pts in first remission and 2 favorable-risk pts in second remission). Of these, 2 (50%) received myeloablative conditioning and 1 (25%) developed VOD. At last follow-up, 23 of 29 pts (79%) remained alive, with a median overall survival not reached (range 1-29 months) and a median EFS of 20 months (9-31). The percentage of ELN favorable-, intermediate-, and adverse-risk pts who remained event-free at last follow-up was 75%, 33%, and 43%, respectively. Discussion: This single-center, retrospective cohort describes the outcomes of pts with "non-adverse" risk AML who received induction chemotherapy with 7+3+GO according to a pre-defined algorithm. Using this algorithm, 30% of all pts receiving 7+3-based inductions received GO. Of these, nearly 25% were ultimately found to have adverse-risk AML as defined by ELN 2017 criteria, largely driven by long turn-around times for karyotyping and NGS multigene panel results. No patient with genotypically adverse-risk AML by ELN criteria responded to induction chemotherapy, and 75% of cytogenetically adverse-risk pts who proceeded to HCT developed VOD. Routine use of 7+3+GO induction outside of the context of cytogenetically favorable-risk AML remains controversial, and further study is needed to define the role of GO, particularly for pts with ELN genotypically adverse-risk AML. Table Disclosures Gotlib: Blueprint Medicines Corporation: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Chair of the Response Adjudication Committee and Research Funding, Research Funding; Deciphera: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: co-chair of the Study Steering Committee and Research Funding. Liedtke:Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria; GSK: Membership on an entity's Board of Directors or advisory committees; Adaptive: Membership on an entity's Board of Directors or advisory committees; Caelum: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees. Muffly:Adaptive: Research Funding; Amgen: Consultancy; Servier: Research Funding. Mannis:AbbVie, Agios, Bristol-Myers Squibb, Genentech: Consultancy; Glycomimetics, Forty Seven, Inc, Jazz Pharmaceuticals: Research Funding.

Background: Patients with hematologic malignancies are less likely to be referred to palliative care (PC) compared to those with solid malignancies. There is little that is known about the healthcare utilization of patients with hematologic malignancies who receive outpatient PC concurrently with cancer-directed therapy. The aim of this study was to describe the demographic and clinical characteristics and health care utilization of patients with hematologic malignancies who received longitudinal, concurrent outpatient PC. Methods: We conducted a single-center, retrospective cohort study of all patients with hematologic malignancies who received embedded outpatient PC at the malignant hematology clinic between April 1, 2017 and December 31, 2018. Patients were referred to PC by their primary oncologist or hematology nurse practitioner (NP). Patients referred to PC were seen by a PC NP with expertise in hematologic malignancies. Follow-up visits with the outpatient PC NP were scheduled as needed. Demographics, clinical characteristics, and reasons for referral were extracted from the electronic health record. For patients who were followed by PC for at least 6 months, the number of hospitalizations and emergency department (ED) visits, as well as inpatient costs were compared from the 6 months prior to enrollment in PC to the 6 months after enrollment in PC. Approval for this study was obtained from the UCSF IRB. Results: Overall, 80 patients who were seen in the malignant hematology clinic were referred for embedded PC during our study period. Of these patients, 45% (n= 36) were female. Median age was 57 years (range: 27-89). Common primary diagnoses were myeloma (47.3%, n= 38), lymphoma (18.8%, n= 15), and acute myeloid leukemia (15%, n= 12). The most frequent reasons for referral to PC were pain (32.7%, n= 34), fatigue (16.3%, n= 17), and mood disorders (11.5%, n= 12). There were 9 referrals (8.7%) for advance care planning prior to bone marrow transplant (BMT). One quarter of the patients (n= 20) were referred to PC for two or more reasons. Patients were followed in the PC clinic for a median of 3.18 months (mean 8.03 months, range 0 - 36 months, SD 9.6 months) and patients had a median of 3 PC visits (mean 5, range 1-27, SD 6). The median overall survival of the patient population was 36.5 months (SD 35.8 months). There were 31 patients who were followed in the PC clinic for at least 6 months and were included in our healthcare utilization analyses. The total number of hospital encounters decreased from 1.48 inpatient admissions/ED visits in the 6-months before enrollment in PC to 0.71 per patient in the 6-months after enrollment in PC (p=0.04). Total inpatient direct costs per patient were $52,250.65 in the 6 months before PC enrollment and $30,360.90 in the 6 months after enrollment (p=0.18). The cost of inpatient medical hospitalizations went from $23,457.68 to $4,621.26 per patient (p=0.05), the cost of procedure-based hospitalizations, which included hospitalization for BMT, went from $27,667.84 to $25,434.48 (p=0.90), and the cost of ED visits went from $1,125.13 to $305.16 (p=0.25). Conclusion: Our study suggests that outpatient PC has an important role for patients with hematologic malignancies far upstream of the end-of-life period. Patients were referred for a wide variety of reasons, including management of various symptoms and advance care planning prior to BMT. There was a statistically significant and substantial decrease in the number of hospital and ED encounters per patient after enrollment in PC. There was also a trend towards overall cost savings, although this did not reach statistical significance. Further research is warranted to explore the effects of outpatient PC co-management on symptoms, rates of advance care planning, and patient/family experience for patients with hematologic malignancies. Disclosures Schoenbeck: American Society of Hematology: Research Funding. Mannis:Glycomimetics, Forty Seven, Inc, Jazz Pharmaceuticals: Research Funding; AbbVie, Agios, Bristol-Myers Squibb, Genentech: Consultancy.

Ivosidenib (AG-120) is an oral, targeted agent that suppresses production of the oncometabolite 2-hydroxyglutarate via inhibition of the mutant isocitrate dehydrogenase 1 (IDH1; mIDH1) enzyme. From a phase 1 study of 258 patients with IDH1-mutant hematologic malignancies, we report results for 34 patients with newly diagnosed acute myeloid leukemia (AML) ineligible for standard therapy who received 500 mg ivosidenib daily. Median age was 76.5 years, 26 patients (76%) had secondary AML, and 16 (47%) had received ≥1 hypomethylating agent for an antecedent hematologic disorder. The most common all-grade adverse events were diarrhea (n = 18; 53%), fatigue (n = 16; 47%), nausea (n = 13; 38%), and decreased appetite (n = 12; 35%). Differentiation syndrome was reported in 6 patients (18%) (grade ≥3 in 3 [9%]) and did not require treatment discontinuation. Complete remission (CR) plus CR with partial hematologic recovery (CRh) rate was 42.4% (95% confidence interval [CI], 25.5% to 60.8%); CR 30.3% (95% CI, 15.6% to 48.7%). Median durations of CR+CRh and CR were not reached, with 95% CI lower bounds of 4.6 and 4.2 months, respectively; 61.5% and 77.8% of patients remained in remission at 1 year. With median follow-up of 23.5 months (range, 0.6-40.9 months), median overall survival was 12.6 months (95% CI, 4.5-25.7). Of 21 transfusion-dependent patients (63.6%) at baseline, 9 (42.9%) became transfusion independent. IDH1 mutation clearance was seen in 9/14 patients achieving CR+CRh (5/10 CR; 4/4 CRh). Ivosidenib monotherapy was well-tolerated and induced durable remissions and transfusion independence in patients with newly diagnosed AML. This trial was registered at www.clinicaltrials.gov as #{"type":"clinical-trial","attrs":{"text":"NCT02074839","term_id":"NCT02074839"}}NCT02074839.

Background: Patients with BCR-ABL-negative myeloproliferative neoplasms (MPNs) have high symptom burdens that negatively impact quality of life, including risk for developing chronic pain and psychosocial complications. The NCCN guidelines recommended the use of the MPN Symptom Assessment Form Total Symptom Score (MPN-SAF TSS) starting in 2017 to assess symptom burden. Our primary aim was to determine if the MPN-SAF TSS has been incorporated into patient care, and if not, how well BCR-ABL-negative MPN symptoms are captured by review of systems (ROS). Our secondary aim was to evaluate the prevalence of anxiety, depression, chronic pain, and opiate use in our patient population. Methods: We performed a single-center, cross-sectional study of all active BCR-ABL-negative MPN patients in the UCSF Hematology Clinic between January 2017 and March 2019. We reviewed all hematology visits for completion of the MPN-SAF TSS, and the most recent visit for the number symptoms from the MPN-SAF TSS explicitly captured in ROS or problem list and relevant medications. Descriptive statistics were used to summarize the data. Patients whose disease transformed into acute leukemia or were post-allogeneic stem cell transplantation were excluded. Results: Of 299 patients with BCR-ABL-negative MPN diagnoses, the median age was 66 (range 20-98) with an equal number of males (n=150) and females (n=149). Essential thrombocythemia (ET) was the most common diagnosis (n=109; 37%), followed by polycythemia vera (PV) (n=90; 30%), primary myelofibrosis (MF) (n=49; 16%), post-PV or post-ET MF (n=29; 10%), and MPN-Unclassifiable or overlap (n=22; 7%). Most were JAK2 V617F positive (n=213; 71%) and high-risk (n=148; 49.5%) by clinical criteria, IPSET-thrombosis, and DIPSS-plus. Nearly all were on active treatment (91%), with aspirin (n=205; 69%), hydroxyurea (n=130; 43.5%), phlebotomy (n=61; 20%), and ruxolitinib (n=37; 12%) being the most frequent treatments. Significant disease-related vascular complications were documented in 20.7% of patients. The 299 patients were evaluated by 22 hematology providers. The MPN-SAF TSS was formally documented in 1 patient (0.3%). Of the 10 symptoms in the MPN-SAF TSS, the median number documented as positive or negative on ROS was 3 (range 0-8), with 0 or 1 symptoms documented in 82 patients (27.4%). The mean number of positive symptoms was 0.7 (range 0-4) with at least 1 positive symptom reported by 44.7%. The most frequently charted symptoms were fever (n=182; 60.9%), unintentional weight loss (n=137; 45.8%), abdominal pain (n=137; 45.8%), and night sweats (n=130; 43.5%). More unique MPN symptoms were documented less frequently, including pruritis (n=89; 29.8%), early satiety (n=56; 18.7%), bone pain (n=28; 9.4%), and problems with concentration (n=3; 1%). The most common positive symptoms were fatigue (n=90; 73%), pruritis (n=30; 33.7%) and bone pain (n=9; 32%). Pain and psychological symptoms were infrequently charted in hematology clinic. Pain medications were used by 20.4% with nearly half (48%) on opiates, but chronic pain was on the provider problem list for only 5.7% of patients. Anxiety/depression medications were used by 20.4%, but anxiety/depression was on the provider problem list in only 4% of patients. Conclusions: To our knowledge, this is the first study to assess the implementation of the MPN-SAF TSS into clinical practice since the NCCN recommendations went into effect. The MPN-SAF TSS is not being utilized in regular practice at our site and a low number of disease-related symptoms are documented in clinic notes. Fatigue is the predominant symptom in our patients, which is similar to previously published studies. The discrepancy between medications taken and symptoms documented suggests that patients have a higher symptom burden than reported. Implementing a standardized way of consistently capturing patients' MPN-related symptoms in hematology practice will be explored in future quality improvement research. Disclosures Damon: Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees. Logan:Incyte: Membership on an entity's Board of Directors or advisory committees; Abbvie: Consultancy; Agios: Consultancy, Membership on an entity's Board of Directors or advisory committees; Jazz: Research Funding; Kite: Research Funding; Kadmon: Research Funding; Pharmacyclics: Research Funding; Novartis: Consultancy; TeneoBio: Consultancy; Kiadis: Consultancy; Astellas: Research Funding; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees. Mannis:Jazz: Membership on an entity's Board of Directors or advisory committees; Agios: Consultancy, Membership on an entity's Board of Directors or advisory committees; Kite: Membership on an entity's Board of Directors or advisory committees; Abbvie/Genentech: Membership on an entity's Board of Directors or advisory committees; Forty Seven: Membership on an entity's Board of Directors or advisory committees; Curis: Membership on an entity's Board of Directors or advisory committees. Olin:Spectrum: Research Funding; Novartis: Research Funding; Mirati Therapeutics: Research Funding; MedImmune: Research Funding; Ignyta: Research Funding; Clovis: Research Funding; Daiichi Sankyo: Research Funding; Astellas: Research Funding; Genentech: Consultancy, Research Funding; Pfizer: Research Funding; Jazz Pharmaceuticals: Consultancy, Honoraria; Revolution Medicine: Consultancy; AstraZeneca: Research Funding. Shah:Bristol-Myers Squibb: Research Funding. Atreya:Immunotherapeutics: Honoraria; Guardant Health: Research Funding; Novartis: Research Funding; Merck: Research Funding; Kura Oncology: Research Funding; Array Biopharma: Honoraria; Pionyr: Honoraria; Bristol-Meyers Squibb: Research Funding. Smith:Astellas Pharma: Research Funding; Abbvie: Research Funding; fujiFilm: Research Funding; Revolution Medicines: Research Funding.

The pathogenesis of primary and secondary central nervous system (CNS) lymphoma poses a unique set of diagnostic, prognostic, and therapeutic challenges. During the past 10 years, there has been significant progress in the elucidation of the molecular properties of CNS lymphomas and their microenvironment, as well as evolution in the development of novel treatment strategies. Although a CNS lymphoma diagnosis was once assumed to be uniformly associated with a dismal prognosis, it is now reasonable to anticipate long-term survival, and possibly a cure, for a significant fraction of CNS lymphoma patients. The pathogenesis of CNS lymphomas affects multiple compartments within the neuroaxis, and proper treatment of the CNS lymphoma patient requires a multidisciplinary team with expertise not only in hematology/oncology but also in neurology, neuroradiology, neurosurgery, clinical neuropsychology, ophthalmology, pathology, and radiation oncology. Given the evolving principles of management and the evidence for improvements in survival, our goal is to provide an overview of current knowledge regarding the pathogenesis of CNS lymphomas and to highlight promising strategies that we believe to be most effective in establishing diagnosis, staging, and therapeutic management.

Intensification of therapy for adults with ALL using pediatric regimens with intensive asparagine depletion is feasible. Targeted therapies are improving outcomes. We hypothesized that the UCSF 8707 regimen (Linker et al.JCO 2002;20:2462) could be safely intensified with the addition of pegylated asparaginase (peg asp), cyclophosphamide, rituximab, dasatinib, and intrathecal liposomal cytarabine. Methods: Patients (pts) enrolled at 4 centers. The primary objective was 3-year (yr) EFS (goal >55%). Eligible pts were age 18-60 yrs with untreated ALL or LBL. Treatment consisted of induction Course 1A (C1A): daunorubicin 60 mg/m2 IV d1-3, vincristine (VCR) 1.4 mg/m2 (2 mg if age >50 yrs) IV day 1,8,15,22, prednisone 60 mg/m2 orally (PO) d1-28, peg-asp 2,000 IU/m2 (cap 3,750 IU; 1,000 IU/m2 if age >50 yrs) IV d15, cyclophosphamide 750 mg/m2 IV d1,15 (or 500 mg/m2 IV q12h d15,16 if d14 marrow M2 or M3). ALL pts in CR/CRi and LBL pts in CR or PR proceeded to post-remission Course 1B (C1B): methotrexate (MTX) 220 mg/m2 IV bolus then 60 mg/m2/hr CIV for 36 hrs d1,15 with leucovorin rescue, 6-mercaptopurine (6-MP) 60 mg/m2 PO d1-7, 15-21, peg-asp 2,000 IU/ m2 (cap 3,750 IU; 1,000 IU/m2 if age >50 yrs) IV d16. Course 1C (C1C) consisted of cytarabine 2,000 mg/m2 IV d1-4 and etoposide 500 mg/m2 IV d1-4. Courses A-C repeated once then a third course B given. Maintenance POMP (6-MP 60 mg/m2 PO daily, VCR 1.4 mg/m2 (2 mg age >50 yrs) IV monthly, MTX 20 mg/m2 PO weekly, prednisone 60 mg/m2 PO d1-5) repeated monthly for 12 months then POMP with every other month VCR and prednisone for 12 months. Peg asp was given d16 of maintenance month 1. If B-ALL (+/- CD20 expression), rituximab 375 mg/m2 IV was given every 2 weeks for 8 doses starting day 1 of C1A. If Ph+ ALL, dasatinib 140 mg PO daily was given but held during high-dose MTX then restarted when serum [MTX] was Results: Between 4/2014 and 2/2017, 31 pts enrolled and 29 were eligible. Median age was 28 yrs (20-54), 62% were male, 52% were Hispanic, and 86% had ALL. The end induction ORR (CR + PR) was 90% (2 ALL with PR, 1 early death). ORR for LBL was 100% (n= 4). The CR rate for ALL was 88%. For Ph- B-ALL (n=16), the CR rate was 86% with MRD 0.1%. Five pts underwent allogeneic HCT in first CR to study therapy. With a median follow up of 32 months (16-44), the 2- and 3-yr EFS were 59%. EFS was similar for B-ALL, T- ALL, LBL, Ph- B-ALL, and Ph+ B-ALL. Five pts relapsed. The 2- and 3-yr RFS were 66%. Concomitant marrow and CNS relapse occurred in 1 pt. No isolated CNS relapses occurred. Transplant-censored 2- and 3-yr OS were 80% and 72%. Uncensored 2- and 3-yr OS were 75% and 70%. Among eligible pts, 8 died: 4 after relapse, 1 in induction from infection, 2 in CR from infection, and 1 from allogeneic HCT complications. Three reversible grade 3-4 events were attributed to liposomal cytarabine, all grade 3: syncope, pseudotumor cerebri, and headache. Grade 3-5 possible peg asp toxicities were transaminitis (58%), hyperbilirubinemia (42%), hyperglycemia (29%), hypertriglyceridemia (26%), elevated GGT/alkaline phosphatase (19%), thrombosis (19%, 1 cerebral venous), hypoalbuminemia (10%), hypersensitivity (6.5%), elevated lipase (6.5%), pancreatitis (3.2%), encephalopathy (3.2%), and avascular necrosis (3.2%). One pt died from encephalopathy. Conclusions: Intensification of UCSF 8707 is feasible and effective. Post-induction remissions were deep with high MRD-negativity rates. EFS, RFS, and OS are favorable with follow up and accrual ongoing (NCT02043587). Strategies to limit peg asp toxicity are needed. Disclosures Wieduwilt: Amgen: Research Funding; Merck: Research Funding; Shire: Research Funding; Daiichi Sankyo: Membership on an entity's Board of Directors or advisory committees; Reata Pharmaceuticals: Equity Ownership; Leadiant: Research Funding. Schiller:Astellas Pharma: Membership on an entity's Board of Directors or advisory committees, Research Funding; bluebird bio: Research Funding. Mannis:AbbVie: Membership on an entity's Board of Directors or advisory committees; Agios: Research Funding; NKarta: Membership on an entity's Board of Directors or advisory committees. Curtin:Amgen: Research Funding; Onconova: Research Funding; Pharmacyclics: Research Funding; Celgene: Research Funding. Andreadis:Genentech: Consultancy, Employment; Bayer: Consultancy; Astellas: Consultancy; Gilead: Consultancy; Juno: Research Funding; Celgene: Consultancy; Pharmacyclics: Consultancy; Novartis: Consultancy, Research Funding; Kite: Consultancy; Seattle Genetics: Consultancy. Logan:Adaptive Biotech: Consultancy; Napajen: Consultancy; Shire: Consultancy; Pfizer: Consultancy; Novartis: Consultancy, Research Funding; Incyte: Consultancy; Jazz Pharmaceuticals: Consultancy, Research Funding; Amgen: Consultancy; Astellas: Research Funding; Pharmacyclics: Research Funding; Kite: Research Funding. Damon:Actelion: Other: spouse's relationship with company; Boston Scientific: Other: spouse's relationship with company; Novartis: Other: spouse's relationship with company; Gilead Sciences Inc: Other: spouse's relationship with company.

Introduction Decitabine and hypomethylating agents are considered non-curative treatments for patients with acute myeloid leukemia (AML) and are a standard approach for those patients not fit for intensive induction chemotherapy, usually due to age and multiple comorbidities. A phase 2 study reported a better overall response rate of 64% with a 10-day schedule of decitabine (Blum, Garzon et al. 2010). A second study reported on a higher rate of response among patients with TP53 mutations (Welch, Petti et al. 2016). However, these responses were not considered durable with median duration of response of about 11 months. We herein describe four patients with longer than expected response duration to decitabine, two of which were able to discontinue therapy with sustained multi-year remission and an apparent cure of their AML. Methods We sought to evaluate the clinical and pathological characteristics of patients with a particular long-term response to decitabine. We screened patients at two institutions who have been in complete remission (CR) for greater than 2 years with single-agent decitabine therapy. Current efforts are on-going to identify patients from five other institutions that also meet these criteria and will be added for the final presentation of this data. Results Four patients have been identified who have experienced CR for over 2 years with average age at diagnosis of 70 years (range 60-76). Three patients had cytogenetically normal (CN) AML and one had core-binding factor (CBF) with t(8;21). Time to treatment response for CR was as follows: 2 patients required 2 cycles, 1 required 1 cycle, and 1 required 4 cycles of decitabine. Two CN patients received 27 cycles of decitabine in total before therapy discontinuation because of trial termination [1]. One patient has remained in CR for 4 years while the second CR lasted for 8 years after cessation of therapy. Both patients were lost to follow-up after those time periods. The other CN patient remains in CR and continues on therapy (30 cycles). The CBF patient relapsed after 28 cycles of therapy and unfortunately succumbed to complications of relapsed AML. Molecular testing was performed on 2 of 4 patients as listed in Table 1 with no clear correlation to outcomes with this limited number of patients. Discussion Currently, the only acceptable long-term cure for patients with AML is intensive induction followed by consolidation with high-dose chemotherapy or allogeneic stem cell transplant. Elderly patients and patients with multiple comorbid conditions are not candidates for this aggressive approach. Here we present 4 patients with prolonged responses to 10-day decitabine induction therapy with 2 patients who appear to be cured of their AML with this approach. Further study is warranted to better characterize these super-responders and determine if there is a particular subpopulation of patients with AML that can achieve long-term survival without the perils of intensive chemotherapy or stem-cell transplantation. Disclosures Mannis: NKarta: Membership on an entity's Board of Directors or advisory committees; Agios: Research Funding; AbbVie: Membership on an entity's Board of Directors or advisory committees. Mims:Abbvie Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy; Agios Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees.

BACKGROUND: Isocitrate dehydrogenase 1 (IDH1) mutations are seen in 6-10% of patients with acute myeloid leukemia (AML). Ivosidenib (AG-120), an oral, potent, targeted inhibitor of the mutant IDH1 protein (mIDH1), is a therapeutic candidate for mIDH1 AML. Ivosidenib suppresses production of the oncometabolite 2-hydroxyglutarate (2-HG), leading to clinical responses via differentiation of malignant cells. AIM: To determine the safety and efficacy of single-agent ivosidenib in patients with untreated AML enrolled in the first-in-human, phase 1, dose escalation and expansion study of patients with mIDH1 advanced hematologic malignancies (NCT02074839). METHODS: This ongoing study assesses the safety, maximum tolerated dose (MTD), pharmacokinetics, pharmacodynamics, and clinical activity of ivosidenib. Enrollment completed on 08May2017. In dose escalation, patients received single-agent ivosidenib orally once daily (QD) or twice daily in 28-day cycles. MTD was not reached; 500 mg QD was selected as the dose for expansion cohorts. Overall response rate (ORR) was defined as complete remission (CR) + CR with incomplete hematologic or platelet recovery + partial response + morphologic leukemia-free state. CR with partial hematologic recovery (CRh) was defined as CR except absolute neutrophil count >0.5 × 109/L [500/µL] and platelet count >50 × 109/L [50,000/µL]). Exploratory biomarker assessments included baseline co-occurring mutations (next-generation sequencing panel for hematologic malignancies) and mIDH1 variant allele frequency (VAF) in bone marrow mononuclear cells (BEAMing Digital PCR; lower limit of detection for mIDH1, 0.02-0.04%). Here, we present data for all patients with untreated AML whose starting dose was 500 mg QD. RESULTS: In all, 258 patients (78 in dose escalation, 180 in expansion) received ivosidenib, including 34 patients with untreated AML (9 from dose escalation, 25 from expansion) who received ivosidenib 500 mg QD. Baseline characteristics for these 34 patients were: 19 male/15 female with median age 76.5 years (range 64-87); 56% were ≥75 years of age; 79% had secondary AML and 53% had prior MDS; 41% had ≥1 hypomethylating agent for antecedent hematologic disorder. As of 10Nov2017, 9 of 34 (26.5%) patients remained on treatment. Three (8.8%) patients discontinued treatment for allogeneic stem cell transplantation. Median duration of exposure to ivosidenib was 4.3 months (range 0.3-29.1). Treatment was well tolerated; the most common adverse events (AEs) (n=34) of any grade, irrespective of causality, occurring in ≥20% of patients were diarrhea (50.0%), fatigue (44.1%), nausea (38.2%), decreased appetite (32.4%), leukocytosis (26.5%), anemia (26.5%), peripheral edema (26.5%), dyspnea (23.5%), thrombocytopenia (23.5%), hypomagnesemia (23.5%), constipation (20.6%), dizziness (20.6%), and insomnia (20.6%). The majority of AEs were grade 1-2 and reported as unrelated to treatment. IDH differentiation syndrome (IDH-DS) was seen in 6 of 34 (17.6%) patients, and was grade ≥3 in 3 (8.8%); ivosidenib was held due to IDH-DS in 3 patients (8.8%), but IDH-DS did not lead to permanent treatment discontinuation or death. CR rate was 26.5% (95% CI 12.9%, 44.4%), CR+CRh rate was 41.2% (95% CI 24.6%, 59.3%), and ORR 58.8% (95% CI 40.7%, 75.4%; 20/34 patients). Median durations of CR, CR+CRh, and overall response were not estimable (lower bound of 95% CI 4.2, 6.5, and 4.2 months, respectively); 12-month durations of response were 75.0%, 56.4%, and 54.3%, respectively. Of patients who were transfusion dependent at baseline, 38.1% became transfusion independent for ≥56 consecutive days on treatment. Longitudinal mIDH1 VAF data were available for 23 patients with untreated AML in expansion: IDH1 mutation clearance was seen in 6 of 11 patients who achieved CR+CRh, including 3 of 7 patients with CR and 3 of 4 with CRh. The relationship between baseline co-occurring mutations and response will be presented. CONCLUSION: Ivosidenib monotherapy was well tolerated in patients with untreated mIDH1 AML, and induced durable remissions and transfusion independence in a molecularly defined, poor prognosis, elderly patient population with high rates of secondary AML, and prior hypomethylating agent exposure. These results support the role of ivosidenib as an effective, oral, targeted treatment for patients with untreated mIDH1 AML who are not eligible for intensive chemotherapy. Disclosures Roboz: Argenx: Consultancy; Orsenix: Consultancy; Jazz Pharmaceuticals: Consultancy; Cellectis: Research Funding; Sandoz: Consultancy; Aphivena Therapeutics: Consultancy; Pfizer: Consultancy; Roche/Genentech: Consultancy; Celgene Corporation: Consultancy; Bayer: Consultancy; Otsuka: Consultancy; Novartis: Consultancy; Orsenix: Consultancy; Pfizer: Consultancy; Celgene Corporation: Consultancy; Celltrion: Consultancy; Otsuka: Consultancy; Novartis: Consultancy; Eisai: Consultancy; AbbVie: Consultancy; Celltrion: Consultancy; Astex Pharmaceuticals: Consultancy; Janssen Pharmaceuticals: Consultancy; Cellectis: Research Funding; Janssen Pharmaceuticals: Consultancy; Daiichi Sankyo: Consultancy; Roche/Genentech: Consultancy; Astex Pharmaceuticals: Consultancy; Jazz Pharmaceuticals: Consultancy; Sandoz: Consultancy; Eisai: Consultancy; Argenx: Consultancy; Bayer: Consultancy; Daiichi Sankyo: Consultancy; AbbVie: Consultancy; Aphivena Therapeutics: Consultancy. DiNardo:Karyopharm: Other: Advisory role; Medimmune: Other: Advisory role; Celgene: Other: Advisory role; Bayer: Other: Advisory role; Agios: Consultancy, Other: Advisory role; AbbVie: Consultancy, Other: Advisory role. Stein:Agios: Consultancy; Bayer: Consultancy; Daiichi Sankyo: Consultancy; Celgene: Consultancy; Novartis: Consultancy; Pfizer: Consultancy. de Botton:Agios: Research Funding; Celgene: Honoraria, Research Funding. Mims:Agios Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; Abbvie Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy. Altman:Pfizer: Other: payment to the institution to conduct clinical trial work; Celgene: Membership on an entity's Board of Directors or advisory committees, Other: payment to the institution to conduct clinical trial work; Agios: Other: Payment to the institution to conduct the trial ; Janssen Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Bayer: Other: payment to the institution to conduct clinical trial work; GSK: Other: payment to the institution to conduct clinical trial work; Epizyme: Other: payment to the institution to conduct clinical trial work; Ariad: Other: payment to the institution to conduct clinical trial work; Boeringer Ingelheim: Other: payment to the institution to conduct clinical trial work; Immune Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Incyte: Other: payment to the institution to conduct clinical trial work; Astellas Pharma: Other; FujiFilm: Other: payment to the institution to conduct clinical trial work; Syros: Membership on an entity's Board of Directors or advisory committees; Cyclacel: Other: payment to the institution to conduct clinical trial work; BMS: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Celator: Other: payment to the institution to conduct clinical trial work; Genetech: Other: Payment to the institution to conduct clinical trial work. Arellano:Cephalon: Research Funding. Mannis:Agios: Research Funding; AbbVie: Membership on an entity's Board of Directors or advisory committees; NKarta: Membership on an entity's Board of Directors or advisory committees. Pollyea:Gilead: Consultancy; Celyad: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Karyopharm: Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Argenx: Consultancy, Membership on an entity's Board of Directors or advisory committees; Curis: Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy, Research Funding; Agios: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Stein:Celgene: Speakers Bureau; Amgen: Speakers Bureau. Uy:GlycoMimetics: Consultancy; Curis: Consultancy. Watts:Jazz Pharma: Consultancy, Speakers Bureau; Takeda: Research Funding. Fathi:Astellas: Honoraria; Seattle Genetics: Consultancy, Honoraria; Boston Biomedical: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Research Funding; Jazz: Honoraria; Takeda: Consultancy, Honoraria; Agios: Honoraria, Research Funding. Kantarjian:Orsenix: Honoraria; Novartis: Research Funding; Immunogen: Honoraria; BMS: Honoraria, Research Funding; Astex: Research Funding; ARIAD: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Actinium: Honoraria; AbbVie: Honoraria; Pfizer: Honoraria, Research Funding. Tallman:AbbVie: Research Funding; BioSight: Other: Advisory board; AROG: Research Funding; Daiichi-Sankyo: Other: Advisory board; Orsenix: Other: Advisory board; ADC Therapeutics: Research Funding; Cellerant: Research Funding. Choe:Agios: Employment, Equity Ownership. Dai:Agios: Employment, Equity Ownership. Fan:Agios: Employment, Equity Ownership. Wang:Agios: Employment, Equity Ownership. Zhang:Agios: Employment, Equity Ownership. Yen:Agios: Employment, Equity Ownership. Kapsalis:Agios: Employment, Equity Ownership. Hickman:Agios: Employment, Equity Ownership. Liu:Agios: Employment, Equity Ownership. Agresta:Agios: Employment, Equity Ownership. Wu:Agios: Employment, Equity Ownership, Patents & Royalties. Attar:Agios: Employment, Equity Ownership. Stone:Merck: Consultancy; Cornerstone: Consultancy; AbbVie: Consultancy; Orsenix: Consultancy; Ono: Consultancy; Fujifilm: Consultancy; Otsuka: Consultancy; Celgene: Consultancy, Other: Data and Safety Monitoring Board, Steering Committee; Jazz: Consultancy; Astellas: Consultancy; Argenx: Other: Data and Safety Monitoring Board; Arog: Consultancy, Research Funding; Sumitomo: Consultancy; Novartis: Consultancy, Research Funding; Amgen: Consultancy; Agios: Consultancy, Research Funding; Pfizer: Consultancy.

Introduction The challenges posed by the increasing incidence of hematologic malignancies in older patients are significant and while during the past 20 years there has been a dramatic expansion in the therapeutic armamentarium against hematologic malignancies, there is a need for data to guide treatment decisions for older adults, particularly with respect to the use of novel targeted or immunotherapeutic agents. To a large extent, this is a consequence of the under-representation of this growing demographic in cancer-related clinical trials. Management of primary CNS lymphoma (PCNSL) in patients age ≥ 70 years represents a significant problem. While it is established that older PCNSL patients benefit from high-dose methotrexate-based induction regimens, whole brain irradiation consolidation is not a favored option because of excessive neurotoxicity. While there is evidence that high‐dose chemotherapy improves outcomes in patients age < 70, dose‐intensive chemotherapy is not an option for most older PCNSL patients. Given that the median age of PCNSL at diagnosis is ~ 60 years, determination of the optimal consolidative approach for older patients is an important question. This problem is particularly significant given that the incidence of PCNSL continues to rise in this older age group. While PCNSL increasingly appears to be a curable brain tumor, outcomes for patients age > 60 remain poor, with 1-year progression-free survival (PFS) of ~ 40% and median overall survival of 14-30 months. Population-based registry data suggests a median overall survival for PCNSL patients age > 70 of approximately 7 months over the past decade. New therapeutic approaches are needed for the particularly vulnerable older PCNSL patient population. Given the evidence for activity of low-dose lenalidomide in relapsed primary and secondary CNS lymphoma, in 2011, we began using low-dose lenalidomide as maintenance in consecutive older PCNSL patients (age ≥ 70 years, HIV negative) following standard methotrexate/rituximab-based induction, in lieu of surveillance, whole brain irradiation or high-dose chemotherapeutic consolidation. Here we report on the characteristics, outcomes, toxicities, progression-free and overall survival of the first 11 PCNSL patients, age ≥ 70, to receive lenalidomide maintenance after high-dose methotrexate-based induction at our institution. Results Eleven patients age > 70 received low-dose lenalidomide maintenance 5-10 mg/d on a 21-d cycle after induction therapy for PCNSL.Median age of the cohort is 77 years (range 70-86). Median Karnofsky performance status (KPS) is 60 (range 50-80); median IELSG prognostic risk score is 4 (range 3-5). The median methotrexate dose administered was 2.5 grams/m2 (range 0.5 - 8). With overall median follow-up of 30 months, median time on lenalidomide maintenance is 14.8 months (range 0.9 - 65.2). Two patients received lenalidomide plus maintenance rituximab, every 6 months. Median PFS is 48 months (range 16.8 - 84.8). Median OS has not been reached, and there have been no deaths (Figure 1). Four patients experienced disease progression on lenalidomide; 3 of them continued maintenance lenalidomide after salvage and 1 received maintenance pomalidomide. Lenalidomide maintenance has generally been well-tolerated. However, 5 toxicities potentially related to therapy have mandated cessation of lenalidomide: 1 grade 2 arthralgia, 1 subdural hematoma, 1 pneumonia, 1 grade 3 fatigue, 1 deep vein thrombosis. Conclusions These encouraging preliminary results of prolonged PFS and OS with low-dose lenalidomide illustrate the feasibility and challenges, as well as suggest a potential benefit of maintenance therapy with low-dose lenalidomide in older patients with PCNSL. Nine of 11 patients were able to complete at least 8 months of lenalidomide maintenance after induction therapy. Toxicities were manageable and strikingly, there have been no deaths. Recently, lenalidomide has been shown to enhance the proliferation, survival, and chemotactic responses in T-cells isolated from older subjects. This suggests a potential mechanistic basis by which low-dose lenalidomide may improve immunity in the elderly and potentiate response to chemotherapy. Future studies are needed to prospectively test the benefit and mechanisms of lenalidomide maintenance in older patients with PCNSL. Figure 1. Figure 1. Disclosures Rubenstein: Genentech: Research Funding; Celgene: Research Funding. Mannis:AbbVie: Membership on an entity's Board of Directors or advisory committees; Agios: Research Funding; NKarta: Membership on an entity's Board of Directors or advisory committees.

Introduction: Allogeneic hematopoietic cell transplantation (alloHCT) has historically been reserved for younger, fit patients with hematologic malignancies. With the introduction of non-myeloablative conditioning regimens and improved supportive care, alloHCT has been increasingly offered to older adults. Objectives: To determine the association between functional status as measured by a cancer-specific comprehensive geriatric assessment (CGA) and post-transplant outcomes in an older alloHCT patient population. Methods: We conducted a prospective cohort study of patients aged 50 or older who underwent alloHCT at the University of California San Francisco between October 2011 and September 2017. A cancer-specific CGA (1) was administered prior to alloHCT, which included measures of functional status such as Lawton Instrumental Activities of Daily Living (IADL), Medical Outcomes Study (MOS) Physical Health scale, and patient-reported Karnofsky Performance Status (KPS). Post-transplant outcomes included length of hospital stay (LOS), non-relapse mortality (NRM), progression-free survival (PFS), and overall survival (OS). Results: A total of 148 patients were included in the analysis. The median age at transplant was 62 (range 50-76). Disease types included acute myeloid leukemia (43%), myelodysplastic syndrome (26%), myeloproliferative neoplasm (12%), acute lymphoblastic leukemia (10%), non-Hodgkin lymphoma (5%), multiple myeloma (1%), and other (3%); 68% received non-myeloablative conditioning. Median follow-up was 16.3 months (range 0.9-72.7 months). Median PFS and OS were 22.9 months and 47.6 months, respectively. At baseline, 39% had at least one IADL deficit, and 88% had at least one MOS Physical Health scale deficit. The mean patient-KPS was 82.4 and mean provider-KPS was 91.6; these were weakly correlated (Spearman's r=0.39, p In univariate analysis, the presence of any IADL deficit was associated with inferior PFS (HR 1.78, p=0.01) and OS (HR 1.68, p=0.04) (Figure). MOS Physical Health score was associated with increased NRM (HR 1.06 per 1-point change in 20-point scale, p=0.04), inferior OS (HR 1.05, p=0.04), increased LOS (difference 0.63 days, p=0.007), but not with PFS (HR 1.04, p=0.06). Neither patient- nor provider-KPS was associated with NRM, PFS, or OS, but lower patient-KPS was associated with increased LOS (difference 1.94 days, p=0.01). In this study, the Hematopoietic Cell Transplantation-Comorbidity Index (HCT-CI), disease risk by American Society for Blood and Marrow Transplantation (ASBMT) classification, and conditioning intensity were not associated with NRM, PFS, or OS. Notably, chronologic age was not associated with NRM, PFS, or OS (Figure). In addition, age was not associated with baseline IADL score (r=-0.02, p=0.26) or MOS Physical Health score (r=-0.13, p=0.06). Conclusion: IADL impairment was associated with inferior PFS and OS, supporting previous studies (2, 3) identifying IADL as an important predictor for alloHCT. In univariate analysis, IADL was a stronger predictor of post-transplant outcomes than traditional prognostication tools such as age, HCT-CI, and provider-KPS. MOS Physical Health score was associated with multiple poor outcomes including NRM and LOS, suggesting a primary impact on alloHCT toxicity. Multivariate analyses, as well as examination of other CGA variables, are ongoing. References:J Clin Oncol. 2011 Apr 1;29(10):1290-6.Haematologica. 2014 Aug;99(8):1373-9.Bone Marrow Transplant. 2018 May;53(5):565-575. Figure. Figure. Disclosures Andreadis: Genentech: Consultancy, Employment; Gilead: Consultancy; Juno: Research Funding; Novartis: Consultancy, Research Funding; Pharmacyclics: Consultancy; Seattle Genetics: Consultancy; Kite: Consultancy; Celgene: Consultancy; Bayer: Consultancy; Astellas: Consultancy. Logan:Napajen: Consultancy; Adaptive Biotech: Consultancy; Shire: Consultancy; Pfizer: Consultancy; Novartis: Consultancy, Research Funding; Incyte: Consultancy; Jazz Pharmaceuticals: Consultancy, Research Funding; Amgen: Consultancy; Astellas: Research Funding; Pharmacyclics: Research Funding; Kite: Research Funding. Mannis:Agios: Research Funding; AbbVie: Membership on an entity's Board of Directors or advisory committees; NKarta: Membership on an entity's Board of Directors or advisory committees. Smith:Astellas Pharma: Research Funding. Martin:Roche: Consultancy; Amgen: Research Funding; Sanofi: Research Funding. Damon:Novartis: Other: spouse's relationship with company; Boston Scientific: Other: spouse's relationship with company; Actelion: Other: spouse's relationship with company; Gilead Sciences Inc: Other: spouse's relationship with company. Olin:Synapse: Honoraria; Astellas: Research Funding; Daiichi Sankyo: Research Funding; Genentech: Research Funding.

BACKGROUND: Recurrent isocitrate dehydrogenase (IDH) 1 mutations are observed in 6-10% of patients with acute myeloid leukemia (AML). Ivosidenib (AG-120), a potent, selective, oral, small-molecule inhibitor of the mutant IDH1 (mIDH1) protein, is a promising therapeutic candidate for the treatment of patients with mIDH1 AML. Through inhibition of mIDH1, ivosidenib suppresses the abnormal production of the oncometabolite 2-hydroxyglutarate (2-HG), leading to clinical responses via differentiation of malignant cells. AIM: To report safety and efficacy data from the first-in-human phase 1 study of ivosidenib in patients with mIDH1 advanced hematologic malignancies including relapsed/refractory (R/R) AML (NCT02074839). This is the first report of data from the 4 expansion cohorts, with a total of 258 patients treated on study. METHODS: The ongoing phase 1 study assesses the safety, maximum tolerated dose (MTD), pharmacokinetics, pharmacodynamics, and clinical activity of ivosidenib in mIDH1 hematologic malignancies. Enrollment was completed on May 8, 2017. During dose escalation, patients received ivosidenib as a single agent orally once daily (QD) or twice daily (BID) in 28-day cycles. The MTD was not reached and 500 mg QD was selected as the recommended dose to be tested in 4 expansion cohorts: R/R AML (Arms 1 and 4, where Arm 1 patients are those with relapse after transplantation, second or later relapse, resistance to initial induction or reinduction treatment, or relapse within 1 year of initial treatment, and Arm 4 patients have R/R AML but are not eligible for Arm 1); untreated AML (Arm 2); and other advanced hematologic malignancies including myelodysplastic syndrome (MDS) (Arm 3). Updated safety data will be presented for all patients. Efficacy outcomes will be presented for all R/R AML patients treated at 500 mg QD across the dose escalation and expansion cohorts who received their first dose of ivosidenib at least 6 months prior to the analysis cut-off date of May 12, 2017, as well as for the poorest prognosis Arm 1 subset. Efficacy data for all treated patients from the other expansion cohorts (untreated AML and other advanced hematologic malignancies including MDS) will also be presented. RESULTS: In all, 258 patients (78 in dose escalation, 180 in expansion) were treated with ivosidenib. As of May 12, 2017, 62 of 258 (24%) patients were continuing on treatment. The median duration of exposure to ivosidenib was 3.5 months (range 0.1-33.5). Twenty-two (8.5%) patients discontinued treatment to proceed to allogeneic stem cell transplantation. Treatment was well tolerated; the most common adverse events (AEs) (n=258) of any grade irrespective of causality occurring in ≥20% of patients were diarrhea (33%), leukocytosis (30%), nausea (30%), fatigue (29%), febrile neutropenia (25%), dyspnea (24%), anemia (23%), QT prolongation (23%), peripheral edema (22%), pyrexia (21%), and decreased appetite (20%). The majority of these AEs were grades 1-2 and reported as unrelated to treatment. Differentiation syndrome (DS) was observed in 29 of 258 (11.2%) patients, including grade ≥3 DS in 14 (5.4%); study drug was held owing to DS in 11 patients (4.3%), and no instances of DS led to permanent treatment discontinuation or death. The primary efficacy endpoint for R/R AML is the CR+CRh rate, i.e., the rate of complete remission (CR according to modified IWG 2003 criteria plus CR with partial hematologic recovery, defined as CR except absolute neutrophil count >0.5 × 109/L [500/µL] and platelet count >50 × 109/L [50,000/µL]). Among 125 Arm 1 R/R AML patients receiving ivosidenib 500 mg QD across dose escalation and expansion who received their first dose at least 6 months prior to the analysis cutoff date, the CR+CRh rate was 30.4% (95% CI 22.5%, 39.3%), including CR in 27 (21.6%) and CRh in 11 (8.8%) patients. Median duration of CR+CRh was 8.2 months (95% CI 5.5, 12.0), and duration of CR was 9.3 months (95% CI 5.6, 18.3). The overall response rate (CR+CRi/CRp+PR+MLFS) was 41.6% (95% CI 32.9%, 50.8%) (52/125 patients). CONCLUSION: Ivosidenib monotherapy is well tolerated in patients with mIDH1 AML and other advanced hematologic malignancies. In a high-risk, molecularly defined R/R AML patient population with unmet medical need, ivosidenib induced durable remissions and improved patient outcomes. These findings support the role of ivosidenib as an effective, oral, targeted treatment for patients with mIDH1 AML. Disclosures DiNardo: Celgene: Honoraria, Research Funding; AbbVie: Honoraria, Research Funding; Agios: Honoraria, Research Funding; Daiichi-Sankyo: Honoraria, Research Funding; Novartis: Honoraria, Research Funding. De Botton: Pfizer: Honoraria; Novartis: Honoraria; Celgene: Honoraria; Servier: Honoraria; Agios: Honoraria, Research Funding. Stein: GSK: Other: Advisory Board, Research Funding; Constellation Pharma: Research Funding; Seattle Genetics: Research Funding; Agios Pharmaceuticals, Inc.: Consultancy, Research Funding; Celgene Corporation: Consultancy, Other: Travel expenses, Research Funding; Pfizer: Consultancy, Other: Travel expenses; Novartis: Consultancy, Research Funding. Roboz: AbbVie, Agios, Amgen, Amphivena, Array Biopharma Inc., Astex, AstraZeneca, Celator, Celgene, Clovis Oncology, CTI BioPharma, Genoptix, Immune Pharmaceuticals, Janssen Pharmaceuticals, Juno, MedImmune, MEI Pharma, Novartis, Onconova, Pfizer, Roche Pharmace: Consultancy; Cellectis: Research Funding. Mims: Novartis: Honoraria. Pollyea: Takeda, Ariad, Alexion, Celgene, Pfizer, Pharmacyclics, Gilead, Jazz, Servier, Curis: Membership on an entity's Board of Directors or advisory committees; Agios, Pfizer: Research Funding. Altman: Syros: Consultancy; NCCN: Other: Educational speaker; BMS: Consultancy; Celgene: Consultancy; Astellas: Consultancy; Ceplene: Consultancy; Janssen Pharmaceuticals: Consultancy; Novartis: Consultancy; ASH: Other: Educational speaker. Collins: Celgene Corporation: Research Funding; Agios: Research Funding; Arog: Research Funding; BMS: Research Funding. Mannis: Curis: Honoraria; Juno: Research Funding; Agios: Research Funding; Amgen: Honoraria. Uy: GlycoMimetics: Consultancy; Novartis: Consultancy, Other: Travel Suppport; Boehringer Ingelheim: Consultancy. Fathi: Juno: Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Honoraria; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Research Funding; Agios: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Medimmune: 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. Stein: Amgen: Consultancy, Speakers Bureau; Stemline: Consultancy. Erba: Celgene: Consultancy, Other: Chair, Scientific Steering Committee , Speakers Bureau; Incyte: all research support paid to University of Alabama, Consultancy, Speakers Bureau; Jazz: Consultancy, Speakers Bureau; Novartis: Consultancy, Speakers Bureau; Amgen: Consultancy, Other: all research support paid to University of Alabama, Research Funding; Daiichi Sankyo: Consultancy, Other: all research support paid to University of Alabama, Research Funding; ImmunoGen: Consultancy, Other: all research support paid to University of Alabama, Research Funding; MacroGen: Consultancy; Ono: Consultancy; Pfizer: Consultancy; Seattle Genetics: Consultancy, Other: all research support paid to University of Alabama, Research Funding; Sunesis: Consultancy; Millennium/Takeda: Consultancy, Other: all research support paid to University of Alabama, Research Funding; Agios: Other: all research support paid to University of Alabama, Research Funding; Juno: Other: all research support paid to University of Alabama, Research Funding; Astellas: Other: all research support paid to University of Alabama, Research Funding; Celator: Other: all research support paid to University of Alabama, Research Funding; Janssen: Other: all research support paid to University of Alabama, Research Funding; Glycomimetics: Other: Chair, Data and Safety Monitoring Committee. Traer: ImmunoGen: Consultancy; Tolero: Consultancy; Notable Labs: Equity Ownership. Stuart: Pharmacyclics LLC, an AbbVie Company: Research Funding; Amgen: Consultancy, Honoraria; Agios: Research Funding; Celator/Jazz: Research Funding; Sunesis: Consultancy, Honoraria, Other: Travel Support, Research Funding; Bayer: Research Funding; Novartis: Research Funding; Incyte: Research Funding; ONO: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Research Funding; MedImmune: Research Funding; Cantex: Research Funding; Astellas: Research Funding. Arellano: Cephalon Oncology: Research Funding. Sekeres: Celgene: Membership on an entity's Board of Directors or advisory committees. Yen: Agios: Employment, Equity Ownership. Kapsalis: Agios: Employment, Equity Ownership. Liu: Agios Pharmaceuticals, Inc.: Employment, Equity Ownership. Goldwasser: Agios: Employment, Equity Ownership. Agresta: Agios Pharmaceuticals, Inc.: Employment, Equity Ownership. Attar: Agios: Employment, Equity Ownership. Stone: Novartis: Consultancy; Celgene: Consultancy; Amgen: Consultancy; Abbvie: Consultancy; Fuji Film: Consultancy; Jazz: Consultancy; Astellas: Consultancy; Pfizer: Consultancy; Arog: Consultancy; Ono: Consultancy; Agios: Consultancy; Sumitomo: Consultancy. Kantarjian: ARIAD: Research Funding; Bristol-Meyers Squibb: Research Funding; Delta-Fly Pharma: Research Funding; Amgen: Research Funding; Pfizer: Research Funding; Novartis: Research Funding.

Background: Isatuximab (ISA) is an anti-CD38 mAb with potent anti-myeloma (MM) activity given alone or in combination with lenalidomide (LEN) and dexamethasone in relapsed and refractory MM (RRMM). Carfilzomib (CFL) is a second generation proteasome inhibitor approved for the treatment of RRMM. This is an initial report of safety and efficacy data from an ongoing Phase Ib dose-escalation trial combining ISA and CFL in RRMM. (clinicaltrials.gov: NCT02332850) Objectives: The primary objective is to determine the maximum tolerated dose (MTD) of ISA with standard dose CFL in RRMM. Secondary objectives include characterization of pharmacokinetics, safety (including immunogenicity) and disease response (overall response rate [ORR]; IMWG criteria). Methods: ISA is given IV every 2 weeks (Q2W), or weekly (QW) for 4 doses then Q2W in combination with standard CFL (20®27 mg/m2: Day 1, 2, 8, 9, 15, 16, every 28 days). Three ISA dosing levels (DL) have been tested: 10 mg/kg Q2W, 10 mg/kg QW x 4 then Q2W and 20 mg/kg QW x 4 then Q2W using a classic 3+3 dose escalation design based on dose-limiting toxicities. Standard premedications (dex 20 mg IV/PO, acetaminophen 650 mg, diphenhydramine 25-50 mg IV/PO and famotidine 20mg IV) were given prior to each ISA infusion. Results: Eleven patients have been treated across the 3 DL (DL1=3, DL2=3, DL3=5). Treatment disposition: 4 patients have progressed, 7 remain on therapy. This was a heavily pretreated population with a median of 4.5 prior lines of therapy (range: 2-8). All subjects had received prior LEN, 10/11 had received prior BORT and 9/11 had received prior CFL. 10/11 were refractory (refr) to their previous regimen (4 quad refr and 7/11 refr to CFL). 10 patients are evaluable for response. The ORR is 80%: 2VGPR, 6 PR, and CBR is 90% (DL1: 2PR, 1SD; DL2: 3PR; DL3:2VGPR, 1PR, 1MR). The median # of cycles given is 6 (range 1-20). No DLT's or severe adverse drug reactions have been observed. No dose reduction for ISA or CFL have been needed. The most frequent occurring non-hematologic (NH) adverse events ( occurring in ≥ 15%) at all DLs are dyspnea (45%), fatigue (45%), nausea (45%), pain (back, chest wall and pelvis; 36%), peripheral neuropathy (36%), HTN (27%), cough (27%), anorexia (27%), GERD (18%), constipation (18%), diarrhea (18%), nasal congestion (18%) and hypokalemia (18%); Conclusion: Combining ISA and CFL appears to be well tolerated; no unexpected adverse drug reactions were noted. MTD has not been reached. Encouraging anti-MM activity is reported in heavily pretreated patients with RRMM. Expanded accrual is ongoing, additional safety, pharmacokinetics and response data will be presented. (Figure 1: spider plot of % change in serum m-protein over time) Figure 1. Figure 1. Disclosures Martin: Sanofi Aventis: Research Funding; Amgen: Research Funding. Chari:Amgen Inc.: Honoraria, Research Funding; Pharmacyclics: Research Funding; Array Biopharma: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Celgene: Consultancy, Research Funding. Campana:Sanofi Aventis: Employment. Hui:Sanofi Aventis: Employment. Wolf:Pharmacyclics: Honoraria; Telomere Diagnostics: Consultancy; Amgen: Honoraria; Takeda: Honoraria; Celgene: Honoraria.

INTRODUCTION Recurrent somatic mutations in the metabolic enzymes isocitrate dehydrogenase 1 and 2 (IDH1/2) confer gain-of-function activity in cancer cells, resulting in accumulation of the oncometabolite, D-2-hydroxyglutarate (2-HG). High levels of 2-HG result in epigenetic changes and impaired cellular differentiation. IDH mutations have been identified in multiple solid tumors and hematologic malignancies. Approximately 6-10% and 9-13% of adults with acute myeloid leukemia (AML) carry mutations in IDH1 (mIDH1) or IDH2 (mIDH2), respectively. AG-120 is a first-in-class, oral, potent, reversible, selective inhibitor of the IDH1 mutant enzyme under evaluation in multiple ongoing single agent and combination clinical trials [NCT02074839, NCT02073994, NCT02632708, NCT02677922]. This is the first report of IDH1 mutation clearance assessed by variant allele frequency (VAF) analysis using next-generation sequencing (NGS) in patients treated on the dose escalation portion of the first-in-human phase 1 study [NCT02074839]. METHODS Patients with advanced mIDH1-positive hematologic malignancies received AG-120 as a single agent orally once daily (QD) or twice daily (BID) continuously in 28-day cycles. Primary objectives were determination of safety, maximum tolerated dose (MTD), and selection of a dose schedule for expansion cohorts and future studies. Secondary objectives included clinical activity assessed by investigators using modified 2003 International Working Group Criteria in AML. Determination of mIDH1 VAF was performed using the FoundationOne® Heme test on mononuclear cells from the bone marrow or peripheral blood at screening and subsequent time points on study. This NGS assay reports IDH1 mutations for samples with VAF ≥1%, with median coverage 500X. Patients with IDH1 mutational clearance (IDH1-MC) were defined as having mIDH1 at baseline and at least one on-study sample with no reported mIDH1. RESULTS Seventy-eight patients were treated in the dose escalation portion, which is now closed to enrollment. As of the data cut-off of May 12, 2016, the median duration on treatment was 3.2 months and 9 (11.5%) patients remain on treatment, with an additional 8 (10.3%) patients transitioned to stem cell transplant. Doses ranged from 300-1200 mg QD with 1 cohort at 100 mg BID. Though the MTD was not reached, the recommended phase 2 dose was determined to be 500 mg QD. The majority of adverse events (AEs) were grade 1 and 2, the most common (≥30%) being diarrhea, fatigue, and nausea; the most common grade ≥3 AEs (≥15%) were febrile neutropenia, anemia, leukocytosis and pneumonia. The most common serious AEs were febrile neutropenia (16.7%) and pneumonia (12.8%). The overall response rate (ORR) was 38.5% (n=30), with 17.9% (n=14) achieving a complete remission (CR). Longitudinal mIDH1 VAF data were available for 51 patients; of these, 22% (n=11) achieved a CR. IDH1-MC was observed in 27.3% (3/11) patients who achieved CR (Figure 1). In contrast, only 1/40 patients who did not achieve CR experienced IDH1-MC. This occurred in a patient with an initially low mIDH1 VAF who had clinical progression despite IDH1-MC (Figure 1, bottom right). In all 3 patients with CR who achieved IDH1-MC, an initial increase in mIDH1 VAF, or early peak, was observed prior to IDH1-MC, suggesting that early clonal expansion might have occurred as part of the mechanism of action of AG-120. CONCLUSION This is the first demonstration that treatment with single agent AG-120 can result in mIDH1 clearance as determined by NGS. Further analysis of the mutational profiles is planned. AG-120, a potent, selective, oral inhibitor of mIDH1 continues to demonstrate a well-tolerated safety profile in patients with advanced hematologic malignancies, and induced objective single-agent durable responses. The data continue to support the efficacy and safety of single agent AG-120 and provide evidence that the underlying biology of the disease is altered by treatment. Figure 1. VAF analysis using FoundationOne® Heme NGS assay in 4 AML patients with IDH1-MC treated with AG-120 Figure subscript: Y-axis is mIDH1 VAF, x-axis is days on treatment. Text indicates investigator-assessed clinical response. CR, complete remission; CRi, CR with incomplete neutrophil recovery; CRp, CR with incomplete platelet recovery; R/R, relapsed/refractory; SD, stable disease; PD, progressive disease; *post-transplant sample Figure 1. VAF analysis using FoundationOne® Heme NGS assay in 4 AML patients with IDH1-MC treated with AG-120. / Figure subscript: Y-axis is mIDH1 VAF, x-axis is days on treatment. Text indicates investigator-assessed clinical response. CR, complete remission; CRi, CR with incomplete neutrophil recovery; CRp, CR with incomplete platelet recovery; R/R, relapsed/refractory; SD, stable disease; PD, progressive disease; *post-transplant sample Disclosures DiNardo: Daiichi Sankyo: Other: advisory board, Research Funding; Novartis: Other: advisory board, Research Funding; Abbvie: Research Funding; Celgene: Research Funding; Agios: Other: advisory board, Research Funding. de Botton:Novartis: Consultancy; Agios: Consultancy, Research Funding; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy; Servier: Consultancy; Pierre Fabre: Consultancy. Stein:Agios: Other: advisory board; Celgene: Other: advisory board; Novartis: Other: advisory board. Roboz:Cellectis: Research Funding; Agios, Amgen, Amphivena, Astex, AstraZeneca, Boehringer Ingelheim, Celator, Celgene, Genoptix, Janssen, Juno, MEI Pharma, MedImmune, Novartis, Onconova, Pfizer, Roche/Genentech, Sunesis, Teva: Consultancy. Pollyea:Alexion: Other: advisory board; Pfizer: Other: advisory board, Research Funding; Ariad: Other: advisory board; Glycomimetics: Other: DSMB member; Celgene: Other: advisory board, Research Funding. Fathi:Bexalata: Other: Advisory Board participation; Agios Pharmaceuticals: Other: Advisory Board participation; Seattle Genetics: Consultancy, Other: Advisory Board participation, Research Funding; Merck: Other: Advisory Board participation; Celgene: Consultancy, Research Funding. Altman:Syros: Honoraria; BMS: Honoraria; Janssen Pharmaceuticals: Honoraria; Novartis: Honoraria. Flinn:Janssen: Research Funding; Pharmacyclics LLC, an AbbVie Company: Research Funding; Gilead Sciences: Research Funding; ARIAD: Research Funding; RainTree Oncology Services: Equity Ownership. Foran:novartis: Honoraria; Millennium Pharmaceuticals, Inc.: Research Funding; karyopharm: Honoraria; medscape: Honoraria; pfizer: Honoraria; boehringer ingelheim: Research Funding; agios: Research Funding; Cellerant: Research Funding. Pigneux:Sunesis: Consultancy, Honoraria; Agios: Consultancy, Honoraria. Kantarjian:ARIAD: Research Funding; Bristol-Myers Squibb: Research Funding; Amgen: Research Funding; Pfizer Inc: Research Funding; Delta-Fly Pharma: Research Funding; Novartis: Research Funding. Liu:Agios Pharmaceuticals, Inc.: Employment, Equity Ownership. Attar:Agios Pharmaceuticals, Inc.: Employment, Equity Ownership. Sacolick:Agios Pharmaceuticals, Inc.: Employment, Equity Ownership. Yen:Agios Pharmaceuticals, Inc.: Employment, Equity Ownership. Hurov:Agios Pharmaceuticals, Inc.: Employment, Equity Ownership. Choe:Agios Pharmaceuticals, Inc.: Employment, Equity Ownership. Wu:Agios Pharmaceuticals, Inc.: Employment, Equity Ownership. Stone:Amgen: Consultancy; Sunesis Pharmaceuticals: Consultancy; Pfizer: Consultancy; Roche: Consultancy; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Agios: Consultancy; Celator: Consultancy; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Karyopharm: Consultancy; Novartis: Consultancy; Jansen: Consultancy; ONO: Consultancy; Juno Therapeutics: Consultancy; Merck: Consultancy; Seattle Genetics: Consultancy; Xenetic Biosciences: Consultancy.

While commonly used in other hematological malignancies, high dose chemotherapy followed by autologous hematopoietic cell transplantation (auto-HCT) has not been widely adopted in acute myeloid leukemia (AML) due to concerns regarding high post-transplant relapse rates. These relapses may be due, in part, to autograft contamination with AML. High sensitivity methods to detect residual AML have demonstrated the ability to correctly identify patients in morphological complete remission (CR) at risk of relapse. We sought to determine if testing of the graft prior to transplantation could predict post auto-HCT relapse. Prior studies investigating the utility of measurable residual disease (MRD) in auto-HCT have been limited by small patient cohorts and/or by the use of a single biomarker to detect AML, a heterogeneous cancer. We report here the largest retrospective study to date of adult auto-HCT AML patients tested for measurable residual disease (MRD) by both molecular methods (RQ-PCR) and multi-parameter flow cytometry (MPFC). Seventy-two patients transplanted between 2004-2013 at a single academic medical center (UCSF) were eligible for this study based on availability of cryopreserved GCSF mobilized autologous peripheral blood progenitor cell (PBPCs) specimens. All samples were collected on IRB approved research protocols. The median age at time of transplant was 48 (24-69), 54% were female, cytogenetics were known in 94% (of which 24% were favorable, 69% intermediate, 7% poor), 99% were in CR at the time of HCT (64/72 in CR1, 6 in CR2, 1 in CR3). Following auto-HCT 1 year RFS was 50% (1 year relapse rate 43%) and 2 year RFS was 40% (2 year relapse rate 47%). Wilms tumor 1 (WT1) is expressed in up to 90% of AML, but sufficiently over-expressed in peripheral blood to have utility as a sensitive marker of MRD in less than 50% of cases. RQ-PCR detectable WT1 above the previously established European LeukemiaNet threshold was found in 9 patients, of whom 6 relapsed in the first year after auto-HCT (19% sensitivity, 93% specificity, PPV: 67%, NPV: 60%). We have previously reported that multi-gene testing can augment WT1 based MRD detection in AML. We were unable however to use one component of our previously reported AML MRD panel, PR3, due to increased baseline expression in these GCSF stimulated PBPC products. Increased PR3 expression following GCSF administration, correlating with neutrophilia, was also observed in an independent cohort of healthy donors. Testing for PRAME, MSLN, CCNA1, t(8,21), Inv16, t(15:17) and NPM1 mutations A, B and D, as a supplement for WT1, in pre-HCT PBPCs resulted in substantially improved ability to predict post auto-HCT relapse (52% sensitivity, 80% specificity, PPV: 67%, NPV: 69%). Addition of these extra genes allowed for correct identification of 10 additional MRD+ patients who relapsed within 1yr after transplant, and added 5 false positive patients (1 of whom suffered early non-relapse mortality, and another who did relapse but more than 1 year after HCT). Finally, in expert hands, flow cytometry can identify residual AML with high sensitivity. Forty PBPC samples from the above cohort were also assessed for MRD using MPFC. CD34 positive cells comprised 0.05-12.5% of autograft specimen mononuclear cells. Due to immunophenotypic changes likely attributable to GCSF mobilization, and without leukemia associated immunophenotypes from diagnosis available, MPFC was unable to identify MRD in any of 40 patients tested. In summary, no single MRD test on autografts could completely predict post-HCT AML relapse. Auto-HCT presents unique challenges for AML MRD testing due to masking effects of GCSF on MPFC and RQ-PCR gene expression signatures. Additionally, detection of any AML autograft contamination must be extremely sensitive to be useful for predicting relapse given the absence of any potentially protective graft versus leukemia effect following an auto-HCT. Here we show combinations of molecular MRD assays can overcome some, but not all, of these limitations (Figure). Figure 1. Figure 1. Disclosures Radich: Incyte: Consultancy; Ariad: Consultancy; Novartis: Consultancy; Novartis: Other: Lab Contract. Andreadis:Cellerant: Consultancy; Novartis: Consultancy; McGraw Hill: Other: Publishers; Pharmacyclics: Honoraria. Damon:Sunesis: Research Funding; McGraw Hill: Other: Chapter Royalties; Atara: Consultancy; Sigms Tau: Research Funding. Logan:Jazz Pharmaceuticals: Consultancy; Amgen: Consultancy; Pharmacyclics: Consultancy. Martin:Sanofi: Consultancy.

Background Although multiple studies have shown superiority of allogeneic hematopoietic cell transplantation (alloHCT) over autologous hematopoietic cell transplantation (autoHCT) for patients with "high-risk" acute lymphoblastic leukemia (ALL), these findings may be explained, in part, by contamination of the peripheral blood progenitor cell (PBPC) leukapheresis product by residual leukemic cells in patients undergoing autoHCT. Methods We retrospectively evaluated minimal residual disease (MRD) via next-generation sequencing (NGS) (Adaptive Biotechnologies, S. San Francisco, CA) in the PBPC leukapheresis products from 32 ALL patients who underwent autoHCT. All patients had "high-risk" ALL, as defined by B-lineage disease with WBC at diagnosis >30,000/uL; high-risk cytogenetics including t(9;22), t(4;11), other 11q23 abnormalities, or monosomy 7; or primary refractory disease. Peripheral hematopoietic cell mobilization consisted of cytarabine 2000mg/m2 IV every 12 hours (16,000mg/m2 cumulative) concurrent with etoposide 40mg/kg cumulative by continuous IV infusion over 4 days. The autoHCT conditioning consisted of 1320cGy total body irradiation (TBI) given in 11 fractions from day -8 to -5, etoposide 60mg/kg IV on day -4, and cyclophosphamide 100mg/kg IV on day -2. Tyrosine kinase inhibitors (TKI) were allowed for patients with Philadelphia chromosome-positive (Ph+) B-ALL. Seven patients (22%) participated in a multi-institutional trial in which the PBPC graft underwent ex vivo complement-mediatedpurging using monoclonal antibodies against CD9/CD10/CD19/CD20 for patients with B-lineage disease, or against CD2/CD3/CD4/CD5/CD8 for patients with T-lineage disease. Kaplan-Meier curves were generated using GraphPad Prism (GraphPad Software, La Jolla, CA) and statistical differences assessed via Log-Rank and Wilcoxon analyses, with a p-value of Results Twenty-eight patients (88%) had diagnostic bone marrow samples with quantifiable immunoglobulin or T cell receptor (Ig/TCR) gene rearrangements suitable for MRD quantification in the PBPC collections. Twelve (38%) patients had Ph+ B-ALL, 12 (38%) had Ph-neg B-ALL, and 4 (14%) had T-cell ALL. The majority of patients were male, in first complete remission, and autografted between 2000-2009, with a median age at autoHCT of 32 (range 19-55). With a median follow-up of 41 months (range 3-217), median relapse-free survival (RFS) and overall survival (OS) for the entire cohort are 3.2 and 4.2 years, respectively. At 5 years post-autoHCT, 42% of patients remain alive and relapse-free. Of the 28 diagnostic bone marrow specimens, 21 (75%) had rearrangements in more than 1 immunoreceptor locus (Figure 1A). A total of 73 rearrangements were identified across all patients. Clonal Ig heavy chain (IGH) sequences with complete VDJ rearrangement were the most commonly identified rearrangement, present in 17 of 28 patients (61%) and representing 30 of the 73 (41%) total rearrangements. When stratified by graft MRD burden, the median RFS for patients with MRD detectable at a level ≥10-6 (n=13) was 6.5 months, and has not been reached for patients without detectable MRD above this threshold (n=15; p=0.0005; Figure 1B). Ex vivo antibody-based purging failed to eradicate leukemia cells from the PBPC collections of 3 patients with detectable MRD who received a purged graft (Figure 1C), all of whom ultimately relapsed. Of the Ph+ cohort, 6 (50%) had detectable MRD in the PBPC graft. Two (33%) of these patients were not treated with a TKI; 1 relapsed at 4 months post-autoHCT and the other died from non-relapse mortality. Of the 4 Ph+ patients with detectable MRD who received a TKI, 2 (50%) remain long-term relapse-free survivors. Of the 6 patients without MRD who were treated with a post-autoHCT TKI, 5 (83%) remain relapse-free. Conclusion We demonstrate that the NGS-based immunosequencing platform identifies ALL MRD in leukapheresed PBPC collections. The presence of MRD in the autograft strongly predicts relapse, with only 15% RFS in patients harboring ≥10-6 MRD at stem cell collection versus 73% in patients with undetectable MRD. The absence of MRD in PBPC may thus identify a subset of "high-risk" patients likely to achieve long-term remissions without alloHCT. TKI therapy for patients with Ph+ B-ALL may also, in some cases, abrogate the need for alloHCT, even with quantifiable MRD prior to high-dose therapy. Disclosures Damon: Atara: Consultancy; Sunesis: Research Funding; Sigma-Tau: Research Funding; McGraw-Hill: Patents & Royalties: Book Chapter. Andreadis:McGraw Hill: Honoraria; Novartis: Consultancy; Cellerant: Consultancy; Pharmacyclics: Honoraria. Olin:Daiichi-Sankyo: Research Funding. Kong:Adaptive Biotechnologies: Employment, Equity Ownership. Faham:Adaptive Biotechnologies: Employment, Equity Ownership.

Introduction Arsenic trioxide (ATO)-based therapy for acute promyelocytic leukemia (APL) is highly effective and has been incorporated into standard therapeutic algorithms for patients with newly diagnosed and relapsed disease. Therapy for patients with high-risk or relapsed APL also includes high-dose chemotherapy with autologous stem cell transplantation (autoSCT). Both treatments have independently been demonstrated to improve long-term disease-free survival; however, the use of ATO prior to autoSCT has not been well studied. We sought to determine whether use of ATO prior to autologous stem cell collection impacts hematopoietic recovery following autoSCT. Methods Clinical histories of 31 consecutive patients undergoing autoSCT for APL at our institution since 1994 were reviewed. Viable CD34-positive cell recovery from cryo-preserved autograft products was assessed by pre- and post-thaw 7-amino-actinomycin D (7-AAD) staining. Student's t-tests and chi-squared tests were used for statistical analyses. Results A total of 32 autoSCTs were performed in this population. Twenty-four transplants (75.0%) were performed for patients in first complete remission (CR1) versus 8 transplants (25.0%) for patients in second complete remission (CR2). Seven of the 32 transplants (21.8%) were performed for patients who received ATO therapy prior to autologous stem cell collection. One patient received ATO with initial induction and consolidation therapy, 1 patient received ATO with initial consolidation therapy only, and 5 patients received ATO with re-induction therapy for relapsed disease. A significantly higher proportion of patients who received ATO were transplanted in CR2 (71.5% vs 12.0%, p10,000/uL at presentation (28.6% vs 45.8%, p=0.42), mean CD34-positive cells collected (94.5 x106/kg vs 69.9x106/kg, p=0.35), or mean CD34-positive cells infused (41.4x106/kg vs 39.7x106/kg, p=0.90). Four cases (12.5%) of delayed hematopoietic recovery were identified, defined as requiring >16 days after stem cell infusion to recover an absolute neutrophil count (ANC) >1,000/uL. Three of 7 patients (43%) who received prior ATO had delayed hematopoietic recovery, compared with 1 of 24 patients (4.2%) not previously treated with ATO (p Compared to ATO-naïve patients, ATO-treated patients experienced significantly longer time to ANC recovery (mean 19.7 days vs 10.4 days, p50,000/uL, was also significantly delayed in the ATO-treated group (198.8 days vs 36.5 days, p Of 7 assessable APL patient samples, the mean viable CD34-positive cell recovery was 39 +/- 25.1%. This was significantly lower than the viable CD34-recovery (71.3 +/- 27.3%, p=0.02) evaluated in a random selection of 11 other cryo-preserved autologous stem cell products from patients with lymphoma (n=2) and multiple myeloma (n=9). Samples from 2 ATO-treated APL patients who experienced delayed hematopoietic recovery exhibited viable CD34-positive cell recoveries of only 3% and 26%. Conclusions There is an association between ATO exposure and delayed hematopoietic recovery after autoSCT for APL, but a causal relationship is not yet established. Because of the increasing frequency with which ATO is being used in the front-line treatment of APL, larger studies are warranted to validate these findings and to determine the potential mechanism of delayed hematopoietic recovery after autoSCT. Lower-than-expected viable CD34-positive cell recovery from APL patients suggests a possible detrimental contribution of prior ATO exposure. Our institution is now prospectively examining pre- and post-thaw CD34-positive cell recovery, viability, and colony-forming assays prior to autoSCT in patients who have previously received ATO. Disclosures: No relevant conflicts of interest to declare.