Abstract: Background: Venetoclax (ven) combined with azacitidine (aza/ven), decitabine (dec/ven), and low-dose cytarabine (LDAC/ven) is approved as frontline therapy for older or otherwise unfit AML patients (pts) and also frequently used for pts with relapsed/refractory (RR)-AML. However, clinical outcomes of AML pts who receive an allogeneic stem cell transplant (alloSCT) after ven combination (ven combo) therapy are unclear. Methods: All AML pts who received treatment with aza/ven, dec/ven or LDAC/ven as either initial induction or for RR disease at Memorial Sloan Kettering Cancer Center from 08/2016 to 02/2020 and underwent a subsequent allo-SCT were included. The response to ven therapy prior to alloSCT was determined using the 2017 European LeukemiaNet response criteria. The overall response rate was defined as the combination of the complete response (CR) + complete response with incomplete count recovery (CRi) + morphologic leukemia free state (MLFS) rate. Measurable residual disease (MRD) was assessed by multiparameter flow cytometric analysis of bone marrow aspirate samples. Any level of residual disease was considered MRD+. Overall survival (OS) after alloSCT was calculated from the day of graft infusion until death or time of last follow-up. Results: A total of 130 pts were treated with ven combo therapy with 18 pts (13.8% of all pts) receiving a subsequent alloSCT. Median age was 65 years (A). While 3 pts received a ven combo as the first treatment for AML, 15 pts had RR-AML. Aza/ven was most commonly used (72%) and the majority of pts (83%) received 1-2 cycles of ven therapy prior to alloSCT. For 7, 6, 4 and 1 pts the donor was a matched related, a matched unrelated, a mismatched unrelated, or haploidentical; only one pt had received a prior alloSCT for AML (B). Unmodified peripheral blood stem cells (66%) and reduced intensity conditioning regimens (77%) were most commonly used. In pts who proceeded to an alloSCT, 12/18 pts achieved a response after ven combination therapy: 4/18 MRD-CR/CRi, 4/18 MRD+CR/CRi, 4/18 MLFS; 6/18 pts had persistent disease (C and D). It is important to note that these response rates were specific to patients who received an alloSCT after ven combination therapy. While pts with DNMT3A, NPM1, IDH1/2 and FLT3 mutations had a high response rate to ven therapy prior to alloSCT, none of the pts with TP53 or NRAS mutations achieved a response prior to alloSCT (E). Only DNMT3A mutations were statistically significantly associated with a high response rate prior to alloSCT (ORR 100%, CR/CRi 63%, p=0.01). AlloSCT was able to convert pts with MRD+ or persistent disease into an MRD- state in 50% of cases (F). With a median follow up of 10 months, the median OS was not reached; 56% of pts relapsed after alloSCT. Median time to relapse for all pts was 18 months (95% CI 4 months-not reached [NR]). Disease status prior to alloSCT was a powerful predictor of post-transplant outcomes. Pts who achieved CR, CRi, or MLFS with ven therapy prior to alloSCT had significantly prolonged OS (median OS not reached) compared with pts who had persistent disease prior to alloSCT (median OS 7 months, 95% CI 2.14 months-NR; p=0.029; G). The poor OS for pts with persistent disease prior to alloSCT was mainly driven by a high incidence of relapse for these pts compared to pts who achieved a response to ven combos (H). The median time to relapse after alloSCT was 17.9 months (95% CI 6.1 months-NR) for pts who achieved CR, CRi, or MLFS prior to alloSCT, and only 3.3 months (95% CI 1.9 months-NR, p=0.052) for pts with persistent disease prior to alloSCT. While 67% of pts experienced grade I-II acute graft versus host disease (aGVHD), only 1 pt was found to have grade III aGVHD and no pt experienced grade IV aGVHD. Median time to aGVHD after alloSCT was 1.4 months (95% CI 0.89 months-NR). Conclusion: Venetoclax combination therapy can bridge some AML pts to subsequent alloSCT. Most pts who underwent alloSCT received reduced-intensity conditioning given their advanced age and comorbidities. Pts who achieved CR, CRi, or MLFS with ven-based therapy prior to alloSCT had more favorable outcomes after alloSCT. With more widespread use of venetoclax, we anticipate that alloSCT following good responses to venetoclax combination therapy will become more common in pts with AML. Longer-term studies are needed to determine durability of post-alloSCT responses following pre-alloSCT venetoclax combination therapy. Figure Disclosures Ponce: Kadmon: Membership on an entity's Board of Directors or advisory committees; Generon: Membership on an entity's Board of Directors or advisory committees; Ceramedix: Membership on an entity's Board of Directors or advisory committees; Takeda: Research Funding. Young:Amgen: Other: Common stock; Merck: Other: Common stock; Pfizer: Other: Common stock. Gyurkocza:Actinium: Research Funding. Chan:AbbVie: Current equity holder in publicly-traded company; Bristol-Myers Squibb: Current equity holder in publicly-traded company. Xiao:Stemline Therapeutics: Research Funding. Glass:Gerson Lehman Group: Consultancy. King:Abbvie: Other: advisory board. Cai:Imago Biosciences, Inc.: Consultancy, Current equity holder in private company; DAVA Oncology: Honoraria. Stein:Celgene Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Agios Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy; Abbvie: Consultancy; Seattle Genetics: Consultancy; Syndax: Consultancy, Research Funding; Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bayer: Research Funding; Biotheryx: Consultancy; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; PTC Therapeutics: Membership on an entity's Board of Directors or advisory committees; Syros: Membership on an entity's Board of Directors or advisory committees; Astellas Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; Daiichi-Sankyo: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Giralt:GSK: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Actinuum: Other: Advisory board, Research Funding; Amgen: Other: Advisory Board, Research Funding; OMEROS: Research Funding; Jensenn: Membership on an entity's Board of Directors or advisory committees, Research Funding; Johnson & Johnson: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees; TAKEDA: Membership on an entity's Board of Directors or advisory committees, Research Funding; JAZZ Pharmaceutical: Membership on an entity's Board of Directors or advisory committees; MILTENYI: Research Funding; PFIZER: Membership on an entity's Board of Directors or advisory committees, Research Funding; Sanofi: Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Membership on an entity's Board of Directors or advisory committees, Research Funding; SPECTRUM Pharma: Membership on an entity's Board of Directors or advisory committees; KITE: Membership on an entity's Board of Directors or advisory committees. Perales:Omeros: Honoraria, Membership on an entity's Board of Directors or advisory committees; Medigene: Membership on an entity's Board of Directors or advisory committees, Other; NexImmune: Membership on an entity's Board of Directors or advisory committees; Servier: Membership on an entity's Board of Directors or advisory committees, Other; Cidara Therapeutics: Other; Takeda: 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; Nektar Therapeutics: 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; MolMed: Membership on an entity's Board of Directors or advisory committees; Merck: Consultancy, Honoraria; Miltenyi Biotec: Research Funding; Kite/Gilead: Honoraria, Research Funding; Incyte Corporation: Honoraria, Research Funding; Bristol Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria; Bellicum: Honoraria, Membership on an entity's Board of Directors or advisory committees. Tallman:Novartis: Membership on an entity's Board of Directors or advisory committees; Cellerant: Research Funding; Orsenix: Research Funding; ADC Therapeutics: Research Funding; UpToDate: Patents & Royalties; Abbvie: Research Funding; Roche: Membership on an entity's Board of Directors or advisory committees; Glycomimetics: Research Funding; Rafael: Research Funding; Amgen: Research Funding; Bioline rx: Membership on an entity's Board of Directors or advisory committees; Daiichi-Sankyo: Membership on an entity's Board of Directors or advisory committees; KAHR: Membership on an entity's Board of Directors or advisory committees; Rigel: Membership on an entity's Board of Directors or advisory committees; Delta Fly Pharma: Membership on an entity's Board of Directors or advisory committees; Oncolyze: Membership on an entity's Board of Directors or advisory committees; BioSight: Membership on an entity's Board of Directors or advisory committees, Research Funding; Jazz Pharma: Membership on an entity's Board of Directors or advisory committees. Goldberg:Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees; Daiichi Sankyo: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Consultancy; Aptose: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; ADC Therapeutics: Research Funding; Aprea: Research Funding; AROG: Research Funding; Celularity: Research Funding; Pfizer: Research Funding; Dava Oncology: Honoraria.

Abstract: Background: Venetoclax combined with azacitidine (aza/ven), decitabine (dec/ven), and low-dose cytarabine (LDAC/ven) is commonly used off-label in relapsed/refractory (RR)-AML patients; however, predictors of response and survival are incompletely understood. Objectives: To report clinical outcomes of RR-AML patients (pts) treated with venetoclax combination therapy and to analyze molecular predictors of these outcomes. Methods: All pts with RR-AML, who received treatment with aza/ven, dec/ven or LDAC/ven from 08/2016 to 02/2020 at Memorial Sloan Kettering Cancer Center in New York City were included. The best response to therapy was determined using the 2017 European LeukemiaNet (ELN) response criteria. The overall response rate (ORR) was defined as the combination of the complete response (CR) + complete response with incomplete count recovery (CRi) + morphologic leukemia free state (MLFS) rate. Measurable residual disease (MRD) was assessed by multiparameter flow cytometric analysis of bone marrow aspirate samples and any level of residual disease was considered MRD+. Overall survival (OS) was calculated from cycle 1 day 1 of therapy until death or time of last follow-up. Results: A total of 86 pts were treated with venetoclax-based combination therapy (A). Median age was 67 years. More than half of the pts had received prior HMA therapy, 17% had received a prior allogeneic stem cell transplant. The majority of pts received aza/ven (41%) while 23% and 31% received dec/ven and LDAC/ven, respectively. Treatment trajectories of all patients are shown in the Swimmers' plot in panel (B). While the ORR was 31% and 24% of patients achieved a CR/CRi, 60% of pts were refractory to venetoclax therapy; 45% of responding pts eventually relapsed with a median follow up of 12 months (B, C). Oncoprint showing associations between molecular patterns and response to venetoclax combination therapy is shown in panel (D). Mutations in NPM1 (CR/CRi 46%, ORR 62%; OR 4.53, 95% CI 1.31-15.66, p=0.02) and IDH1 (CR/CRi 56%, ORR 67%; OR 5.3, 95% CI 1.21-23.24, p=0.03) but not in IDH2 (CR/CRi 40%, ORR 40%; OR 1.57, 95% CI 0.49-4.99, p=0.54) were associated with statistically significantly increased response rates. Adverse cytogenetics predicted lower odds of response (CR/CRi 11%, ORR 20%; OR 0.32, 95% CI 0.11-0.9, p=0.03). While TP53 (0%), NRAS/KRAS (20%/0%), SF3B1 (0%), ASXL1 (17%) and EZH2 (0%) mutations were associated with low response rates, due to small sample size, these associations were not statistically significant. Median OS for all pts was 6.1 months (95%CI: 4.9-10 month) (E). Pts who were treated with aza/ven had a median OS of 25 months (95% CI 5.8 months-NR), as compared to 5.4 months for patients treated with dec/ven (95% CI 3.9 months-NR; HR 1.63, p=0.2) and 3.9 months for patients treated with LDAC/ven (OS 3.9 months, 95% CI 2.5-8.3 months; HR 2.71, p=0.002). Presence of adverse cytogenetics, TP53 and KRAS/NRAS mutations was associated with poor OS (4.1 months, 95% CI 3.2-6.1 months) compared to a favorable OS when these features were absent (15 months, 95% CI 7.1 months-NA, p=0.001; F). In contrast, presence of mutations in IDH1/2, NPM1 or STAG2 was associated with prolonged OS (15 months, 95% CI 7.1 months-NA) whereas absence of these favorable mutations predicted poor OS (4.4 months, 95% CI 3.5-6.4 months, p=0.0051). Additionally, EZH2 (HR 4.13, p=0.01; H) and SF3B1 (HR 2.5, p=0.02; I) mutations predicted worse OS. Conclusion: Response rates to venetoclax combination therapy in RR-AML pts appeared lower than what has been reported for AML pts who receive venetoclax therapy as first line treatment. However, response rates were high and survival favorable for RR-AML pts with mutations in NPM1, IDH1 and STAG2. In contrast, RR-AML pts with high-risk molecular features such as adverse cytogenetics and mutations in TP53, KRAS/NRAS, EZH2 and SF3B1 had poor outcomes. Clinical trials combining aza/ven with novel therapeutics targeting specific adverse molecular characteristics are urgently needed to improve the outcomes of venetoclax therapy in RR-AML patients. Figure Disclosures Xiao: Stemline Therapeutics: Research Funding. Glass:Gerson Lehman Group: Consultancy. King:Abbvie: Other: advisory board. Abdel-Wahab:Merck: Consultancy; Janssen: Consultancy; Envisagenics Inc.: Current equity holder in private company; H3 Biomedicine Inc.: Consultancy, Research Funding. Levine:Novartis: Consultancy; Celgene: Consultancy, Honoraria, Research Funding; Roche: Consultancy, Honoraria, Research Funding; Lilly: Consultancy, Honoraria; Janssen: Consultancy; Astellas: Consultancy; Morphosys: Consultancy; Amgen: Honoraria; Isoplexis: Current equity holder in private company, Membership on an entity's Board of Directors or advisory committees; Gilead: Honoraria; Imago: Current equity holder in private company, Membership on an entity's Board of Directors or advisory committees; C4 Therapeutics: Current equity holder in private company, Membership on an entity's Board of Directors or advisory committees; Loxo: Current equity holder in private company, Membership on an entity's Board of Directors or advisory committees; Prelude Therapeutics: Research Funding; Qiagen: Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees. Stein:Amgen: Consultancy; Astellas Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; Agios Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Biotheryx: Consultancy; Abbvie: Consultancy; Seattle Genetics: Consultancy; Syndax: Consultancy, Research Funding; Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bayer: Research Funding; Syros: Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; PTC Therapeutics: Membership on an entity's Board of Directors or advisory committees; Daiichi-Sankyo: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Tallman:UpToDate: Patents & Royalties; Novartis: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees; Jazz Pharma: Membership on an entity's Board of Directors or advisory committees; Oncolyze: Membership on an entity's Board of Directors or advisory committees; Delta Fly Pharma: Membership on an entity's Board of Directors or advisory committees; Rigel: Membership on an entity's Board of Directors or advisory committees; KAHR: Membership on an entity's Board of Directors or advisory committees; Daiichi-Sankyo: Membership on an entity's Board of Directors or advisory committees; Bioline rx: Membership on an entity's Board of Directors or advisory committees; Amgen: Research Funding; Rafael: Research Funding; Glycomimetics: Research Funding; BioSight: Membership on an entity's Board of Directors or advisory committees, Research Funding; ADC Therapeutics: Research Funding; Orsenix: Research Funding; Cellerant: Research Funding; Abbvie: Research Funding. Goldberg:Aptose: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Consultancy; Daiichi Sankyo: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees; ADC Therapeutics: Research Funding; Aprea: Research Funding; AROG: Research Funding; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celularity: Research Funding; Pfizer: Research Funding; Dava Oncology: Honoraria. OffLabel Disclosure: venetoclax therapy for the treatment for realpsed and treatment refractory AML

Abstract: Azacitidine + venetoclax, decitabine + venetoclax, and low-dose cytarabine + venetoclax are now standard treatments for newly diagnosed older or unfit patients with acute myeloid leukemia (AML). Although these combinations are also commonly used in relapsed or refractory AML (RR-AML), clinical and molecular predictors of response and survival in RR-AML are incompletely understood. We retrospectively analyzed clinical and molecular characteristics and outcomes for 86 patients with RR-AML who were treated with venetoclax combinations. The complete remission (CR) or CR with incomplete hematologic recovery (CRi) rate was 24%, and the overall response rate was 31% with the inclusion of a morphologic leukemia-free state. Azacitidine + venetoclax resulted in higher response rates compared with low-dose cytarabine + venetoclax (49% vs 15%; P = .008). Median overall survival (OS) was 6.1 months, but it was significantly longer with azacitidine + venetoclax compared with low-dose cytarabine + venetoclax (25 vs 3.9 months; P = .003). This survival advantage of azacitidine + venetoclax over low-dose cytarabine + venetoclax persisted when patients were censored for subsequent allogeneic stem cell transplantation (8.1 vs 3.9 months; P = .035). Mutations in NPM1 were associated with higher response rates, whereas adverse cytogenetics and mutations in TP53, KRAS/NRAS, and SF3B1 were associated with worse OS. Relapse was driven by diverse mechanisms, including acquisition of novel mutations and an increase in cytogenetic complexity. Venetoclax combination therapy is effective in many patients with RR-AML, and pretreatment molecular characteristics may predict outcomes. Trials that evaluate novel agents in combination with venetoclax therapy in patients with RR-AML that have adverse risk genomic features are warranted.