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: 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: Acute myeloid leukemia (AML) remains a therapeutic challenge in elderly or unfit patients (pts) and high-risk subgroups. DEC10-VEN has shown high efficacy in these pts. However, outcomes in specific mutational subgroups are unknown. Here we present the results in mutational subgroups and resistance patterns in pts treated with DEC10-VEN (NCT03404193). Methods: This single-institution phase II study enrolled pts with newly diagnosed (ND) AML ( & gt;60 years) ineligible for intensive chemotherapy, relapsed or refractory (R/R) AML, and secondary AML (sAML) with or without prior therapy. DEC was given 20 mg/m2 IV daily on day 1-10 until CR/CRi, followed by 5-day cycles. VEN was given for 21-28 days in cycle 1 and day 1-21 or shorter duration thereafter. BCR-ABL1 and FLT3 inhibitors (FLT3i) were allowed as appropriate. Amplicon-based next-generation sequencing targeting the entire coding regions of 81 myeloid genes was performed on screening bone marrow aspirate with a MiSeq platform. The analytical sensitivity was established at 5% mutant reads in a background of wild type reads. Previously described somatic mutations registered in COSMIC were considered as potential driver mutations. Results: High response rates were noted across mutational subgroups of both previously untreated and previously treated AML (Table 1 and 2). The median follow-up for the entire cohort was 8.1 months (mo). In previously untreated AML (ND AML and untreated sAML, n=49), the CR/CRi rate in NPM1mut pts was 100% (n=13), in RUNX1mut pts was 100% (n=8), in IDH1/2mut pts was 92% (n=12), in TP53mut pts was 85% (n=13), and in N/KRASmut pts was 77% (n=13, Table 1). The median overall survival (OS) among previously untreated NPM1mut pts was not reached (NR), for RUNX1mut pts was NR, for IDH1/2mut pts was 12.4 mo, for TP53mut pts was 5.8 mo, and for N/KRASmut was 12.4 mo. The median DOR for NPM1mut pts was 8.5 mo, for RUNX1mut pts was NR, for IDH1/2mut pts was NR, for TP53mut pts was 5.7 mo, and for N/KRASmut pts was 6.7 mo (Table 1). The one pt with NPM1mut who relapsed had co-occurring ASXL1mut and NRASmut at screening. In previously treated AML (treated sAML and R/R AML, n=52), the CR/CRi rate in NPM1mut pts was 60% (n=10), in IDH1/2mut pts was 50% (n=8), and in TP53mut pts was 21% (n=14, Table 2). The median OS for NPM1mut pts was NR, for IDH1/2mut pts was 7.8 mo, and for TP53mut pts was 4.5 mo. The median DOR for NPM1mut pts was NR, for IDH1/2mut pts was NR, and for TP53mut pts was 3.2 mo (Table 2). The only grade 4 TLS event occurred in a pt with NPM1mut and IDH2mut and baseline WBC of 28x109/L. 2 other pts with high % of PB blasts and FLT3mut experienced grade 3 TLS. Among 15 pts with FLT3-ITD/TKD, 8 pts received sorafenib, 5 pts received midostaurin, and 2 pts did not receive FLT3i (1 insurance non-approval and 1 very low ITD ratio). Among ND FLT3mut AML pts (n=7), the CR/CRi rate was 100% (n=5) in pts receiving FLT3i with negative MRD by flow cytometry (FCM) in 80% pts, with median OS of 8.8 mo and median DOR not reached (Table 1). Of the 2 FLT3-ITD pts not receiving FLT3i, 1 pt with FLT3-ITD of 0.47 did not respond, and 1 pt with low FLT3-ITD of 0.02 achieved CR MRD-. Among previously treated FLT3mut pts (n=8), all received FLT3i with a CR/CRi rate of 38% (n=5) and negative MRD by FCM in 75% pts tested (3/4). The median OS was 6.4 mo and the median DOR was 6.6 mo (Table 2). 2 pts had received prior FLT3i, 1 pt achieved morphologic leukemia-free state (MLFS), and the other pt did not respond. 1 pt with new t(9;22) identified at 4th relapse achieved a MLFS after 1 cycle with addition of ponatinib and transitioned to allogeneic transplant. Overall, pts with durable CR/CRi/MLFS sustained without relapse till data cut-off, had significantly higher proportion of mutations in NPM1 and DNA methylation pathways (DNMT3A, TET2, IDH1/2) compared to pts refractory to, or relapsing after DEC10-VEN (Table 3, Fig. 1). Pts with relapsed or refractory disease to DEC10-VEN had significantly higher frequency of N/KRASmut, ASXL1mut, and TP53mut compared to pts with durable CR/CRi/MLFS (Table 3, Fig. 1). TP53mut associated with worse OS on multivariable analysis (HR 2.9, 95% CI 1.4-5.7, p=0.003). Conclusion: DEC10-VEN is an effective regimen for AML. Addition of FLT3i to DEC10-VEN was safe and may improve upon responses in FLT3mut pts. Mutations in NPM1 and DNA methylation pathways were associated with more durable responses while mutations in ASXL1, RAS and TP53 were associated with refractory disease or relapse. Disclosures Maiti: Celgene: Other: research funding. Cortes:BiolineRx: Consultancy; Forma Therapeutics: Consultancy, Honoraria, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Daiichi Sankyo: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria, Research Funding; Astellas Pharma: Consultancy, Honoraria, Research Funding; Jazz Pharmaceuticals: Consultancy, Research Funding; Sun Pharma: Research Funding; Immunogen: Consultancy, Honoraria, Research Funding; Merus: Consultancy, Honoraria, Research Funding; Biopath Holdings: Consultancy, Honoraria. Pemmaraju:samus: Research Funding; celgene: Consultancy, Honoraria; abbvie: Consultancy, Honoraria, Research Funding; incyte: Consultancy, Research Funding; mustangbio: Consultancy, Research Funding; 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. Daver:Servier: Research Funding; Agios: Consultancy; Abbvie: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Agios: Consultancy; Celgene: Consultancy; Hanmi Pharm Co., Ltd.: Research Funding; Forty-Seven: Consultancy; Forty-Seven: Consultancy; Immunogen: Consultancy, Research Funding; Immunogen: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Astellas: Consultancy; BMS: Consultancy, Research Funding; Astellas: Consultancy; Daiichi Sankyo: Consultancy, Research Funding; Daiichi Sankyo: Consultancy, Research Funding; Jazz: Consultancy; Jazz: Consultancy; NOHLA: Research Funding; Karyopharm: Consultancy, Research Funding; Incyte: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; Servier: Research Funding; Genentech: Consultancy, Research Funding; Incyte: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Karyopharm: Consultancy, Research Funding; Abbvie: Consultancy, Research Funding; Glycomimetics: Research Funding; Sunesis: Consultancy, Research Funding; Otsuka: Consultancy; NOHLA: Research Funding; Celgene: Consultancy; Otsuka: Consultancy; Glycomimetics: Research Funding; Novartis: Consultancy, Research Funding; Sunesis: Consultancy, Research Funding; Hanmi Pharm Co., Ltd.: Research Funding; Pfizer: Consultancy, Research Funding. Ravandi:Cyclacel LTD: Research Funding; Macrogenix: Consultancy, Research Funding; Xencor: Consultancy, Research Funding; Menarini Ricerche: Research Funding; Selvita: 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:Cyclacel: Research Funding; AbbVie: Research Funding; Eli Lilly and Co.: Research Funding; Xbiotech USA: Research Funding; Merck: Research Funding; Bayer Healthcare AG: Research Funding; Agensys: Research Funding; Janssen: Research Funding; NKarta: Consultancy; BioTheryX: Membership on an entity's Board of Directors or advisory committees; Arvinas: Research Funding; Incyte: Research Funding; Tetralogic Pharmaceuticals: Research Funding; Strategia Therapeutics: Research Funding; Oncoceutics: Research Funding; BioLine Rx: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Oncoceutics, Inc.: Research Funding; GSK: Research Funding; BMS: 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; PTC Therapeutics: Consultancy; Novartis: Research Funding; Eisai: Research Funding; Polaris: Research Funding; AstraZeneca: Research Funding. Short:Takeda Oncology: Consultancy, Research Funding; AstraZeneca: Consultancy; Amgen: Honoraria. Alvarado:Jazz Pharmaceuticals: Research Funding; Abbott: Honoraria. Kadia:AbbVie: Consultancy, Research Funding; Amgen: 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; Jazz: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Research Funding; Bioline RX: Research Funding; BMS: 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:Janssen Pharmaceuticals, Inc.: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; 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; Genentech: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Research Funding; Pfizer: 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; 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. Sasaki:Otsuka: Honoraria; Pfizer: Consultancy. Andreeff: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; Reata: Equity Ownership; 6 Dimensions Capital: Consultancy; Center for Drug Research & Development: Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy; AstaZeneca: Consultancy; Daiichi Sankyo, Inc.: Consultancy, Patents & Royalties: Patents licensed, royalty bearing, Research Funding; Jazz Pharmaceuticals: Consultancy; Celgene: Consultancy; 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:CTI BioPharma: Research Funding; Promedior: Research Funding; NS Pharma: Research Funding; 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. Jabbour:Pfizer: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; AbbVie: Consultancy, Research Funding; Adaptive: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; Cyclacel LTD: Research Funding; BMS: 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:Daiichi-Sankyo: Research Funding; BMS: Research Funding; Cyclacel: Research Funding; Ariad: Research Funding; AbbVie: Honoraria, Research Funding; Takeda: Honoraria; Novartis: Research Funding; Pfizer: Honoraria, Research Funding; Jazz Pharma: Research Funding; Immunogen: Research Funding; Amgen: Honoraria, Research Funding; Astex: Research Funding; Agios: Honoraria, Research Funding; Actinium: Honoraria, Membership on an entity's Board of Directors or advisory committees. Konopleva:Genentech: Honoraria, Research Funding; Ascentage: Research Funding; Kisoji: Consultancy, Honoraria; Reata Pharmaceuticals: Equity Ownership, Patents & Royalties; Ablynx: Research Funding; Astra Zeneca: Research Funding; Eli Lilly: Research Funding; Cellectis: Research Funding; Amgen: Consultancy, Honoraria; F. Hoffman La-Roche: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Honoraria, Research Funding; Forty-Seven: Consultancy, Honoraria; Stemline Therapeutics: Consultancy, Honoraria, Research Funding; Calithera: Research Funding; Agios: Research Funding. DiNardo:agios: Consultancy, Honoraria; medimmune: Honoraria; notable labs: Membership on an entity's Board of Directors or advisory committees; syros: Honoraria; jazz: Honoraria; abbvie: Consultancy, Honoraria; celgene: Consultancy, Honoraria; daiichi sankyo: Honoraria. OffLabel Disclosure: FLT3 inhibitors, used in combination with decitabine and venetoclax

Abstract: Background: Low-dose dasatinib was shown to be safe and effective in patients with newly diagnosed chronic myeloid leukemia in chronic phase (CML-CP). There is no randomized clinical trials to compare the outcome with the standard-dose dasatinib. The aim of this study is to compare responses and outcome of patients with newly diagnosed CML-CP treated with frontline dasatinib 50 mg/day with those who received standard-dose dasatinib 100 mg/day. Method: We analyzed 233 patients with newly diagnosed CML-CP who were treated with low-dose dasatinib 50 mg/day (N=83) or standard-dose dasatinib 100 mg/day (N=150). Responses criteria were previously defined. Failure-free survival (FFS) was calculated from the start date of therapy to the dates of treatment discontinuation for any reason except of treatment-free remission; event-free survival (EFS), to the date of any of the events while on study as defined in the IRIS study; transformation-free survival (TFS), to the date of transformation to accelerated or blast phases during study; overall survival (OS), to the date of death from any cause at any time or date of last follow-up. Patients on low-dose dasatinib who had suboptimal response by European LeukemiaNet criteria had an option to increase the dose to 100 mg/day. Propensity score analysis with 1:1 matching was performed with the nearest neighbor matching method using calipers of width equal to 0.2. Multiple imputation was performed to minimize the bias. Propensity scores were calculated with logistic regression from baseline covariates including age, spleen size by examination, white blood cell count, hemoglobin, platelet count, percentage of basophils, percentage of blasts in peripheral blood and bone marrow, the presence of clonal evolution, and Sokal risk classification to minimize difference. Results: Propensity score matching identified 77 patients in each cohort without significant baseline difference (Table 1). The overall median follow-up was 60 months: 48 months and 131 months for low-dose and standard-dose, respectively. The 12-month major molecular response (MMR) rates were 82% and 75% for low-dose and standard-dose groups, respectively (P=0.229). The cumulative incidence of molecular response (MR)4, MR4.5, and complete molecular response (CMR) rates within 1 year were higher in the low-dose dasatinib group compared with the standard-dose group (63% and 43%, 53% and 36%, and 46% and 33% for each)(P=0.009; P=0.031; P=0.060). The incidence of pleural effusion was 6% and 21% in the low-dose and standard-dose, respectively (P=0.016). The 4-year FFS rates were 89% and 77% in the low-dose dasatinib and standard-dose dasatinib, respectively (P=0.041) (Figure 1). The 4-year TFS rates were 100% and 100%, respectively (P=1.000); the 4-year EFS rates were 95% and 92%, respectively (P=0.556); the 4-year OS rates were 97% and 96%, respectively (P=0.781). Conclusions: The low-dose dasatinib is as effective as standard-dose dasatinib with less intolerance, resulting in favorable outcome. Figure 1 Figure 1. Disclosures Sasaki: Novartis: Consultancy, Research Funding; Daiichi-Sankyo: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees. Jabbour: Amgen, AbbVie, Spectrum, BMS, Takeda, Pfizer, Adaptive, Genentech: Research Funding. Issa: Syndax Pharmaceuticals: Research Funding; Novartis: Consultancy, Research Funding; Kura Oncology: Consultancy, Research Funding. Yilmaz: Pfizer: Research Funding; Daiichi-Sankyo: Research Funding. Ferrajoli: Janssen: Other: Advisory Board ; AstraZeneca: Other: Advisory Board, Research Funding; BeiGene: Other: Advisory Board, Research Funding. Bose: Incyte Corporation: Honoraria, Research Funding; Pfizer: Research Funding; Astellas: Research Funding; Constellation Pharmaceuticals: Research Funding; Blueprint Medicines: Honoraria, Research Funding; CTI BioPharma: Honoraria, Research Funding; Sierra Oncology: Honoraria; Kartos Therapeutics: Honoraria, Research Funding; Novartis: Honoraria; NS Pharma: Research Funding; BMS: Honoraria, Research Funding; Celgene Corporation: Honoraria, Research Funding; Promedior: Research Funding. Thompson: Janssen: Consultancy, Honoraria; AbbVie: Other: Institution: Advisory/Consultancy, Honoraria, Research Grant/Funding; Gilead: Other: Institution: Advisory/Consultancy, Honoraria; Genentech: Other: Institution: Advisory/Consultancy, Honoraria, Research Grant/Funding; Amgen: Other: Institution: Honoraria, Research Grant/Funding; Adaptive Biotechnologies: Other: Institution: Advisory/Consultancy, Honoraria, Research Grant/Funding, Expert Testimony; Pharmacyclics: Other: Institution: Advisory/Consultancy, Honoraria, Research Grant/Funding. Alvarado: Sun Pharma: Consultancy, Research Funding; Jazz Pharmaceuticals: Research Funding; FibroGen: Research Funding; BerGenBio: Research Funding; CytomX Therapeutics: Consultancy; MEI Pharma: Research Funding; Daiichi-Sankyo: Research Funding; Astex Pharmaceuticals: Research Funding. Jain: ADC Therapeutics: Honoraria, Research Funding; Cellectis: Honoraria, Research Funding; Janssen: Honoraria; Aprea Therapeutics: Research Funding; Pfizer: Research Funding; Beigene: Honoraria; Precision Biosciences: Honoraria, Research Funding; Servier: Honoraria, Research Funding; Fate Therapeutics: Research Funding; Bristol Myers Squibb: Honoraria, Research Funding; Incyte: Research Funding; TG Therapeutics: Honoraria; Adaptive Biotechnologies: Honoraria, Research Funding; AstraZeneca: Honoraria, Research Funding; Genentech: Honoraria, Research Funding; AbbVie: Honoraria, Research Funding; Pharmacyclics: Research Funding. Takahashi: GSK: Consultancy; Novartis: Consultancy; Symbio Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene/BMS: Consultancy. Borthakur: GSK: Consultancy; Astex: Research Funding; Protagonist: Consultancy; University of Texas MD Anderson Cancer Center: Current Employment; ArgenX: Membership on an entity's Board of Directors or advisory committees; Ryvu: Research Funding; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees. Pemmaraju: HemOnc Times/Oncology Times: Membership on an entity's Board of Directors or advisory committees; Roche Diagnostics: Consultancy; Abbvie Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other, Research Funding; LFB Biotechnologies: Consultancy; Cellectis S.A. ADR: Other, Research Funding; Dan's House of Hope: Membership on an entity's Board of Directors or advisory committees; DAVA Oncology: Consultancy; CareDx, Inc.: Consultancy; Incyte: Consultancy; Daiichi Sankyo, Inc.: Other, Research Funding; Springer Science + Business Media: Other; ASH Communications Committee: Membership on an entity's Board of Directors or advisory committees; Novartis Pharmaceuticals: Consultancy, Other: Research Support, Research Funding; Aptitude Health: Consultancy; Stemline Therapeutics, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other, Research Funding; Samus: Other, Research Funding; Plexxicon: Other, Research Funding; ASCO Leukemia Advisory Panel: Membership on an entity's Board of Directors or advisory committees; MustangBio: Consultancy, Other; Sager Strong Foundation: Other; Celgene Corporation: Consultancy; Affymetrix: Consultancy, Research Funding; Protagonist Therapeutics, Inc.: Consultancy; Clearview Healthcare Partners: Consultancy; Blueprint Medicines: Consultancy; Bristol-Myers Squibb Co.: Consultancy; ImmunoGen, Inc: Consultancy; Pacylex Pharmaceuticals: Consultancy. Cortes: Sun Pharma: Consultancy, Research Funding; Bio-Path Holdings, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb, Daiichi Sankyo, Jazz Pharmaceuticals, Astellas, Novartis, Pfizer, Takeda, BioPath Holdings, Incyte: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Takeda: Consultancy, Research Funding. Kantarjian: Precision Biosciences: Honoraria; Immunogen: Research Funding; Jazz: Research Funding; Taiho Pharmaceutical Canada: Honoraria; Ascentage: Research Funding; Pfizer: Honoraria, Research Funding; Astra Zeneca: Honoraria; Daiichi-Sankyo: Research Funding; BMS: Research Funding; AbbVie: Honoraria, Research Funding; Astellas Health: Honoraria; Novartis: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Aptitude Health: Honoraria; NOVA Research: Honoraria; KAHR Medical Ltd: Honoraria; Ipsen Pharmaceuticals: Honoraria.

Abstract: Background: Blockade of PD-1/PD-L1 pathways enhances anti-leukemic responses in pre-clinical studies. PD1 inhibition alone had limited clinical activity in AML. CLTA4 inhibition demonstrated encouraging single-agent CR's in postASCT patients (pts), especially for extra-medullary (EMD) relapses (Davis M et al, NEJM 2016). AZA+Nivo up-regulated CTLA4 on bone marrow (BM) CD8 cells in both responders (R) and non-responders (NR) on treatment (Daver N, et al, Cancer Discovery 2019), suggesting a triplet of AZA+Nivo+Ipi may abrogate PD-1 mediated resistance. Methods: Pts were eligible for the AZA+Nivo (cohort 1, n=59) if they had R/R AML, ECOG ≤ 2, and adequate organ function. This cohort has completed enrollment. A cohort of AZA+Nivo+Ipi was opened (cohort 2), with the same eligibility criteria. Ipi 1mg/kg Q6 weeks was added to the established AZA+Nivo schedule and found to be safe in a lead-in dose cohort. Results: Cohort 1 (59 R/R AML) pts were treated with Aza+Nivo (Daver et al., Cancer Discovery 2019). CR/CRi and OS were superior to contemporary historic HMA-based clinical trial controls at MDACC (Table 1). Pts with low pretherapy BM blasts ( & lt;20% BM blasts) and early salvage (salvage 1) had encouraging median (med) OS 11 months (mos), indicating progressive T-cell exhaustion with multiple relapses. Importantly, on 40-parametric CYTOF assessment, Rs to AZA+Nivo had a higher frequency of pre-therapy BMA CD3+ and CD8+ cells compared with NRs (optimal CD3+ cutoff 13.2%: ORR 56% versus 23%), suggesting pre-existing BM T-cell infiltration may be a pre-requisite of response to PD1 based therapies, as PD1 inhibitors have limited ability to mobilize peripheral T-cells (Fig 1A). The pre-therapy BM CD4 polyfunctional strength index (PSI) defined as percentage of polyfunctional cells in the sample, multiplied by the intensities of the secreted cytokines, assessed by single cell cytokine analysis was dramatically different between Rs and NRs (P=0.03). Single-cell RNA-seq on 113,394 BM cells collected longitudinally from 8 pts (3R, 2 stable disease (SD), 3NR) demonstrated that deletion 7/7q, LSC signature enrichment, and activated metabolic/oxidative pathways, were associated with resistance to AZA+Nivo (Abbas H et al, ASH 2020). Importantly, AZA+Nivo induced novel and expanded T cell clonotypes, almost exclusively in Rs. Cohort 2 (36 R/R AML) pts were treated with Aza+Nivo+Ipi, with med age 67 years (25-83), secondary AML (50%), ELN unfavorable cytogenetics (67%), TP53 (36%), med salvage 2 (range, 1-3), and prior HMA based therapies in 67%. All 36 pts are evaluable. Per ELN 2017, CR/CRi was noted in 7 (19%) and PR in 1 (3%). Five (14%) pts had durable stable disease (SD) (defined as absence of CR, CRi, PR; with SD on treatment for ≥6 months), and 23 (64%) were NRs (Table 1). Interestingly, 4 pts with EMD were enrolled and 3 had CR/PR [med DOR 8 (5-13) mos]. The 4- and 8-week mortalities were 0 and 6%, respectively. Grade 3/4 immune toxicities noted in 8 pts (19%), including rash, pneumonitis, colitis, pyrexia. One pt required ICU stay, but no deaths attributed to immune toxicity. Other grade ≥2 toxicities were as expected for R/R AML population and were mostly infections/febrile neutropenia. Converse to AZA+Nivo, on CYTOF, R did not have a higher frequency of pre-therapy BM CD8+ infiltration, but did have progressive BM CD8+ infiltration on therapy, compared with NRs, demonstrating that Ipi (unlike Nivo) may be able to mobilize peripheral T-cells to the BM (Fig 1B). Expansion of a cluster of antigen experienced CD8+ T cells was associated with response (Fig 1B). In all salvage the med OS with Aza+Ipi+Nivo versus Aza+Nivo versus contemporary HMA-controls in R/R AML, were 7.6, 5.9, and 4.6 mos, respectively (P=0.01) (Fig 1C). The 1-year OS in R/R AML pts with AZA+Nivo+Ipi was 25%. The med OS with Aza+Ipi+Nivo was comparable to med OS 6-8 mos reported with HMA+VEN salvage in numerous studies. Conclusion: The OS with Aza+Nivo+Ipi was modestly improved over AZA+Nivo and HMA-controls in R/R AML. Single-cell cytokine profiling and single-cell RNA-seq from Aza+Nivo showed striking pre- and on-treatment differences among R and NR not only in T-cell fitness and clonality, but also in the tumor microenvironment. Ipi may be uniquely able to mobilize peripheral T-cell to BM and EMD. This underappreciated immune diversity suggests a critical need for biomarker-based trials (as we are doing with molecular therapies) for immunotherapies in AML. Disclosures Daver: Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Trovagene: Research Funding; Fate Therapeutics: Research Funding; ImmunoGen: Research Funding; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Jazz: Consultancy, Membership on an entity's Board of Directors or advisory committees; Trillium: Consultancy, Membership on an entity's Board of Directors or advisory committees; Syndax: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; KITE: Consultancy, Membership on an entity's Board of Directors or advisory committees; Agios: Consultancy, Membership on an entity's Board of Directors or advisory committees; Daiichi Sankyo: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol-Myers Squibb: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Karyopharm: Research Funding; Servier: Research Funding; Genentech: Research Funding; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Astellas: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novimmune: Research Funding; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Garcia-Manero:Merck: Research Funding; Onconova: Research Funding; Novartis: Research Funding; Jazz Pharmaceuticals: Consultancy; Helsinn Therapeutics: Consultancy, Honoraria, Research Funding; H3 Biomedicine: Research Funding; AbbVie: Honoraria, Research Funding; Acceleron Pharmaceuticals: Consultancy, Honoraria; Amphivena Therapeutics: Research Funding; Astex Pharmaceuticals: Consultancy, Honoraria, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Konopleva:Eli Lilly: Research Funding; Rafael Pharmaceutical: Research Funding; Genentech: Consultancy, Research Funding; Stemline Therapeutics: Consultancy, Research Funding; Agios: Research Funding; Cellectis: Research Funding; Calithera: Research Funding; AstraZeneca: Research Funding; Ascentage: Research Funding; Reata Pharmaceutical Inc.;: Patents & Royalties: patents and royalties with patent US 7,795,305 B2 on CDDO-compounds and combination therapies, licensed to Reata Pharmaceutical; Sanofi: Research Funding; Kisoji: Consultancy; Amgen: Consultancy; F. Hoffmann La-Roche: Consultancy, Research Funding; AbbVie: Consultancy, Research Funding; Ablynx: Research Funding; Forty-Seven: Consultancy, Research Funding. Kadia:Pulmotec: Research Funding; Astellas: Research Funding; Cellenkos: Research Funding; Amgen: Research Funding; Genentech: Honoraria, Research Funding; BMS: Honoraria, Research Funding; Cyclacel: Research Funding; JAZZ: Honoraria, Research Funding; Celgene: Research Funding; Incyte: Research Funding; Astra Zeneca: Research Funding; Ascentage: Research Funding; Pfizer: Honoraria, Research Funding; Novartis: Honoraria; Abbvie: Honoraria, Research Funding. DiNardo:AbbVie: Consultancy, Honoraria, Research Funding; Takeda: Honoraria; Agios: Consultancy, Honoraria, Research Funding; Daiichi Sankyo: Consultancy, Honoraria, Research Funding; Calithera: Research Funding; Jazz: Honoraria; MedImmune: Honoraria; Celgene: Consultancy, Honoraria, Research Funding; Syros: Honoraria; Notable Labs: Membership on an entity's Board of Directors or advisory committees; ImmuneOnc: Honoraria; Novartis: Consultancy. Borthakur:Abbvie: Research Funding; Novartis: Research Funding; Incyte: Research Funding; PTC Therapeutics: Research Funding; Curio Science LLC: Consultancy; FTC Therapeutics: Consultancy; Argenx: Consultancy; PTC Therapeutics: Consultancy; BioLine Rx: Consultancy; BioTherix: Consultancy; Nkarta Therapeutics: Consultancy; Treadwell Therapeutics: Consultancy; Oncoceutics: Research Funding; Xbiotech USA: Research Funding; Polaris: Research Funding; AstraZeneca: Research Funding; BMS: Research Funding; BioLine Rx: Research Funding; Cyclacel: Research Funding; GSK: Research Funding; Jannsen: Research Funding. Pemmaraju:AbbVie: Honoraria, Research Funding; Daiichi Sankyo: Research Funding; Stemline Therapeutics: Honoraria, Research Funding; DAVA Oncology: Honoraria; Incyte Corporation: Honoraria; Celgene: Honoraria; Novartis: Honoraria, Research Funding; SagerStrong Foundation: Other: Grant Support; Plexxikon: Research Funding; LFB Biotechnologies: Honoraria; Blueprint Medicines: Honoraria; Samus Therapeutics: Research Funding; Affymetrix: Other: Grant Support, Research Funding; Pacylex Pharmaceuticals: Consultancy; MustangBio: Honoraria; Roche Diagnostics: Honoraria; Cellectis: Research Funding. Jabbour:Takeda: Other: Advisory role, Research Funding; Adaptive Biotechnologies: Other: Advisory role, Research Funding; Pfizer: Other: Advisory role, Research Funding; BMS: Other: Advisory role, Research Funding; Amgen: Other: Advisory role, Research Funding; AbbVie: Other: Advisory role, Research Funding; Genentech: Other: Advisory role, Research Funding. Sasaki:Novartis: Consultancy, Research Funding; Otsuka: Honoraria; Pfizer Japan: Consultancy; Daiichi Sankyo: Consultancy. Yilmaz:Pint Pharma: Honoraria; Pfizer: Research Funding; Daicho Sankyo: Research Funding. Issa:Syndax: Research Funding; Celegene: Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees. Short:AstraZeneca: Consultancy; Amgen: Honoraria; Astellas: Research Funding; Takeda Oncology: Consultancy, Honoraria, Research Funding. Andreeff:Amgen: Research Funding; Centre for Drug Research & Development; Cancer UK; NCI-CTEP; German Research Council; Leukemia Lymphoma Foundation (LLS); NCI-RDCRN (Rare Disease Clin Network); CLL Founcdation; BioLineRx; SentiBio; Aptose Biosciences, Inc: Membership on an entity's Board of Directors or advisory committees; Daiichi-Sankyo; Breast Cancer Research Foundation; CPRIT; NIH/NCI; Amgen; AstraZeneca: Research Funding; Daiichi-Sankyo; Jazz Pharmaceuticals; Celgene; Amgen; AstraZeneca; 6 Dimensions Capital: Consultancy. Cortes:Novartis: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; Sun Pharma: Research Funding; BioPath Holdings: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Telios: Research Funding; Astellas: Research Funding; Amphivena Therapeutics: Research Funding; Arog: Research Funding; BiolineRx: Consultancy, Research Funding; Bristol-Myers Squibb: Research Funding; Daiichi Sankyo: Consultancy, Research Funding; Jazz Pharmaceuticals: Consultancy, Research Funding; Immunogen: Research Funding; Merus: Research Funding. Ravandi:Jazz Pharmaceuticals: Consultancy, Honoraria, Research Funding; BMS: Consultancy, Honoraria, Research Funding; Abbvie: Consultancy, Honoraria, Research Funding; Astellas: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria; Macrogenics: Research Funding; Orsenix: Consultancy, Honoraria, Research Funding; AstraZeneca: Consultancy, Honoraria; Xencor: Consultancy, Honoraria, Research Funding. Allison:BioAlta: Consultancy, Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees; Apricity Health: Consultancy, Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees; Achelois: Consultancy, Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees; Codiak BioSciences: Consultancy, Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees; Dragonfly Therapeutics: Consultancy, Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees; Forty-Seven Inc.: Consultancy, Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees; Hummingbird: Consultancy, Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees; ImaginAB: Consultancy, Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees; Jounce Therapeutics: Consultancy, Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties; Lava Therapeutics: Consultancy, Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees; Lytix Biopharma: Consultancy, Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees; Marker Therapeutics: Consultancy, Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees; Polaris: Consultancy, Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees; BioNTech: Consultancy, Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees; Adaptive Biotechnologies: Consultancy, Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees. Kantarjian:Cyclacel: Research Funding; BMS: Research Funding; Takeda: Honoraria; Agios: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding; Astex: Research Funding; AbbVie: Honoraria, Research Funding; Jazz Pharma: Research Funding; Amgen: Honoraria, Research Funding; Daiichi-Sankyo: Research Funding; Actinium: Honoraria, Membership on an entity's Board of Directors or advisory committees; Immunogen: Research Funding; Novartis: Research Funding; Ariad: Research Funding. Sharma:Achelois: Consultancy, Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees; Apricity Health: Consultancy, Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees; BioAlta: Consultancy, Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees; Codiak BioSciences: Consultancy, Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees; Constellation: Consultancy, Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees; Dragonfly Therapeutics: Consultancy, Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees; Forty-Seven Inc.: Consultancy, Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees; Hummingbird: Consultancy, Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees; ImaginAb: Consultancy, Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees; Jounce Therapeutics: Consultancy, Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties; Lava Therapeutics: Consultancy, Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees; Lytix Biopharma: Consultancy, Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees; Marker Therapeutics: Consultancy, Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees; Oncolytics: Consultancy, Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees; Infinity Pharma: Consultancy, Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees; BioNTech: Consultancy, Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees; Adaptive Biotechnologies: Consultancy, Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees; Glympse: Consultancy, Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees; Polaris: Consultancy, Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees. OffLabel Disclosure: Nivolumab and Ipilimumab based combinations for AML, will be discussed. These agents do not have an on label indication for AML at this time.

Abstract: Background: Therapy-related acute myeloid leukemia (t-AML) is associated with higher risk cytogenetics and disease biology, which partly account for poorer outcomes compared with de novo AML. Normal karyotype (NK) among patients (pts) with t-AML is rare, and the relative contribution of prior chemotherapy or radiotherapy exposure to outcomes of pts with AML with NK is uncertain. Methods: We reviewed all pts with newly diagnosed AML treated at MD Anderson Cancer Center between 2007 and 2019. Patients were separated into two groups (t-AML and de novo AML) based on their prior administration of chemotherapy or radiotherapy for an antecedent neoplasm. We analyzed patients' characteristics and outcomes including remission rates, relapse rates and survival. Survival curves were estimated by Kaplan-Meier method. Gray's method was used for cumulative incidence of relapse (CIR) analysis. Multivariate analyses for relapse-free survival (RFS) and overall survival (OS) were conducted using Cox proportional hazards regression model including age, t-AML (vs. de novo AML), European LeukemiaNet (ELN) 2017 risk classification, and type of therapy (intensive chemotherapy vs. low intensity/hypomethylating agent-based therapy) as covariates. Results: A total of 1977 pts with AML who had complete cytogenetic information available were identified. Among 742 pts (38%) with NK, 61 pts (8%) had t-AML and 681 pts (92%) had de novo AML. NK was present in 18% of all t-AML (61/340 pts). Prior therapy in pts with NK t-AML was chemotherapy (24 pts, 39%), radiation (21 pts, 34%), or both (16 pts, 26%). Characteristics of pts with NK AML are summarized in Table 1. Median age was higher for t-AML vs. de novo AML (71 years [range, 48-89] vs. 64 years [range, 18-92] , p 〈 0.01). No statistically significant difference was noted by mutational status or ELN 2017 risk category. Pts with t-AML were less likely to receive intensive induction chemotherapy (26% vs. 52%, p 〈 0.01). However, rates of allogeneic stem cell transplant were similar (15% and 22% in t-AML and de novo AML, respectively, p = 0.17). Response rates by type of treatment are shown in Table 2. In pts who received low-intensity therapy, no significant difference was seen in CR/CRi rates between t-AML and de novo AML (60% vs. 61%, p=0.92). However, in pts who received intensive chemotherapy, there was a trend for higher CR/CRi rates in pts with de novo AML compared with t-AML (86% vs. 69%, p=0.05). With a median follow-up of 54 months, median OS was significantly shorter for pts with t-AML compared with de novo AML: 10.2 months vs. 20.6 months (hazard ratio [HR] 2.07, 95% confidence interval [CI] , 1.54-2.78, p 〈 0.01, Figure 1A). Similarly, RFS was significantly worse for t-AML with a median of 12.0 months compared to 14.8 months for de novo AML (HR 1.55, 95% CI 1.06-2.26, p = 0.02, Figure 1B). Although pts with t-AML had worse OS and RFS, interestingly, this was not driven by higher relapse rates. The 5-year CIR rate was similar for pts with t-AML and de novo AML (42% vs. 56%, p = 0.21, Figure 1C). In contrast, the 5-year cumulative incidence of death in CR/CRi was significantly higher in patients with t-AML compared to patients with de novo AML (51% vs 16%, p 〈 0.01, Figure 1D), suggesting that non-relapse death is the main driver of worse outcomes for pts with t-AML. In multivariate analysis, age ≥60 was independently associated with shorter OS (HR 1.79, 95% CI 1.06-3.01, p=0.03) whereas favorable ELN 2017 risk category was prognostic of longer OS (HR 0.62, 95% CI 0.40-0.96, p=0.03). Additionally, there was a trend toward poor OS for adverse ELN 2017 risk category (HR 1.35, 95% CI 0.99-1.86, p=0.06) and better OS with intensive chemotherapy (HR 0.64, 95% CI 0.40-1.01, p=0.06). However, t-AML was not independently associated with OS (HR 1.34, 95% CI 0.83-2.17, p = 0.24) or RFS (HR 1.02, 95% CI 0.53-1.98, p = 0.95). Conclusions: t-AML with NK is rare entity that comprises 〈 5% of all AML cases. In this large cohort, although the mutation frequency of these pts was similar to those with de novo disease, t-AML with NK was associated with worse survival, which was mostly driven by older age, decreased likelihood of receiving intensive chemotherapy, and a higher rate of death in remission compared to pts with de novo AML with NK. Together, these findings suggest that a clinical history of prior chemotherapy or radiation in patients with NK AML should not impact prognostication or therapeutic decisions. Disclosures Ravandi: Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Cyclacel LTD: Research Funding; Macrogenix: Consultancy, Research Funding; Selvita: Research Funding; Menarini Ricerche: Research Funding; Xencor: Consultancy, Research Funding. Kadia:Pfizer: Membership on an entity's Board of Directors or advisory committees, Research Funding; Jazz: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: 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. Daver:Astellas: Consultancy; Sunesis: Consultancy, Research Funding; Servier: Research Funding; Karyopharm: Consultancy, Research Funding; Forty-Seven: Consultancy; Incyte: Consultancy, Research Funding; Agios: Consultancy; Hanmi Pharm Co., Ltd.: Research Funding; NOHLA: Research Funding; BMS: Consultancy, Research Funding; Glycomimetics: Research Funding; Pfizer: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Otsuka: Consultancy; Daiichi Sankyo: Consultancy, Research Funding; Immunogen: Consultancy, Research Funding; Celgene: Consultancy; Abbvie: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; Jazz: Consultancy. DiNardo:notable labs: Membership on an entity's Board of Directors or advisory committees; celgene: Consultancy, Honoraria; agios: Consultancy, Honoraria; syros: Honoraria; daiichi sankyo: Honoraria; abbvie: Consultancy, Honoraria; jazz: Honoraria; medimmune: Honoraria. 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. Borthakur:Bayer Healthcare AG: Research Funding; AstraZeneca: Research Funding; BMS: Research Funding; Eli Lilly and Co.: Research Funding; Argenx: Membership on an entity's Board of Directors or advisory committees; Oncoceutics: Research Funding; Xbiotech USA: Research Funding; Novartis: Research Funding; FTC Therapeutics: Membership on an entity's Board of Directors or advisory committees; Eisai: Research Funding; Cantargia AB: Research Funding; Merck: Research Funding; Arvinas: Research Funding; Agensys: Research Funding; Strategia Therapeutics: Research Funding; Polaris: Research Funding; BioLine Rx: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Research Funding; Incyte: Research Funding; GSK: Research Funding; Cyclacel: Research Funding; BioTheryX: Membership on an entity's Board of Directors or advisory committees; Tetralogic Pharmaceuticals: Research Funding; Janssen: Research Funding; PTC Therapeutics: Consultancy; NKarta: Consultancy; Oncoceutics, Inc.: 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:Forma Therapeutics: Consultancy, Honoraria, Research Funding; Daiichi Sankyo: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Research Funding; Jazz Pharmaceuticals: Consultancy, Research Funding; Merus: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria, Research Funding; Immunogen: Consultancy, Honoraria, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Sun Pharma: Research Funding; Biopath Holdings: Consultancy, Honoraria; BiolineRx: Consultancy; Astellas Pharma: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding. Kantarjian:Cyclacel: Research Funding; Takeda: Honoraria; Immunogen: Research Funding; Pfizer: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Daiichi-Sankyo: Research Funding; Novartis: Research Funding; Actinium: Honoraria, Membership on an entity's Board of Directors or advisory committees; Ariad: Research Funding; Jazz Pharma: Research Funding; Agios: Honoraria, Research Funding; BMS: Research Funding; AbbVie: Honoraria, Research Funding; Astex: Research Funding. Short:AstraZeneca: Consultancy; Takeda Oncology: Consultancy, Research Funding; Amgen: Honoraria.

Abstract: Despite promising results with FLT3 inhibitors (FLT3i), response durations remain short. We studied pretreatment and relapse bone marrow samples from patients with FLT3-mutated acute myeloid leukemia (AML) treated with FLT3i-based therapies (secondary resistance cohort), and pretreatment bone marrow samples from patients with no response to FLT3i-based therapies (primary resistance cohort). Targeted next-generation sequencing (NGS) at relapse identified emergent mutations involving on-target FLT3, epigenetic modifiers, RAS/MAPK pathway, and less frequently WT1 and TP53. RAS/MAPK and FLT3-D835 mutations emerged most commonly following type I and II FLT3i-based therapies, respectively. Patients with emergent mutations at relapse had inferior overall survival compared with those without emergent mutations. Among pretreatment RAS-mutated patients, pretreatment cohort-level variant allelic frequencies for RAS were higher in nonresponders, particularly with type I FLT3i-based therapies, suggesting a potential role in primary resistance as well. These data demonstrate distinct pathways of resistance in FLT3-mutated AML treated with type I versus II FLT3i. Significance: Sequential NGS-based mutational analysis at relapse after FLT3i-based therapies showed distinct pathways of secondary resistance between type I and II FLT3i. FLT3 mutations may be lost at relapse after FLT3i-based therapies. Pretreatment RAS/MAPK mutations may also be associated with primary resistance in patients treated with type I FLT3i. See related commentary by Shastri et al., p. 113.

Abstract: 1574 Background: Improvements in prevention, early detection and therapy of cancer have decreased cancer related mortality yet health disparities continue to exist. We investigated the impact of such disparities in cancer survival. Methods: In the Surveillance, Epidemiology, and End Results, we identified 784,341 patients with cancer from 1990 to 2016 in Georgia; 68,493 in 1990-1999, 371,353 in 2000-2009, and 322,932 in 2010-2016. We assessed overall survival (OS) of patients with all cancers, chronic myeloid leukemia (CML), and lung cancer given the dramatic improvement in patient outcomes in CML since 2000 compared to the consistently poor outcome in lung cancer. We assessed distance from each county to the one National Cancer Institute-designated cancer center (NCI-CC) in Georgia. Results: The 5-year OS of patients with any cancer was 55% with median OS 80 months; the 5-y OS of each county ranged from 33% to 82% (interquartile range[IQR], 51%-65%)(P 〈 0.001). The improvement of OS was minimal over decades: 5-year OS was 52%, 55%, and 55% in 1990-1999, 2000-2009, and 2010-2016, respectively; the median was 69 months, 80 months, not reached, respectively (P 〈 0.001). In patients with lung cancer and CML, the 5-year OS was 15% and 52% with the median of 9 months and 67 months, respectively. The geographic difference between counties was relatively small and constant over time in patients with lung cancer, represented by the width in the range and IQR: range 5%-17%, IQR 9%-13%, median 13% in 1990-1999; range 2%-24%, IQR 10%-14%, median 14% in 2000-2009; and range 4%-24%, IQR 12%-17%, median 17% in 2010-2016. However, the geographic difference was more prominent in patients with CML and widened after introduction of modern therapy: range 20%-42%, IQR 26%-34%, median 32% in 1990-1999; range 14%-83%, IQR 38%-64%, median 53% in 2000-2009; and range 14%-80%, IQR 40%-57%, median 57% in 2010-2016. Multivariate Cox regression showed age (hazard ratio[HR],1.040;95% confidence interval[CI] ,1.039-1.040;P 〈 0.001), median county income (HR,0.919;95% CI,0.916-0.921;P 〈 0.001), African American (HR,1.021;95% CI,1.210-1.227;P 〈 0.001), and distance to NCI-CC (each 100 kilometers) (HR,1.021;95% CI,1.017-1.025;P 〈 0.001) as predictive factors. Conclusions: The disparity of cancer care exists between geographic locations. The geographic difference of survival seems more prominent when highly effective therapies are available.