Abstract: Background: Treated secondary acute myeloid leukemia (ts-AML), defined as AML arising from previously treated antecedent hematologic disorder, is a high-risk disease with dismal outcomes. CPX-351 is approved for the treatment of secondary AML, although it did not improve outcomes within the subgroup of patients (pts) with secondary AML with prior exposure to hypomethylating agents (HMAs). In clinical practice, either chemotherapy or HMA plus venetoclax (Ven) are often used for pts with ts-AML, although there are little data to guide the optimal therapy in this setting Methods: We conducted a retrospective analysis of pts with AML arising from either MDS or CMML who received first AML therapy at our institution from 6/2004 to 1/2021 and who had prior HMA exposure for preceding MDS/CMML. Pts treated with prior intensive chemotherapy (IC) or Ven were excluded. Treatment regimens were classified as IC, low-intensity chemotherapy (LIC), or HMA plus Ven. Results: Among 562 pts with ts-AML, 271 (47%) were treated with IC, 237 (41%) with LIC, 54 (9%) with HMA+Ven. Baseline characteristics were similar between pts treated with different treatment regimens (Table 1), although pts treated with IC were significantly younger than those treated with LIC or HMA+Ven (median age: 65 vs. 72 years, P & lt;0.0001). The median number of prior therapies for previous MDS/CMML diagnosis was 1 (range, 1-5). The entire cohort was enriched with adverse risk mutations, including ASXL1 (IC-41%, LIC-28%, HMA+Ven-52%), RUNX1 (IC-22%, LIC-35%, HMA+Ven-56%), and TP53 (IC-45%, LIC-24%, HMA+Ven-40%). In the entire cohort, the CR/CRi rate was 26% and the overall response rate (ORR; defined as CR+CRi+MLFS) was 34%. CR/CRi rates and ORR were similar between IC and LIC (CR/CRi rates: 24% vs 26%; ORR: 30% vs 35%, respectively). Compared with IC/LIC, treatment with HMA+Ven was associated with higher CR/CRi rates (39% vs 25%; P=0.03) and ORR (54% vs 33%; P=0.002). 60-day mortality was similar between the treatment groups (IC-14%, LIC-9%, HMA+Ven-13%). Hematopoietic stem cell transplant rates for pts who received IC, LIC and HMA+Ven were 13%, 5%, and 9%, respectively. In the entire cohort, the median overall survival (OS) was 4.8 months (m), and relapse-free survival (RFS) was 5.9m. OS was similar between those treated with IC or LIC (median OS 4.5m vs. 4.8m; 1-year [yr] OS 14% vs. 22%; P=0.16) but was superior for those who received HMA+Ven compared with those who received IC/LIC (median OS 5.8m vs. 4.7m; 1-yr OS 35% vs. 17%; P=0.05 (Figure 1). RFS was also numerically higher in pts who received HMA+Ven compared with those treated with IC/LIC (median RFS 14.4m vs. 5.4m; 1-yr RFS 59% vs. 29%; P=0.17). The impact of therapies on outcomes in ts-AML was influenced by karyotype. In those with adverse risk karyotype, the outcomes were dismal regardless of treatment approach. ORR was similar between IC/LIC and HMA+Ven (24% vs 28%, P=0.66) and these groups also had similar OS (median OS: 3.3m vs. 4.1m; 1-yr OS 8% vs. 11%; P=0.41). However, among those with non-adverse risk karyotype, HMA+Ven was associated with significantly higher CR/CRi rates (57% vs 30%; P=0.008) and ORR (78% vs 39%, P=0.0003) compared with IC/LIC. HMA+ven also resulted in superior OS in this non-adverse risk group (13.7m vs 5.5m, 1-yr OS 24% vs. 55%, respectively; P=0.04) (Figure 2). The superior outcomes with HMA+Ven were also observed when the comparison was restricted to those treated with IC (P=0.01). Then we evaluated the impact of age specifically in pts treated with IC (stratified into & lt;60 and ≥60 yrs) and HMA+Ven (of any age). Pts treated with HMA+Ven (93% of whom were ≥60 yrs of age) had significantly higher OS compared with pts ≥60 yrs of age who received IC (5.8m vs 4.1m, 1-yr OS 35% vs. 12%; P=0.009) (Figure 3). Although not statistically significant, there was also a trend towards superior OS with HMA+Ven compared to IC in pts & lt;60 yrs of age who received IC (5.8m vs 5.0m, 1-yr OS 35% vs. 16%; P=0.16). Conclusion: For pts with ts-AML and prior HMA exposure, HMA+Ven yielded significantly higher ORR rates and improved OS compared to IC/LIC, particularly in pts with non-adverse risk karyotype and in pts ≥60 yrs of age. These results suggest that HMA+Ven should be preferentially considered for pts with ts-AML and prior HMA exposure, rather than chemotherapy-based approaches. Our results also highlight the very poor outcomes of ts-AML, a poor-risk subgroup of AML for which novel, effective therapies are still needed. Figure 1 Figure 1. Disclosures Kadia: Amgen: Other: Grant/research support; AstraZeneca: Other; Cure: Speakers Bureau; BMS: Other: Grant/research support; Jazz: Consultancy; Genentech: Consultancy, Other: Grant/research support; Liberum: Consultancy; Novartis: Consultancy; Pfizer: Consultancy, Other; Pulmotech: Other; Sanofi-Aventis: Consultancy; Cellonkos: Other; Ascentage: Other; Genfleet: Other; Astellas: Other; Dalichi Sankyo: Consultancy; Aglos: Consultancy; AbbVie: Consultancy, Other: Grant/research support. Ravandi: Amgen: Honoraria, Research Funding; AstraZeneca: Honoraria; Bristol Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Xencor: Honoraria, Research Funding; AbbVie: Honoraria, Research Funding; Jazz: Honoraria, Research Funding; Agios: Honoraria, Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Astex: Honoraria, Research Funding; Novartis: Honoraria; Prelude: Research Funding; Taiho: Honoraria, Research Funding; Syros Pharmaceuticals: Consultancy, Honoraria, Research Funding. DiNardo: ImmuneOnc: Honoraria, Research Funding; GlaxoSmithKline: Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria; Notable Labs: Current holder of stock options in a privately-held company, Membership on an entity's Board of Directors or advisory committees; Agios/Servier: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Research Funding; Novartis: Honoraria; Bristol Myers Squibb: Honoraria, Research Funding; Forma: Honoraria, Research Funding; Foghorn: Honoraria, Research Funding; Celgene, a Bristol Myers Squibb company: Honoraria, Research Funding. Daver: FATE Therapeutics: Research Funding; Glycomimetics: Research Funding; Amgen: Consultancy, Research Funding; Abbvie: Consultancy, Research Funding; Novartis: Consultancy; Novimmune: Research Funding; Bristol Myers Squibb: Consultancy, Research Funding; Gilead Sciences, Inc.: Consultancy, Research Funding; Trovagene: Consultancy, Research Funding; Jazz Pharmaceuticals: Consultancy, Other: Data Monitoring Committee member; Pfizer: Consultancy, Research Funding; Sevier: Consultancy, Research Funding; Hanmi: Research Funding; Trillium: Consultancy, Research Funding; ImmunoGen: Consultancy, Research Funding; Astellas: Consultancy, Research Funding; Daiichi Sankyo: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; Dava Oncology (Arog): Consultancy; Celgene: Consultancy; Syndax: Consultancy; Shattuck Labs: Consultancy; Agios: Consultancy; Kite Pharmaceuticals: Consultancy; SOBI: Consultancy; STAR Therapeutics: Consultancy; Karyopharm: Research Funding; Newave: Research Funding. Borthakur: Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; University of Texas MD Anderson Cancer Center: Current Employment; GSK: Consultancy; Protagonist: Consultancy; Ryvu: Research Funding; Astex: Research Funding; ArgenX: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees. Konopleva: Rafael Pharmaceuticals: Other: grant support, Research Funding; Cellectis: Other: grant support; Novartis: Other: research funding pending, Patents & Royalties: intellectual property rights; Sanofi: Other: grant support, Research Funding; Reata Pharmaceuticals: Current holder of stock options in a privately-held company, Patents & Royalties: intellectual property rights; AstraZeneca: Other: grant support, Research Funding; AbbVie: Consultancy, Honoraria, Other: Grant Support, Research Funding; Eli Lilly: Patents & Royalties: intellectual property rights, Research Funding; Agios: Other: grant support, Research Funding; Genentech: Consultancy, Honoraria, Other: grant support, Research Funding; Stemline Therapeutics: Research Funding; Ablynx: Other: grant support, Research Funding; F. Hoffmann-La Roche: Consultancy, Honoraria, Other: grant support; KisoJi: Research Funding; Ascentage: Other: grant support, Research Funding; Calithera: Other: grant support, Research Funding; Forty Seven: Other: grant support, Research Funding. Yilmaz: Pfizer: Research Funding; Daiichi-Sankyo: Research Funding. Issa: Syndax Pharmaceuticals: Research Funding; Novartis: Consultancy, Research Funding; Kura Oncology: Consultancy, Research Funding. Kantarjian: Ipsen Pharmaceuticals: Honoraria; NOVA Research: Honoraria; Astellas Health: Honoraria; Immunogen: Research Funding; Novartis: Honoraria, Research Funding; AbbVie: Honoraria, Research Funding; Aptitude Health: Honoraria; Astra Zeneca: Honoraria; KAHR Medical Ltd: Honoraria; Jazz: Research Funding; Pfizer: Honoraria, Research Funding; Daiichi-Sankyo: Research Funding; BMS: Research Funding; Ascentage: Research Funding; Amgen: Honoraria, Research Funding; Precision Biosciences: Honoraria; Taiho Pharmaceutical Canada: Honoraria. Short: Novartis: Honoraria; NGMBio: Consultancy; AstraZeneca: Consultancy; Jazz Pharmaceuticals: Consultancy; Astellas: Research Funding; Takeda Oncology: Consultancy, Research Funding; Amgen: Consultancy, Honoraria.

Abstract: Background: Trabectedin is an FDA-approved DNA minor groove binder (MGB) that has activity against translocation-associated sarcomas. Lurbinectedin is a next-generation MGB with pre-clinical activity against myeloid leukemia cells. A dose-finding phase 1 clinical trial was performed in patients with acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) with further assessment of safety and tolerability. Methods: Forty-two patients with relapsed/refractory AML/MDS received lurbinectedin administered as a 1-hour intravenous infusion in a 3+3 study design. Two dosing schedules were used: 3.5 mg, 5 mg, 7 mg, or 6 mg on days 1 and 8 or 2 mg, 3 mg, 1 mg, or 1.5 mg for 3 consecutive days on days 1 to 3. Patients 18 years or older with a diagnosis of advanced, relapsed/refractory AML (non-acute promyelocytic leukemia) and MDS were eligible and treated on study. Eligible patients had adequate hepatic, renal, and cardiac function and an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2. Patients with uncontrolled infection, human immunodeficiency virus, cardiac and neurological disorders, or those who were pregnant were ineligible. Clinical trial information: NCT01314599. Results: Three patients experienced dose-limiting toxicities of rhabdomyolysis (grade 4), hyperbilirubinemia (grade 3), and oral herpes (grade 3) with the days 1 and 8 schedule. Otherwise, adverse events mainly consisted of gastrointestinal manifestations (n=11), febrile neutropenia/infections (n=4), pulmonary toxicity (n=2), and renal failure (n=2). The most common laboratory abnormalities observed were an increase in creatinine (93%) and anemia, neutropenia, and thrombocytopenia (100%). Overall, 33 of 42 patients (79%) had reduction in blasts in peripheral blood or bone marrow. One patient achieved a partial response and two patients a morphologic leukemia-free state. Most (n=30, 71%) were discontinued due to progressive disease. Early deaths occurred from disease-related causes that were not attributable to lurbinectedin. Four patients with a chromosome 11q21-23 abnormality had significantly greater bone marrow blast reduction than those without such abnormality, with decrease of 31±14% (n=4) vs. 8±8% (n=16), respectively (P=0.04). Conclusions: Overall, lurbinectedin was safe and tolerated using the schedules and dose levels tested. While no sustained remissions were observed, single-agent lurbinectedin was transiently leukemia suppressive for some patients. Disclosures Rodríguez: PharmaMar: Employment. Ravandi:Bristol-Myers Squibb: Research Funding; Jazz: Honoraria; Abbvie: Research Funding; Seattle Genetics: Research Funding; Abbvie: Research Funding; Amgen: Honoraria, Research Funding, Speakers Bureau; Orsenix: Honoraria; Seattle Genetics: Research Funding; Astellas Pharmaceuticals: Consultancy, Honoraria; Sunesis: Honoraria; Orsenix: Honoraria; Macrogenix: Honoraria, Research Funding; Astellas Pharmaceuticals: Consultancy, Honoraria; Jazz: Honoraria; Xencor: Research Funding; Bristol-Myers Squibb: Research Funding; Amgen: Honoraria, Research Funding, Speakers Bureau; Macrogenix: Honoraria, Research Funding; Xencor: Research Funding; Sunesis: Honoraria. Daver:Sunesis: Consultancy; Alexion: Consultancy; Daiichi-Sankyo: Research Funding; BMS: Research Funding; ImmunoGen: Consultancy; Kiromic: Research Funding; Incyte: Research Funding; Pfizer: Consultancy; Incyte: Consultancy; ARIAD: Research Funding; Karyopharm: Consultancy; Pfizer: Research Funding; Karyopharm: Research Funding; Novartis: Consultancy; Sunesis: Research Funding; Novartis: Research Funding; Otsuka: Consultancy. Jain:Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; ADC Therapeutics: Research Funding; Infinity: Research Funding; Pfizer: Research Funding; Novimmune: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Research Funding; Servier: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Research Funding; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Genentech: Research Funding; ADC Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Adaptive Biotechnologioes: Research Funding; Pharmacyclics: Research Funding; Incyte: Research Funding; Verastem: Research Funding; Seattle Genetics: Research Funding; Pharmacyclics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Astra Zeneca: Research Funding; Astra Zeneca: Research Funding; Servier: Research Funding; Celgene: Research Funding; Seattle Genetics: Research Funding; Verastem: Honoraria, Membership on an entity's Board of Directors or advisory committees; Astra Zeneca: Honoraria, Membership on an entity's Board of Directors or advisory committees; Infinity: Research Funding; Adaptive Biotechnologies: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Research Funding; Cellectis: Research Funding; ADC Therapeutics: Research Funding; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Adaptive Biotechnologioes: Research Funding; Pharmacyclics: Research Funding; Cellectis: Research Funding; Verastem: Research Funding; Servier: Research Funding; Abbvie: Research Funding; Incyte: Research Funding; Genentech: Research Funding; Abbvie: Research Funding; BMS: Research Funding; Astra Zeneca: Honoraria, Membership on an entity's Board of Directors or advisory committees; Verastem: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; ADC Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Servier: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novimmune: Honoraria, Membership on an entity's Board of Directors or advisory committees; Adaptive Biotechnologies: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees. Maiti:Celgene Corporation: Other: Research funding to the institution. Martinez:PharmaMar: Employment. Siguero:PharmaMar: Employment. Al-Kali:Novartis: Research Funding.

Abstract: Background: Acute myeloid leukemia (AML) outcomes in the elderly, particularly intensive chemotherapy (IC)-ineligible patients (pts), are poor. Venetoclax (VEN), a BCL2 inhibitor, in combination with low-intensity regimens has shown excellent efficacy in AML and is approved for IC-ineligible pts as frontline therapy. Outcomes and expectations of AML after failure of frontline VEN-based regimens are unknown. Methods: We conducted a retrospective study to determine pt outcomes after failure of frontline therapy with VEN and hypomethylating agents (HMA). Newly diagnosed (ND) AML pts enrolled on 2 clinical trials of VEN+HMA (NCT02203773, NCT03404193) with refractory AML or relapse after initial response to VEN+HMA were included. In 1 trial, ND IC-ineligible AML pts (≥65 years [yr]) received VEN 400-1200 mg daily with decitabine (DEC) for 5 days or azacitidine (AZA) for 7 days. The other trial enrolled ND IC-ineligible AML pts ( & gt;60 yrs) who received VEN 400 mg daily or equivalent with DEC for 10 days until CR/CRi, followed by 5-day cycles. FLT3 inhibitors (FLT3i) were allowed in FLT3mut pts. Overall survival (OS) was measured from date of diagnosis of refractory AML or relapse after VEN+HMA therapy, till death or censored at last follow-up. The data cut-off date was 07.08.19. Results: Between November 2014 and February 2019, out of 103 ND AML pts treated with VEN+HMA, 41 pts were identified to have refractory AML, or relapse after VEN+HMA. The median age was 74 yrs (range 62-85), 12 pts (29%) had sAML, 7 pts (17%) had therapy-related AML, 33 pts (81%) had ELN adverse risk AML, 16 pts (39%) had TP53mut, 12 pts (29%) had N/KRASmut, and 5 pts (12%) had FLT3-ITD (Table 1, Fig 1). Pts had received a median of 4 cycles of VEN+HMA (range 1-29). The median follow-up duration for all pts was 21.2 months (mo). With frontline VEN+ HMA, 19 pts (46%) achieved CR, 11 pts (27%) achieved CRi, 3 pts (7%) achieved morphologic leukemia free state (MLFS), and 8 pts (20%) had primary refractory disease. Pts obtaining initial response relapsed after a median duration of response (DOR) of 5.3 mo (range 0.9-34.1). After VEN+ HMA failure, median OS for all 41 pts was 2.4 mo (range 0.1-21.2, Fig 2a). Pts who received salvage therapy (n=24) had longer OS compared to pts who did not receive salvage therapy (n=17, 2.9 vs 1.3 mo, HR=0.41, 95% CI 0.19-0.88, p=0.003, Fig 2b). Median OS for de novo AML at relapse/failure was 2.5 mo, for sAML was 2.8 mo, and for t-AML was 1.1 mo (Fig 2c). Pts with primary refractory AML vs relapsed AML had comparable OS of 1.7 mo vs 2.3 mo, respectively (Fig 2d). Of the 24 pts who received salvage therapy (Table 2, Fig 2e), 5 pts (21%) responded; CR in 1 pt, CRi in 2 pts and MLFS in 2 pts. Among 3 pts with primary refractory AML, 1 pt achieved CR and 1 pt achieved MLFS. Among 21 pts with relapse after VEN+HMA, 2 pts achieved CRi and 1 pt achieved MLFS. 8 pts received IC, and 2/8 pts (notably both with NRASmut) achieved CR and CRi with CLIA, and CLIA + gemtuzumab ozogamicin, respectively. 7 pts received HMA-based regimens, and 2/7 pts responded with CRi and MLFS with AZA + quizartinib, and AZA + nivolumab + ipilimumab, respectively. The former pt had FLT3-ITD and NRASmut and the latter pt had TP53mut. Of the remaining 9 pts receiving other therapies, 1 pt with FLT3-ITD achieved a MLFS with quizartinib + low-dose ara-c. These 5 responding pts continue in remission with median DOR not reached (NR, range 0.7-20.1, Fig 2f) and OS also NR (range, 2-21.2). All pts with NPM1mut and IDH1/2mut who relapsed had adverse-risk cytogenetics or co-occurring mutations in TP53, N/KRAS, FLT3, and/or KIT. Of FLT3-ITDmut pts, 2 of 5 pts (40%) responded to salvage therapy including a FLT3i. Of 11 RASmut pts, 3 pts (27%) responded to salvage therapy including both IC and HMA-based regimens. 1 of 6 TP53mut pts receiving salvage therapy achieved MLFS with AZA + nivolumab + ipilimumab. This pt was also the only one among 7 pts with complex cytogenetics who responded to salvage therapy. Conclusion: Older IC-ineligible pts with ND AML who fail frontline VEN+HMA have high-risk disease biology including t-AML, sAML, complex cytogenetics, FLT3-ITD, TP53mut, N/KRASmut. These known high-risk features decrease likelihood of response and confer poor OS, confirmed in this analysis. The median OS after frontline VEN+HMA failure was 2.4 mo. Notably some pts with FLT3-ITD responded well to salvage regimens with FLT3i. Novel therapies to abrogate VEN resistance, especially in high risk genotypes, are urgently needed. Disclosures Maiti: Celgene: Other: research funding. Cortes:Takeda: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Forma Therapeutics: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria, Research Funding; Jazz Pharmaceuticals: Consultancy, Research Funding; Daiichi Sankyo: Consultancy, Honoraria, Research Funding; Astellas Pharma: Consultancy, Honoraria, Research Funding; Sun Pharma: Research Funding; Biopath Holdings: Consultancy, Honoraria; BiolineRx: Consultancy; Novartis: Consultancy, Honoraria, Research Funding; Immunogen: Consultancy, Honoraria, Research Funding; Merus: Consultancy, Honoraria, Research Funding. Pemmaraju:mustangbio: Consultancy, Research Funding; abbvie: Consultancy, Honoraria, Research Funding; samus: Research Funding; celgene: Consultancy, Honoraria; cellectis: Research Funding; Stemline Therapeutics: Consultancy, Honoraria, Research Funding; novartis: Consultancy, Research Funding; plexxikon: Research Funding; Daiichi-Sankyo: Research Funding; sagerstrong: Research Funding; affymetrix: Research Funding; incyte: Consultancy, Research Funding. Daver:Immunogen: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Hanmi Pharm Co., Ltd.: Research Funding; Jazz: Consultancy; Daiichi Sankyo: Consultancy, Research Funding; Servier: Research Funding; Abbvie: Consultancy, Research Funding; Forty-Seven: Consultancy; Glycomimetics: Research Funding; Celgene: Consultancy; Astellas: Consultancy; Immunogen: Consultancy, Research Funding; Daiichi Sankyo: Consultancy, Research Funding; Astellas: Consultancy; Celgene: Consultancy; NOHLA: Research Funding; Agios: Consultancy; Otsuka: Consultancy; BMS: Consultancy, Research Funding; Sunesis: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Servier: Research Funding; Glycomimetics: Research Funding; Pfizer: Consultancy, Research Funding; NOHLA: Research Funding; Genentech: Consultancy, Research Funding; Sunesis: Consultancy, Research Funding; Incyte: Consultancy, Research Funding; Abbvie: Consultancy, Research Funding; Karyopharm: Consultancy, Research Funding; Agios: Consultancy; Karyopharm: Consultancy, Research Funding; Forty-Seven: Consultancy; Otsuka: Consultancy; Jazz: Consultancy; Incyte: Consultancy, Research Funding; Hanmi Pharm Co., Ltd.: Research Funding. Ravandi:Xencor: Consultancy, Research Funding; Macrogenix: Consultancy, Research Funding; Selvita: Research Funding; Cyclacel LTD: Research Funding; Menarini Ricerche: Research Funding; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, 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. Borthakur:AstraZeneca: Research Funding; BioLine Rx: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; NKarta: Consultancy; Cyclacel: Research Funding; Janssen: Research Funding; Incyte: Research Funding; Novartis: Research Funding; Xbiotech USA: Research Funding; Eisai: Research Funding; Tetralogic Pharmaceuticals: Research Funding; Polaris: Research Funding; Arvinas: Research Funding; Merck: Research Funding; Cantargia AB: Research Funding; FTC Therapeutics: Membership on an entity's Board of Directors or advisory committees; Argenx: Membership on an entity's Board of Directors or advisory committees; BioTheryX: Membership on an entity's Board of Directors or advisory committees; PTC Therapeutics: Consultancy; Strategia Therapeutics: Research Funding; Bayer Healthcare AG: Research Funding; Agensys: Research Funding; Oncoceutics: Research Funding; GSK: Research Funding; BMS: Research Funding; Oncoceutics, Inc.: Research Funding; Eli Lilly and Co.: Research Funding; AbbVie: Research Funding. Short:Takeda Oncology: Consultancy, Research Funding; Amgen: Honoraria; AstraZeneca: Consultancy. Alvarado:Jazz Pharmaceuticals: Research Funding; Abbott: Honoraria. Kadia:Pfizer: Membership on an entity's Board of Directors or advisory committees, Research Funding; Bioline RX: 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; AbbVie: Consultancy, Research Funding; Celgene: Research Funding; Jazz: Membership on an entity's Board of Directors or advisory committees, Research Funding. Takahashi:Symbio Pharmaceuticals: Consultancy. Jain:Adaptive Biotechnologies: 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; Janssen Pharmaceuticals, Inc.: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; 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; AbbVie: 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; Precision Biosciences: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; ADC Therapeutics: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Incyte: Research Funding; AstraZeneca: 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. Sasaki:Otsuka: Honoraria; Pfizer: Consultancy. Andreeff:BiolineRx: Membership on an entity's Board of Directors or advisory committees; Leukemia Lymphoma Society: Membership on an entity's Board of Directors or advisory committees; CLL Foundation: Membership on an entity's Board of Directors or advisory committees; German Research Council: Membership on an entity's Board of Directors or advisory committees; NCI-CTEP: Membership on an entity's Board of Directors or advisory committees; Cancer UK: Membership on an entity's Board of Directors or advisory committees; Center for Drug Research & Development: Membership on an entity's Board of Directors or advisory committees; NIH/NCI: Research Funding; CPRIT: Research Funding; Breast Cancer Research Foundation: Research Funding; Oncolyze: Equity Ownership; Oncoceutics: Equity Ownership; Senti Bio: Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Eutropics: Equity Ownership; Aptose: Equity Ownership; Daiichi Sankyo, Inc.: Consultancy, Patents & Royalties: Patents licensed, royalty bearing, Research Funding; Jazz Pharmaceuticals: Consultancy; Celgene: Consultancy; Amgen: Consultancy; AstaZeneca: Consultancy; 6 Dimensions Capital: Consultancy; Reata: Equity Ownership; NCI-RDCRN (Rare Disease Cliln Network): Membership on an entity's Board of Directors or advisory committees. Bose:Incyte Corporation: Consultancy, Research Funding, Speakers Bureau; Celgene Corporation: Consultancy, Research Funding; Blueprint Medicine Corporation: Consultancy, Research Funding; Kartos: Consultancy, Research Funding; Constellation: Research Funding; Pfizer: Research Funding; Astellas: Research Funding; NS Pharma: Research Funding; Promedior: Research Funding; CTI BioPharma: Research Funding. Jabbour:Takeda: Consultancy, Research Funding; Cyclacel LTD: Research Funding; Pfizer: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Adaptive: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; AbbVie: Consultancy, Research Funding. Thompson:AbbVie: Research Funding; Amgen: Consultancy, Research Funding; Pfizer: Research Funding; Pharmacyclics: Research Funding; Genentech: Consultancy, Honoraria; Gilead: Consultancy, Honoraria. Zhang:The University of Texas M.D.Anderson Cancer Center: Employment. Kantarjian:Agios: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Immunogen: Research Funding; Daiichi-Sankyo: Research Funding; Pfizer: Honoraria, Research Funding; Ariad: Research Funding; Cyclacel: Research Funding; Jazz Pharma: Research Funding; Actinium: Honoraria, Membership on an entity's Board of Directors or advisory committees; AbbVie: Honoraria, Research Funding; Novartis: Research Funding; Takeda: Honoraria; Astex: Research Funding; BMS: Research Funding. Konopleva:Calithera: Research Funding; Stemline Therapeutics: Consultancy, Honoraria, Research Funding; Forty-Seven: Consultancy, Honoraria; Kisoji: Consultancy, Honoraria; Ascentage: Research Funding; Eli Lilly: Research Funding; AbbVie: Consultancy, Honoraria, Research Funding; Cellectis: Research Funding; Amgen: Consultancy, Honoraria; Genentech: Honoraria, Research Funding; F. Hoffman La-Roche: Consultancy, Honoraria, Research Funding; Astra Zeneca: Research Funding; Agios: Research Funding; Reata Pharmaceuticals: Equity Ownership, Patents & Royalties; Ablynx: Research Funding. DiNardo:jazz: Honoraria; abbvie: Consultancy, Honoraria; celgene: Consultancy, Honoraria; medimmune: Honoraria; syros: Honoraria; notable labs: Membership on an entity's Board of Directors or advisory committees; agios: Consultancy, Honoraria; daiichi sankyo: Honoraria.

Abstract: Severe congenital neutropenia (SCN) is frequently associated with mutations in the ELANE gene encoding neutrophil elastase (NE), an azurophilic granule protein which represents a major fraction of all protein synthesized by neutrophilic promyelocytes and myelocytes. The reduction of mutant ELANE translation inversely correlates with neutrophil differentiation. Chronic administration of granulocyte colony-stimulating-factor (G-CSF) has been successfully used to treat some of these patients, especially those ones with mutations in C-terminus translating exons-4 and -5. Patients with proximal mutations of ELANE tend to be resistant to G-CSF therapy. The SCN pathobiology is poorly understood due to the lack of efficient disease animal models, and difficulty in obtaining relevant primary cell populations from patients. We have demonstrated that ELANE exon-3 mutations, sensitive to higher doses of G-CSF administration, cause maturation arrest and apoptosis of promyelocyte and myelocyte stages due to mutant NE inducing unfolded protein response (UPR) and endoplasmic reticulum (ER) stress. We have also shown that SCN patients with mutations in ELANE at its translation initiation codon (ELANE-ATG mut) result in synthesis of alternate truncated neutrophil elastase peptides from downstream in-frame ATG due to the presence of internal ribosomal entry sites. However, the mechanisms of SCN pathogenesis associated with mutations at the translation initiation codon of ELANE gene associated with G-CSF resistance remain unclear. We employed a disease-in-a-dish approach by directed hematopoietic and granulopoietic differentiation of gene edited (CRISPR/Cas9) isogenic patient-derived iPSC lines. We used four iPSC lines (healthy donor 28L and its start codon knock-in isogenic 28L-GTG; and patient-derived ATG mut SCN110 and its isogenic corrected line SCN110C) to evaluate if ELANE start codon mutations are both necessary and sufficient to cause disease pathogenesis, and to unravel the underlying molecular mechanisms. We found that myeloid precursors derived from 28-GTG and SCN110 iPSC lines generate low molecular weight truncated NE that is detected by a C-terminal region (C225-H238) specific anti-NE antibody (Ab). The survival, expansion and differentiation of ELANE start codon mutant hematopoietic progenitors were significantly reduced in cytokine supplemented in vitro myelopoiesis cultures, and the correction of the mutation (SCN110C) restored the granulocytic precursor expansion and differentiation. The reduced expansion in 28L-GTG and SCN110 lines was associated with both increased apoptosis and expression of proapoptotic BH3-only proteins in comparison to their isogenic 28L and SCN110C lines. However, this apoptosis was not associated with UPR/ER-stress in ELANE-ATG mut myeloid precursors. Granulopoietic differentiation of the 28L-GTG and SCN110 iPSC derived hematopoietic progenitors was significantly reduced, while it was rescued in corrected isogenic lines. Correlating with their clinical behavior, high-dose G-CSF in vitro did not restore the granulopoietic differentiation of ELANE ATG mutant hematopoietic progenitors. Mechanistically, 28L-GTG and SCN110 myeloid precursors contained high-molecular weight, sodium dodecyl sulfate (SDS) resistant NE bands that were detected by anti-NE Ab specific for the C-terminal (C225-238), but not the N-terminal region (C19-38), suggesting that truncated mutant NE generates insoluble NE aggregates. The association of truncated NE with classical autophagy marker LC3B strongly suggested the activation of an aggrephagy process in these cells. We found that SERF1 (small EDRK-rich factor), an RNA-chaperoning protein, known to localize in misfolded protein aggregates of neurodegenerative diseases, was highly upregulated in GTG knock-in and SCN patient myeloid precursors. SERF1 was distributed in both nucleus and cytoplasm, co-localized and physically interacted with mutant truncated NE in the cytoplasm of ELANE-ATG mut cells as shown by proximity ligation assays. Silencing of SERF1 made the survival and differentiation of 28L-GTG and SCN110 derived myeloid precursors sensitive to G-CSF. ELANE translation initiation mutant was associated with truncated NE aggregates and induced apoptosis mediated by SERF1. This data opens a path for therapeutic intervention of G-CSF resistant ELANEmut SCN. Disclosures Kalfa: Agios Pharmaceuticals, Inc.: Other: Steering Committee, Research Funding; FORMA Therapeutics, Inc: Research Funding. Lutzko: Aruvant Sciences: Patents & Royalties: preclinical vector development. Cancelas: Hemerus LLC: Research Funding; Vascular Solutions Inc.: Research Funding; Westat Inc: Research Funding; Fresenius-Kabi LLC: Research Funding; Cytosorbents Inc: Research Funding; Hemanext: Membership on an entity's Board of Directors or advisory committees, Research Funding; TerumoBCT: Research Funding; Cerus Co: Research Funding; University of South Florida/MEQU Inc: Research Funding.

Abstract: Background: Elderly patients (pt) with acute myeloid leukemia (AML) or pts with relapsed/refractory (R/R) AML have dismal outcomes. Venetoclax (VEN) synergizes with hypomethylating agents (HMA) and is now an approved combination for newly diagnosed (ND) AML in older/intensive chemotherapy (IC)-ineligible patients. We hypothesized that VEN with 10-day decitabine (DEC) may offer superior efficacy in AML. Methods: Between January and November 2018 we enrolled 101 pts with ND AML (n=40), untreated secondary AML (sAML, n=9), treated sAML (n=19) and R/R AML (n=33). Eligibility included ECOG PS ≤3, WBC ≤10 x109/L, and adequate organ function. DEC was given 20 mg/m2 IV daily on day 1-10 until CR/CRi, followed by 5-day cycles. VEN was given on day 1-28 in cycle 1 but was interrupted on C1D21 until count recovery if the day 21 bone marrow (BM) had ≤5% blasts. VEN could be reduced further to 14, 10 or 7 days in subsequent cycles for pts with ongoing cytopenias/myelosuppression. VEN dose was 400 mg PO daily (reductions allowed for concomitant CYP3A4 inhibitors) All pts received tumor lysis syndrome (TLS) prophylaxis. Cytoreduction prior to start, and concomitant BCR-ABL1 (n=1) and FLT3 inhibitors (n=15) were allowed as indicated. Primary objective was overall response rate and secondary objectives included safety and overall survival. The data cut-off date was 03.08.19. Results: This high-risk cohort included 52% of pts ≥70 yrs (interquartile range [IQR], 61-74), 54% pts were men, 28% pts had ECOG PS ≥2, and 67% pts had adverse-risk AML (Table 1). 30 and 60-day mortality were both 2.5% for ND pts, and 5% and 9%, respectively, for all pts. Notable treatment-emergent adverse events were infections with grade 3/4 neutropenia (61%), febrile neutropenia (35%), and TLS (4%, Table 2). Four pts developed grade 3 or 4 reversible TLS; their median WBC count was 7.1x109/L (1.6, 2.1, 12, 28) and median peripheral blasts was 64% (IQR 39-83) and led to a subsequent requirement for WBC ≤10 x109/L prior to start. The CR/CRi rate in ND AML was 95%, in untreated sAML was 67%, in treated sAML was 37%, and in R/R AML was 27% (Table 3). Out of 67 pts with C1D21±3 BM, ≤5% blasts was achieved in 57%, and 74% of ND pts. In previously untreated AML (defined as ND AML + untreated sAML), CR/CRi rate in ELN favorable, intermediate and adverse risk pts were 100% (n=11), 100% (n=6), and 84% (n=32). CR/CRi rate in t-AML was 100% (n=7). In previously treated AML (treated sAML + R/R AML), CR/CRi rate in HMA refractory pts was 39% (n=18), in pts with prior IC was 21% (n=33), in pts with prior HMA and IC was 17% (n=12), in pts with prior stem cell transplantation (SCT) was 22% (n=18). At median follow-up of 8.1 months (mo), the 6-mo OS in ND AML was 90%, in untreated sAML was 56%, in treated sAML was 62%, and R/R AML was 53% (Fig. 1). Among all pts, achievement of CR conferred better duration of response (DOR) and OS compared to CRi/MLFS (median DOR not reached [NR] vs 4.0 mo, censored at SCT, hazard ratio [HR] 0.21, 95% confidence interval [CI] 0.09-0.49, p=0.002, and median OS NR vs 7.8 mo, censored at SCT, HR 0.31, 95% CI 0.13-0.74). 70% of all responding pts were minimal residual disease negative (MRD-) by flow cytometry and MRD- status was associated with longer OS (NR vs 7.8 mo, censored at SCT, HR 0.35, 95% CI 0.14-0.88, p=0.01, Fig. 2a). Median DOR in pts achieving CR/CRi in ND AML was 8.5 mo, in the untreated sAML was 6.3 mo, in treated sAML was 4.8 mo, and in R/R AML was 6.6 mo. Among ND AML pts achieving CR/CRi, median time to count recovery after 1st, 2nd and 3rd cycles for ANC 〉 0.5x109/L was 42 days (95% CI 37-46), 40 days (95% CI 35-44), and 38 days (95% CI 32-NR), respectively; and for platelet ≥50 x109/L was 28 days (95% CI 25-32), 25 days (95% CI 0-34), and 26 days (95% CI 19-33), respectively. 78 pts (77%) discontinued treatment, and 59 pts (58%) are alive. Common reasons for discontinuation were non-response in 24 pts (24%), SCT in 20 pts (20%), and relapse in 18 pts (18%). Pts receiving SCT (n= 20) had excellent outcomes with 100-day post-SCT mortality of 0% (Fig 2b and c). Baseline BCL2 expression in CD34+ blasts showed a trend between higher BCL2 expression and MRD- rate (Fig. 2d). Conclusions: DEC10-VEN is an effective therapy for ND elderly pts, as well as in R/R AML as an effective bridge to SCT. Trial continues to accrue (NCT03404193). Disclosures Maiti: Celgene: Other: research funding. DiNardo:jazz: Honoraria; medimmune: Honoraria; abbvie: Consultancy, Honoraria; daiichi sankyo: Honoraria; celgene: Consultancy, Honoraria; agios: Consultancy, Honoraria; notable labs: Membership on an entity's Board of Directors or advisory committees; syros: Honoraria. Cortes:Astellas Pharma: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria, Research Funding; Daiichi Sankyo: Consultancy, Honoraria, Research Funding; Forma Therapeutics: Consultancy, Honoraria, Research Funding; Biopath Holdings: Consultancy, Honoraria; BiolineRx: Consultancy; Immunogen: Consultancy, Honoraria, Research Funding; Sun Pharma: Research Funding; Jazz Pharmaceuticals: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Merus: Consultancy, Honoraria, Research Funding. Pemmaraju:mustangbio: Consultancy, Research Funding; abbvie: Consultancy, Honoraria, Research Funding; samus: Research Funding; celgene: Consultancy, Honoraria; cellectis: Research Funding; Stemline Therapeutics: Consultancy, Honoraria, Research Funding; novartis: Consultancy, Research Funding; plexxikon: Research Funding; Daiichi-Sankyo: Research Funding; sagerstrong: Research Funding; affymetrix: Research Funding; incyte: Consultancy, Research Funding. Daver:Pfizer: Consultancy, Research Funding; Servier: Research Funding; Hanmi Pharm Co., Ltd.: Research Funding; Novartis: Consultancy, Research Funding; Abbvie: Consultancy, Research Funding; Jazz: Consultancy; Servier: Research Funding; Daiichi Sankyo: Consultancy, Research Funding; Karyopharm: Consultancy, Research Funding; Astellas: Consultancy; Incyte: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Immunogen: Consultancy, Research Funding; Sunesis: Consultancy, Research Funding; NOHLA: Research Funding; Forty-Seven: Consultancy; Novartis: Consultancy, Research Funding; Glycomimetics: Research Funding; Agios: Consultancy; Otsuka: Consultancy; Abbvie: Consultancy, Research Funding; Celgene: Consultancy; Genentech: Consultancy, Research Funding; Hanmi Pharm Co., Ltd.: Research Funding; Incyte: Consultancy, Research Funding; NOHLA: Research Funding; Glycomimetics: Research Funding; Celgene: Consultancy; Agios: Consultancy; Genentech: Consultancy, Research Funding; Sunesis: Consultancy, Research Funding; Karyopharm: Consultancy, Research Funding; Otsuka: Consultancy; Pfizer: Consultancy, Research Funding. Ravandi:Menarini Ricerche: Research Funding; Cyclacel LTD: Research Funding; Macrogenix: Consultancy, Research Funding; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Selvita: Research Funding; Xencor: Consultancy, Research Funding. Garcia-Manero:AbbVie: Research Funding; Celgene: Consultancy, Research Funding; Astex: Consultancy, Research Funding; Onconova: Research Funding; H3 Biomedicine: Research Funding; Merck: Research Funding; Amphivena: Consultancy, Research Funding; Helsinn: Research Funding; Novartis: Research Funding. Borthakur:BMS: Research Funding; Argenx: Membership on an entity's Board of Directors or advisory committees; Eisai: Research Funding; Tetralogic Pharmaceuticals: Research Funding; Novartis: Research Funding; Strategia Therapeutics: Research Funding; Cyclacel: Research Funding; BioLine Rx: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; AstraZeneca: Research Funding; PTC Therapeutics: Consultancy; Arvinas: Research Funding; Oncoceutics: Research Funding; GSK: Research Funding; Janssen: Research Funding; Incyte: Research Funding; AbbVie: Research Funding; Xbiotech USA: Research Funding; Merck: Research Funding; Bayer Healthcare AG: Research Funding; BioTheryX: Membership on an entity's Board of Directors or advisory committees; Eli Lilly and Co.: Research Funding; Cantargia AB: Research Funding; NKarta: Consultancy; Agensys: Research Funding; Polaris: Research Funding; Oncoceutics, Inc.: Research Funding; FTC Therapeutics: Membership on an entity's Board of Directors or advisory committees. Short:Takeda Oncology: Consultancy, Research Funding; AstraZeneca: Consultancy; Amgen: Honoraria. Alvarado:Jazz Pharmaceuticals: Research Funding; Abbott: Honoraria. Kadia:Amgen: Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Research Funding; Bioline RX: Research Funding; Celgene: 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; AbbVie: Consultancy, 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. Jain: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; Precision Biosciences: 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; BMS: Research Funding; Genentech: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Verastem: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; ADC Therapeutics: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; 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; Adaptive Biotechnologies: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Incyte: Research Funding; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Sasaki:Otsuka: Honoraria; Pfizer: Consultancy. Andreeff:Daiichi Sankyo, Inc.: Consultancy, Patents & Royalties: Patents licensed, royalty bearing, Research Funding; Celgene: Consultancy; Jazz Pharmaceuticals: Consultancy; Amgen: Consultancy; AstaZeneca: Consultancy; 6 Dimensions Capital: Consultancy; Reata: Equity Ownership; Aptose: Equity Ownership; Eutropics: Equity Ownership; Senti Bio: Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Oncoceutics: Equity Ownership; Oncolyze: Equity Ownership; Breast Cancer Research Foundation: Research Funding; CPRIT: Research Funding; NIH/NCI: Research Funding; Center for Drug Research & Development: Membership on an entity's Board of Directors or advisory committees; Cancer UK: Membership on an entity's Board of Directors or advisory committees; NCI-CTEP: Membership on an entity's Board of Directors or advisory committees; German Research Council: Membership on an entity's Board of Directors or advisory committees; Leukemia Lymphoma Society: Membership on an entity's Board of Directors or advisory committees; NCI-RDCRN (Rare Disease Cliln Network): Membership on an entity's Board of Directors or advisory committees; CLL Foundation: Membership on an entity's Board of Directors or advisory committees; BiolineRx: Membership on an entity's Board of Directors or advisory committees. Bose:Blueprint Medicine Corporation: Consultancy, Research Funding; Incyte Corporation: Consultancy, Research Funding, Speakers Bureau; Celgene Corporation: Consultancy, Research Funding; Kartos: Consultancy, Research Funding; Constellation: Research Funding; Pfizer: Research Funding; Astellas: Research Funding; NS Pharma: Research Funding; Promedior: Research Funding; CTI BioPharma: Research Funding. Jabbour:Cyclacel LTD: Research Funding; Pfizer: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; AbbVie: Consultancy, Research Funding; Adaptive: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Takeda: Consultancy, Research Funding. Thompson:AbbVie: Research Funding; Amgen: Consultancy, Research Funding; Pfizer: Research Funding; Pharmacyclics: Research Funding; Genentech: Consultancy, Honoraria; Gilead: Consultancy, Honoraria. Zhang:The University of Texas M.D.Anderson Cancer Center: Employment. Kantarjian:Amgen: Honoraria, Research Funding; Actinium: Honoraria, Membership on an entity's Board of Directors or advisory committees; Cyclacel: Research Funding; BMS: Research Funding; Daiichi-Sankyo: Research Funding; Novartis: Research Funding; Jazz Pharma: Research Funding; Astex: Research Funding; Immunogen: Research Funding; AbbVie: Honoraria, Research Funding; Agios: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding; Takeda: Honoraria; Ariad: Research Funding. Konopleva:Forty-Seven: Consultancy, Honoraria; Genentech: Honoraria, Research Funding; Ablynx: Research Funding; Kisoji: Consultancy, Honoraria; Astra Zeneca: Research Funding; Ascentage: Research Funding; Cellectis: Research Funding; Amgen: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria, Research Funding; Reata Pharmaceuticals: Equity Ownership, Patents & Royalties; F. Hoffman La-Roche: Consultancy, Honoraria, Research Funding; Calithera: Research Funding; Agios: Research Funding; Stemline Therapeutics: Consultancy, Honoraria, Research Funding; Eli Lilly: Research Funding.

Abstract: Background: Patients (pt) with acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) who are elderly, or have secondary AML (sAML), or relapsed/refractory (R/R) disease have poor outcomes. Venetoclax (VEN), an oral BCL2 inhibitor, has shown activity in R/R AML as single-agent and in combination with hypomethylating agents (HMA) in newly diagnosed unfit AML. We designed a phase II trial to evaluate the safety and efficacy of VEN with 10-days (D) of decitabine (DEC) in AML and high risk MDS. Methods: Eligible AML pts included those who had failed prior therapy, or were newly diagnosed (ND) elderly pts ( 〉 60 years), or had sAML. ECOG score ≤3, WBC count ≤10 x109/L, and adequate organ function were required. VEN was given on day 1-28 in cycle (cy) 1 and D1-21 in cy 2 onwards; and was interrupted on C1D21 if the 21D bone marrow showed clearance of blasts, until count recovery. VEN was dosed 200 mg PO daily (50% dose reduction) in pts needing CYP3A4 inhibitors. DEC was given 20 mg/m2 IVdaily on D1-10 until CR/CRi, followed by 5-day cycles. Hydroxyurea or ara-C could be used for cytoreduction prior to starting therapy. Prophylactic antimicrobials were used until neutrophil recovery. Tyrosine kinase inhibitors could be used in applicable patients. Primary objective was to determine overall response rate (ORR) including complete remission (CR), CR with incomplete blood count recovery (CRi), partial remission (PR), and morphologic leukemia-free state in pts with AML. Secondary objectives were to determine safety of the combination; duration of response (DOR), disease-free survival (DFS) and overall survival (OS). Results: 48 pts were enrolled between January and May 2018 (Table 1). 24 pts (50%) had ND AML, 7 pts (15%) had sAML, and 16 pts (33%) had R/R AML. Prior therapies are listed in Table 1. The overall CR/CRi rate was 71% (34/48). CR/CRi rate for ND, sAML and R/R AML were 92%, 71% and 44%, respectively (Table 2). Negative minimal residual disease (MRD-) by flow cytometry at the time of response was achieved in 16/33 responding pts (49%). CR/CRi with MRD- was achieved in 11/21 pts with ND AML (52%), 2/5 pts with sAML (40%), and 3/6 pts w R/R AML (50%). CR/CRi rate in TP53 mutated pts was 67% (8/12, Table 2). Additional therapies included ponatinib in 1 pt with AML and t(9;22) who achieved a CRi; and sorafenib in 5 pts (4 FLT3-ITD, 1 FLT3 S749L variant) of which 2 ITD pts achieved CRi and 3 pts did not respond. Median time to first response was 43D (range 20-110) with a median of 1 cy to best response (range 1-3). At a median follow-up of 2.3 months (mo; range 1.4-5.7), pts had received a median of 2 cy (range 2-5) and 32 pts continue on study. Reasons for discontinuation are shown in Table 3. Median OS has not been reached (NR) for ND and sAML pts (NR, range 1.8 mo-NR) and R/R AML (NR, range 0.4 mo-NR, Fig 1a). Median DFS (Fig 1b) and DOR for ND and sAML pts are also NR (range 0.9 mo-NR). Median DFS and DOR for R/R AML pts were 3.3 mo (range 0.5-NR). 10 pts received GCSF. 59 treatment-emergent adverse events (TEAE) occurred in 31 pts, out of which 48 were grade (gr) 3/4. The most frequent gr 3/4 TEAE were infections, with gr 3/4 neutropenia (53%), febrile neutropenia (14%), and tumor lysis syndrome (TLS, n=2, 4%). 1 pt with WBC count 12 x109/L developed TLS on C1D2 which resolved with rasburicase and holding VEN; another pt with WBC count 28 x109/L developed TLS on C1D2 needing hemodialysis for 12 days, prompting study amendment to the current baseline WBC≤10 x109/L. Time to blood count recovery are shown in Table 4. There were total 6 deaths, all in pts with R/R AML (n=5) and treated sAML (n=1), including 3 deaths in hospice, 2 early deaths in relapsed AML pts due to infection; and 1 early death in a relapsed MDS pt due to pneumonia and acute kidney injury unrelated to therapy. There were no deaths in the ND AML pts. 30D and 60D mortality rates were 8% and 10%, respectively. Preliminary BH3 profiling data in R/R cohort showed BCL-2 priming (by assessing cytochrome C release to recombinant BAD peptide and ABT-199) in 7/8 pts irrespective of their response; however, pts who failed to achieve CR/CRi demonstrated co-dependence on other anti-apoptotic proteins MCL-1, BCL-XL and A1 (Fig 2). Additional BH3 profiling and CyTOF analyses are ongoing. Conclusion: The DEC10-VEN regimen had an acceptable safety profile and excellent response rates with CR/CRi of 92% in ND AML, 71% in sAML, and 44% in R/R AML with MRD- in 52% of ND AML, 40% of sAML and 50% of R/R AML. Trial is continuing to accrue (NCT03404193). Disclosures Maiti: Celgene Corporation: Other: Research funding to the institution. DiNardo:AbbVie: Consultancy, Other: Advisory role; Agios: Consultancy, Other: Advisory role; Bayer: Other: Advisory role; Celgene: Other: Advisory role; Medimmune: Other: Advisory role; Karyopharm: Other: Advisory role. Cortes:Novartis: Consultancy, Research Funding; Arog: Research Funding; Daiichi Sankyo: Consultancy, Research Funding; Astellas Pharma: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding. Pemmaraju:plexxikon: Research Funding; novartis: Research Funding; Affymetrix: Research Funding; samus: Research Funding; cellectis: Research Funding; celgene: Consultancy, Honoraria; SagerStrong Foundation: Research Funding; abbvie: Research Funding; daiichi sankyo: Research Funding; stemline: Consultancy, Honoraria, Research Funding. Kadia:Celgene: Research Funding; Amgen: Consultancy, Research Funding; Jazz: Consultancy, Research Funding; Takeda: Consultancy; BMS: Research Funding; BMS: Research Funding; Pfizer: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; Novartis: Consultancy; Celgene: Research Funding; Abbvie: Consultancy; Jazz: Consultancy, Research Funding; Abbvie: Consultancy; Novartis: Consultancy; Takeda: Consultancy; Pfizer: Consultancy, Research Funding. Ravandi:Amgen: Honoraria, Research Funding, Speakers Bureau; Abbvie: Research Funding; Bristol-Myers Squibb: Research Funding; Jazz: Honoraria; Sunesis: Honoraria; Abbvie: Research Funding; Xencor: Research Funding; Sunesis: Honoraria; Seattle Genetics: Research Funding; Seattle Genetics: Research Funding; Macrogenix: Honoraria, Research Funding; Orsenix: Honoraria; Astellas Pharmaceuticals: Consultancy, Honoraria; Xencor: Research Funding; Astellas Pharmaceuticals: Consultancy, Honoraria; Jazz: Honoraria; Bristol-Myers Squibb: Research Funding; Amgen: Honoraria, Research Funding, Speakers Bureau; Macrogenix: Honoraria, Research Funding; Orsenix: Honoraria. Short:Takeda Oncology: Consultancy. Daver:BMS: Research Funding; ImmunoGen: Consultancy; Incyte: Consultancy; Otsuka: Consultancy; Daiichi-Sankyo: Research Funding; Incyte: Research Funding; Novartis: Consultancy; Sunesis: Research Funding; Karyopharm: Research Funding; Pfizer: Research Funding; Alexion: Consultancy; Karyopharm: Consultancy; Pfizer: Consultancy; Sunesis: Consultancy; Kiromic: Research Funding; ARIAD: Research Funding; Novartis: Research Funding. Sasaki:Otsuka Pharmaceutical: Honoraria. Thompson:Gilead Sciences: Honoraria, Membership on an entity's Board of Directors or advisory committees; Adaptive Biotechnologies: Research Funding; AbbVie: Honoraria, Research Funding; Pharmacyclics: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Genentech: Honoraria, Membership on an entity's Board of Directors or advisory committees. Jain:Servier: Honoraria, Membership on an entity's Board of Directors or advisory committees; Servier: Research Funding; Adaptive Biotechnologies: Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Research Funding; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Research Funding; ADC Therapeutics: Research Funding; Adaptive Biotechnologies: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Research Funding; ADC Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Verastem: Honoraria, Membership on an entity's Board of Directors or advisory committees; Cellectis: Research Funding; Pharmacyclics: Research Funding; Novimmune: Honoraria, Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Research Funding; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Research Funding; Infinity: Research Funding; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novimmune: Honoraria, Membership on an entity's Board of Directors or advisory committees; Adaptive Biotechnologioes: Research Funding; Genentech: Research Funding; Verastem: Research Funding; Servier: Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Research Funding; ADC Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Astra Zeneca: Research Funding; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Research Funding; Verastem: Honoraria, Membership on an entity's Board of Directors or advisory committees; Incyte: Research Funding; Astra Zeneca: Honoraria, Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Research Funding; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees; ADC Therapeutics: Research Funding; Pharmacyclics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Adaptive Biotechnologioes: Research Funding; Pfizer: Research Funding; Cellectis: Research Funding; Verastem: Research Funding; BMS: Research Funding; Servier: Research Funding; Infinity: Research Funding; Astra Zeneca: Research Funding; Celgene: Research Funding; Genentech: Research Funding; Incyte: Research Funding; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Astra Zeneca: Honoraria, Membership on an entity's Board of Directors or advisory committees. Jabbour:Pfizer: Consultancy, Research Funding; Novartis: Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; Abbvie: Research Funding. Andreeff:AstraZeneca: Research Funding. Konopleva:Stemline Therapeutics: Research Funding.