ALBERT

Description: Despite advances in understanding of the biology of acute myeloid leukemia (AML), cure remains elusive for the majority of patients. Pro-survival molecules of BCL-2 family play critical roles in leukemia transformation and chemoresistance. The anti-leukemia potency of selective BCL-2 inhibitor venetoclax (ABT-199/GDC-0199) has been demonstrated in AML models (Pan et al. Cancer Discovery 2014). However, venetoclax is often associated with resistance due to its poor inhibition of MCL-1. RAF/MEK/ERK (MAPK) pathway is commonly activated in AML, and can stabilize anti-apoptotic MCL-1 and inactivate the pro-apoptotic BIM. In this study, we evaluated the anti-leukemia effects of concomitant BCL-2 and MAPK blockade by venetoclax in combination with MEK1/2 inhibitor GDC-0973 (cobimetinib). First, anti-leukemia activity of cobimetinib and venetoclax was examined in 18 primary AML samples with diverse genetic alterations. The combination significantly enhanced cell death, as compared to the single agent treatment (Fig 1A). Cobimetinib inhibited cell proliferation in the majority of AML cases (34.2 ± 23.7%) and the cell growth suppression was more profound in the combination group (60.2 ± 28.8%, p

Description: Background: The Hyper-CVAD regimen is safe and effective in the frontline treatment of B-ALL. The addition of rituximab to the Hyper-CVAD regimen (HCVAD-R) improved the 3-year overall survival (OS) to 60% in pts with B-ALL. Ofatumumab is an anti-CD20 monoclonal antibody that binds to the small extracellular loop of the CD20 molecule and has greater in vitro potency and increased complement-mediated cell lysis compared to rituximab. We hypothesized that ofatumumab plus Hyper-CVAD may increase the rates of complete remission (CR) and measurable residual disease negativity (MRD-) and improve survival by decreasing relapse rates. Methods: Pts were eligible if they had newly diagnosed untreated or minimally treated (≤ 1 cycle) Philadelphia chromosome (Ph)-negative CD20+ B-ALL. CD20 positivity was defined as ≥ 1% positive B-ALL cells. Pts received 8 alternating cycles of Hyper-CVAD and high-dose methotrexate/cytarabine (MTX/AraC). Ofatumumab was administered on days 1 and 11 of cycles 1 and 3; and days 1 and 8 of cycles 2 and 4. Pts then received POMP maintenance on cycles 1-5, 8-17 and 20-30 and late intensifications on cycles 6-7 and 18-19 (Hyper-CVAD + ofatumumab followed by MTX + peg-asparaginase). Pts received a total of 8 intrathecal injections of MTX and AraC for CNS prophylaxis. The primary endpoint was relapse-free survival (RFS) and secondary endpoints include CR rates, MRD negativity rates and OS. On a subset of 27 patient samples, transcriptome sequencing (RNA-seq) was performed to identify translocations and RNA expression signature for Ph-like ALL. We also performed a comprehensive detection of fusions and mutations reported in Ph-like ALL on RNA from these 27 samples using a multiplex fusion and mutation detection assay (Archer® FusionPlex® ALL). Results: Between August 2011 and May 2017, 69 pts were enrolled, including 4 already in CR at baseline after receiving 1 cycle of chemotherapy. Pts characteristics are summarized in Table 1. The median age was 41 years (18-71) and 48% pts were in the adolescent and young adult (AYA) age category (18-39 year-old). 7 of the 27 pts (26%) who had RNA-seq had Ph-like ALL gene expression signature. Among the 7 pts; 5 had Ph-like ALL fusions identified by Archer and/or RNA-seq-based fusion detection, including 2 P2RY8-CRLF2, 1 IGH-CRLF2, 1 BCR-FGFR1, and 1 ATF71P-PDGFRB. One patient had high CRLF2 expression with an unknown fusion partner. The remaining case lacked a fusion by either platform. Pts with Ph-like ALL had a higher median WBC of 41 x 109/L (range, 2 - 184). 43 pts (62%) had CD20 expression on ≥20% of the leukemic cells. 10/44 tested pts (23%) had TP53 mutation and 10/37 (27%) had CRLF2 overexpression by flow cytometry (4/5 CRLF2 rearrangement confirmed by Archer). 4 pts (6%) had low-hypodiploidy / near triploidy (Ho-Tr) and 2 (3%) pts had complex karyotype (CK). All but 1 pt (98%) achieved CR (2 after 2 cycles); only 1 pt (2%) died during induction. The MRD- rate was 65% after cycle 1 and 93% overall. These rates were 14% and 71%, respectively for pts with Ph-like ALL. The median time to MRD- was 0.7 month (range, 0.4-8 months) overall and 3 months (range, 0.7-6.5 months) for pts with Ph-like ALL. A total of 13 pts (19%) underwent allogeneic stem cell transplantation for adverse-risk cytogenetics (CK or Ho-Tr), Ph-like ALL (n=1/7), or persistent MRD+. The most common non-hematologic grade 3-4 toxicity was infection which occurred in 56% and 81% of pts, during induction and consolidation, respectively. With a median follow-up of 44 months, 46 pts (64%) are alive, including 37 pts (54%) in CR1. The median RFS and OS were 52 months (95% CI, 43 - NR) and not reached (95% CI, 65 - NR), respectively. The estimated 4-yr RFS and OS rates were 60% (95% CI, 49 - 73%) and 68% (95% CI, 58 - 81%), respectively (Figure 1A-1B). For AYA pts, the 4-yr OS rate was 74% (95% CI, 60 - 91%) (Figure 2A). The 4-yr OS rates were 54% (95%, 26 - 100%) for pts with Ph-like ALL compared to 74% (95% CI, 57 - 97%) for pts without Ph-like ALL (Figure 2B). There was no difference in OS according to the CD20 expression level (20% cut-off; p = 0.31). Using historical control pts, there was a trend towards improved OS with HCVAD-O versus HCVAD-R for pts with CD20 ≥ 20% (4-yr OS rate 63% vs 49%, p = 0.16) and HCVAD-O versus HCVAD alone for pts with CD20 1-19% (4-yr OS rate 73% vs 62%, p = 0.46). Conclusion: HCVAD-O is a safe and highly effective regimen in pts with CD20+ Ph-negative B-ALL. This regimen achieves excellent outcomes in the AYA population. Disclosures Kantarjian: BMS: Research Funding; AbbVie: Honoraria, Research Funding; Takeda: Honoraria; Daiichi-Sankyo: Research Funding; Amgen: Honoraria, Research Funding; Jazz Pharma: Research Funding; Immunogen: Research Funding; Cyclacel: Research Funding; Pfizer: Honoraria, Research Funding; Ariad: Research Funding; Astex: Research Funding; Novartis: Research Funding; Agios: Honoraria, Research Funding; Actinium: Honoraria, Membership on an entity's Board of Directors or advisory committees. Konopleva:Agios: Research Funding; AbbVie: Consultancy, Honoraria, Research Funding; Astra Zeneca: Research Funding; Ablynx: Research Funding; Calithera: Research Funding; Kisoji: Consultancy, Honoraria; Cellectis: Research Funding; Amgen: Consultancy, Honoraria; Ascentage: Research Funding; Genentech: Honoraria, Research Funding; F. Hoffman La-Roche: Consultancy, Honoraria, Research Funding; Reata Pharmaceuticals: Equity Ownership, Patents & Royalties; Stemline Therapeutics: Consultancy, Honoraria, Research Funding; Eli Lilly: Research Funding; Forty-Seven: Consultancy, Honoraria. Ravandi:Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Cyclacel LTD: Research Funding; Menarini Ricerche: Research Funding; Xencor: Consultancy, Research Funding; Macrogenix: Consultancy, Research Funding; Selvita: Research Funding. Jain:AstraZeneca: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Servier: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Cellectis: Research Funding; Verastem: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Precision Biosciences: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Adaptive Biotechnologies: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pharmacyclics, an AbbVie company: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen Pharmaceuticals, Inc.: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Incyte: Research Funding; ADC Therapeutics: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Research Funding; Genentech: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Short:AstraZeneca: Consultancy; Amgen: Honoraria; Takeda Oncology: Consultancy, Research Funding. 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. Cortes:Daiichi Sankyo: Consultancy, Honoraria, Research Funding; Merus: Consultancy, Honoraria, Research Funding; Biopath Holdings: Consultancy, Honoraria; Immunogen: Consultancy, Honoraria, Research Funding; Forma Therapeutics: Consultancy, Honoraria, Research Funding; Sun Pharma: Research Funding; Jazz Pharmaceuticals: Consultancy, Research Funding; Astellas Pharma: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; BiolineRx: Consultancy. Sasaki:Otsuka: Honoraria; Pfizer: Consultancy. Kadia:Celgene: Research Funding; Bioline RX: Research Funding; BMS: Research Funding; Jazz: Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Membership on an entity's Board of Directors or advisory committees, Research Funding; Genentech: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy, Research Funding. DiNardo:celgene: Consultancy, Honoraria; medimmune: Honoraria; abbvie: Consultancy, Honoraria; jazz: Honoraria; syros: Honoraria; agios: Consultancy, Honoraria; daiichi sankyo: Honoraria; notable labs: Membership on an entity's Board of Directors or advisory committees. Verstovsek:Astrazeneca: Research Funding; Ital Pharma: Research Funding; Protaganist Therapeutics: Research Funding; Constellation: Consultancy; Pragmatist: Consultancy; Incyte: Research Funding; Roche: Research Funding; NS Pharma: Research Funding; Celgene: Consultancy, Research Funding; Gilead: Research Funding; Promedior: Research Funding; CTI BioPharma Corp: Research Funding; Genetech: Research Funding; Blueprint Medicines Corp: Research Funding; Novartis: Consultancy, Research Funding; Sierra Oncology: Research Funding; Pharma Essentia: Research Funding. Mullighan:Loxo Oncology: Research Funding; AbbVie: Research Funding; Pfizer: Honoraria, Other: speaker, sponsored travel, Research Funding; Illumina: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: sponsored travel; Amgen: Honoraria, Other: speaker, sponsored travel. O'Brien:AbbVie: Consultancy, Honoraria; Acerta: Research Funding; Alexion: Consultancy; Amgen: Consultancy; Astellas: Consultancy; Aptose Biosciences, Inc: Consultancy; Celgene: Consultancy; Kite: Research Funding; GlaxoSmithKline: Consultancy; Eisai: Consultancy; Gilead: Consultancy, Research Funding; Janssen: Consultancy, Honoraria; Pharmacyclics LLC, an AbbVie Company: Consultancy, Research Funding; TG Therapeutics: Consultancy, Research Funding; Sunesis: Consultancy, Research Funding; Regeneron: Research Funding; Vaniam Group LLC: Consultancy; Verastem: Consultancy; Pfizer: Consultancy, Honoraria, Research Funding. 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. OffLabel Disclosure: Ofatumumab is not approved by the FDA for treatment of B-cell acute lymphoblastic leukemia.

Description: Background: We have previously shown that CMR predicts better outcomes in Ph+ ALL. The lack of achievement of CMR and particularly major molecular response (MMR) at 3 months may confer poor outcomes. We sought to investigate the outcomes of pts who did not achieve CMR at 3 months as best response in terms of progression free survival (PFS) and overall survival (OS), and the role of allogeneic stem cell transplant (ASCT) in this population. Methods: We reviewed 204 pts with newly diagnosed Ph+ ALL treated at our institution between January 2001 and June 2019 with the combination of Hyper-CVAD plus tyrosine kinase inhibitors (TKI); dasatinib (n=88, 43%), ponatinib (n=72, 35%) and imatinib (n= 44, 22%). PFS was defined from the start of therapy to relapse or death. OS was defined from diagnosis to death or last follow-up. Backward multivariate Cox regression was used to identify prognostic factors for PFS and OS after variable selection at a p-value cutoff of 0.200. Time to ASCT was handled as a time-dependent variable. Survival curves were estimated by Kaplan-Meier method. Landmark analysis at the median time to ASCT was analyzed to evaluate the impact of ASCT. Results: We identified 94 pts (46%) who did not achieve 3-month CMR. Of pts treated with imatinib, 29 (66%) did not achieve 3-month CMR and 16 pts (36%) achieved 3-month MMR. Of pts treated with dasatinib, 42 (48%) did not achieve 3-month CMR and 29 pts (33%) achieved 3-month MMR. Of pts treated with ponatinib, 23 (32%) did not achieve 3-month CMR and 17 pts (24%) achieved 3-month MMR. Patient characteristics are summarized in table 1. Median age was 54 years (range: 21-80). The TKI administered was dasatinib, imatinib and ponatinib in 42 (45%), 29 (31%) and 23 (24%) pts, respectively. Overall, ASCT was performed in 28 pts (30%); 21 out of 62 pts (34%) with 3-month MMR, and 7 out of 32 pts (22%) who did not achieve MMR, within a median time of 5 months (range, 2.3-12.3). After a median follow-up of 97 months, median PFS was 21 months and median OS was 46 months. There was no difference in survival by TKI choice. The 5-year PFS and OS rates were 52% and 23% (p=0.001) (Figure 1A), and 58% and 26% (p=0.001) (Figure 1B) for pts with and without 3-month MMR, respectively. In multivariate analysis (table 2), 3-month MMR predicted longer PFS (p

Description: INTRODUCTION: Most clinical trials exclude patients with poor performance, organ dysfunction, and presence of other active malignancies or comorbidities. Although some of these criteria are based on clinical reasoning, patients with such clinical features have dismal expected outcomes and limited therapeutic options and could therefore have a more favorable risk/benefit ratio if treated with a low intensity investigational intervention. The current study was designed to test whether it is feasible to treat patients not eligible for conventional studies in a clinical trial. METHODS: We conducted an initial Bayesian designed single-arm study and a subsequent randomized study for patients with AML or higher-risk MDS (intermediate-2 or high risk by IPSS) with either ECOG performance status (PS) ≥3, creatinine or bilirubin ≥2mg/dL, presence of other malignancy or other comorbidities. Primary endpoint was survival at day 60. The study included stopping rules for survival, response and toxicity. All patients received azacitidine 75mg/m2 sc daily for 5 days. Patients in the single-arm study and in the combination arm of the randomized study also received vorinostat 200mg tid for 5 days. Cycles could be repeated every 3-8 weeks. Responses were evaluated following the revised 2006 IWG criteria for patients with MDS and the IWG 2003 recommendations for patients with AML. Comorbidities were evaluated using the Adult Comorbidity Evaluation-27 (ACE-27) index. Adverse events (AEs) were assessed and graded according to the CTCAE v4 criteria. Overall survival (OS) was censored at the time of transplant. Event-free survival (EFS) was defined as the time interval between treatment start and date of resistance, progression or death. RESULTS: A total of 30 patients (16 with MDS, 14 with AML) were enrolled in the initial single-arm study. Patient characteristics and inclusion criteria are detailed in Table 1. Median age was 73 years (44-83). Median follow-up was 7.4 months (0.3-29). Sixty-day survival was 83%. Median number of cycles administered was 3.5 (1-12). The overall response rate (ORR) was 40% with 8 (27%) patients achieving CR, 4 with AML and 4 with MDS. Median OS was 7.8 months (0.3-29, CI 7.54-8.03) (Figure 1A) and median EFS was 5.1 months (0.3-15.9, CI 4.87-5.37) (Figure 1B). Stopping rules for survival and response were not met. Main adverse events (AEs) where grade 1-2 gastrointestinal toxicities. Mortality at 4 and 8 weeks was 10 and 20% respectively. A total of 79 patients were enrolled in the subsequent randomized study: 27 to azacitidine (A) and 52 to azacitidine and vorinostat (A+V). Patient characteristics and inclusion criteria are also shown in Table 1. Median age was 70 years (30-90). Forty-seven (59%) patients had MDS and 32 (41%) had AML. Median follow-up was 22.7 months (12.6-47.5). Sixty-day survival rates were 67% (A) and 85% (A+V), respectively (p=0.07). No differences in ORR (48% vs 46%, p=0.87), OS (6.1 vs 7.6 months, p=0.49) (Figure 1C) or EFS (3 vs 5.5 months, p=0.05) (Figure 1D) were observed between groups. Main AEs included grade 1-2 gastrointestinal toxicities with a higher proportion of AEs with A+V (81 vs 56%). Mortality at 4 and 8 weeks was 10% (A: 4, A+V: 4) and 19% (A: 9, A+V: 6) respectively. By univariate analysis neither PS ≥3, creatinine or bilirubin ≥2mg/dL nor presence of other malignancy were predictive for 60-day survival, OS or EFS. There were no significant differences in survival between patients with ACE-27 scores of 0-1 compared to 2-3 both in the single-arm (6.3 vs 7 months, HR=0.88, 95% CI 0.41-1.91, p=0.75) and the randomized phase of the study (A: 13.5m vs 6.1m, HR 0.93, 95% CI 0.27-3.17, p=0.9 and A+V: 12.1m vs 7.4m, HR 1.38, 95% CI 0.61-3.14, p=0.4). CONCLUSION: Most enrolled patients met the study's primary endpoint of survival at 60 days without major toxicity. Patients obtained clinical benefit with acceptable responses and survival despite their high comorbidity burden. Our results support the feasibility of treating patients with MDS or AML not eligible to other clinical trials due to poor performance status, comorbidities or organ dysfunction, with low intensity therapies within a clinical trial. These findings suggest relaxation of such criteria may likely increase the pool of clinical trial patient candidates and allow access to potential beneficial therapies for patients with otherwise dismal prognosis. Table 1 Table 1. Figure 1 Figure 1. Disclosures Jabbour: ARIAD: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Novartis: Research Funding; BMS: Consultancy. DiNardo:Abbvie: Research Funding; Novartis: Research Funding; Agios: Research Funding; Daiichi Sankyo: Research Funding; Celgene: Research Funding. Cortes:ARIAD: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Teva: Research Funding. Wierda:Genentech: Research Funding; Gilead: Research Funding; Novartis: Research Funding; Acerta: Research Funding; Abbvie: Research Funding. Konopleva:Reata Pharmaceuticals: Equity Ownership; Abbvie: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; Stemline: Consultancy, Research Funding; Eli Lilly: Research Funding; Cellectis: Research Funding; Calithera: Research Funding. Jain:Novimmune: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria, Research Funding; Pharmacyclics: Consultancy, Honoraria, Research Funding; Celgene: Research Funding; ADC Therapeutics: Consultancy, Honoraria, Research Funding; Genentech: Research Funding; Abbvie: Research Funding; Infinity: Research Funding; Incyte: Research Funding; Seattle Genetics: Research Funding; BMS: Research Funding; Novartis: Consultancy, Honoraria; Servier: Consultancy, Honoraria.

Description: Background. Lenalidomide (Len) is an immunomodulatory drug with single agent activity in patients (pts) with treatment-naïve (TN) CLL, (overall response rate (ORR) 56-65%, Chen JCO 2011, Ferrajoli Blood 2011). Given the encouraging results of the combination of Len and rituximab (R) in relapsed CLL, we explored this combination as initial therapy. TN pts could derive greater benefit than relapsed pts from Len + R given their less compromised immune function. Methods. Fifty-eight pts were enrolled between 01/2012 and the present time. All patients had treatment indications per IWCLL 2008 criteria, WHO performance status ≤2 and adequate hepatic and renal function. Patients with HIV, hepatitis B or C infection were excluded. Treatment consisted of R 375 mg/m2 IV given weekly for 4 weeks then monthly during months (mo) 3-12 and Len 10 mg PO/day from day 9 for 24 mo. Allopurinol 300 mg PO daily was given for the first 2 weeks. No pts received antibiotic or DVT prophylaxis. Use of growth factors was allowed according to ASCO guidelines. Responses were assessed (2008 IWG criteria) at mo 3, 6 and every 6mo thereafter. Results. Forty-eight patients are evaluable for response and toxicity (8 too early, 1 lost to follow-up and 1 diagnosed with metastatic colonic adenocarcinoma within 1 week of study entry). Median age was 66 yrs (42-79). 29 (59%) pts were ≥age 65. 22 pts (46%) had Rai stage III-IV disease. Median β2M level was 3.8 mg/dL (1.4-10.5). 24/37 pts (65%) had unmutated IGHV gene and 31 pts (65%) expressed ZAP-70. 4 pts (8%) had del(17p) and 15 pts (32%) del(11q). Forty pts responded (ORR 83%). 7 pts (14.6%) achieved CR (1 MRD negative) and 33 (68.8%) achieved PR (including 7 nodular PRs). Median time to CR was 11mo (range 5-27). 5 pts discontinued therapy before the 3mo evaluation (4 due to toxicity and 1 due to unrelated co-morbidities). Six pts discontinued between 3 and 6mo (4 for refractory disease and 2 for toxicity after achieving PR). ORR was similar for patients with mutated and unmutated IGHV gene (85 vs 83%, p=0.96), age ≥65 and

Description: INTRODUCTION: Overexpression of CD123, the alpha subunit of the IL-3 receptor, in multiple hematological malignancies, including acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), and blastic plasmacytoid dendritic cell neoplasm (BPDCN), makes this antigen an attractive target for the development of new therapeutics. IMGN632 is a CD123-targeting antibody-drug conjugate comprising a novel humanized anti-CD123 antibody coupled, via a peptide linker, to a unique DNA-alkylating payload of the recently developed IGN (indolinobenzodiazepine pseudodimer) class of cytotoxic compounds. In preclinical models, IMGN632 exhibited potent antitumor activity with a wide therapeutic index in AML, BPDCN, and ALL, suggesting the potential for robust efficacy along with favorable tolerability in patients with leukemia. We report the initial safety and antileukemia activity findings from the dose-escalation stage of the first-in-human trial of IMGN632. METHODS: The objectives of this ongoing Phase I study (NCT03386513) include determination of the dose-limiting toxicity (DLT), safety, pharmacokinetics (PK), pharmacodynamics (PD), and preliminary antileukemia activity of IMGN632. Adult patients with CD123-positive, relapsed or refractory AML or BPDCN are eligible to enroll in the dose-escalation stage. IMGN632 is administered intravenously on Day 1 of a 21-day cycle using a standard 3+3 design. The starting dose of IMGN632 was 0.015 mg/kg, with escalation following a modified Fibonacci schema. Adverse events (AEs) are evaluated by CTCAE v4.03 and tumor responses assessed according to the European LeukemiaNet (ELN) response criteria. RESULTS: At the time of this analysis, a total of 12 patients had received IMGN632 across four dose-escalation cohorts, with dosing successfully escalated from 0.015 mg/kg up to 0.18 mg/kg. The median age of the patients was 66 years (range, 40-80). All patients were diagnosed with AML, including five with relapsed refractory disease and six enrolled at first relapse. Eight patients had received prior intense therapy, including stem cell transplant in two individuals. Seven patients had adverse risk cytogenetics and 50% had secondary AML. No DLTs have been observed at doses up to 0.18 mg/kg (cohort 4) and no discontinuations due to an AE have occurred. The most commonly observed treatment-emergent AEs of any grade were primarily gastrointestinal (decreased appetite, diarrhea, nausea; 25-42%), hematologic (febrile neutropenia; 42%), or vascular (peripheral edema, hypotension, sinus tachycardia; 25-33%). The most frequent Grade 3+ AEs were febrile neutropenia (5 patients; 42%) and lung infection (3 patients; 25%); none of these events were considered related to IMGN632. No grade 3 or higher vascular events were noted. No correlations between the severity, frequency, or nature of reported AEs with increasing dose have been observed. Post-infusion reactions were seen in nine patients (75%). These events typically manifested as mild (grade 1) fever, chills, tachycardia, or nausea/vomiting, occurred less than 24 hours following infusion, and resolved with standard medical care. Steroid premedication has now been implemented at cohort 4. Three deaths occurred, all due to disease progression and unrelated to study drug. In 12 evaluable patients, four (33%) achieved an objective response, including one complete remission (CR) and three complete remissions with incomplete recovery (CRi). Maximal bone marrow blast decreases from baseline seen for patients are presented in Figure 1A. PK analyses showed that systemic IMGN632 exposure and maximum concentrations increased with dose; similarly, PD determinations revealed that the extent and duration of CD123 saturation also increased with dose (Figure 1B). CONCLUSIONS: Objective responses (CR and CRis) were seen in one third of relapsed/refractory AML patients during the initial stages of dose escalation in this first-in-human clinical trial with IMGN632, a novel CD123-targeting ADC. No dose limiting toxicities have been observed, and PK and PD data support continued dose escalation, which is ongoing. Figure 1. A. Maximum percent changes in bone marrow blasts from baseline. Patients who achieved an objective response (CR or CRi) are shown in gray. B. CD123 receptor saturation. Average saturation curves for the first four cohorts are presented. Disclosures Daver: Karyopharm: Research Funding; ARIAD: Research Funding; ImmunoGen: Consultancy; Novartis: Research Funding; Novartis: Consultancy; Otsuka: Consultancy; Karyopharm: Consultancy; Pfizer: Research Funding; Incyte: Research Funding; Kiromic: Research Funding; Pfizer: Consultancy; Sunesis: Research Funding; Daiichi-Sankyo: Research Funding; Alexion: Consultancy; Incyte: Consultancy; Sunesis: Consultancy; BMS: Research Funding. Erba:Jazz: Consultancy, Speakers Bureau; Takeda/Millenium: Research Funding; Agios: Consultancy, Speakers Bureau; Daiichi Sankyo: Consultancy, Research Funding; Novartis: Consultancy, Speakers Bureau; Novartis: Consultancy, Speakers Bureau; Jazz: Consultancy, Speakers Bureau; Amgen: Research Funding; Astellas: Research Funding; Novartis: Consultancy, Speakers Bureau; Amgen: Research Funding; Immunogen: Consultancy, Research Funding; Amgen: Research Funding; Seattle Genetics: Consultancy, Research Funding; Takeda/Millenium: Research Funding; Incyte: Consultancy, Speakers Bureau; Janssen: Research Funding; Seattle Genetics: Consultancy, Research Funding; Pfizer: Consultancy, Other: grant; Celgene: Consultancy, Speakers Bureau; Astellas: Research Funding; Astellas: Research Funding; Novartis: Consultancy, Speakers Bureau; Pfizer: Consultancy, Other: grant; Daiichi Sankyo: Consultancy, Research Funding; Immunogen: Consultancy, Research Funding; Janssen: Research Funding; Astellas: Research Funding; Amgen: Research Funding; Celgene: Consultancy, Speakers Bureau; Incyte: Consultancy, Speakers Bureau; Glycomimetics: Consultancy, Other: Chair, Data and Safety Monitoring Committee; Janssen: Research Funding; Glycomimetics: Consultancy, Other: Chair, Data and Safety Monitoring Committee; MacroGenics: Consultancy; Pfizer: Consultancy, Other: grant; MacroGenics: Consultancy; Juno: Research Funding; Pfizer: Consultancy, Other: grant; Juno: Research Funding; Agios: Consultancy, Speakers Bureau; Seattle Genetics: Consultancy, Research Funding; Agios: Consultancy, Speakers Bureau; Incyte: Consultancy, Speakers Bureau; Seattle Genetics: Consultancy, Research Funding; Incyte: Consultancy, Speakers Bureau; Jazz: Consultancy, Speakers Bureau; Takeda/Millenium: Research Funding; Immunogen: Consultancy, Research Funding; Jazz: Consultancy, Speakers Bureau; Takeda/Millenium: Research Funding; Celgene: Consultancy, Speakers Bureau; Immunogen: Consultancy, Research Funding; MacroGenics: Consultancy; Glycomimetics: Consultancy, Other: Chair, Data and Safety Monitoring Committee; MacroGenics: Consultancy; Celgene: Consultancy, Speakers Bureau; Daiichi Sankyo: Consultancy, Research Funding; Juno: Research Funding; Glycomimetics: Consultancy, Other: Chair, Data and Safety Monitoring Committee; Juno: Research Funding; Daiichi Sankyo: Consultancy, Research Funding; Agios: Consultancy, Speakers Bureau. Papadantonakis:Agios pharmaceuticals: Honoraria, Other: advisory board. DeAngelo:ARIAD: Consultancy, Research Funding; Blueprint Medicines: Honoraria, Research Funding; Takeda: Honoraria; Incyte: Consultancy, Honoraria; BMS: Consultancy; Glycomimetics: Research Funding; Shire: Honoraria; Amgen: Consultancy; Novartis Pharmaceuticals Corporation: Consultancy, Honoraria; Pfizer Inc: Consultancy, Honoraria. Wang:Pfizer: 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; Jazz: Speakers Bureau; Amgen: Consultancy; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Speakers Bureau; Jazz: Speakers Bureau; Amgen: Consultancy; Novartis: Speakers Bureau; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees. Konopleva:Stemline Therapeutics: Research Funding. Sloss:ImmunoGen: Employment. Culm-Merdek:ImmunoGen: Employment.

Description: Background: Myelodysplastic syndrome (MDS) is a heterogeneous malignant myeloid neoplasm of hematopoietic stem cells due to cytogenetic alterations and somatic mutations in genes (DNA methylation, DNA repair, chromatin regulation, RNA splicing, transcription regulation, and signal transduction). Hypomethylating agents (HMA) are the standard of care for MDS, and 40-60% of patients achieved response to HMA. However, the prediction for response is difficult due to the nature of heterogeneity and the context of clinical conditions such as the degree of cytopenias and the dependency on transfusion. Machine learning outperforms conventional statistical models for prediction in statistical competitions. Prediction with machine learning models may predict response in patients with MDS. The aim of this study is to develop a machine learning model for the prediction of complete response (CR) to HMA with or without additional therapeutic agents in patients with newly diagnosed MDS. Methods: From November 2012 to August 2017, we analyzed 435 patients with newly diagnosed MDS who received frontline therapy as follows; azacitidine (AZA) (3-day, 5-day, or 7-day) ± vorinostat ± ipilimumab ± nivolumab; decitabine (DAC) (3-day or 5-day) ± vorinostat; 5-day guadecitabine. Clinical variables, cytogenetic abnormalities, and the presence of genetic mutations by next generation sequencing (NGS) were included for variable selection. The whole cohort was randomly divided into training/validation and test cohorts at an 8:2 ratio. The training/validation cohort was used for 4-fold cross validation. Hyperparameter optimization was performed with Stampede2, which was ranked as the 15th fastest supercomputer at Texas Advanced Computing Center in June 2018. A gradient boosting decision tree-based framework with the LightGBM Python module was used after hyperparameter tuning for the development of the machine learning model with training/validation cohorts. The performance of prediction was assessed with an independent test dataset with the area under the curve. Results: We identified 435 patients with newly diagnosed MDS who enrolled on clinical trials as follows: 33 patients, 5-day AZA; 23, 5-day AZA + vorinostat; 43, 3-day AZA; 20, 5-day AZA + ipilimumab; 19 patients, AZA + nivolumab; 7, AZA + ipilumumab + nivolumab; 114, 5-day DAC; 74, 3-day DAC; 4, DAC + vorinostat; 97, 5-day guadecitabine. In the whole cohort, the median age at diagnosis was 68 years (range, 13.0-90.3); 117 (27%) patients had a history of prior radiation or cytotoxic chemotherapy; the median white blood cell count was 2.9 (×109/L) (range, 0.5-102); median absolute neutrophil count, 1.1 (×109/L) (range, 0.0-55.1); median hemoglobin count, 9.5 (g/dL) (range, 4.7-15.4); median platelet count, 63 (×109/L) (range, 2-881); and median blasts in bone marrow, 8% (range, 0-20). Among 411 evaluable patients for the revised international prognostic scoring system, 15 (4%) had very low risk disease; 42 (10%), low risk; 68 (17%), intermediate risk; 124 (30%), high risk; and 162 (39%), very high risk. Overall, 153 patients (53%) achieved CR. Hyperparameter tuning identified the optimal hyperparameters with colsample by tree of 0.175, learning rate of 0.262, the maximal depth of 2, minimal data in leaf of 29, number of leaves of 11, alpha regularization of 0.010, lambda regularization of 2.085, and subsample of 0.639. On the test cohort with 87 patients, the machine learning model accurately predicted response in 65 patients (75%); 53 non-CR among 56 non-CR (95% accuracy); and 12 CR among 31 CR (39% accuracy). The trend of accuracy improvement by iteration (i.e., the number of decision trees) is shown in Figure 1. The area under the curve was 0.761521 in the test cohort. Conclusion: Our machine learning model with clinical, cytogenetic, and NGS data can predict CR to HMA in patients with newly diagnosed MDS. This approach can identify patients who may benefit from HMA therapy with and without additional agents for response, and can optimize the timing of allogeneic stem cell transplant. Disclosures Sasaki: Otsuka: Honoraria; Pfizer: 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. Ravandi:Cyclacel LTD: Research Funding; Selvita: Research Funding; Menarini Ricerche: Research Funding; Macrogenix: Consultancy, Research Funding; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Xencor: Consultancy, Research Funding. Kadia:Pfizer: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Research Funding; Bioline RX: Research Funding; Jazz: Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Consultancy, Research Funding; BMS: Research Funding; Amgen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Genentech: Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees. Takahashi:Symbio Pharmaceuticals: Consultancy. DiNardo:syros: Honoraria; jazz: Honoraria; agios: Consultancy, Honoraria; celgene: Consultancy, Honoraria; notable labs: Membership on an entity's Board of Directors or advisory committees; medimmune: Honoraria; abbvie: Consultancy, Honoraria; daiichi sankyo: Honoraria. Cortes:Novartis: Consultancy, Honoraria, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Immunogen: Consultancy, Honoraria, Research Funding; Sun Pharma: Research Funding; Pfizer: Consultancy, Honoraria, Research Funding; Astellas Pharma: Consultancy, Honoraria, Research Funding; Jazz Pharmaceuticals: Consultancy, Research Funding; Merus: Consultancy, Honoraria, Research Funding; Forma Therapeutics: Consultancy, Honoraria, Research Funding; Daiichi Sankyo: Consultancy, Honoraria, Research Funding; BiolineRx: Consultancy; Biopath Holdings: Consultancy, Honoraria; Takeda: Consultancy, Research Funding. Kantarjian:AbbVie: Honoraria, Research Funding; Cyclacel: Research Funding; Pfizer: Honoraria, Research Funding; Astex: Research Funding; Agios: Honoraria, Research Funding; Jazz Pharma: Research Funding; Daiichi-Sankyo: Research Funding; Novartis: Research Funding; Actinium: Honoraria, Membership on an entity's Board of Directors or advisory committees; Immunogen: Research Funding; Takeda: Honoraria; BMS: Research Funding; Ariad: Research Funding; Amgen: Honoraria, Research Funding. 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.

Description: Background: Allogeneic stem cell transplant (ASCT) is a curative option for patients with higher risk myelodysplastic syndromes (MDS). Hypomethylating agents (HMA) have been shown to improve survival of patients with MDS and have an excellent toxicity profile. In eligible patients, HMA and ASCT are used as complementary strategies. The aim of this study is to compare outcome with HMA alone vs HMA+ASCT where ASCT is used as consolidation approach or as salvage therapy after HMA failure. Methods: We performed a retrospective analysis of 216 patients with high-risk MDS who received HMA treatment at our institution from between April 2004 and October 2012; after HMA therapy, 61 (28%) patients underwent ASCT: 25 (41%) of them received as a consolidation treatment and 36 (59%) as a salvage therapy. The remaining 155 patients continued on HMA therapy until relapse or progression and did not receive a further ASCT. We used SPSS v.20 for all statistical analysis. Categorical and continuous variables were compared by chi-square and Student’s t test, respectively, and survival analysis was conducted using Kaplan-Meier analysis with the log-rank test and Cox regression for multivariate models. We also implemented a landmark survival analysis that considered median time to transplant. Results: Median age was 65 (20-89), and patients were older in the group that did not receive ASCT (69 vs 58 years; p=0.000). WHO diagnoses were RA/RARS in 31 patients (15%), RCMD in 43 patients (19.9%), RAEB in 133 patients (62%), CMML in 23 patients (11%), and unclassifiable MDS in 18 patients (8.3%). IPSS risk was int-2 in 107 patients (50%) and high in 61 (28%), and the percentage of inttermediate-2/high-risk MDS was higher in the ASCT group (89% vs 73%; p=0.001). High-risk cytogenetics were found in 71% of patients (82% in ASCT vs 67% in HMA alone; p=0.02). Patients received a median of 6 (1-58) courses of HMA. Overall response rate (ORR) to HMA was 45% (n=97), with 38% (n=82) having complete response (CR), 2% (n=5) partial response, and 5% (n=10) hematologic improvement. There were no significant differences between response to HMA in the ASCT group when compared to the group that did not receive ASCT (ORR: 46% vs 43%, p=0.3; CR: 38% vs 37%, p= 0.5). When we further analyzed the 61 ASCT patients, 25 (41%) received it as a consolidation after achieving response and 36 (59%) as a salvage therapy after treatment failure. Response to ASCT was CR in 65% of patients, and 20% were not evaluable due to early mortality. Median overall survival (OS) for the whole series was 14 months (12-16), with 1- and 2-year OS rates of 57% and 24%, respectively. To adjust for early mortality after ASCT and to eliminate any bias, we performed a landmark analysis after a median time of 7 months after ASCT. Patients who received ASCT had better survival. This advantage was more evident among patients who received ASCT as salvage therapy, although there were no differences between both strategies, with respective median survivals of 14 months for consolidation ASCT and 23 months for salvage ASCT (p=0.29)Furthermore, no significant differences in survival were observed between patients who received HMA alone and those who received ASCT as a consolidation therapy (median survival of 14 and 16 months; p=0.498), although there was a tendency for a better OS after 2 years of follow up: the OS for HMA treatment and HMA+ASCT consolidation were 68% and 56% at 1 year, 25% and 31% at 2 years, and 10% and 31% at 3 years. The 1-year survival rates for patients who received HMA alone, HMA followed by ASCT as consolidation, and HMA followed by ASCT as salvage were 68%, 56%, and 78%, respectively, and the 2-year survival rates were 25%, 31%, and 42%, respectively. In a Cox regression model to analyze effects on OS, receiving an ASCT (median OS of 13 (7-19) vs 10 months (8-12); HR 0.62 [0.42 – 0.92], p=0.018) and hemoglobin levels at diagnosis (HR 0.829 [0.73 – 0.93], p=0.002) had a significant impact. Conclusions: ASCT is a feasible and curative strategy for patients with MDS, both as a consolidation or a salvage therapy, and thus it can be a good option after HMA failure. However, its benefits as a consolidation therapy after HMA treatment compared with continuation of HMA treatment are not clear owing to early mortality related to procedure, so ASCT should be carefully considered in patients responding to HMA. Disclosures Borthakur: Tetralogic Pharmaceuticals: Research Funding. Cortes:Ariad: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Teva: Consultancy, Research Funding. Ravandi:Incyte Corporation: Research Funding. Kadia:GSK: Research Funding; ARIAD: Honoraria. Champlin:Otsuka: Research Funding. Kantarjian:ARIAD: Research Funding; Pfizer: Research Funding; Amgen: Research Funding.

Description: Background: MPN-AML, MPN-AP, and DIPSS-plus high risk PMF are associated with a poor response to therapy and shortened survival. Several studies have shown clinical activity of hypomethylating agents (DNA methyltransferase inhibitors) in these situations. We reviewed our database to evaluate the clinical outcome of patients (pts) with MPN-AML, MPN-AP and DIPSS-plus high risk PMF who received decitabine (DAC; a hypomethylating agent) in the course of their treatment at our institution. Methods: Retrospective chart review identified 21 pts with MPN-AML, 13 with MPN-AP and 11 with DIPSS-plus high risk PMF treated with DAC in our center over last 7 years. MPN- AP was defined by 10%-19% blasts in the peripheral blood or bone marrow (BM). DIPSS-plus is a prognostic model for PMF and can be applied at any point during the disease course (Gagnat et al. J Clin Oncol 2011; 29:392-7). Responses in MPN-AML were defined according to published recommendations (Mascarenhas et al. Leuk Res 2012; 36:1500-4). Responses in MPN-AP and DIPSS-plus high risk PMF were defined according to the revised IWG-MRT and ELN consensus report (Tefferi et al. Blood 2013; 122: 1395-8). Results: MPN-AML pts characteristics: median age 64 yrs (range, 45-82); initial MPN: ET 4 (19%), PV 5 (24%), PMF 10 (48%), and MPN unclassified 2 (10%) pts. The median number (no.) of prior therapies for MPN was 1 (range, 0-4). The median time for transformation from MPN to MPN-AML was 93 mo (range, 1.4-292). Thirteen (39%) pts had unfavorable cytogenetics. DAC was given as first-line therapy in 12 (57%) pts, as second-line therapy in 8 (38%), and as third-line in 1 (5%). The median no. of DAC cycles given was 2 (range, 1-15). MPN-AP pts characteristics: median age 63 yrs (range, 50-81); initial MPN: ET 2 pts (15%), PV 5 (39%), and PMF 6 (46%). The median no. of prior therapies for MPN was 2 (range, 0-5). The median time from diagnosis of MPN to DAC was 65 (0-389) mo. The median no. of DAC cycles given was 2 (range 1-37). PMF with DIPSS-plus high risk pts characteristics: median age 67 yrs (range, 55-77). Seven (64%) pts had a JAK2 mutation. The median hemoglobin (Hb) was 9.2 g/dl (range, 7.7-11.7), median WBC was 41.5 K/uL (range, 2-140), median platelet (plt) count was 69 K/uL (range, 9-860) and bone marrow blast percentage (BM BL %) was 2% (range, 0-9). The median number of DIPSS-plus risk factors was 6 (range, 4-8), and median no. of prior therapies was 1 (range, 0-4). The median time to DAC from diagnosis of PMF was 19 (3-195) mo. The median no. of DAC cycles given was 3 (range 1-8). Six (29%) MPN-AML pts responded to DAC: 3 CR, 2 CRi and 1 PR. Two pts who achieved CR, received DAC as second line after falling induction chemotherapy for AML. The median time to response was 2.6 mo (range, 1-13.5). Among non-responders; 10(48%) pts died due to disease progression, 3 (14%) pts died due to sepsis, one is alive with stable disease (SD) on therapy, and one pt died 2 months after bone marrow transplant (BMT). The median response duration (defined as time to next therapy/death/last follow up) was 7 mo (range, 2-24). One patient responding to DAC had BMT after 2 months of maintaining the response. The median OS from the time of post MPN-AML acquisition was 6.9 mo. The OS was 10.5 mo in responders vs 4 mo in non-responders (p= 0.024) (Fig. 1A). Among MPN-AP, 1 pt had clinical improvement (CI) in Hb and plt, and 7 had SD (with improvements in blood count), for overall benefit in 8 (61%) pts. The median benefit duration was 6.5 mo. (1.8-14). Four (31%) pts with SD after improvement in leukocytosis and BM BL % had BMT. The median OS from the time of MPN-AP acquisition was 9.7 mo. The OS in responders was 11.8 mo. vs 4 mo. in non-responders (p=0.28) (Fig.1B). Among non-responders 3 (23%) pts transformed to AML, one pt received next line of therapy and had BMT, one pt died due to disease progression. Nine (82%) pts with DIPSS-plus high risk PMF benefited from DAC: 1 had CI in plt, 1 had CI in spleen, and 7 had SD (with improvements in blood count). Median response duration was 9 mo (1-23). Three (27%) pts had BMT after improvement in leukocytosis and BM BL %. Both pts who did not respond, progressed to AML and died due to infectious complication. The median OS was 36.6 mo: OS in responders was 190 mo vs 4.7 mo in non-responders (p=0.027) (Fig. 1C). Conclusion: DAC is a viable therapeutic option for pts with MPN-AML, MP-AP and high-risk PMF. Prospective clinical studies combining DAC with other clinically active agents are needed to improve overall outcome. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.