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Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned co-primary or secondary analyses are not yet available. Clinical Trial Updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported. Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is an aggressive myeloid malignancy. We report long-term results, including data from the continued access phase, of the largest prospective BPDCN trial evaluating the CD123-targeted therapy tagraxofusp (TAG) in adults with treatment-naive and relapsed/refractory BPDCN. The primary outcome was complete response (CR) + clinical CR (CRc: CR with residual skin abnormality not indicative of active disease). Eighty-four (65 treatment-naive and 19 relapsed/refractory) of 89 patients received TAG 12 μg/kg once daily; the median follow-up was 34.0 months. For treatment-naive patients, the overall response rate was 75%; 57% achieved CR + CRc. The median time to remission was 39 (range, 14-131) days, and the median CR + CRc duration was 24.9 (95% CI, 3.8 to not reached) months. Nineteen patients (51%) with CR + CRc were bridged to stem-cell transplant, with a median CR + CRc duration of 22.2 (range, 1.5-57.4) months. Most common adverse events were increased alanine (64%) or aspartate (60%) aminotransferase and hypoalbuminemia (51%); most occurred in cycle 1 and were transient. Capillary leak syndrome occurred in 21% of patients (grade ≥ 3: 7%). In first-line patients with BPDCN, TAG monotherapy resulted in high and durable responses, allowing many to bridge to stem-cell transplant. TAG was generally well-tolerated with a predictable and manageable safety profile.

Purpose: The anti-CD33 antibody lintuzumab has modest activity against acute myeloid leukemia (AML). To increase its potency, lintuzumab was conjugated to actinium-225 (225Ac), a radionuclide yielding 4 α-particles. This first-in-human, phase I trial was conducted to determine the safety, pharmacology, and biological activity of 225Ac-lintuzumab. Patients and Methods: Eighteen patients (median age, 64 years; range, 45–80) with relapsed or refractory AML received a single infusion of 225Ac-lintuzumab at activities of 18.5 to 148 kBq/kg. Results: The maximum tolerated dose was 111 kBq/kg. Dose-limiting toxicities included myelosuppression lasting > 35 days in one patient receiving 148 kBq/kg and death from sepsis in two patients treated with 111 and 148 kBq/kg. Myelosuppression was the most common toxicity. Significant extramedullary toxicities were limited to transient grade 3 liver function abnormalities. Pharmacokinetics were determined by gamma counting serial whole blood, plasma, and urine samples at energy windows for the 225Ac daughters, francium-221 and bismuth-213. Two-phase elimination kinetics were seen with mean plasma t1/2 − α and t1/2 − β of 1.9 and 38 hours, respectively. Peripheral blood blasts were eliminated in 10 of 16 evaluable patients (63%) but only at doses of ≥ 37 kBq/kg. Bone marrow blasts were reduced in 10 of 15 evaluable patients (67%), including 3 patients with marrow blasts ≤ 5% and one patient with a morphologic leukemia-free state. Conclusions: Therapy for AML with the targeted α-particle generator 225Ac-lintuzumab was feasible with an acceptable safety profile. Elimination of circulating blasts or reductions in marrow blasts were observed across all dose levels.

Introduction The combination of the BCL-2 inhibitor venetoclax with an HMA (HMA/Ven) has improved outcomes in previously untreated patients with AML not eligible for intensive induction therapy. In a phase Ib study, 67% of patients achieved a complete remission (CR) or CR with incomplete recovery of blood counts (CRi) with a median overall survival (OS) of 17.5 months (DiNardo CD et al. Blood 2019; 133(1):7-17). HMA/Ven has also demonstrated efficacy in a heavily pretreated population with relapsed or refractory (R/R) AML, the majority of whom had prior HMA exposure (DiNardo CD et al. Am J Hematol 2018; 93(3):401-7). Measurable residual disease (MRD) is recognized as an independent prognostic indicator important for risk stratification and treatment planning (Schuurhuis GJ et al. Blood 2018; 131(12):1275-91). To date, however, there have been few reports on the effect of HMA/Ven on MRD. Methods This is a retrospective case series of patients with AML at a single-center tertiary-care institution. Patients ≥ 18 years of age who were treated with HMA/Ven between January 2017 and June 2020, either in the upfront or salvage setting, for AML were included. Outcomes included CR/CRi rate, MRD response, relapse free survival (RFS), and OS. MRD was assessed via multicolor flow cytometry with a sensitivity of 10-3 (0.1%). Results Nineteen patients were identified, 12 (63%) of whom were female. The median age at the time of HMA/Ven initiation was 71 years (range, 21 - 87 years). Ten (53%) patients had de novo AML and 9 had secondary or therapy-related AML. By 2017 ELN criteria, 3 (16%) patients had favorable-risk, 9 (47%) had intermediate-risk, and 7 (37%) had adverse-risk AML. Nine (47%) patients had R/R AML; 5 received HMA/Ven as first salvage therapy, and 4 as 2nd or greater salvage. Three (16%) patients had prior HMA exposure. No patient had prior venetoclax exposure. Median follow-up was 9.1 months (range, 1-21.1 months). Ten (53%) patients received azacitidine and 9 (47%) were given decitabine. Venetoclax doses ranged from 50 to 400 mg daily, depending on participation in a clinical trial and concomitant medications. Eight patients achieved a CR and 7 patients achieved a CRi for a combined CR/CRi rate of 79%. The CR/CRi rate was 90% (9/10) in the upfront setting, and 66% (6/9) in the salvage setting. The median time and number of cycles to best clinical response was 2.3 months (range, 0.9-3.9 months) and 2 (range, 1-3 cycles), respectively. Eleven (73%) of the 15 responders achieved MRD clearance after a median of 2 cycles (range, 1-3 cycles) (Table 1). Two of 4 (50%) MRD-positive patients relapsed, while 4 (36%) of 11 MRD-negative patients relapsed (Figure 1). Relapse occurred at a median of 2.0 months (range, 1.3-2.7 months) in the MRD positive group and 11.0 months (range, 2.8-14 months) in the MRD negative group. One patient died of infectious complications while MRD negative. Three patients, all of whom were treated for R/R disease, proceeded to an allogeneic stem cell transplant (HSCT). Two were MRD negative at the time of HSCT and all remained in remission. At the time of data cutoff, 7 (64%) of 11 MRD-negative patients were alive, and all 4 MRD-positive patients were alive. Causes of death in the MRD-negative group included disease relapse (3 patients) and infection (1 patient). Median overall survival in the entire cohort (range, 32 days-NR) was not reached. Conclusions HMA/Ven was highly effective as both upfront and salvage therapy. Surprisingly, the salvage CR/CRi rate in this series was 66%, allowing half of the responders to proceed to HSCT. The majority (73%) of responders achieved MRD negativity. While MRD status influenced RFS, 36% of MRD-negative patients relapsed. Additionally, the same percentage of MRD-negative patients died during follow-up, versus none of the patients with MRD-positivity. This indicates the need for more sensitive methods to assess MRD and for novel therapeutic strategies to eliminate MRD, thereby improving long-term outcomes. Larger prospective studies are needed to define the role of MRD assessment with venetoclax-containing regimens. Disclosures Jurcic: AbbVie:Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding;Celgene:Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding;Syros Pharmaceuticals:Research Funding;PTC Therapeutics:Research Funding;Arog Pharmaceuticals:Research Funding;Kura Oncology:Research Funding;Forma Therapeutics:Research Funding;Astellas:Research Funding;Genentech:Research Funding;Novartis:Consultancy, Membership on an entity's Board of Directors or advisory committees;Daiichi-Sankyo:Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding;BMS:Consultancy, Research Funding.Campbell:AstraZeneca:Consultancy.Lee:Genentech:Research Funding;Sumitomo Dainippon Pharma Oncology, Inc.:Research Funding;AbbVie:Research Funding;Novartis:Research Funding;Bayer:Research Funding;Celgene:Consultancy;Forty Seven:Research Funding.Heaney:Blueprint Medicines Corporation:Research Funding;BMS:Research Funding;CTI Biopharma:Consultancy, Research Funding;Deciphera:Research Funding;Incyte:Research Funding;Novartis:Consultancy, Research Funding;Sierra Oncology:Research Funding;AbbVie:Consultancy;Partner Therapeutics:Consultancy.Lamanna:Janssen:Consultancy, Membership on an entity's Board of Directors or advisory committees;Octapharma:Research Funding;Juno:Other: Institutional research grants, Research Funding;Gilead:Consultancy, Membership on an entity's Board of Directors or advisory committees;Astra Zeneca:Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Institutional research grants, Research Funding;Pharmacyclics:Consultancy, Membership on an entity's Board of Directors or advisory committees;Genentech:Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Institutional research grants, Research Funding;Bei-Gene:Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Institutional research grants, Research Funding;Abbvie:Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Institutional research grants, Research Funding;Oncternal, Verastem, TG Therapeutics:Other: Institutional research grants, Research Funding;MingSight:Other: Institutional research grants, Research Funding;Loxo:Research Funding;Celgene:Consultancy, Membership on an entity's Board of Directors or advisory committees;Columbia University Medical Center:Current Employment.

Summary Background Guadecitabine is a next-generation hypomethylating agent whose active metabolite decitabine has a longer in-vivo exposure time than intravenous decitabine. More effective hypomethylating agents are needed for the treatment of myelodysplastic syndromes. In the present study, we aimed to compare the activity and safety of two doses of guadecitabine in hypomethylating agent treatment-naive or relapsed or refractory patients with intermediate-risk or high-risk myelodysplastic syndromes. Methods This phase 2 part of the phase 1/2, randomised, open-label study enrolled patients aged 18 years or older from 14 North American medical centres with International Prognostic Scoring System intermediate-1-risk, intermediate-2-risk, or high-risk myelodysplastic syndromes, or chronic myelomonocytic leukaemia. They were either hypomethylating agent treatment-naive or had relapsed or refractory disease after previous hypomethylating agent treatment as determined by the investigators' judgment. Eligible patients had Eastern Cooperative Oncology Group performance status of 0–2. Patients were randomly assigned (1:1) using a computer algorithm for dynamic randomisation to subcutaneous guadecitabine 60 or 90 mg/m2 on days 1–5 of a 28-day treatment cycle. Treatment was stratified by previous treatment with hypomethylating agents and neither patients nor investigators were masked. The primary endpoint was overall response (a composite of complete response, partial response, marrow complete response, and haematological improvement) assessed in all patients who received at least one dose of study drug. This study is registered with ClinicalTrials.gov, number NCT01261312. Findings Between July 9, 2012, and April 7, 2014, 105 patients were enrolled: 55 (52%) were allocated to guadecitabine 60 mg/m2 (28 patients were treatment-naive and 27 had relapsed or refractory disease after previous hypomethylating agent treatment) and 50 (48%) patients to 90 mg/m2 (23 patients were treatment-naive and 27 had relapsed or refractory disease). Three (3%) patients of 105 did not receive study treatment and were excluded from analyses. Median follow-up was 3·2 years (IQR 2·8–3·5). The proportion of patients achieving an overall response did not significantly differ between dose groups (21 of 53 [40%, 95% CI 27–54] with 60 mg/m2 and 27 of 49 [55%, 95% CI 40–69] with 90 mg/m2; p=0·16). 25 of 49 (51%, 95% CI 36–66) patients who were treatment-naive and 23 of 53 (43%, 30–58) patients with relapsed or refractory disease achieved an overall response. The most common grade 3 or worse adverse events in both groups, regardless of relationship to treatment, were thrombocytopenia (22 [41%] of 53 patients in the 60 mg/m2 group and 28 [57%] of 49 in the 90 mg/m2 group), neutropaenia (21 [40%] and 25 [51%]), anaemia (25 [47%] and 24 [49%]), febrile neutropaenia (17 [32%] and 21 [43%]), and pneumonia (13 [25%] and 15 [31%]). Seven (7%) of 102 patients died due to adverse events (three with 90 mg/m2 and four with 60 mg/m2), and all except one were in the relapsed or refractory cohort. Two deaths were deemed treatment related (septic shock with 60 mg/m2; pneumonia with 90 mg/m2). Interpretation Guadecitabine was clinically active with acceptable tolerability in patients with intermediate-risk and high-risk myelodysplastic syndromes. Responses and overall survival in the relapsed or refractory cohort offer the potential of a new therapeutic option for patients for whom currently available hypomethylating agents are not successful. We therefore recommend guadecitabine at a dose of 60 mg/m2 on a 5-day schedule for these patients. Funding Astex Pharmaceuticals and Stand Up To Cancer.

Introduction: The interleukin-3 receptor alpha chain (CD123) is a cell-surface target aberrantly expressed on various myeloid neoplasms including blastic plasmacytoid dendritic cell neoplasm (BPDCN), acute myeloid leukemia (AML), chronic myelomonocytic leukemia (CMML), and myelofibrosis (MF). Tagraxofusp (TAG, SL-401), a first-in-class CD123-targeted therapy, is the only treatment approved by the FDA and EMA for patients (pts) with BPDCN. It has also been investigated in phase 1/2 clinical trials for AML (including pts with minimal residual disease [MRD]), CMML, and MF. We report the aggregated safety data of TAG monotherapy from trials in BPDCN, AML, CMML, and MF. Methods: An integrated safety analysis was performed for pts who received TAG monotherapy in three phase 1/2, multicenter clinical studies: Study 0114 (NCT02113982; BPDCN/AML), Study 0214 (NCT02270463; AML with/without MRD), and Study 0314 (NCT02268253; CMML/MF; Table 1). Pts received the recommended phase 2 dose of 12 mcg/kg/day (d) IV on d1-3 (MF and CMML) or d1-5 (BPDCN and AML) and were analyzed for incidence and timing of treatment-related adverse events (TRAEs), AEs of interest, and discontinuations. Safety data for TAG monotherapy, reported as individual case study reports (ICSRs) postapproval (US) and from an early access program (EAP; EU) are also presented. Results: In total, 201 pts receiving TAG (12 mcg/kg/d) in a clinical trial setting were included: BPDCN, n=86; AML, n=36; AML with/without MRD, n=10; CMML, n=33; MF, n=36. As of Jul 2021, 11 (6%) pts discontinued TAG due to any-grade (Gr) TRAE. Most common TRAEs (any-Gr) are shown in Table 2 and included hypoalbuminemia (41%), increased alanine aminotransferase (ALT; 40%), increased aspartate aminotransferase (AST; 39%), and thrombocytopenia (26%). The most common Gr ≥3 TRAEs were thrombocytopenia (n=41; 20%), increased AST (n=40; 20%), and increased ALT (n=35; 17%). Tumor lysis syndrome occurred in 5% of pts and 1.5% had infusion-related reactions. Any-Gr and Gr ≥3 hematologic TRAEs are presented in Table 3. Most common was thrombocytopenia. All TRAEs were transient in nature; prolonged bone marrow suppression was not observed. Overall, 23% (47/201) of pts experienced ≥1 treatment-related serious AE. Onset of most TRAEs, irrespective of Gr, commonly occurred in cycle 1 and resolved by cycle 2. Although the number of pts in cycles ≥2 was lower than in cycle 1, the incidence rates of common TRAEs also substantially decreased in subsequent cycles. Capillary leak syndrome (CLS) occurred in 17% of the overall 201 pts. The majority of all CLS events were nonsevere, Gr ≤2 (n=22; 63%); also reported were Gr 3, n=10 (29%); Gr 4, n=3 (9%), and 2 pts experienced a Gr 5 event. Onset of CLS was usually within the first week of cycle 1 (median time to onset [range], d: 5.5 [1-51]) and resolved quickly (median time to resolution [range], d: 5.0 [2-69]); no pts experienced the first onset after cycle 2. Of the 15 pts who resumed treatment after an initial CLS event, only 1 pt experienced a recurrence. The most common AEs reported as ICSRs postapproval and from an EAP (December 2018 to June 2021) were CLS, blood albumin decreased, thrombocytopenia, pyrexia, and hepatic enzyme increased. No new safety signals that would alter the safety profile were observed. Conclusions: This integrated analysis represents the largest collection of safety data (N=201) following treatment with TAG monotherapy. TAG has an established and manageable safety profile, with the vast majority of AEs reported as transient and decreasing in frequency/severity with increasing cycles. CLS was reported in 17% of pts; onset was usually within cycle 1, resolved quickly (median time to resolution: 5.0 d) by early intervention measures including holding treatment, and no pts experienced first onset after cycle 2. Risk-minimization guidelines for CLS were developed and implemented during clinical trials and incorporated into prescribing information. No myelosuppression or cumulative toxicity was observed over multiple treatment cycles. The safety profile observed postapproval and in the EAP was consistent with the clinical trial data reported, reflecting successful adoption of risk-management strategies in real-world practice. These data confirm the favorable benefit-risk profile of TAG monotherapy has been maintained in the 3 years following US approval. Figure 1 Figure 1. Disclosures Pemmaraju: ASCO Leukemia Advisory Panel: Membership on an entity's Board of Directors or advisory committees; Sager Strong Foundation: Other; Blueprint Medicines: Consultancy; Incyte: Consultancy; Bristol-Myers Squibb Co.: Consultancy; Pacylex Pharmaceuticals: Consultancy; Cellectis S.A. ADR: Other, Research Funding; Aptitude Health: Consultancy; Celgene Corporation: Consultancy; CareDx, Inc.: Consultancy; Springer Science + Business Media: Other; Daiichi Sankyo, Inc.: Other, Research Funding; Samus: Other, Research Funding; Clearview Healthcare Partners: Consultancy; Dan's House of Hope: Membership on an entity's Board of Directors or advisory committees; MustangBio: Consultancy, Other; Abbvie Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other, Research Funding; HemOnc Times/Oncology Times: Membership on an entity's Board of Directors or advisory committees; ASH Communications Committee: Membership on an entity's Board of Directors or advisory committees; LFB Biotechnologies: Consultancy; Novartis Pharmaceuticals: Consultancy, Other: Research Support, Research Funding; Protagonist Therapeutics, Inc.: Consultancy; Affymetrix: Consultancy, Research Funding; DAVA Oncology: Consultancy; Plexxicon: Other, Research Funding; Roche Diagnostics: Consultancy; Stemline Therapeutics, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other, Research Funding; ImmunoGen, Inc: Consultancy. Kantarjian: NOVA Research: Honoraria; Aptitude Health: Honoraria; Immunogen: Research Funding; BMS: Research Funding; Precision Biosciences: Honoraria; Novartis: Honoraria, Research Funding; Ascentage: Research Funding; Pfizer: Honoraria, Research Funding; Astra Zeneca: Honoraria; Astellas Health: Honoraria; Jazz: Research Funding; Ipsen Pharmaceuticals: Honoraria; Amgen: Honoraria, Research Funding; Daiichi-Sankyo: Research Funding; KAHR Medical Ltd: Honoraria; AbbVie: Honoraria, Research Funding; Taiho Pharmaceutical Canada: Honoraria. Sweet: Astellas: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; AROG: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees; Bristol Meyers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees. Wang: Kite Pharmaceuticals: Consultancy, Honoraria, Other: Advisory Board; Jazz Pharmaceuticals: Consultancy, Honoraria, Other: Advisory Board; DAVA Oncology: Consultancy, Speakers Bureau; BMS/Celgene: Membership on an entity's Board of Directors or advisory committees; Stemline Therapeutics: Consultancy, Honoraria, Other: Advisory board, Speakers Bureau; Genentech: Membership on an entity's Board of Directors or advisory committees; GlaxoSmithKline: Consultancy, Honoraria, Other: Advisory Board; Takeda: Consultancy, Honoraria, Other: Advisory board; Astellas: Consultancy, Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Honoraria, Other: Advisory Board, Speakers Bureau; Kura Oncology: Consultancy, Honoraria, Other: Advisory board, steering committee, Speakers Bureau; Novartis: Consultancy, Honoraria, Other: Advisory Board; Mana Therapeutics: Consultancy, Honoraria; Rafael Pharmaceuticals: Other: Data safety monitoring committee; Gilead: Consultancy, Honoraria, Other: Advisory board; Daiichi Sankyo: Consultancy, Honoraria, Other: Advisory board; PTC Therapeutics: Consultancy, Honoraria, Other: Advisory board; Genentech: Consultancy; MacroGenics: Consultancy. Lane: N-of-One: Consultancy, Honoraria; Stemline Therapeutics: Research Funding; Qiagen: Consultancy, Honoraria; AbbVie: Research Funding. Ali: Incyte: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BMS: Speakers Bureau; CTI BioPharma: Membership on an entity's Board of Directors or advisory committees. Stein: Amgen: Consultancy, Speakers Bureau; Celgene: Speakers Bureau; Stemline: Speakers Bureau. Yacoub: Agios: Membership on an entity's Board of Directors or advisory committees; Acceleron Pharma: Membership on an entity's Board of Directors or advisory committees; CTI Biopharma: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Incyte: Speakers Bureau. Rizzieri: Celltron/Teva: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: presentation to FDA for biosimilar review ; AROG: Other; Amgen: Other: personal fee; Bayer: Consultancy, Honoraria; Kite: Other: personal fee; Mustang: Consultancy, Honoraria; Stemline Therapeutics: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Incyte: Other: personal fee; Gilead: Other: personal fee; Jazz: Other: personal fee; Pharmacyclics: Other. Vasu: Seattle Genetics: Other: travel support; Boehringer Ingelheim: Other: Travel support; Kiadis, Inc.: Research Funding; Omeros, Inc.: Membership on an entity's Board of Directors or advisory committees. Gupta: AbbVie: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Consultancy; Constellation Pharma: Consultancy, Honoraria; Pfizer: Consultancy; BMS-Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Sierra Oncology: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Incyte: Honoraria, Research Funding. Lee: BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pin Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees; Innate: Consultancy, Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees. Schiller: Sangamo: Research Funding; Actinium Pharmaceuticals, Inc: Research Funding; FujiFilm: Research Funding; Pfizer: Current equity holder in publicly-traded company, Research Funding; Abbvie: Research Funding; Karyopharm: Research Funding; Onconova: Research Funding; Celator: Research Funding; Actuate: Research Funding; Incyte: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Trovagene: Research Funding; Deciphera: Research Funding; Gamida Cell Ltd.: Research Funding; Forma: Research Funding; Ono-UK: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Arog: Research Funding; Takeda: Research Funding; Geron: Research Funding; Jazz: Consultancy, Honoraria, Research Funding, Speakers Bureau; PrECOG: Research Funding; Kite/Gilead: Honoraria, Research Funding, Speakers Bureau; Mateon: Research Funding; Constellation Pharmaceuticals: Research Funding; Daiichi-Sankyo: Research Funding; Tolero: Research Funding; Stemline Therapeutics, Inc.: Honoraria, Research Funding, Speakers Bureau; Samus: Research Funding; Astellas: Honoraria, Research Funding, Speakers Bureau; Regimmune: Research Funding; BMS/Celgene: Consultancy, Current equity holder in publicly-traded company, Research Funding, Speakers Bureau; Agios: Consultancy, Research Funding, Speakers Bureau; Amgen: Consultancy, Current equity holder in publicly-traded company, Honoraria, Research Funding, Speakers Bureau; Bio: Research Funding; Elevate: Research Funding; Delta-Fly: Research Funding; Genentech-Roche: Research Funding; Ariad: Research Funding; Sanofi: Honoraria, Research Funding, Speakers Bureau; Pharma: Consultancy; Johnson & Johnson: Current equity holder in publicly-traded company; Biomed Valley Discoveries: Research Funding; Eli Lilly: Research Funding; ASH foundation: Other: Chair-unpaid; Sellas: Research Funding; Ono: Consultancy; Incyte: Consultancy; AstraZeneca: Consultancy; Kaiser Permanente: Consultancy; Cyclacel: Research Funding; MedImmune: Research Funding; Ambit: Research Funding; Leukemia & Lymphoma Society: Research Funding; Bluebird Bio: Research Funding; Boehringer-Ingleheim: Research Funding; Cellerant: Research Funding; CTI Biopharma: Research Funding; Janssen: Research Funding; Kura Oncology: Research Funding; Pharmacyclics: Honoraria, Speakers Bureau; Millennium: Research Funding; National Marrow Donor Program: Research Funding; NIH: Research Funding; Onyx: Research Funding; Pharmamar: Research Funding; UC Davis: Research Funding; UCSD: Research Funding; Evidera: Consultancy; NCI: Consultancy; Novartis: Speakers Bureau. Foran: trillium: Research Funding; actinium: Research Funding; aptose: Research Funding; novartis: Honoraria; OncLive: Honoraria; servier: Honoraria; gamida: Honoraria; takeda: Research Funding; boehringer ingelheim: Research Funding; abbvie: Research Funding; certara: Honoraria; bms: Honoraria; pfizer: Honoraria; sanofi aventis: Honoraria; revolution medicine: Honoraria; taiho: Honoraria; syros: Honoraria; kura: Research Funding; h3bioscience: Research Funding; aprea: Research Funding; sellas: Research Funding; stemline: Research Funding. Walter: Macrogenics: Consultancy, Research Funding; Jazz: Research Funding; Pfizer: Consultancy, Research Funding; Selvita: Research Funding; Amphivena: Consultancy, Other: ownership interests; Agios: Consultancy; Astellas: Consultancy; BMS: Consultancy; Genentech: Consultancy; Janssen: Consultancy; Kite: Consultancy; Immunogen: Research Funding; Celgene: Consultancy, Research Funding; Aptevo: Consultancy, Research Funding; Amgen: Research Funding. Sieminski: Stemline Therapeutics: Current Employment, Current holder of stock options in a privately-held company. Patnaik: Kura Oncology: Research Funding; Stemline Therapeutics: Membership on an entity's Board of Directors or advisory committees; Stemline Therapeutics: Membership on an entity's Board of Directors or advisory committees. Mughal: Oxford University Press, Informa: Other: financial benefit and/or patents ; Stemline: Current Employment, Current holder of stock options in a privately-held company. Konopleva: Calithera: Other: grant support, Research Funding; Reata Pharmaceuticals: Current holder of stock options in a privately-held company, Patents & Royalties: intellectual property rights; Genentech: Consultancy, Honoraria, Other: grant support, Research Funding; Agios: Other: grant support, Research Funding; Ascentage: Other: grant support, Research Funding; AstraZeneca: Other: grant support, Research Funding; Rafael Pharmaceuticals: Other: grant support, Research Funding; Forty Seven: Other: grant support, Research Funding; Ablynx: Other: grant support, Research Funding; Eli Lilly: Patents & Royalties: intellectual property rights, Research Funding; Novartis: Other: research funding pending, Patents & Royalties: intellectual property rights; Stemline Therapeutics: Research Funding; KisoJi: Research Funding; F. Hoffmann-La Roche: Consultancy, Honoraria, Other: grant support; Cellectis: Other: grant support; Sanofi: Other: grant support, Research Funding; AbbVie: Consultancy, Honoraria, Other: Grant Support, Research Funding.

Background: Despite the efficacy of venetoclax (VEN) in frontline CLL, optimal combination regimens and duration of treatment remain unclear. We hypothesized that cytoreduction with bendamustine/rituximab (BR) induction followed by venetoclax/rituximab (VR) consolidation for a fixed 1-year duration would be associated with an increased rate of undetectable minimal residual disease (uMRD) compared to historical controls and a reduction in the risk of tumor lysis syndrome (TLS). Here we report data from an ongoing phase 2 multicenter, US, single-arm, open-label study (NCT03609593) designed to assess the safety and efficacy of BR-VR in previously untreated CLL patients (pts). Methods: Previously untreated CLL/SLL pts ≥ 18 years requiring therapy per iwCLL criteria initially received 3 cycles of bendamustine 50-90 mg/m 2 daily for 2 days and rituximab 375 mg/m 2 every 28 days for 3 cycles. Following BR, VEN was initiated with a standard dose escalation from 20 mg to 400 mg daily over 5 weeks. This was followed by 6 cycles of VR with rituximab given monthly and 5 cycles of VEN alone (12 cycles of VEN in total). Additional eligibility included: ECOG PS ≤ 2, hemoglobin ≥8g/dL, ANC ≥1000/mm 3, and platelets ≥50,000/mm 3. Response was assessed by 2018 iwCLL criteria with uMRD testing by central flow cytometry at a level of Results: As of data cutoff on 30 May 2021, 26 pts were accrued with additional recruitment ongoing. Baseline demographics were as follows: male/female (16/10), median age 60 yrs (range 44-77). Baseline prognostic studies showed unmutated IGHV in 16 (62%) pts, TP53 aberrant (either del(17p) and/or TP53 mutation) in 1 (4%) pt, del(11q) in 3 (12%) pts, and complex karyotype in 4 (15%) pts. TLS risk among 24 evaluable pts at baseline was high (H) in 3 (12.5%), medium (M) in 15 (62.5%), and low (L) in 6 (25%). At a median follow-up of 12.9 mo. (range, 1.9-27.5), 23 pts remain on study. Of 12 pts with at least 15 mo. follow-up (completing all therapy), the ORR was 100% (92% CR/CRi, 8% PR [due to small residual nodes]). 3 pts died on study (2 due to COVID-19 and 1 developed newly metastatic squamous cell carcinoma and taken off study after achieving a CR post-VEN ramp-up). Bendamustine was administered at doses of 50 mg/m 2 in 47%, 70 mg/m 2 in 11%, and 90mg/m 2 in 42% of pts. In 20 evaluable pts, response assessments after cytoreduction with BR demonstrated 15% of pts achieved CR/CRi and 85% achieved PR. For evaluable pts at 16 mo., uMRD ( The most common treatment-emergent AEs during BR induction were (any grade/grade ≥3) anemia in 6/2 (21%/7%) pts, nausea in 6/0 (21%/0%), neutropenia in 5/2 (18%/7%), rash in 5/0 (18%/0%), constipation 4/0 (14%/0%), and transaminitis in 3/0 (11%/0%). 2 pts (7%) developed febrile neutropenia during BR. Emergent AEs during VEN treatment included diarrhea in 10/0 (36%/0%) pts, neutropenia in 6/3 (21%/11%), leukopenia in 5/2 (18%/7%), and nausea in 4/0 (14%/0%). TLS risk was substantially reduced after BR lead-in. Of 3 H-risk pts at baseline, none remained H-risk after BR; of 15 M-risk pts, only 1 remained M-risk, with the remainder at L-risk (94% reduction in H- or M- risk TLS). Conclusions: BR-VR is a safe and well-tolerated regimen in untreated CLL pts. BR debulking substantially reduces TLS risk, and this sequential strategy achieves high rates of PB and BM uMRD across all prognostic risk groups. Figure 1 Figure 1. Disclosures Hill: Celgene (BMS): Consultancy, Honoraria, Research Funding; AstraZenica: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Gentenech: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Honoraria, Research Funding; Kite, a Gilead Company: Consultancy, Honoraria, Other: Travel Support, Research Funding; Karyopharm: Consultancy, Honoraria, Research Funding; Beigene: Consultancy, Honoraria, Research Funding; Epizyme: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Research Funding; Incyte/Morphysis: Consultancy, Honoraria, Research Funding. Jurcic: AbbVie, BMS/Celgene, Novartis: Consultancy; AbbVie, Arog Pharmaceuticals, Astellas, BMS/Celgene, Forma Therapeutics, Genentech, Gilead Sciences, PTC Therapeutics, Syros Pharmaceuticals: Research Funding. Heaney: CTI: Honoraria, Research Funding; Blueprint: Honoraria, Research Funding; Novartis: Honoraria; Sierra Oncology: Research Funding; Cogent: Research Funding; BMS: Research Funding; Kartos: Research Funding. Lamanna: MingSight Pharmaceuticals, Inc.: Research Funding; Gilead Sciences, Inc.: Consultancy; AbbVie: Consultancy, Research Funding; AstraZeneca: Consultancy, Research Funding; Juno Therapeutics, Inc.: Research Funding; Oncternal Therapeutics: Research Funding; Celgene Corporation: Consultancy; Genentech, Inc.: Consultancy, Research Funding; Verastem Oncology: Research Funding; TG Therapeutics, Inc: Research Funding; Janssen Pharmaceuticals, Inc.: Consultancy; BeiGene: Consultancy; Pharmacyclics: Consultancy. OffLabel Disclosure: Venetoclax, Bendamustine, and Rituximab are all FDA approved for use in first-line CLL. The combination of these three agents and dosing schedule utilized in this clinical trial is novel and therefore technically reflects an off-label use.

Summary Background The hypomethylating drugs azacitidine and decitabine have shown efficacy in myelodysplastic syndromes and acute myeloid leukaemia, but complete tumour responses are infrequent and of short duration, possibly because of the short half-lives and suboptimal bone marrow exposure of the drugs. Guadecitabine, a next-generation hypomethylating drug, has a longer half-life and exposure than its active metabolite decitabine. A phase 1 study established 60 mg/m 2 guadecitabine for 5 days as an effective treatment schedule. In this phase 2 study, we aimed to assess the safety and activity of two doses and schedules of guadecitabine in older (≥65 years) patients with treatment-naive acute myeloid leukaemia who were not candidates for intensive chemotherapy. Methods We did a multicentre, randomised, open-label, phase 1/2 study of guadecitabine in cohorts of patients with treatment-naive acute myeloid leukaemia, relapsed or refractory acute myeloid leukaemia, and myelodysplastic syndromes; here we report the phase 2 results from the cohort of treatment-naive patients with acute myeloid leukaemia. We included patients aged at least 65 years from 14 US medical centres (hospitals and specialist cancer clinics) who were not candidates for intensive chemotherapy and randomly assigned them (1:1) using a computer algorithm (for dynamic randomisation) to guadecitabine 60 or 90 mg/m 2 on days 1–5 (5-day schedule) of a 28-day treatment cycle. Treatment allocation was not masked. We also assigned additional patients to guadecitabine 60 mg/m 2 in a 10-day schedule in a 28-day treatment cycle after a protocol amendment. The primary endpoint was composite complete response (complete response, complete response with incomplete platelet recovery, or complete response with incomplete neutrophil recovery regardless of platelets). Response was assessed in all patients (as-treated) who received at least one dose of guadecitabine. We present the final analysis, although at the time of the database lock, 15 patients were still in follow-up for overall survival. This study is registered with ClinicalTrials.gov, number NCT01261312. Findings Between Aug 24, 2012, and Sept 15, 2014, 107 patients were enrolled: 54 on the 5-day schedule (26 randomly assigned to 60 mg/m 2 and 28 to 90 mg/m 2 ) and 53 were assigned to the 10-day schedule. Median age was 77 years (range 62–92), and median follow-up was 953 days (IQR 721–1040). All treated patients were assessable for a response. The number of patients who achieved a composite complete response did not differ between dose groups or schedules (13 [54%, 95% CI 32·8–74·4] with 60 mg/m 2 on the 5-day schedule; 16 [59%; 38·8–77·6] with 90 mg/m 2 on the 5-day schedule; and 26 [50%, 35·8–64·2] with 60 mg/m 2 on the 10-day schedule). The most frequent grade 3 or worse adverse events, regardless of relationship to treatment, were febrile neutropenia (31 [61%] of 51 patients on the 5-day schedule vs 36 [69%] of 52 patients on the 10-day schedule), thrombocytopenia (25 [49%] vs 22 [42%]), neutropenia (20 [39%] vs 18 [35%]), pneumonia (15 [29%] vs 19 [37%]), anaemia (15 [29%] vs 12 [23%]), and sepsis (eight [16%] vs 14 [27%]). The most common serious adverse events, regardless of relationship to treatment, for the 5-day and 10-day schedules, respectively, were febrile neutropenia (27 [53%] vs 25 [48%]), pneumonia (14 [27%] vs 16 [31%]), and sepsis (eight [16%] vs 14 [27%]). 23 (22%) patients died because of adverse events (mainly from sepsis, eight [8%]; and pneumonia, five [5%]); four deaths were from adverse events deemed treatment-related (pneumonia, two [2%]; multiorgan failure, one [1%]; and sepsis, one [1%], all in the 10-day cohort). Interpretation More than half of older treatment-naive patients with acute myeloid leukaemia achieved a composite complete response with guadecitabine at all drug doses and schedules investigated, with tolerable toxicity. The recommended guadecitabine regimen for this population is 60 mg/m 2 in a 5-day schedule. A phase 3 study in this patient population is ongoing (NCT02348489) to assess guadecitabine 60 mg/m 2 in a 5-day schedule versus standard of care. Funding Astex Pharmaceuticals and Stand Up To Cancer.

Background Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare, hematologic malignancy, comprised of clonal plasmacytoid dendritic cells that are CD123-positive and associated with historically poor outcomes. In 2018, tagraxofusp (TAG), a targeted therapy directed to CD123, became the first-in-class FDA approved treatment for children and adults with BPDCN ages 2 years and older. Treatment with TAG resulted in durable clinical responses with a manageable safety profile in both treatment-naive and relapsed/refractory (R/R) patients. Herein, we present long-term follow-up results ( NCT02113982 ). Objectives To assess the safety and efficacy of TAG in patients with untreated and previously treated BPDCN. Methods In this multicenter, multi-stage, single-arm trial 44 patients with treatment-naive or R/R BPDCN were treated at the indicated dose (12 mcg/kg). In Stage 1 (dose escalation) patients received TAG daily IV infusions at 7 or 12 mcg/kg on days 1–5 of a 21-day cycle. In Stage 2 (expansion) and Stage 3 (pivotal, confirmatory), TAG was dosed at 12 mcg/kg. Key efficacy measures included objective response rate (ORR), complete response (CR), clinical CR (CRc), defined as CR with residual skin abnormality not indicative of active disease, and overall survival (OS). Results Twenty-nine treatment-naive and 15 R/R BPDCN patients were treated for a median duration of 5 and 3 cycles, respectively. Most common treatment emergent adverse events (TEAEs) include hypoalbuminemia, increased transaminases, thrombocytopenia, nausea, fatigue and pyrexia. The most serious adverse event was capillary leak syndrome (CLS), 19% in all grades (one patient with Grade 4 and two with Grade 5). Incidence of TEAEs leading to TAG discontinuation was 2%; temporary dose interruptions for TEAE management were common (68%). In treatment-naive patients ORR was 90%, CR+CRc rate was 72%, and 45% were bridged to stem cell transplant. Median time to response was rapid; 65% of patients achieved complete response by C2. Median overall survival was 26 months; 24-month survival probabilities of 52%. In R/R patients, ORR was 67%, including 2 CR+CRc. Conclusions In the largest prospectively designed study conducted to date, TAG demonstrated robust and durable responses with a median OS of 26 months and a well-characterized safety profile including recognition for CLS.

A National Cancer Institute consensus study on prioritization of cancer antigens ranked the Wilms tumor 1 (WT1) protein as the top immunotherapy target in cancer. We previously reported a pilot study of a multivalent WT1 peptide vaccine (galinpepimut-S) in acute myeloid leukemia (AML) patients. We have now conducted a phase 2 study investigating this vaccine in adults with AML in first complete remission (CR1). Patients received 6 vaccinations administered over 10 weeks with the potential to receive 6 additional monthly doses if they remained in CR1. Immune responses (IRs) were evaluated after the 6th and 12th vaccinations by CD4+ T-cell proliferation, CD8+ T-cell interferon-γ secretion (enzyme-linked immunospot), or the CD8-relevant WT1 peptide major histocompatibility complex tetramer assay (HLA-A*02 patients only). Twenty-two patients (7 males; median age, 64 years) were treated. Fourteen patients (64%) completed ≥6 vaccinations, and 9 (41%) received all 12 vaccine doses. Fifteen patients (68%) relapsed, and 10 (46%) died. The vaccine was well tolerated, with the most common toxicities being grade 1/2 injection site reactions (46%), fatigue (32%), and skin induration (32%). Median disease-free survival from CR1 was 16.9 months, whereas the overall survival from diagnosis has not yet been reached but is estimated to be ≥67.6 months. Nine of 14 tested patients (64%) had an IR in ≥1 assay (CD4 or CD8). These results indicated that the WT1 vaccine was well tolerated, stimulated a specific IR, and was associated with survival in excess of 5 years in this cohort of patients. This trial was registered at www.clinicaltrials.gov as #NCT01266083.

Background: Guadecitabine is a next generation subcutaneous (SC) hypomethylating agent (HMA) resistant to degradation by cytidine deaminase which results in prolonged in vivo exposure to the active metabolite decitabine. We conducted a phase 2 study of guadecitabine in 206 AML patients. International guidelines recommend a minimum of 4 to 6 cycles of HMA treatment to gain maximum benefit, but some suggest that treatment may not be beneficial if no response was observed after 4 cycles. No prospective studies have confirmed the correlation between an HMA number of cycles with response and survival using landmark methodology. We present here the results of landmark response and survival analyses based on number of cycles and whether patients had an objective response or not. M ethods: Landmark response (CR, CRi, or CRp based on 2003 IWG criteria, grouped together as composite CR or CRc), and overall survival (OS) analyses for patients alive at or beyond month 3 and month 5 (time of planned start of cycle 4 and cycle 6 respectively) were conducted. Landmark OS was compared between patients who received at least 4 or 6 cycles and those who did not. The landmark methodology avoids the bias of early deaths before cycles 4 and 6 attributing a survival benefit in those who did not die early and were able to get more cycles. We also compared the result in responding and non-responding patients to see if survival benefit was restricted to responding patients only. Results: The study completed enrolment with 206 AML patients: 103 patients (50%) for each of Treatment Naïve (TN) unfit for intensive chemotherapy, and relapsed/refractory (r/r) AML. Median age was 68.5y (range 22-92y), ECOG PS ≥2 in 26%, poor risk cytogenetics in 41%, secondary AML in 26%, and median baseline BM blasts % was 40% in the total AML population. 108 patients (52.4%), and 155 patients (75%) received Summary/Conclusions: In a prospective phase 2 study of 206 TN and r/r AML patients treated with the HMA guadecitabine, patients who were alive at or beyond 3 and 5 months who continued treatment for at least 4 or 6 cycles respectively achieved a highly significant response and survival benefit compared to those who discontinued treatment before cycle 4 or 6. The survival benefit was evident even in patients who did not have an objective response. Reasons for treatment discontinuation should be weighed carefully before stopping HMA treatment with guadecitabine before 4 or 6 cycles in AML patients to maximize response and survival benefit. Failure to achieve an objective response after 4 cycles should not be a reason for treatment discontinuation as long as patient can still benefit. Disclosures Yee: MedImmune: Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Astex: Research Funding; Hoffman La Roche: Research Funding; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Merck: Research Funding; Millennium: Research Funding; Astellas: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees. Roboz:AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Actinium: Consultancy, Membership on an entity's Board of Directors or advisory committees; Agios: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amphivena: Consultancy, Membership on an entity's Board of Directors or advisory committees; Argenx: Consultancy, Membership on an entity's Board of Directors or advisory committees; Astex: Consultancy, Membership on an entity's Board of Directors or advisory committees; Astellas: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bayer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celltrion: Consultancy, Membership on an entity's Board of Directors or advisory committees; Daiichi Sankyo: Consultancy, Membership on an entity's Board of Directors or advisory committees; Eisai: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Jazz: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; MEI Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees; Orsenix: Consultancy, Membership on an entity's Board of Directors or advisory committees; Otsuka: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Roche/Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees; Sandoz: Consultancy, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees; Trovagene: Consultancy, Membership on an entity's Board of Directors or advisory committees. O'Connell:BMS: Membership on an entity's Board of Directors or advisory committees; Shionogi: Membership on an entity's Board of Directors or advisory committees; Astex: Membership on an entity's Board of Directors or advisory committees, Research Funding; Genentech: Research Funding; Pfizer: Membership on an entity's Board of Directors or advisory committees. Griffiths:Boston Scientific: Consultancy; Boston Scientific: Consultancy; Abbvie, Inc.: Consultancy; Persimmune: Consultancy; Genentech, Inc.: Research Funding; Novartis Inc.: Consultancy; Novartis Inc.: Consultancy; New Link Genetics: Consultancy; Appelis Pharmaceuticals: Other: PI on a clinical trial; Partner Therapeutics: Consultancy; Appelis Pharmaceuticals: Other: PI on a clinical trial; Onconova Therapeutics: Other: PI on a clinical trial; New Link Genetics: Consultancy; Abbvie, Inc.: Consultancy, PI on a clinical trial; Celgene, Inc: Consultancy, Research Funding; Onconova Therapeutics: Other: PI on a clinical trial; Partner Therapeutics: Consultancy; Astex Phramaceuticals/Otsuka Pharmaceuticals: Consultancy, Research Funding; Persimmune: Consultancy; Celgene, Inc: Consultancy, Research Funding; Astex Phramaceuticals/Otsuka Pharmaceuticals: Consultancy, Research Funding; Genentech, Inc.: Research Funding. Stock:Daiichi: Membership on an entity's Board of Directors or advisory committees; Agios: Membership on an entity's Board of Directors or advisory committees; Astellas: Membership on an entity's Board of Directors or advisory committees; Research to Practice: Honoraria; Kite, a Gilead Company: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; UpToDate: Honoraria. Garcia-Manero:Amphivena: Consultancy, Research Funding; Helsinn: Research Funding; Novartis: Research Funding; AbbVie: Research Funding; Celgene: Consultancy, Research Funding; Astex: Consultancy, Research Funding; Onconova: Research Funding; H3 Biomedicine: Research Funding; Merck: Research Funding. Savona:AbbVie: Membership on an entity's Board of Directors or advisory committees; Selvita: Membership on an entity's Board of Directors or advisory committees; Incyte Corporation: Membership on an entity's Board of Directors or advisory committees, Research Funding; Sunesis: Research Funding; Karyopharm Therapeutics: Consultancy, Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Boehringer Ingelheim: Patents & Royalties; Celgene Corporation: Membership on an entity's Board of Directors or advisory committees; TG Therapeutics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding. Ravandi:Macrogenix: Consultancy, Research Funding; Selvita: Research Funding; Cyclacel LTD: Research Funding; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Menarini Ricerche: Research Funding; Xencor: Consultancy, Research Funding. Daver:Astellas: Consultancy; Daiichi Sankyo: Consultancy, Research Funding; Forty-Seven: Consultancy; Incyte: Consultancy, Research Funding; Servier: Research Funding; Incyte: Consultancy, Research Funding; NOHLA: Research Funding; Jazz: Consultancy; Glycomimetics: Research Funding; NOHLA: Research Funding; Abbvie: Consultancy, Research Funding; Agios: Consultancy; Celgene: Consultancy; Sunesis: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; Karyopharm: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; Abbvie: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Astellas: Consultancy; Hanmi Pharm Co., Ltd.: Research Funding; Forty-Seven: Consultancy; Agios: Consultancy; Otsuka: Consultancy; Jazz: Consultancy; Immunogen: Consultancy, Research Funding; Glycomimetics: Research Funding; Sunesis: Consultancy, Research Funding; Hanmi Pharm Co., Ltd.: Research Funding; Karyopharm: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Otsuka: Consultancy; Celgene: Consultancy; Daiichi Sankyo: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Servier: Research Funding; BMS: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Immunogen: Consultancy, Research Funding. Jabbour:AbbVie: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Cyclacel LTD: Research Funding; Adaptive: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; BMS: Consultancy, Research Funding. Su:Astex Pharmaceuticals, Inc.: Employment. Azab:Astex Pharmaceuticals, Inc.: Employment. Kantarjian:Pfizer: Honoraria, Research Funding; Astex: Research Funding; Actinium: Honoraria, Membership on an entity's Board of Directors or advisory committees; Cyclacel: Research Funding; Takeda: Honoraria; Immunogen: Research Funding; Jazz Pharma: Research Funding; Amgen: Honoraria, Research Funding; AbbVie: Honoraria, Research Funding; Agios: Honoraria, Research Funding; BMS: Research Funding; Ariad: Research Funding; Daiichi-Sankyo: Research Funding; Novartis: Research Funding.

Background: Guadecitabine is a next generation subcutaneous (SC) hypomethylating agent (HMA) resistant to degradation by cytidine deaminase which results in prolonged in vivo exposure to the active metabolite decitabine. We conducted a phase 2 study of guadecitabine in 102 Myelodysplastic Syndromes (MDS), and Chronic Myelomonocytic leukemia (CMML) patients. International guidelines recommend a minimum of 4 to 6 cycles of HMA treatment to gain maximum benefit, but some suggest that treatment may not be beneficial if no response was observed after 4 cycles. No prospective studies have confirmed the correlation between an HMA number of cycles with response and survival using landmark methodology. We present here the results of landmark response and survival analyses based on number of cycles and whether patients had an objective response or not. M ethods: Landmark response based on 2006 IWG criteria, and overall survival (OS) analyses for patients alive at or beyond month 3 and month 5 (time of planned start of cycle 4 and cycle 6 respectively) were conducted. Objective response (OR) was defined as patients who had Complete Response (CR), Partial Response (PR), marrow (m)CR, or Hematological Improvement (HI). Landmark OS was compared between patients who received at least 4 or 6 cycles and those who did not. The landmark methodology avoids the bias of early deaths before cycles 4 and 6 attributing a survival benefit in those who did not die early and were able to get more cycles. We also compared the result in responding and non-responding patients to see if survival benefit was restricted to responding patients only. Results: The study completed enrolment with 102 patients: 53 patients after HMA failure (relapsed/refractory or r/r), and 49 HMA-naive patients (Treatment Naïve or TN) with a median follow up for the entire study of 3.2 years (IQR 2.9-3.5 years). Median age was 71 and 72 years for TN MDS/CMML and r/r MDS/CMML patients respectively. Median OS was 23.4 months (m) for TN MDS/CMML patients and 11.7 m for r/r MDS/CMML patients. Of the 102 patients treated, 37 patients (36.3%) and 58 (56.9%) received less than 4 and 6 cycles respectively. The landmark analysis population was 91 patients for the 4-cycle analysis and 87 patients for the 6-cycle analysis. In those patients, the primary reasons for treatment discontinuation before cycle 4 or 6 respectively were patient decision (9.8% and 11.8%), and investigator decision (5.9% and 9.8%) while early progression accounted for 3.9% and 10.8% of those patients. There were no major baseline characteristics difference between patients who received at least 4 and 6 cycles and those who did not in the patients included in the landmark analyses. In the landmark analysis, patients who received at least 4 cycles (65 patients) had an OR rate of 68% compared to 15% in 26 patients who received Summary/Conclusions: In a prospective phase 2 study of 102 MDS/CMML patients treated with the HMA guadecitabine, patients who were alive at the planned start of cycle 4 and cycle 6 did not continue treatment primarily because of patient or investigator decision in addition to early progression. Those who were alive and continued treatment for at least 4 or 6 cycles achieved highly significant objective response benefit compared to those who did not. Survival benefit was highly significant for those who received at least 6 cycles and was not restricted to patients who had an objective response. It is important to weigh reasons for treatment discontinuation carefully before discontinuing guadecitabine HMA treatment in MDS/CMML patients before 6 cycles to maximize response and survival benefit. Disclosures Savona: Selvita: Membership on an entity's Board of Directors or advisory committees; Incyte Corporation: Membership on an entity's Board of Directors or advisory committees, Research Funding; Karyopharm Therapeutics: Consultancy, Equity Ownership, Membership on an entity's Board of Directors or advisory committees; AbbVie: Membership on an entity's Board of Directors or advisory committees; Boehringer Ingelheim: Patents & Royalties; Celgene Corporation: Membership on an entity's Board of Directors or advisory committees; Sunesis: Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; TG Therapeutics: Membership on an entity's Board of Directors or advisory committees, Research Funding. Kantarjian:Takeda: Honoraria; Astex: Research Funding; Immunogen: Research Funding; Cyclacel: Research Funding; Ariad: Research Funding; Pfizer: Honoraria, Research Funding; BMS: Research Funding; Agios: Honoraria, Research Funding; Actinium: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Research Funding; Daiichi-Sankyo: Research Funding; AbbVie: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Jazz Pharma: Research Funding. Roboz:Trovagene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees; Sandoz: Consultancy, Membership on an entity's Board of Directors or advisory committees; Roche/Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Otsuka: Consultancy, Membership on an entity's Board of Directors or advisory committees; Orsenix: Consultancy, Membership on an entity's Board of Directors or advisory committees; MEI Pharma: 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; Jazz: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Eisai: Consultancy, Membership on an entity's Board of Directors or advisory committees; Daiichi Sankyo: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celltrion: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bayer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Astellas: Consultancy, Membership on an entity's Board of Directors or advisory committees; Astex: Consultancy, Membership on an entity's Board of Directors or advisory committees; Argenx: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amphivena: Consultancy, Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Actinium: Consultancy, Membership on an entity's Board of Directors or advisory committees; Agios: Consultancy, Membership on an entity's Board of Directors or advisory committees. O'Connell:Genentech: Research Funding; Pfizer: Membership on an entity's Board of Directors or advisory committees; Astex: Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Membership on an entity's Board of Directors or advisory committees; Shionogi: Membership on an entity's Board of Directors or advisory committees. Yee:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Astex: Research Funding; Hoffman La Roche: Research Funding; MedImmune: Research Funding; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Merck: Research Funding; Millennium: Research Funding; Astellas: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Stock:Research to Practice: Honoraria; UpToDate: Honoraria; Kite, a Gilead Company: Membership on an entity's Board of Directors or advisory committees; Agios: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Daiichi: Membership on an entity's Board of Directors or advisory committees; Astellas: Membership on an entity's Board of Directors or advisory committees. Griffiths:Appelis Pharmaceuticals: Other: PI on a clinical trial; Abbvie, Inc.: Consultancy, PI on a clinical trial; Celgene, Inc: Consultancy, Research Funding; Astex Phramaceuticals/Otsuka Pharmaceuticals: Consultancy, Research Funding; Appelis Pharmaceuticals: Other: PI on a clinical trial; Onconova Therapeutics: Other: PI on a clinical trial; Astex Phramaceuticals/Otsuka Pharmaceuticals: Consultancy, Research Funding; Abbvie, Inc.: Consultancy; New Link Genetics: Consultancy; Persimmune: Consultancy; Boston Scientific: Consultancy; Genentech, Inc.: Research Funding; Genentech, Inc.: Research Funding; Boston Scientific: Consultancy; Persimmune: Consultancy; Onconova Therapeutics: Other: PI on a clinical trial; Novartis Inc.: Consultancy; Celgene, Inc: Consultancy, Research Funding; New Link Genetics: Consultancy; Partner Therapeutics: Consultancy; Novartis Inc.: Consultancy; Partner Therapeutics: Consultancy. Jabbour:Takeda: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Adaptive: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; AbbVie: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Cyclacel LTD: Research Funding. Podoltsev:Boehringer Ingelheim: Research Funding; Genentech: Research Funding; Blueprint Medicines: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Daiichi Sankyo: Research Funding; Sunesis Pharmaceuticals: Research Funding; Alexion: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Agios Pharmaceuticals: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Incyte: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Kartos Therapeutics: Research Funding; Astellas Pharma: Research Funding; Samus Therapeutics: Research Funding; Jazz Pharmaceuticals: Research Funding; Astex Pharmaceuticals: Research Funding; Celgene: Other: Grant funding, Research Funding; Arog Pharmaceuticals: Research Funding; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; AI Therapeutics: Research Funding; Pfizer: Research Funding; CTI Biopharma: Research Funding. Su:Astex Pharmaceuticals, Inc.: Employment. Azab:Astex Pharmaceuticals, Inc.: Employment. Garcia-Manero:AbbVie: Research Funding; Celgene: Consultancy, Research Funding; Helsinn: Research Funding; Novartis: Research Funding; Amphivena: Consultancy, Research Funding; Astex: Consultancy, Research Funding; Onconova: Research Funding; H3 Biomedicine: Research Funding; Merck: Research Funding.

BACKGROUND: Despite recent advances, outcomes remain poor in secondary and relapsed/refractory (R/R) acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS). We previously demonstrated that combination thioguanine (6TG) and decitabine restores therapeutic efficacy in vitro in R/R AML (O'Dwyer K et al. Blood 2010;114:2657). Based on these data, we completed a Phase I dose-escalation study of 6TG with decitabine in advanced myeloid malignancies with an overall response rate (ORR) of 67% and median progression-free survival (PFS) of 42 weeks in responding patients (Lee DJ, et al. Blood 2016;128:2816). Moreover, 5 of the 6 study participants who had previously received a hypomethylating agent (HMA) responded, suggesting that 6TG in combination with decitabine can overcome HMA resistance. Because of these results, a cohort of patients with high-risk and R/R AML and MDS were treated with combination 6TG and decitabine at Columbia University Irving Medical Center, and we now report our clinical experience with this regimen. METHODS: A retrospective chart review was performed of all adult patients at our institution with advanced myeloid malignancies who had received at least one cycle of 6TG and decitabine between 2013-2017. The treatment regimen utilized the maximum tolerated dose of 6TG identified in the phase I trial. Up to 2 cycles of induction with 6TG 80 mg/m2/day PO in 2 divided doses was given on Days 1-12. Decitabine 20 mg/m2 IV was given on Days 3-12. Following this, maintenance cycles consisted of 6TG on Days 1-7 and decitabine on Days 3-7 at the same doses. Treatment was continued until the time of hematopoietic stem cell transplant (HSCT), disease progression, or toxicity. The primary objective of this retrospective analysis was to determine the ORR. Secondary objectives were to evaluate PFS and overall survival (OS) in this population. RESULTS: Forty-two patients were identified, 55% of whom were female, with a median age of 68 years (range, 23-83 years). Thirty-three percent of the patients had secondary AML; 62% had R/R AML; 2% had R/R MDS; and 2% had chronic myelomonocytic leukemia. By ELN genetic risk stratification, 38% were adverse-risk, 43% were intermediate, and 17% were favorable, while 2% were unknown. However, 36 (86%) patients failed prior therapy, suggesting that nearly all of the treated patients were poor-risk. Nineteen (45%) patients had received prior HMA therapy, and 6 (14%) had undergone previous HSCT. Patients received a median of 2 cycles of therapy (range, 1-10). Five (12%) patients achieved complete remission (CR), 7 (16%) obtained a CR with incomplete count recovery (CRi/p), and 2 (5%) had morphologic leukemia-free state (MLFS), for an ORR of 33% (CR+CRi/p+MLFS). One notable patient who achieved CR was a 73-year-old with secondary AML, complex cytogenetics, and a TP53 mutation who subsequently went on to HSCT. Another 5 (36%) responders had complex karyotypes or poor-risk genetics. Ten of the 14 responders (71%) failed prior therapy. Of the 19 who had received prior HMA therapy, 6 (32%) responded. Six of 14 (43%) responders proceeded to HSCT. Two additional patients had significant blast reduction and underwent HSCT. Responses and maximum blast reduction were obtained after two cycles of therapy. For the responders, the median PFS was 38 weeks (range, 11-not reached), while the median OS was 43 weeks (range, 11-not reached). CONCLUSIONS: Combined 6TG and decitabine is a highly active regimen in advanced myeloid malignancies, with an ORR of 33% in this cohort, and median PFS and OS of 38 and 43 weeks, respectively, in responding patients. This compares favorably to the expected response rate of 10-20% with decitabine monotherapy in this poor-risk population consisting of mostly secondary and R/R AML. These data also confirm our prior phase I study findings that the addition of 6TG to decitabine can overcome prior HMA resistance, with 32% of those who had previously failed HMA therapy responding. This combination remains a viable therapeutic option for elderly and unfit patients with high-risk and R/R AML who cannot tolerate intensive chemotherapy. Disclosures Heaney: BMS: Research Funding; Partner Therapeutics: Consultancy; Roche: Consultancy, Research Funding; Incyte: Consultancy, Research Funding; Celgene: Research Funding; Novartis: Consultancy; AbbVie: Consultancy; Deciphera: Research Funding; Constellation: Research Funding; Blueprint: Research Funding; CTI: Research Funding. Lamanna:Ming: Research Funding; Celgene: Consultancy; Oncternal: Research Funding; TG Therapeutics: Research Funding; Infinity/ Verastem: Research Funding. Jurcic:Syros Pharmaceuticals: Research Funding; Astellas: Research Funding; AbbVie Inc: Consultancy; Daiichi Sankyo: Research Funding; Celgene: Consultancy, Research Funding; Incyte: Consultancy; Kura Oncology: Research Funding; Forma Therapeutics: Research Funding; Genentech: Research Funding; Novartis: Consultancy; Actinium Pharmaceuticals: Research Funding. Frattini:Celgene: Employment, Equity Ownership; Lin Bioscience: Consultancy. Lee:Abbvie: Research Funding; Roche: Research Funding; Tolero: Research Funding; Forty Seven, Inc.: Research Funding; Bayer: Research Funding.

Translocation t(11;17) is a well-recognized variant of acute promyelocytic leukemia (APL) and has also been identified in patients with mixed-lineage leukemia (MLL) non-APL acute myeloid leukemia. Here, we describe two patients bearing translocation t(11;17) presenting with a clinical diagnosis of de novo myelodysplastic syndrome (MDS): the first with sole karyotypic abnormality 46,XY,t(11;17)(p11.2; p13) and the second where it represented one of the two karyotypic abnormalities 46,XX,del(5)(q13q33)46,XX,del(5)(q13q33),t(11;17)(q24;q23). Molecular characterization of both cases failed to identify fusion transcripts involving MLL or PLZF-RARA and no collaborating somatic mutations commonly found among MDS patients were seen in either case, suggesting the presence of an as yet unidentified oncogenic fusion protein.

The introduction of all-trans retinoic acid (ATRA) in the late 1980s combined with anthracycline-based chemotherapy has revolutionized the prognosis of acute promyelocytic leukemia (APL) with more than 90% complete response rates and cure rates of approximately 80%. The subsequent advent of arsenic trioxide (ATO) in 1990s and progress in the treatment of APL have changed its course from a highly fatal to a highly curable disease. Despite the dramatic improvement in clinical outcome of APL, treatment failure still occurs due most often to early death. Relapse has become increasingly less frequent, most commonly occurring in patients with high-risk disease. A major focus of research for the past decade has been to develop risk-adapted and rationally targeted nonchemotherapy treatment strategies to reduce treatment-related morbidity and mortality to low- and intermediate-risk or older patients while targeting more intensive or alternative therapy to those patients at most risk of relapse. In this review, emerging new approaches to APL treatment with special emphasis on strategies to reduce early deaths, risk-adapted therapy during induction, consolidation and maintenance, as well as an overview of current and future clinical trials in APL will be discussed.

Background: Guadecitabine SC (SGI-110) is a dinucleotide next generation HMA resistant to degradation by cytidine deaminase resulting in extended in vivo exposure to its active metabolite decitabine. A Phase 1 established 60 mg/m2 QDx5 as the biologically effective dose (BED), and 90 mg/m2 QDx5 as the Maximum tolerated dose (MTD) in MDS patients given in 28-day cycles (Issa et al, 2015, Lancet Oncology). Phase 2 is conducted to evaluate dose response between the BED and MTD in both untreated MDS patients, and patients previously treated with other HMAs. M ethods: Int, or HR MDS, and CMML patients who were either treatment-naïve (TN) or relapsed/refractory to other HMAs (r/r) were randomized to either 60 mg/m2 or 90 mg/m2 QDx5 every 28 days. Efficacy was evaluated by the clinical responses of CR, PR, marrow CR (mCR), and Hematological Improvement (HI) based on the International Working Group Criteria 2006, as well as transfusion-independence, and overall survival (OS). Adverse events (AEs) were graded by the CTCAE v4 criteria. Results: The study completed target enrolment with 102 patients: 53 r/r MDS, and 49 TN MDS. Fifty three patients were randomized to 60 mg/m2 and 49 patients to 90 mg/m2 QDx5 with a median follow up of 3.2 years (IQR 2.8-3.5 years). Median age was 72 and 71 years for r/r and TN MDS respectively. Most baseline patient characteristics were well balanced between the 2 treatment dose groups except that more CMML patients were randomized to the 60 mg/m2 group (28%) vs. 14% in the 90 mg/m2 group, and more patients with baseline BM blasts >5% were in the 90 mg/m2 group (67%) vs. 38% in the 60 mg/m2 group. Most patients were RBC transfusion-dependent at baseline (57%). In the r/r MDS cohort, most patients (58%) received their last HMA treatment Median number of treatment cycles was 5 for both r/r and TN MDS (range 1-37 in r/r MDS and 1-49 in TN MDS). In the TN MDS cohort CR was achieved in 11 (22%) of patients with no major difference between the 2 dose groups (19% in the 60 mg/m2 group vs 27% in the 90 mg/m2 group). Overall CR+mCR was achieved in 18 patients (37%) in TN MDS patients and median OS was 23.4 months. In the r/r MDS cohort, CR was achieved in 4% of patients in each of the 2 dose groups. Overall CR+mCR in the r/r MDS cohort was achieved in 17 patients (32%), with a median duration of response of 7.9 months, and median OS of 11.7 months. No significant difference in response or OS between the 2 dose groups was observed. In patients who were RBC transfusion-dependent at baseline, transfusion independence for at least 8 weeks was achieved in 42% of TN MDS, and 15% in r/r MDS patients. In the overall population of 102 TN and r/r MDS patients there were no major differences in OS based on DNMT3A or TET2 mutation status while patients with TP53 mutations had worse median OS (7.4 months) compared to those without TP53 mutations (22.6 months). Other baseline prognostic factors for worse OS were BM blasts >5%; RBC transfusion-dependence; IPSS High Risk; and ECOG Performance Status of >1. Overall incidence of Grade ≥3 AEs regardless of relationship to treatment was reported in 83 vs. 96% for 60 and 90 mg/m2 dose groups respectively. There was a slightly higher but non-significant difference in Grade ≥3 thrombocytopenia (57 vs 41.5%); neutropenia (51 vs 39.6%); febrile neutropenia (43% vs 32%); and pneumonia (32.7 vs. 26.4%) for the 90 mg/m2 compared to 60 mg/m2 dose group. Early 30, 60, and 90-day all-cause mortality was observed in 0, 3.7%, and 5.7% in the 60 mg/m2 dose group respectively; and in 2%, 4%, and 12% in the 90 mg/m2 dose group respectively. Conclusions: Guadecitabine at both dose groups is a well-tolerated novel HMA with clinical activity in the treatment of both TN and r/r Int and HR MDS, and CMML patients. In TN MDS patient CR rate of 22% and median OS of 23.4 months compare well with first generation HMA efficacy (Fenaux et al, 2009, Lancet Oncology). Activity in r/r MDS who previously failed prior HMAs is particularly promising (CR+mCR in 32% of patients with median duration of response and overall survival of almost 8 and 12 months respectively). A phase 3 trial (ASTRAL-3) of guadecitabine vs Physician Treatment Choice in r/r MDS and CMML patients previously treated with azacitidine or decitabine is actively enrolling (ClinicalTrials.gov ID: NCT02907359). Disclosures Ritchie: NS Pharma: Research Funding; Bristol-Myers Squibb: Research Funding; Novartis: Consultancy, Other: Travel, Accommodations, Expenses, Research Funding, Speakers Bureau; Incyte: Consultancy, Speakers Bureau; Celgene: Consultancy, Other: Travel, Accommodations, Expenses, Speakers Bureau; Pfizer: Consultancy, Research Funding; ARIAD Pharmaceuticals: Speakers Bureau; Astellas Pharma: Research Funding. Savona:Boehringer Ingelheim: Consultancy; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Incyte: Membership on an entity's Board of Directors or advisory committees, Research Funding. Kropf:Celegene: Consultancy; Takeda: Consultancy. Daver:Pfizer: Consultancy; Sunesis: Consultancy; Pfizer: Research Funding; ImmunoGen: Consultancy; ARIAD: Research Funding; Novartis: Research Funding; Incyte: Research Funding; Otsuka: Consultancy; Novartis: Consultancy; Karyopharm: Consultancy; Alexion: Consultancy; Incyte: Consultancy; Karyopharm: Research Funding; BMS: Research Funding; Kiromic: Research Funding; Daiichi-Sankyo: Research Funding; Sunesis: Research Funding. Jabbour:Pfizer: Consultancy, Research Funding; Novartis: Research Funding; Abbvie: Research Funding; Takeda: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding. Yee:Celgene, Novartis, Otsuka: Membership on an entity's Board of Directors or advisory committees; Agensys, Astex, GSK, Onconova, Genentech/Roche: Research Funding. Stock:Jazz Pharmaceuticals: Consultancy. Griffiths:Alexion Inc.: Honoraria, Research Funding; Astex/Otsuka Pharmaceuticals: Honoraria, Research Funding; Celgene, Inc: Honoraria, Research Funding; Novartis, Inc.: Research Funding; Pfizer, Inc.: Research Funding. Podoltsev:Astex Pharmaceuticals: Research Funding; LAM Therapeutics: Research Funding; Sunesis Pharmaceuticals: Research Funding; Genentech: Research Funding; Boehringer Ingelheim: Research Funding; Daiichi Snakyo: Research Funding; Astellas Pharma: Research Funding; Pfizer: Research Funding; Celator: Research Funding; Pfizer: Membership on an entity's Board of Directors or advisory committees; Celgene: Research Funding. Berdeja:Genentech: Research Funding; Bluebird: Research Funding; Amgen: Research Funding; Novartis: Research Funding; Glenmark: Research Funding; Takeda: Research Funding; Bristol-Myers Squibb: Research Funding; Teva: Research Funding; Sanofi: Research Funding; Poseida Therapeutics, Inc.: Research Funding; Celgene: Research Funding; Janssen: Research Funding. Naim:Astex Pharmaceuticals, Inc.: Employment. Hao:Astex Pharmaceuticals, Inc.: Employment. Azab:Astex Pharmaceuticals, Inc.: Employment. Roboz:Orsenix: Consultancy; Roche/Genentech: Consultancy; Roche/Genentech: Consultancy; Otsuka: Consultancy; Bayer: Consultancy; Pfizer: Consultancy; Jazz Pharmaceuticals: Consultancy; Argenx: Consultancy; Sandoz: Consultancy; Celltrion: Consultancy; Bayer: Consultancy; Orsenix: Consultancy; Pfizer: Consultancy; Astex Pharmaceuticals: Consultancy; Daiichi Sankyo: Consultancy; Sandoz: Consultancy; Daiichi Sankyo: Consultancy; Novartis: Consultancy; Janssen Pharmaceuticals: Consultancy; Cellectis: Research Funding; Eisai: Consultancy; Celgene Corporation: Consultancy; Jazz Pharmaceuticals: Consultancy; Celgene Corporation: Consultancy; Janssen Pharmaceuticals: Consultancy; Eisai: Consultancy; Novartis: Consultancy; Otsuka: Consultancy; Argenx: Consultancy; Celltrion: Consultancy; Astex Pharmaceuticals: Consultancy; Aphivena Therapeutics: Consultancy; AbbVie: Consultancy; Aphivena Therapeutics: Consultancy; AbbVie: Consultancy; Cellectis: Research Funding.

Because alpha-particles have a shorter range and a higher linear energy transfer (LET) compared with beta-particles, targeted alpha-particle immunotherapy offers the potential for more efficient tumor cell killing while sparing surrounding normal cells. To date, clinical studies of alpha-particle immunotherapy for acute myeloid leukemia (AML) have focused on the myeloid cell surface antigen CD33 as a target using the humanized monoclonal antibody lintuzumab. An initial phase I study demonstrated the safety, feasibility, and antileukemic effects of bismuth-213 (213Bi)-labeled lintuzumab. In a subsequent study, 213Bi-lintuzumab produced remissions in some patients with AML after partial cytoreduction with cytarabine, suggesting the utility of targeted alpha-particle therapy for small-volume disease. The widespread use of 213Bi, however, is limited by its short half-life. Therefore, a second-generation construct containing actinium-225 (225Ac), a radiometal that generates four alpha-particle emissions, was developed. A phase I trial demonstrated that 225Ac-lintuzumab is safe at doses of 3 μCi/kg or less and has antileukemic activity across all dose levels studied. Fractionated-dose 225Ac-lintuzumab in combination with low-dose cytarabine (LDAC) is now under investigation for the management of older patients with untreated AML in a multicenter trial. Preclinical studies using 213Bi- and astatine-211 (211At)-labeled anti-CD45 antibodies have shown that alpha-particle immunotherapy may be useful as part conditioning before hematopoietic cell transplantation. The use of novel pretargeting strategies may further improve target-to-normal organ dose ratios.

Purpose Most patients with acute myeloid leukemia (AML) eventually experience relapse. Relapsed/refractory AML has a dismal prognosis and currently available treatment options are generally ineffective. The objective of this large, international, randomized clinical trial was to investigate the efficacy of elacytarabine, a novel elaidic acid ester of cytarabine, versus the investigator's choice of one of seven commonly used AML salvage regimens, including high-dose cytarabine, multiagent chemotherapy, hypomethylating agents, hydroxyurea, and supportive care. Patients and Methods A total of 381 patients with relapsed/refractory AML were treated in North America, Europe, and Australia. Investigators selected a control treatment for individual patients before random assignment. The primary end point was overall survival (OS). Results There were no significant differences in OS (3.5 v 3.3 months), response rate (23% v 21%), or relapse-free survival (5.1 v 3.7 months) between the elacytarabine and control arms, respectively. There was no significant difference in OS among any of the investigator's choice regimens. Prolonged survival was only achieved in a few patients in both study arms whose disease responded and who underwent allogeneic stem-cell transplantation. Conclusion Neither elacytarabine nor any of the seven alternative treatment regimens provided clinically meaningful benefit to these patients. OS in both study arms and for all treatments was extremely poor. Novel agents, novel clinical trial designs, and novel strategies of drug development are all desperately needed for this patient population.

Background: Outcomes are poor for older patients with acute myeloid leukemia (AML), high-risk myelodysplastic syndromes (MDS), or relapsed/refractory disease, and new therapies are needed. Using a chemosensitivity screening assay, we previously demonstrated that combination treatment with thioguanine and decitabine can restore therapeutic efficacy in primary leukemia cells isolated from patients with relapsed/refractory AML. To test the safety and synergistic efficacy of this combination in patients with advanced myeloid malignancies, we performed a Phase I dose-escalation trial of thioguanine given with decitabine. Patients and Methods: Patients with untreated AML ≥60 years of age and ineligible for standard induction, relapsed/refractory AML, and high-risk or relapsed MDS were eligible. Two thioguanine dose levels were evaluated: 80 and 120 mg/m2/day, given on Days 1-12 of induction and Days 1-7 of maintenance. Decitabine at 20mg/m2 was administered on Days 3-12 during induction and on Days 3-7 during maintenance. The primary objective was to determine the maximum tolerated dose (MTD) of thioguanine when given with decitabine. Key secondary objectives were to evaluate the overall response rate (ORR) and progression-free survival (PFS). Patient-specific pharmacodynamic measures to assess the biologic activity of thioguanine-decitabine were also performed. These included an in vitro chemosensitivity assay, BH3 profiling to measure the degree to which the leukemic blasts were primed for apoptosis, and genome-wide analysis of DNA methylation changes. Results: Twelve patients (median age 67; range 56-83) with de novo AML (n=1), secondary AML (n=6), relapsed/refractory AML (n=4), and chronic myelomonocytic leukemia (CMML) (n=1) were treated. Three patients experienced dose-limiting toxicity (DLT), which were acute renal failure requiring hemodialysis (80 mg/m2), persistent grade 4 leukopenia and thrombocytopenia (120 mg/m2), and grade 4 sepsis preventing continued treatment (120 mg/m2). Thioguanine at 80 mg/m2 was determined to be the MTD. Eleven of the 12 patients completed the first induction cycle, and 6 patients completed a second, identical induction cycle. The median number of cycles administered was 3 (range 1-8). One patient experienced a DLT prior to the first response assessment and was removed from study. The ORR in this intent-to-treat study was 67% (8/12). Six patients achieved a CR or CRi, one obtained a morphologic leukemia-free state, and one patient had a PR. Responses were observed in all disease types. Five of the 8 responses, including 4 CR/CRi, were achieved with thioguanine at 80 mg/m2, suggesting no loss of efficacy at the MTD compared with the higher dose level. All 11 evaluable patients had ≥50% reduction in bone marrow blast percentages after induction therapy. Six patients had previously received single-agent hypomethylating therapy, and 5 (83%) of these patients responded, demonstrating that thioguanine-decitabine can rescue prior hypomethylating agent failure. Out of the 8 responders, four (50%) proceeded to allogeneic stem cell transplantation (SCT), two relapsed after CR or CRi, one had a CNS-only relapse after achieving a CR, and one patient experienced DLT and was removed from the study. Of the four patients who proceeded to allogeneic SCT, two patients died in CR from transplant-related toxicity, one relapsed, and one patient remains alive and in remission greater than 2 years. Median PFS in responding patients was 42 weeks (range, 10-not reached, weeks). In vitro pharmacodynamic studies currently have been completed on samples from the first 6 patients treated on this trial. The chemosensitivity assay results on pre-treatment mononuclear cells directly correlated with initial response. In addition, significant apoptotic priming of the blasts, as suggested from BH3 profiling, also corresponded to initial clinical response. Conclusions: Thioguanine-decitabine can be administered safely and induce remission, even among patients who had previously been treated with hypomethylating agents. Intriguingly, preliminary results from the chemosensitivity screening assay and BH3 profiling correlated well with clinical responses. Additional correlative studies including DNA methylation analysis are ongoing to better understand the mechanism of synergy between thioguanine and decitabine. A multi-center Phase II trial is planned. Disclosures Jurcic: Astellas: Research Funding. Letai:Astra-Zeneca: Consultancy, Research Funding; Tetralogic: Consultancy, Research Funding; AbbVie: Consultancy, Research Funding.

Adults with relapsed B cell acute lymphoblastic leukemia (B-ALL) have a dismal prognosis. Only those patients able to achieve a second remission with no minimal residual disease (MRD) have a hope for long-term survival in the context of a subsequent allogeneic hematopoietic stem cell transplantation (allo-HSCT). We have treated five relapsed B-ALL subjects with autologous T cells expressing a CD19-specific CD28/CD3ζ second-generation dual-signaling chimeric antigen receptor (CAR) termed 19-28z. All patients with persistent morphological disease or MRD(+) disease upon T cell infusion demonstrated rapid tumor eradication and achieved MRD(-) complete remissions as assessed by deep sequencing polymerase chain reaction. Therapy was well tolerated, although significant cytokine elevations, specifically observed in those patients with morphologic evidence of disease at the time of treatment, required lymphotoxic steroid therapy to ameliorate cytokine-mediated toxicities. Indeed, cytokine elevations directly correlated to tumor burden at the time of CAR-modified T cell infusions. Tumor cells from one patient with relapsed disease after CAR-modified T cell therapy, who was ineligible for additional allo-HSCT or T cell therapy, exhibited persistent expression of CD19 and sensitivity to autologous 19-28z T cell-mediated cytotoxicity, which suggests potential clinical benefit of additional CAR-modified T cell infusions. These results demonstrate the marked antitumor efficacy of 19-28z CAR-modified T cells in patients with relapsed/refractory B-ALL and the reliability of this therapy to induce profound molecular remissions, forming a highly effective bridge to potentially curative therapy with subsequent allo-HSCT.

We hypothesized that the high early death rate (EDR) due to bleeding in acute promyelocytic leukemia (APL) is in part attributable to delays in all- trans retinoic acid (ATRA). We conducted a retrospective analysis of the timing of ATRA administration. 204 consecutive patients with newly diagnosed APL between 1992 and 2009 were identified. The EDR was 11%. 44% of early deaths occurred in the first week. Hemorrhage accounted for 61% of early deaths. ATRA was ordered the day APL was suspected in 31% of patients. Delays in ATRA administration led to increases in the percentage of early deaths from hemorrhage.

7005Background: An NCI consensus study on prioritization of cancer antigens identified WT1 as the #1 ranked immunotherapy target. We previously reported on the safety, immunogenicity, and prolonged...

Introduction: Guadecitabine (SGI-110) is a novel next-generation HMA administered as a small volume subcutaneous (SC) injection which results in extended decitabine exposure. Phase 2 studies have been conducted in TN-AML patients who were not candidates for intensive chemotherapy using two different doses and schedules of guadecitabine. We report here a comparative efficacy and safety analysis of the 5-day and 10-day regimens. Methods: TN-AML patients who were not candidates for intensive chemotherapy based on age (≥ 65 y), poor performance status (PS 2), comorbidities, or poor risk cytogenetics were enrolled in 2 separate treatment cohorts in the Phase 2 study. In the first cohort, patients were randomized (1:1) to either 60 mg/m2/d or 90 mg/m2/d on Days 1-5 (5-day regimen). In the second cohort, patients were treated with 60 mg/m2/d on Days 1-5 and Days 8-12 (10-day regimen) for up to 4 cycles, followed by 60 mg/m2/d Days 1-5 in subsequent cycles. Cycles were scheduled every 28 days for both regimes with dose reductions/delays allowed based on response and tolerability. Patients remained on treatment as long as they continued to benefit with no unacceptable toxicity. The primary endpoint was the composite Complete Response (CRc): Complete Response (CR) + CR with incomplete platelet recovery (CRp) + CR with incomplete neutrophil recovery (CRi) using modified International Working Group (IWG) criteria (Cheson et al, 2003). Secondary endpoints included overall survival (OS), and safety. Results: There was no difference in efficacy or safety between 60 and 90 mg/m2/d on the 5-day regimen (Yee et al, European Hematology Association meeting 2014, S647), so data are reported here for the two doses combined on the 5-day cohort. There were 51 patients treated in the 5-day regimen cohort and 52 treated with the 10-day regimen. There was no statistically significant difference in patient characteristics between the 2 regimens; median age 77.9 vs. 77.3 years ; male 59% vs. 65%; PS 2 or higher 35% vs. 40%; median BM blasts 40.0% vs. 49.5%; poor risk cytogenetics 46% vs. 43% for the 5-day and 10-day cohorts, respectively. Follow up of the 10-day cohort patients was shorter as it started after completion of enrolment of the 5-day cohort. The median follow up was 25.7 and 12.4 months and median number of cycles was 5 (range 1-26) and 3 (range 1-13) for the 5-day and 10-day cohorts, respectively. There was no significant difference in the primary efficacy endpoint, CRc, between the 2 regimens (p=0.43). CRc was achieved in 29/51 patients (57%) on the 5-day regimen (19 CR, 3 CRp, and 7 CRi) and in 25/52 patients (48%) on the 10-day regimen (16 CR, 5 CRp, and 4 CRi). Median OS was 10.5 and 8.7 months for the 5-day and 10-day cohorts, respectively (p=0.89). The 30, 60, and 90-day all-cause mortality rates were not statistically significant between the two cohorts: 5.9%, 15.7%, and 21.6% on the 5-day regimen and 1.9%, 17.3%, and 28.8% on the 10-day regimen. The most common Grade ≥3 AEs regardless of relationship to guadecitabine were: febrile neutropenia 59% vs. 60%, thrombocytopenia 47% vs. 38%, neutropenia 39% vs. 33%, anemia 27% vs. 19%, pneumonia 24% vs. 27%; and sepsis 12% vs. 19%, for the 5-day and 10-day cohorts respectively, none of which was statistically significant. Fifteen patients remain on treatment (5 from the 5-day cohort and 10 from the 10-day cohort). Conclusions: Guadecitabine is clinically active with a good safety profile in TN-AML patients not candidates for intensive chemotherapy. Unlike in relapsed/refractory AML, where the 10-day regimen of guadecitabine showed a trend toward improved efficacy (Roboz et al, Annals of Oncology 25 Supplement 4, 2014), there was no significant difference in either efficacy or safety between the 5-day and 10-day regimens in newly diagnosed AML patients. Guadecitabine 60 mg/m2/d SC Days 1-5 is currently being investigated in an 800-patient multicenter randomized phase 3 study in TN-AML patients unfit to receive intensive chemotherapy (ASTRAL-1 Phase 3 clinical trial: ClinicalTrials.gov reference NCT02348489). Disclosures Kropf: Teva Pharmaceuticals: Consultancy. O'Connell:Celgene: Speakers Bureau; Incyte: Membership on an entity's Board of Directors or advisory committees. Griffiths:Astex: Research Funding; Alexion Pharmaceuticals: Honoraria; Celgene: Honoraria. Rizzieri:Teva: Other: ad board, Speakers Bureau; Celgene: Other: ad board, Speakers Bureau. Stock:Gilead: Membership on an entity's Board of Directors or advisory committees. Savona:Karyopharm: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Incyte: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees. Rosenblat:Astex Pharmaceuticals, Inc.: Research Funding. Berdeja:Celgene: Research Funding; Onyx: Research Funding; BMS: Research Funding; Abbvie: Research Funding; Array: Research Funding; Curis: Research Funding; Acetylon: Research Funding; MEI: Research Funding; Janssen: Research Funding; Novartis: Research Funding; Takeda: Research Funding. Wilson:Astex Pharmaceuticals, Inc.: Employment. Lowder:Astex Pharmaceuticals, Inc.: Employment. Taverna:Astex Pharmaceuticals, Inc.: Employment. Hao:Astex Pharmaceuticals, Inc.: Employment. Azab:Astex Pharmaceuticals, Inc.: Employment. Issa:Janssen: Consultancy; Astex Pharmaceuticals, Inc.: Consultancy.

Although the past decade has brought improvements in the treatment of AML, particularly for younger individuals, most patients succumb to the disease. With current induction therapy, most patients achieve remission, but the optimal strategy for post-remission therapy is unclear. Refinements to risk classification systems that incorporate additional molecular markers may better guide physicians in recommendations for postremission therapy. The prognosis for older patients with AML remains uniformly poor, because only a minority can benefit from intensive chemotherapy and novel HCT strategies. Despite active investigation, no standard of care has emerged for patients who are not suitable candidates for standard induction therapy. The development of less toxic, more effective therapies for this population is sorely needed. Advances in molecular genetics, immunology, and the biology of normal and malignant hematopoiesis pathogenesis have led to an improved understanding of the pathogenesis of AML and to the discovery of potential therapeutic targets. Until a greater proportion of individuals with AML attain long-term survival, patients should routinely be referred to cancer centers and enrolled in investigational studies.

The incidence of early death in a large population of unselected patients with acute promyelocytic leukemia (APL) remains unknown because of the paucity of outcome data available for patients treated outside of clinical trials. We undertook an epidemiologic study to estimate the true rate of early death with data from the Surveillance, Epidemiology, and End Results (SEER) program. A total of 1400 patients with a diagnosis of APL between 1992 and 2007 were identified. The overall early death rate was 17.3%, and only a modest change in early death rate was observed over time. The early death rate was significantly higher in patients aged ≥ 55 years (24.2%; P < .0001). The 3-year survival improved from 54.6% to 70.1% over the study period but was significantly lower in patients aged ≥ 55 years (46.4%; P < .0001). This study shows that the early death rate remains high despite the wide availability of all-trans retinoic acid and appears significantly higher than commonly reported in multicenter clinical trials. These data highlight a need to educate health care providers across a wide range of medical fields, who may be the first to evaluate patients with APL, to have a major effect on early death and the cure rate of APL.

Purpose: Lintuzumab (HuM195), a humanized anti-CD33 antibody, targets myeloid leukemia cells and has modest single-agent activity against acute myeloid leukemia (AML). To increase the potency of the antibody without the nonspecific cytotoxicity associated with β-emitters, the α-particle–emitting radionuclide bismuth-213 (213Bi) was conjugated to lintuzumab. This phase I/II trial was conducted to determine the maximum tolerated dose (MTD) and antileukemic effects of 213Bi-lintuzumab, the first targeted α-emitter, after partially cytoreductive chemotherapy. Experimental Design: Thirty-one patients with newly diagnosed (n = 13) or relapsed/refractory (n = 18) AML (median age, 67 years; range, 37-80) were treated with cytarabine (200 mg/m2/d) for 5 days followed by 213Bi-lintuzumab (18.5-46.25 MBq/kg). Results: The MTD of 213Bi-lintuzumab was 37 MB/kg; myelosuppression lasting >35 days was dose limiting. Extramedullary toxicities were primarily limited to grade ≤2 events, including infusion-related reactions. Transient grade 3/4 liver function abnormalities were seen in five patients (16%). Treatment-related deaths occurred in 2 of 21 (10%) patients who received the MTD. Significant reductions in marrow blasts were seen at all dose levels. The median response duration was 6 months (range, 2-12). Biodistribution and pharmacokinetic studies suggested that saturation of available CD33 sites by 213Bi-lintuzumab was achieved after partial cytoreduction with cytarabine. Conclusions: Sequential administration of cytarabine and 213Bi-lintuzumab is tolerable and can produce remissions in patients with AML. Clin Cancer Res; 16(21); 5303–11. ©2010 AACR.

Background: SGI-110 (guadecitabine) is a novel HMA that prolongs in vivo exposure of the active moiety decitabine following subcutaneous (SC) administration. We previously reported guadecitabine clinical activity in previously untreated elderly AML with Overall Complete Response (CR+CRi+CRp) of 55% using a standard 5-day regimen (Yee et al, 2014). Here we report the first results of a more intensive 10-day regimen in the same patient population. Methods: Elderly AML patients (≥ 65y) with at least one of the following characteristics were enrolled: age ≥ 75y; poor Performance Status (PS) ≥ 2; significant comorbidities particularly cardiopulmonary dysfunction; poor risk cytogenetics; or secondary AML. Guadecitabine 60 mg/m2/d SC was administered for 10 days (Days 1-5; and 8-12) for the first 1-2 cycles followed by the 5-day regimen (Days 1-5) for subsequent cycles. Cycles were scheduled every 28 days. Primary endpoint was Overall Complete Response (Overall CR). Secondary endpoints included Overall Survival, Safety including all-cause 30-day and 60-day early mortality, and global maximum DNA demethylation from baseline by LINE-1 assay. Results: Fifty two patients were treated with median age 77 (range 66-92) including 40 (77%) ≥75y; 34 (65%) male; 21 (40%) PS ≥ 2; 19 (36%) poor risk cytogenetics; and 13 (25%) secondary AML. The median bone marrow blasts percentage was 49% (range 16-98%). All patients had a minimum follow up of 3 months; 26 (50%) patients remain on treatment at the time of the analysis. Overall CR was observed in 24 patients (46%):14 CR (27%), 8 CRi (15%), and 2 CRp (4%). There was no significant difference between median DNA demethylation in responders (- 27%) and non-responders (-28%). Early all-cause 30-day and 60-day mortality occurred in 2 (4%) and 10 (19%) patients respectively. The most common Grade ≥3 Adverse Events considered by investigators to be drug-related were febrile neutropenia (33%), thrombocytopenia (27%), neutropenia (21%), anemia (15%), bacteremia (10%), and pneumonia (6%). Conclusions: Administration of guadecitabine as a more intense 10-day regimen for the first 1-2 cycles was active with acceptable toxicity. However, and although it was not a randomized comparison, the 10-day regimen did not result in higher rate of Overall CR in previously untreated AML than what was previously reported for the 5-day regimen. A Phase III randomized clinical trial in previously untreated AML patients not considered candidates for intensive chemotherapy has been initiated with the 5-day regimen of guadecitabine. Reference: Yee K, Daver N, Kropf P, et al: European Hematology Association Meeting, June 12-15, 2104; Milan, Italy. Abstract S647. Citation Format: Gail Roboz, Hagop Kantarjian, Patricia Kropf, Ellen Richie, Nitin Jain, Elizabeth Griffiths, Nikola A. Podoltsev, Katherine Walsh, Casey O'Connell, Wendy Stock, David Rizzieri, Raoul Tibes, Todd Rosenblat, Woonbok Chung, Pietro Taverna, Xiang Yao Su, Sue Naim, Mohammad Azab, Jean-Pierre Issa. First results of a 10-day regimen of SGI-110 (guadecitabine), a second generation hypomethylating agent (HMA) in previously untreated elderly AML who are not candidates for intensive chemotherapy. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr CT321. doi:10.1158/1538-7445.AM2015-CT321

e18025 Background: Using a chemosensitivity screening assay, we showed that combination decitabine and thioguanine was active in primary leukemia cells from patients with relapsed/refractory acute ...

Context: For patients with relapsed/refractory AML, therapeutic success is unpredictable with current chemotherapeutic regimens. Moreover, multiple courses of therapy have resulted in co-morbid conditions which can preclude the patient from receiving a potentially curative bone marrow transplant. Objective: In order to identify a successful chemotherapeutic regimen for these patients, we have developed a high-throughput assay that utilizes primary (patient-derived) leukemia cells and tested for chemo-sensitivity and resistance against a panel of FDA approved agents used to treat AML. Design: This assay was developed in 1536 well format and optimized against a panel of leukemia and lymphoma cell lines to determine optimal concentration of cells needed to achieve statistically significant reproducible results. Twelve point dose response curves were performed in duplicate for all agents. Alamar Blue reduction and Annexin V staining were used as indicators of cell viability. Results: Using this assay, we demonstrated in vitro resistance against drugs already clinically administered and importantly showed in vitro sensitivity to agents that had not been previously administered. The index patient was a 32-year-old woman with primary refractory AML who had received six different therapeutic regimens prior to testing, all of which demonstrated in vitro resistance using our assay. The blasts were sensitive, however, to 6-thioguanine with an inhibitory concentration (EC50) of 70 nanoM. Based on the in vitro data, she began a combination treatment regimen containing 6-thioguanine. Following a maintenance regimen, her circulating blast count decreased, and she had partial recovery of the neutrophil count, resulting in a dramatic decrease in the overall leukemia burden. This result was not seen with her previous therapies. After over six months of this therapy, her WBC began to rise and repeat testing indicated resistance to 6-thioguanine with EC50 > 10 microM, confirming the response seen in vivo. We have gone on to test samples from more than twenty-five patients with AML and have accurately predicted the in vivo clinical response (both sensitivity and resistance). In the above case, the treatment regimen identified from the screening results is now being tested in a Phase I clinical trial for patients with relapsed/refractory AML or elderly patients unfit to receive standard AML therapy. In other cases, the treatment regimen identified from the screen provided the needed bridge to allogeneic bone marrow transplantation. Conclusions: These data demonstrate that the technology described here to pharmacologically screen drug therapy for patients with relapsed/refractory AML is both clinically useful and has a role in designing individualized treatment regimens for these patients. Citation Format: David Shum, Ruth Santos, Mark Heaney, Renier Brentjens, Peter Maslak, Todd Rosenblat, Joseph Jurcic, Hakim Djaballah, Mark G. Frattini. A novel high-throughput screen of primary leukemia cells to personalize therapy for relapsed/refractory acute myeloid leukemia (AML): Proof of concept and clinical implementation of precision medicine. [abstract]. In: Proceedings of the AACR Precision Medicine Series: Drug Sensitivity and Resistance: Improving Cancer Therapy; Jun 18-21, 2014; Orlando, FL. Philadelphia (PA): AACR; Clin Cancer Res 2015;21(4 Suppl): Abstract nr B10.

Background: Using a chemosensitivity screening assay, we previously demonstrated that decitabine and thioguanine combinations can rescue therapeutic efficacy in primary leukemia cells isolated from patients with relapsed and refractory acute myeloid leukemia (AML). Although both decitabine and thioguanine have single-agent anti-leukemic activity, they have not previously been used concurrently. To test the safety and preliminarily assess possible additive/synergistic activity of this combination, we are performing a Phase I dose escalation trial of thioguanine given with decitabine. Patients and Methods: Patients with untreated AML over 60 years who are not suitable candidates for standard induction therapy, as well as those with relapsed/refractory AML, advanced myelodysplastic syndrome, and chronic myelomonocytic leukemia (CMML) are eligible. Three thioguanine dose levels are being evaluated: 80, 120, and 160 mg/m2/day, given in two divided doses on Days 1-12 of each induction course for up to two cycles and Days 1-7 of maintenance cycles. Decitabine 20 mg/m2 is administered IV on Days 3-12 during induction cycles and on Days 3-7 during maintenance cycles. In addition to standard safety measures and clinical outcomes, the biologic activity of the combination is assessed by patient specific pharmacodynamic measures. These measures include an in vitro chemosensitivity assay, genome-wide analysis of DNA methylation changes, and BH3 profiling in order to measure the degree to which samples are primed to undergo apoptotic cell death. Results: Six patients (median age, 69 yrs; range, 66–83 yrs) with newly diagnosed AML (n=2), relapsed/refractory AML (n=3), and newly diagnosed CMML (n=1) have been treated to date with thioguanine at the 80 mg/m2 dose. Dose-limiting toxicity was seen in one patient who developed acute renal failure (ARF) requiring hemodialysis. Infectious complications were the most common toxicity and included two episodes of grade 3 neutropenic colitis in one patient, grade 3 pseudomonal bacteremia, grade 3 staphylococcal bacteremia, and a dental infection requiring extraction. No other grade 3–4 non-hematologic toxicities were observed. Three patients remain on active treatment three to seven months from the initiation of therapy. Two patients were removed from study due to disease progression (n=1) and grade 4 ARF noted above (n=1). A patient with CMML was removed to undergo allogeneic hematopoietic stem cell transplantation after achieving a hematologic remission with red cell transfusion independence and platelet count normalization. The median number of cycles administered was 3 (range, 1-5). Bone marrow blast reductions to less than 5% were seen in all 4 evaluable patients with AML and included 1 CR and 1 CRi. The overall response rate in this high risk patient population was 67% (4 of 6 patients). Importantly, the patient who achieved a CR was 83 years old with relapsed disease following 4 previous cycles of single-agent decitabine therapy, demonstrating that this regimen can rescue previous hypomethylating agent failures. Clinical activity was well-correlated with the in vitro cytotoxicity assays. The chemosensitivity assay results for thioguanine on pre-treatment mononuclear cells directly correlated with clinical outcome in both response to therapy and clinical resistance. BH3 profiling was also performed on pre-treatment myeloblasts. Significant apoptotic priming corresponded to good initial clinical response. In addition, in the single patient who responded and subsequently relapsed, decreased apoptotic priming was observed in the relapsed sample, suggesting that the thioguanine/decitabine regimen applies selective pressure for reduction in apoptotic priming. Detailed analysis of treatment-related changes in DNA methylation will be presented and compared to prior work showing decitabine-induced hypomethylation in CD34+ leukemic cells during single agent therapy with decitabine. Conclusions: Combination decitabine and thioguanine has been well-tolerated and has shown surprising anti-leukemic activity at the lowest dose level studied. Importantly, the in vitro chemosensitivity testing and BH3 profiling accurately predicted the observed clinical responses while also confirming the etiology of the loss of therapeutic response. Accrual to this trial continues at higher dose levels to determine the maximum tolerated dose. Disclosures Letai: AbbVie, Inc: Consultancy, Research Funding; Tetralogic: Consultancy, Research Funding.

Background: SGI-110 is a second generation HMA formulated as a dinucleotide of decitabine (DAC) and deoxyguanosine delivered as a small volume SC injection that yields longer half-life and more extended DAC exposure than DAC IV infusion. A phase 1 clinical trial of SGI-110 demonstrated a differentiated pharmacokinetic profile from DAC IV, potent hypomethylation, and clinical responses in previously treated patients with MDS and AML (Kantarjian et al. 2012). Phase 1 established 60 mg/m2 QDx5 as the biologically effective dose (BED), and 90 mg/m2QDx5 as the Maximum tolerated dose (MTD) in MDS patients given in 28-day cycles. Phase 2 is conducted to evaluate dose response between the BED and MTD in MDS patients. Methods: Int, or HR MDS, and CMML patients who were either treatment-naïve or previously treated were randomized to either 60 mg/m2 or 90 mg/m2QDx5 every 28 days. Efficacy was evaluated by the clinical responses of CR, PR, marrow CR (mCR), and Hematological Improvement (HI) based on the International Working Group Criteria 2006 as well as transfusion-independence. Adverse events (AEs) as graded by the CTCAE v4 criteria and pharmacodynamic biological activity as measured by Long Interspersed Nucleotide Element LINE-1 (an index of global DNA methylation) were also assessed. Patients are being followed for overall survival. Results: The study completed target enrolment with 102 patients: 53 who were refractory or have relapsed on prior treatment, and 49 previously untreated. Fifty three patients were randomized to 60 mg/m2 and 49 patients to 90 mg/m2 QDx5 with a median follow up of 8.2 months (range 1-21). Most baseline patient characteristics were well balanced between the 2 treatment arms with no significant differences in median age (71.7 vs. 72.5 y); male gender (70 vs. 61%); ECOG PS 2 (15 vs. 12%); HR MDS (28 vs. 37%); transfusion-dependence (57 vs. 55%), median baseline Hb (9.25 vs. 9.3 g/dL); platelets count (42.5 vs. 45 x109/L), and neutrophils count (1.19 vs. 1.16 x109/L) for the 60 and 90 mg/m2 QDx5 respectively. However, there were 15 CMML patients (28%) randomized to 60 mg/m2 vs. only 7 CMML patients (14%) randomized to 90 mg/m2(p=0.097). All but 2 patients in the previously treated group received one or more HMA. At the time of the data cutoff, 38 of 102 patients (37%) were still on treatment. Median number of treatment cycles was 4 for previously treated patients, and 5 for the treatment naïve group (range 1-22 cycles). CR+mCR were observed in 10/53 (19%), and 11/49 (22%) in the 60 and 90 mg/m2 arms respectively (p=0.8). CR was observed in 7/49 treatment naïve patients (14%) while CR+mCR were observed in 11/53 previously treated patients (21%) with no significant differences between 60 and 90 mg/m2 arms. Transfusion independence for at least 8 weeks was reported in 32% and 24% for platelets and RBCs respectively with no difference between the 2 treatment arms. Treatment naïve patients benefited from higher rate of transfusion-independence (58% and 46% for platelets and RBCs respectively). Potent demethylation was achieved in both treatment arms with a mean LINE-1 DNA demethylation of 27.3 and 30.5% for 60 and 90 mg/m2 respectively (p=0.12). Overall incidence of Grade ≥3 AEs regardless of relationship to treatment was reported in 81 vs. 88% for 60 and 90 mg/m2 treatment arms respectively (p=0.42).There was a slightly higher but non-significant difference in Grade ≥3 thrombocytopenia (51 vs 38%) and pneumonia (20 vs. 13%) for the 90 mg/m2 arm compared to 60 mg/m2. Early 8-week any-cause mortality occurred in 3/102 patients treated (3%), 2 at 60 and 1 at 90 mg/m2. Follow up for survival is still ongoing. Conclusions: SC SGI-110 is a well-tolerated novel HMA with biological and clinical activity in the treatment of Int and HR MDS, and CMML patients with particularly promising activity in patients previously treated with azacitidine or decitabine. Clinical responses, transfusion independence, DNA demethylation as assessed by LINE-1, and Safety did not significantly differ between the 2 treatment doses. Disclosures Tibes: Astex Pharmaceuticals, Inc.: Research Funding. Rosenblat:Astex Pharmaceuticals, Inc.: Research Funding. Yee:Astex Pharmaceuticals, Inc.: Research Funding. Griffiths:Astex Pharmaceuticals, Inc.: Research Funding. Issa:Astex Pharmaceuticals, Inc.: Consultancy, Research Funding. Naim:Astex Pharmaceuticals, Inc.: Employment. Taverna:Astex Pharmaceuticals, Inc.: Employment. Hao:Astex Pharmaceuticals, Inc.: Employment. Azab:Astex Pharmaceuticals, Inc.: Employment. Roboz:Astex Pharmaceuticals, Inc.: Consultancy.

Abstract 3815 Background: The activity of DNA methyltransferase inhibitor (DNMTI) monotherapy is suboptimal for most patients (pts) with myelodysplastic syndromes (MDS) and acute myelogenous leukemia (AML). DNMTI combinations studied to date have not convincingly produced higher response rates compared to DNMTI monotherapy, although time to response appears to be improved in some studies. We combined decitabine (DAC) with tretinoin (ATRA), an RAR ligand which can recruit histone acetyltransferases to gene regulatory regions, as a means to upregulate gene expression, and to induce apoptosis or differentiation, as is seen in in vitro studies of non-M3 AML. Our previous phase 1 study established 65 mg/m2/day of ATRA as the MTD (headache was DLT at 85 mg/m2/d) when given on days 10–19 following standard dose decitabine (20 mg/m2/d), given on days 1–5 of a 28-day cycle (Klimek VM, et al. Leuk Res, 2011;35:S70-S). Materials and Methods: MDS pts with any FAB or WHO subtype were enrolled if they had an IPSS score ≥ 0.5, were ineligible for allogeneic stem cell transplant (AlloSCT) at study entry, and had adequate hepatic and renal function. Prior DAC or 5-azacytidine (5-aza) responders who then progressed off treatment, and pts whose MDS progressed on 5-aza were eligible. Pts received up to 10 cycles of DAC (given on days 1–5) and tretinoin (65 mg/m2/d on days 10–19 of a 28-day cycle), allowing for delays due to infection or to allow count recovery as deemed necessary by the treating physician. Those with an ongoing response after 10 cycles continued DAC alone off-study. The primary endpoint is efficacy, assessed after even-numbered cycles using the 2006 Modified International Working Group MDS response criteria. Kaplan-Meier methodology was used to estimate duration of best response due to the censoring for patients undergoing AlloSCT. Results: 36 eligible pts (27M, 9F; median age 66, range 45–84 yrs) were enrolled in the phase 2 cohort as of 6/2012. FAB/WHO subtypes included: RA/RCMD, n=3 (8%); RARS/RCMD-RARS, n=1 (3%); RAEB/RAEB-1 & 2, n= 24 (67%); RAEBt/AML, n= 6 (17%); CMML/CMML-1, n=2 (6%). IPSS risk categories included: Int-1, n=5 (14%); Int-2, n=16 (44%); High Risk, n=11 (31%), and pts with ≥ Int-1 (n=3) or ≥ Int-2 (n=1) risk disease who could not be definitively classified using the IPSS. Most pts (n=20) had IPSS poor risk cytogenetics (CG), 11 had IPSS good risk CG (all with normal karyotype), 3 had intermediate risk CG, and CG results were unknown in 2 pts. 15/36 (42%) had therapy-related disease (t-MDS/AML), all with IPSS poor risk CG and either IPSS Int-2 (n=9) or High Risk (n=6) disease. Marrow blasts were ≥ 5% in 26/36 pts: (5–10%, n=13; 11–20%, n=13; 21–30%, n=6). Prior MDS therapy included lenalidomide (n=2), thalidomide (n=1), 5-aza (n=3), DAC (n=1), and lintuzumab (n=1). Pts received a median of 4 cycles of therapy (range, 1–10), and started therapy 0.6–180 months (median, 1.42 months) from the time of diagnosis. Two pts were classified as treatment failures since they died during the first cycle of therapy. One pt with CMML-1 at baseline progressed to AML during the screening period, and was deemed ineligible. Two pts on study have not yet had a full response assessment. Best responses in the evaluable intent to treat cohort (n=33) include: CR, n=7 (21%); PR, n=1 (3%); mCR, n=3 (9%); mCR+HI, n=3 (9 %); HI alone, n=3 (9 %); Stable disease, n=10 (30%); Disease progression, n= 3 (9%). The composite CR rate (CR+mCR±HI) was 39% (13/33), and the overall response rate (CR+PR+mCR±HI+HI) is 51% (17/33). Median time from diagnosis to start of therapy for responders was 1.7 months (range, 0.8–180). The ORR for the 13 t-MDS/AML pts was 46% (6/13), including 5 pts with monosomy 17 and/or p53 loss by FISH. The median time to initial response and best response is 1.1 months and 2.3 months, respectively. The median response duration is 7.8 months, incorporating the 7 pts censored at the time they came off study to undergo AlloSCT. Conclusions: DAC/ATRA is active in IPSS Int-2 and High Risk MDS and in t-MDS/AML, which is characterized by poor risk cytogenetics and an increased frequency of p53 or chromosome 17p loss. Although our interim ORR appears similar to DAC and 5-aza monotherapy trials, our results were achieved in a higher risk cohort, and the CR rate is equal to or greater than some earlier monotherapy studies with a shorter median time to response. Ongoing and planned correlative studies may define pre-treatment biomarkers for response. Disclosures: Off Label Use: Tretinoin.

Abstract 3624 WT1 is a transcription factor which has been implicated in leukemogenesis and has been used as a marker of minimal residual disease (MRD). We previously demonstrated the feasibility of vaccinating AML patients in CR with a multivalent WT1 peptide vaccine and inducing immune responses. In an effort to further explore the safety and efficacy of this approach, we are conducting a Phase II study in which the vaccine is administered to AML patients in first CR and who completed all planned postremission chemotherapy. Eligible patients had WT1 transcript detectable by RT-PCR. The vaccine consisted of 4 native and derived WT1 peptides administered with the immune adjuvants Montanide and GM-CSF. Patients received 6 vaccinations over 10 weeks. Early toxicity was assessed at weeks 2 and 4. Immune responses were evaluated at week 12 by CD4+ T cell proliferation, CD3+ T cell interferon-g interferon release (ELISPOT) and WT1 peptide tetramer staining. Patients who were clinically stable and without disease recurrence could continue with up to 6 more vaccinations administered approximately every month. To date, 12 patients have been accrued to the study (6-M, 6-F; median age – 66 years, range 26–73 years). Cytogenetic subtypes varied among the study patients (Favorable-3, Intermediate-5, Unfavorable-4). The median time to vaccination after achieving CR was 7.5 months (range: 3–22 months). One patient was removed early because of relapse prior to receiving the first vaccination. Four patients have received at least 6 vaccines and 2 others have completed 12 vaccinations. Eight patients are alive without evidence of disease. One of these patients has an HLA-A02 subtype and was found to have developed T cells reactive with WT1-A (native peptide) HLA tetramers following 6 vaccinations which persisted (at a lower level) until after the 12th vaccination. Three patients relapsed during vaccination (after 1, 5 and 11 vaccines) and 2 of the 3 have died. Two of the relapsed patients who had sample available for immunologic evaluation, did not develop a CD4+ response to any of the peptides tested. Two other patients discontinued vaccination because of toxicity (hypersensitivity/pain with GM-CSF administration). Both remain in CR. No episodes of anaphylaxis or generalized urticaria were observed. Neither median disease free survival nor overall survival has been reached in this small cohort of patients. These preliminary findings demonstrate that the WT1 peptide vaccine is relatively well tolerated and has immunologic activity. Trial accrual is ongoing and further follow-up is required before any beneficial effect on outcome can be determined. Disclosures: Scheinberg: Formula Pharma: WT1 Vaccine inventor, Patent held by MSKCC and Licensed to Formula Pharma, WT1 Vaccine inventor, Patent held by MSKCC and Licensed to Formula Pharma Patents & Royalties.

Abstract 4293 Introduction: The Philadelphia chromosome is the most frequent cytogenetic abnormality in adult ALL, with an overall incidence of 20–30%. When treated with conventional therapy, adult patients with Ph+ ALL have an extremely poor prognosis. While current chemotherapy regimens typically induce complete responses (CRs) in the majority of patients, the quality of remission is poor as most patients relapse within 6–11 months of treatment and subsequently die from the disease. The 1 and 5-year overall survival rates for patients treated with imatinib-based chemotherapy regimens is approximately 60% and 30%, respectively. Previously we in collaboration with others have reported a Phase III randomized study of high-dose cytarabine and mitoxantrone (ALL-2 regimen) as induction therapy versus a more traditional treatment regimen with vincristine-prednisone based induction therapy in newly diagnosed adult ALL patients (Weiss, ASCO 2005). This study was conducted prior to the routine use of tyrosine kinase inhibitors (TKIs) for Ph+ disease. In that randomized study, there were 16 patients with Ph+ ALL treated with the frequency of CRs on the ALL-2 regimen 85% compared to 47% of patients treated on the vincristine-prednisone based arm. At 6 year follow-up, 26% of Ph+ patients treated with the ALL-2 regimen were alive compared to 0% of Ph+ ALL patients treated on the vincristine-prednisone induction arm. Based on this initial favorable response seen with the ALL-2 regimen in Ph+ patients and the emerging use of TKI therapy in Ph+ALL, dasatinib was added to this therapeutic regimen. This is the first report of this combination in newly diagnosed patients with Ph+ ALL or blastic phase CML patients. Methods: Eligible patients included previously untreated or treated adults with a diagnosis of Ph+ ALL or lymphoid blast crisis of known CML. Patients must have evidence of t(9;22) in leukemic cells based on chromosomal or molecular analysis. Patients received induction therapy with high-dose cytarabine (3000 mg/m2 IVPB daily, days 1–5) and mitoxantrone (80mg/m2 IVPB on day 3 for patients ≤ 65 yrs or 40mg/m2 for patients >65 yrs) in combination with dasatinib. Patients in the phase I portion of the study were assigned to one of 3 successive dose cohorts of dasatinib: dose level 1: 70mg daily, dose level 2: 100mg daily; dose level 3: 140mg daily, starting on day 1. Patients then received treatment with Consolidation A: vincristine, dexamethasone, and dasatinib. Following consolidation A, patients who achieved a CR and were ≤ 70 years of age and had a suitable HLA donor were referred for allogeneic stem cell transplant. The remaining patients continued consolidation and maintenance therapy per the ALL-2 regimen with dasatinib as per protocol. Results: Seven patients with Ph+ disease were enrolled between 3/2010-11/2011 (Table 1). All (100%) achieved complete remission after induction; 6 of the seven patients (86%) were in both cytogenetic and molecular remission. Although the numbers are small, there does not seem to be a difference in response depending upon the dose level of dasatinib administered. One patient was taken off study due to recurrent gastrointestinal issues but continued to be followed for response and survival and completed induction therapy as per protocol. Six of the seven patients (86%) went on to receive allogeneic stem cell transplant in first remission. The patient who was ineligible for allogeneic stem cell transplant due to multiple comorbidities continues on maintenance chemotherapy as per protocol. Two patients have died in remission due to post transplant complications. One patient became MRD positive post-transplant and is on nilotinib therapy. Median overall survival has not been reached with median follow-up greater than 20 months. Conclusions: The addition of dasatinib to high-dose cytarabine and mitoxantrone induction therapy for patients with Ph+ ALL is tolerable and efficacious. Patients achieved a higher frequency of CRs compared to our historical study that did not use TKI-based therapy in this patient population. Long-term follow-up of these patients is ongoing. Disclosures: Lamanna: Bristol Meyers Squibb: Research Funding. Off Label Use: dasatinib as part of initial therapy for patients with Philadelphia chromosome + ALL.

6609 Background: While CIT has proven active for younger patients with CLL; studies from Germany and MDACC with fludarabine or fludarabine- based regimens did not benefit the patient over the age of 65 or 70. As the median age of diagnosis is 72, the development of safe, active therapies for older patients is an unmet need in CLL. Lenalidomide is an active drug in CLL. The current clinical trial was designed to assess whether low-dose continuous lenalidomide therapy can provide long-term disease control with minimum toxicity in patients older than 65. Methods: Patients initiate lenalidomide at 2.5mg daily (28-day cycle) and only dose escalate for progressive disease (POD). Results: 18 patients have been enrolled: 12 men and 6 women, med age 70 (range 65-84) with Rai-intermediate (7 pts) or high-risk (11 pts; 61%) disease; med WBC 50.5 (6.7-326.3), HGB 10.3 (8.9-13.9), PLT 121 (44-215), β-2 microglobulin 4.9 (3.0-10.2). 16 (89%) patients had chromosomal abnormalities: 3 with 13q, 6 with tris 12, 3 with 11q, and 4 with 17p. 13 (72%) patients have unmutated IGHV. 5 (28%) patients were previously untreated; 13 (72%) had prior therapy (range 1-5; med 2). Median dose of lenalidomide is 2.5mg (range 2.5mg-10mg); median no. cycles is 7 (range 1-28). 11 patients (61%) are still on therapy (7 previously treated): 6 at 2.5mg; 4 at 5mg, and 1 at 10mg. 7 have discontinued therapy: 1 for ITP; 3 for POD including one with Richter’s, 2 for desquamating rash; and 1 withdrew consent. Only 2 patients had tumor lysis and 10 had tumor flare (8 given steroids briefly). In these older patients on long-term continuous treatment, therapy has been generally well tolerated. There have been no deaths on study. Pneumonia developed in 4 patients (3 of these had prior therapy). 1 patient with history of atrial fibrillation developed DVT/PE. Main hematologic toxicity is neutropenia seen in 11 patients but transient. Grade 3/4 thrombocytopenia and anemia was seen in 5 and 0 patients, respectively. Conclusions: Low-dose continuous lenalidomide therapy iappears to be well-tolerated and may offer long term disease control in some patients with CLL. Additional accrual and longer follow-up will be required to further assess the utility of this strategy.

Abstract 4433 One of the aims of the National Comprehensive Cancer Network (NCCN) is to provide physicians with state-of- the- art treatment pathways for specific malignancies. These guidelines are frequently updated, and disease- based committee members either meet or speak with each other at least once a year. However, it is not known to what extent these guidelines are actually used in clinical practice. In order to determine how physicians in a single large academic cancer center utilize NCCN guidelines for patients with chronic myelogenous leukemia (CML), we reviewed 20 randomly chosen patients with CML diagnosed between 2002 –2007 and 2008– 2010, using 2008 as the year when the more contemporary testing schedule for FISH and PCR was established. Nine physicians, median age 51 years (range 35–61) with a median clinical care experience of 21 years (range 2–30), cared for these patients. The median age of the patients was 58 (range 22–56), 11 were male, and median follow up was 4 years (range 1–8). Eleven patients began treatment in 2008 or later. CML guidelines were divided into two main components: (1) documentation of CML by bone marrow (BM) studies at time of diagnosis, and after 6 and 12 months of imatinib (IM) therapy, and (2) frequency of testing with either BM or peripheral blood (PB) FISH and PCR for BCR-ABL. Of the 20 patients, 17 had diagnostic BMs performed on their initial visit here, and 3 had PB confirmation of disease, having had BMs done on the outside 1, 2, and 5 months prior to their initial visit. Thirteen of the 20 patients had BMs performed after 6 months of IM therapy, and 11 had BMs performed at 12 months; 5 patients had negative karyotype and FISH studies on their 6th month BM and thus did not have a repeat BM at month 12. Thus, NCCN guidelines were followed in 80% of patients. The most common deviation from NCCN guidelines was the frequency of interim PB and/or BM testing using FISH and PCR. While the median interval for PB testing was every 3 months (range 1 to 6), significant numbers of patients had much more frequent testing. For example, 13 of the 20 patients had serial PB FISH performed after at least one negative FISH result; 3 patients had > 5 samples analyzed and one patient had 10 samples tested after at least one negative result. In all these patients, subsequent FISH tests results after the first negative test were also negative. Two patients had BM testing performed after PB PCR was negative in at least two prior samples; BM PCR results were also negative. Three patients had simultaneous BM and PB PCR performed which provided similar results. At the time of last testing, 19 of the 20 patients had a complete cytogenetic response, 13 patients had a complete molecular response, and 6 patients had a major molecular response. One patient with significant co-morbidities took IM intermittently and had no response to therapy. There were no differences between the two groups with regards to frequency of BM or PB FISH or PCR testing. In summary, in this CML patient population, important therapeutic tests such as BM sampling at diagnosis and at treatment decision points (12 months) were met in the majority of patients. However, interim testing varied widely and in many instances, was redundant, even after publication of NCCN contemporary guidelines. In order to eliminate such unnecessary testing and conserve important resources, improved internal audits and communication between the laboratory and the clinical staff is needed. Disclosures: Jurcic: Actinium Pharmaceuticals, Inc.: Membership on an entity’s Board of Directors or advisory committees, Research Funding. Lamanna:Celgene: Membership on an entity’s Board of Directors or advisory committees.

Abstract 942 Background: Early death in APL, most often due to bleeding, has emerged as the major cause of treatment failure now that curative strategies exist. Despite the routine use of ATRA, EDR remains high (Lehmann et al Leukemia 2011, Park et al Blood 2011). Although the optimal strategy to prevent early death is not clear, the recommendation is to initiate ATRA immediately at first suspicion of the disease without waiting for genetic confirmation. Therefore, we examined the timing of ATRA administration. Methods: To determine time interval from initial presentation to ATRA administration, we retrospectively collected data on all newly diagnosed APL pts presenting between 1992–2009 to 4 institutions: Northwestern University, Chicago, IL (university medical center); Memorial Sloan-Kettering Cancer Center, New York, NY (free standing cancer center); John J. Stroger Hospital of Cook County, Chicago, IL (public hospital); and Rambam Medical Center, Haifa, Israel, (Northern Israel's largest hospital; a tertiary referral center). We also examined 3 other time intervals: presentation to suspicion of APL, suspicion of APL to ordering ATRA, and ordering ATRA to its administration. Results: We identified 205 newly diagnosed APL pts: 46% men, median 48 years (range 1.5–85). Median white blood cell (WBC) count at presentation was 2,100/uL (range 300/uL-222,500/uL); 25% had high risk (HR) disease (WBC >10,000/uL). Median time interval from initial presentation to suspicion of APL was 1 day and median time from suspicion of APL to ordering ATRA was an additional day (table 1). ATRA was ordered on the day APL was suspected in 32% pts, the next day in 31%; 2 days after suspicion in 17%; and after 3 or more days in 16%. 89% received ATRA on the day ordered. At least 1 bleeding episode was identified in 34% of 185 pts with bleeding data available. Bleeding was associated with higher WBC count (p=0.0003) and lower hemoglobin (p=0.027) at presentation. 46 of 186 pts with complete information on time from presentation to administration of ATRA died. 23 (12%) died within 30 days of presentation; comprising half of all fatalities. Causes of death were: hemorrhage −15, sepsis −4, suspected MI −2, pneumonia −1, and sepsis plus differentiation syndrome -1. Among deaths within 30 days, 48%, 22%, 26% and 7% were in 1st through 4th weeks, respectively. 4 (18%) of these 23 pts died before ATRA was administered, all day 1 or 2 after presentation and all from bleeding. Only 15/182 pts received ATRA on day of presentation. Two of these 15 (13%) died within 30 days (none from bleeding). In comparison, 7/40 (18%) who received ATRA on day after presentation died within 30 days (71% from bleeding). 10/127 (8%) who received ATRA on day 2 or after died within 30 days (6 from bleeding). 20% in each group who received ATRA on either day of presentation or day 1 after presentation had HR disease. For this subgroup, if ATRA was administered on the day APL was suspected or one of the following 2 days, EDR was 19% (7/37). However, if ATRA was initiated on day 3 or 4, EDR was 80% (4/5); (p=0.013). 59% received ATRA prior to confirmation and 41% received ATRA on the day APL was confirmed or later. Conclusions: (1) APL was suspected rapidly upon presentation, usually within 1 day and ATRA was almost always administered on the day ordered. (2) However, ATRA was not given to most pts the day APL was suspected and for some 2 or more days elapsed. This time interval contributed to the delay in ATRA administration, suggesting physicians waited for marrow morphology or genetic confirmation before ordering ATRA. (3) Although at these centers a lower EDR (12%) than reported from the SEER database (17.3%) was observed, the current recommendation to give ATRA at first suspicion of APL was often not practiced. (4) There appears to be an association between EDR and timing of ATRA administration; other factors contribute to the EDR including variability in blood product support. (5) Our study argues that educating health care professionals who are the first to encounter APL pts as to the urgency of ATRA administration will reduce early deaths that occur even in the ATRA era. Disclosures: No relevant conflicts of interest to declare.

Abstract 768 Background: Lintuzumab, a humanized anti-CD33 antibody, targets myeloid leukemia cells and has modest activity against AML. To increase the antibody's potency yet avoid nonspecific cytotoxicity seen with β-emitting isotopes, the α-emitter bismuth-213 (213Bi) was conjugated to lintuzumab. Substantial clinical activity was seen in phase I and II trials, but the use of 213Bi is limited by its 46-min half-life. The isotope generator, 225Ac (t½=10 days), yields 4 α-emitting isotopes and can be conjugated to a variety of antibodies using DOTA-SCN. 225Ac-labeled immunoconjugates kill in vitro at radioactivity doses at least 1,000 times lower than 213Bi analogs and prolong survival in mouse xenograft models of several cancers (McDevitt et al. Science 2001). Methods: We are conducting a first-in-man phase I dose escalation trial to determine the safety, pharmacology, and biological activity of 225Ac-lintuzumab in AML. Results: Fifteen patients (median age, 62 yrs; range, 45–80 yrs) with relapsed (n=10) or refractory (n=5) AML were treated to date. Patients received a single infusion of 225Ac-lintuzumab at doses of 0.5 (n=3), 1 (n=4), 2 (n=3), 3 (n=3), or 4 (n=2) μCi/kg (total administered activity, 23–402 μCi). No acute toxicities were seen. Myelosuppression was the most common toxicity; the median time to resolution of grade 4 leukopenia was 26 days (range, 0–71 days). DLT was seen in 3 patients, including myelosuppression lasting >35 days in 1 patient receiving 4 μCi/kg and death due to sepsis in 2 patients treated at the 3 and 4 μCi/kg dose levels. Febrile neutropenia was seen in 4 patients, and 4 patients had grade 3/4 bacteremia. Extramedullary toxicities were limited to transient grade 2/3 liver function abnormalities in 4 patients. With a median follow-up of 2 mos (range, 1–24 mos), no evidence of radiation nephritis was seen. We analyzed plasma pharmacokinetics by gamma counting at energy windows for 2 daughters of 225Ac, francium-221 (221Fr) and 213Bi. Two-phase elimination kinetics were seen with mean plasma t½-α and t½-β of 1.9 and 35 hours, respectively. These results are similar to other lintuzumab constructs labeled with long-lived radioisotopes. Peripheral blood blasts were eliminated in 9 of 14 evaluable patients (64%), but only at doses of ≥1 μCi/kg. Bone marrow blast reductions were seen in 8 of 12 evaluable patients (67%) at 4 weeks, including 6 patients (50%) who had a blast reduction of ≥50%. Three patients treated with 1, 3, and 4 μCi/kg achieved bone marrow blast reductions to ≤5%. Conclusions: This is the first study to show that therapy with a targeted α-particle generator is feasible in humans. 225Ac-lintuzumab has antileukemic activity across all dose levels. Accrual to this trial continues to define the MTD. Disclosures: Jurcic: Actinium Pharmaceuticals, Inc.: Membership on an entity's Board of Directors or advisory committees, Research Funding. McDevitt:Actinium Pharmaceuticals, Inc.: Consultancy, Research Funding. Cicic:Actinium Pharmaceuticals, Inc.: Employment, Equity Ownership, Patents & Royalties. Scheinberg:Actinium Pharmaceuticals, Inc.: Membership on an entity's Board of Directors or advisory committees, Patents & Royalties, Research Funding.

6619 Background: Arsenic trioxide (ATO) can induce remission in 80-90% of patients (pts) with relapsed APL. For pts achieving a 2nd remission autologous stem cell transplant (ASCT) improves 5-year ...

6516 Background: Lintuzumab, a humanized anti-CD33 antibody, targets myeloid leukemia cells and has modest activity against AML. To increase the antibody’s potency yet avoid nonspecific cytotoxicity seen with β-emitting isotopes, the α-emitter bismuth-213 (213Bi) was conjugated to lintuzumab. Substantial clinical activity was seen in phase I and II trials, but the use of 213Bi is limited by its 46-min half-life. The isotope generator, 225Ac (t½=10 days), yields 4 α-emitting isotopes and can be conjugated to antibodies using DOTA-SCN. 225Ac-labeled immunoconjugates kill in vitro at doses at least 1,000 times lower than 213Bi analogs and prolong survival in mouse xenograft models of several cancers. Methods: We are conducting a first-in-man phase I dose escalation trial to determine the safety, pharmacology, and biological activity of 225Ac-lintuzumab in AML. Results: Twelve patients (median age, 65 yrs; range, 45-80 yrs) with relapsed/refractory AML were treated to date. Patients received a single infusion...

Abstract 1992 The myeloproliferative neoplasms (MPN) can have a variable natural history. Polycythemia vera and essential thrombocythemia, in particular, are conditions that can extend over decades, but some patients have clinical progression to myelofibrosis or acute myeloid leukemia. As first articulated by Warburg, cancers are metabolically distinguished from normal tissues by the use of glycolysis under aerobic conditions. To metabolically characterize the blood cells of patients with myeloproliferative neoplasms, we measured the mitochondrial membrane potential using the cyanine dye, JC-1. In examining cells derived from the blood and/or marrow of 159 patients with primary myelofibrosis, polycythemia vera and essential thrombocythemia, we found that the mitochondrial membrane potential (FL2/FL1=electrochemical potential/mitochondrial mass) was elevated compared to the blood cells of normal individuals. Thirty five percent of patients with polycythemia vera and essential thrombocythemia had normal MMP. In contrast, 97% of patients with primary myelofibrosis, post-polycythemia myelofibrosis, post-essential thrombocythemia myelofibrosis and acute myeloid leukemia following an MPN had evidence of cell populations with higher mitochondrial membrane potential. Cells with distinctly higher mitochondrial membrane potential could be indentified in platelets and polymorphonuclear leukocytes; however the MMP of lymphocytes was normal, indicating that the alteration in metabolic state likely occurred in a multipotential myeloid stem cell. Cell populations were confirmed by co-staining with anti-CD19, -CD45, -GlycophorinA and -β3-integrin antibodies. Sequential analysis of patient samples found that the acquisition of higher mitochondrial membrane potential was stable and persistent over 2 years or more of follow up and that elevated membrane potential predisposed patients to disease progression. The balance of patients (65%) with ET had evidence of increased MMP suggesting the possibility of disease in an early state of evolution to a more aggressive condition. The increased MMP did not correlate with the presence of mutation in JAK2. These results indicate that clinically advanced MPN can be characterized by changes in mitochondrial physiology that might be identified non-invasively by flow cytometric staining with JC-1. In addition, the early nature of these changes may help to identify therapeutic targets. Disclosures: No relevant conflicts of interest to declare.

Abstract 872 Background: All-trans retinoic acid (ATRA) with contemporary therapeutic strategies for the treatment of patients with newly diagnosed acute promyelocytic leukemia (APL) have dramatically improved outcome. Currently, the major cause for treatment failure is death during induction mostly due to hemorrhage, infection and differentiation syndrome. Since there is virtually no primary resistance to induction and the relapse rate once in complete remission (CR) is very low, reducing the early death rate would be critical to further improve the cure rate. The true rate of early death in the United States (US) is not yet clear. Cooperative group multicenter studies report early death rates of 5–10% within 1 month of starting therapy which is likely an underestimation, in part, due to failure to account for those who die prior to registration on study or possibly other selection biases for enrollment. Methods: We performed an epidemiologic study of the true rate of early death and overall survival (OS) using US population-based datasets of all newly diagnosed patients with APL. The datasets from SEER Program 13 (includes 5 states: Connecticut, Hawaii, Iowa, New Mexico and Utah; 8 metropolitan areas including Detroit, Atlanta, San Francisco-Oakland, Seattle-Puget Sound, Los Angeles, San Jose-Monterey, Alaska Native Registry and rural Georgia) and the New York (NY) State Cancer Registry were used to identify patients with APL registered in the US and NY state from January 1, 1992 to December 31, 2007. Patterns of APL incidence, early death rate, long-term OS over time, and differences in OS by region (urban vs. rural) were analyzed in pre-set time periods of 1992–1996, 1997–2001, and 2002–2007. Results: A total of 1,400 and 721 patients with APL were identified in the SEER program and the NY registry, respectively. The number of registered APL patients was similar between men and women in both datasets, and has steadily increased from 1992–1996 (295 cases in SEER and 143 in NY) to 2002–2007 (681 cases in SEER and 371 in NY). Early death rate, defined as death reported within the first month of diagnosis, was 22.7% in the years 1992–1996, 15.6% in 1997–2001, and 18.1% in 2002–2007 in the SEER program, and 10.9%, 11.9% and 11.2% in the NY registry. No significant differences in the early death rate were observed between urban and rural areas in either datasets. OS at 1 year improved from 59.8% in 1992–1996 to 69.6% in 1997–2001; at 2 years from 53.7% to 65.3%; and at 3 years from 50.2% to 63.7% in the datasets from the SEER program. There were no significant changes in OS from 1997–2001 to 2002–2007, and similar trends in OS were observed in the NY datasets (Figure). Interestingly, when the survival data were analyzed by the urban/rural regions in the SEER program, the greatest improvement was observed in patients treated in the urban counties with absolute increases in 2- and 3-year OS of 15.3% (from 53.1 in 1992–1996 to 68.4% in 2002–2007) and 17.6% (from 49.8 to 67.4%), respectively. In contrast, in patients treated in rural counties, increases in 0.4% (from 62.5 in 1992–1996 to 62.9% in 2002–2007) and 7.3% (from 55.6 to 62.9%) were observed in 2- and 3-year OS, respectively. However, the latter statement should be interpreted with caution since the rural OS estimates are imprecise due to small numbers. Conclusions: The large number of newly diagnosed APL patients and the long follow-up reported here confirm improvement in OS over time in a US population-based study. Disappointingly, the early death rate has changed only modestly since 1992 (22.7% in 1992–1996, and 18.1% in 2002–2007), and appears significantly higher than what is reported in contemporary clinical trials. Furthermore, the long-term OS, though improved over time, appears lower than that reported in clinical trials. In fact, more than 25% of patients are not cured of their disease. OS in patients treated in rural areas appears worse, possibly related, in part, to less access to specialized centers, although the analysis is limited due to small numbers. Strategies to reduce the early death rate in APL and improve OS should include very early introduction of ATRA, arsenic trioxide or both and aggressive blood product support at the very first suspicion of the diagnosis well before genetic confirmation. Disclosures: No relevant conflicts of interest to declare.