PURPOSE Sixty percent of newly diagnosed patients with acute myeloid leukemia (ND-AML) receiving frontline therapy attain a complete response (CR), yet 30%-40% of patients relapse. Relapsed or refractory AML (R/R-AML) remains a particularly adverse population necessitating improved therapeutic options. This phase Ib/II study evaluated the safety and efficacy of fludarabine, cytarabine, granulocyte colony-stimulating factor, and idarubicin combined with the B-cell lymphoma-2 inhibitor venetoclax in ND-AML and R/R-AML. MATERIALS AND METHODS The phase IB portion (PIB) enrolled patients with R/R-AML using a 3 + 3 dose escalation and de-escalation algorithm for identification of maximum tolerated dose and dose-limiting toxicities. The phase II portion enrolled patients into two arms to evaluate response and time-to-event end points: phase IIA (PIIA): ND-AML and phase IIB (PIIB): R/R-AML. RESULTS Sixty-eight patients have enrolled to date (PIB, 16; PIIA, 29; PIIB, 23). Median age was 46 years (range, 20-73). Grade 3 and 4 adverse events occurring in ≥ 10% of patients included febrile neutropenia (50%), bacteremia (35%), pneumonia (28%), and sepsis (12%). The overall response rate for PIB, PIIA, and PIIB was 75%, 97%, and 70% with 75%, 90%, and 61%, respectively, achieving a composite CR. Measurable residual disease–negative composite CR was attained in 96% of ND-AML and 69% of R/R-AML patients. After a median follow-up of 12 months, median overall survival (OS) for both PII cohorts was not reached. Fifty-six percent of patients proceeded to allogeneic hematopoietic stem-cell transplantation (ND-AML, 69%; R/R-AML, 46%). In R/R-AML, allogeneic hematopoietic stem-cell transplantation resulted in a significant improvement in OS (median OS, NR; 1-year OS, 87%). One-year survival post-HSCT was 94% in ND-AML and 78% in R/R-AML. CONCLUSION Fludarabine, cytarabine, granulocyte colony-stimulating factor, and idarubicin + venetoclax represents an effective intensive treatment regimen in ND-AML and R/R-AML patients, associated with deep remissions and a high rate of transition to successful transplantation.

The coronavirus disease 2019 (COVID-19) pandemic poses several challenges to the management of patients with leukemia. The biology of each leukemia and its corresponding treatment with conventional intensive chemotherapy, with or without targeted therapies (venetoclax, FLT3 inhibitors, IDH1/2 inhibitors, Bruton's tyrosine kinase inhibitors), introduce additional layers of complexity during COVID-19 highrisk periods. The knowledge about COVID-19 is accumulating rapidly. An important distinction is the prevalence of "exposure" versus "clinical infectivity," which determine the risk versus benefit of modifying potentially highly curative therapies in leukemia. At present, the rate of clinical infection is < 1-2% worldwide. With a mortality rate of 1-5% in CO-VID-19 patients in the general population and potentially of > 30% in patients with cancer, careful consideration should be given to the risk of COVID-19 in leukemia. Instead of reducing patient access to specialized cancer centers and modifying therapies to ones with unproven curative benefit, there is more rationale for less intensive, yet effective therapies that may require fewer clinic visits or hospitalizations. Here, we offer recommendations on the optimization of leukemia management during high-risk COVID-19 periods.

Acute myeloid leukemia with myelodysplasia‐related changes (AML‐MRC) is a heterogeneous disorder defined by multilineage dysplasia, myelodysplastic syndrome (MDS)‐related karyotype, or history of prior MDS. We evaluated 415 patients with AML‐MRC treated from 2013 to 2018 and analyzed their clinical outcomes based on the diagnostic criteria of AML‐MRC, therapy type and mutation profile. Criteria for AML‐MRC included: cytogenetic abnormalities (AML‐MRC‐C) in 243 (59%), prior history of MDS in 75 (18%) including 47 (11%) with previously untreated MDS (AML‐MRC‐H) and 28 (7%) with previously treated MDS (AML‐MRC‐TS), and 97 (23%) with multilineage dysplasia (AML‐MRC‐M). Median age was 70 years (range 18‐94). Among 95 evaluable patients, a total of 37 (39%) had secondary‐type (ASXL1, BCOR, EZH2, SF3B1, SRSF2, STAG2, U2AF1, ZRSR2) mutations. Mutations in ASXL1, BCOR, SF3B1, SRSF2, and U2AF1 tended to appear in dominant clones. By multivariate analysis, AML‐MRC subtype, age and serum LDH levels were independent predictors of outcome, with patients with AML‐MRC‐M (HR 0.56, CI 0.38‐0.84, P = .004) and AML‐MRC‐H having better OS. Compared to a cohort of 468 patients with AML without MRC, patients with AML‐MRC‐M/AML‐MRC‐H had similar outcomes to those with intermediate risk AML by European LeukemiaNet criteria. Intensive therapy was associated with improved OS in patients with AML‐MRC‐M (HR 0.42, CI 0.19‐0.94, P = .036) and with improved EFS in AML‐MRC‐M and AML‐MRC‐H (HR 0.26, CI 0.10‐0.63, P = .003). This data suggests that not all diagnostic criteria for AML‐MRC define high‐risk patients and that specific subgroups may benefit from different therapeutic interventions.

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.

Background Venetoclax (VEN) in combination with a hypomethylating agent (HMA) has become the standard of care for patients aged >75 years and for those not eligible for intensive chemotherapy who have newly diagnosed acute myeloid leukemia (AML). The benefit of VEN‐based therapy in patients who have newly diagnosed AML with mutations in the TP53 gene (TP53mut) over standard therapy is undefined. Methods In this single‐institutional, retrospective analysis, the authors assessed the clinical outcomes of 238 patients with newly diagnosed TP53mut AML and compared the clinical characteristics, response to different therapies, and outcomes of those who received VEN‐based (n = 58) and non–VEN‐based (n = 180) regimens. Results Patients who received VEN‐based regimens were older (aged >65 years: 81% vs 65%; P = .02) and had higher response rates (complete remission, 43% vs 32%; P = .06) than those who received non–VEN‐based regimens. Compared with patients who received non–VEN‐based regimens, no difference in overall survival (median, 6.6 vs 5.7 months; P = .4) or relapse‐free survival (median, 4.7 vs 3.5 months; P = .43) was observed in those who received VEN‐based regimens, regardless of age or intensity of treatment. Conclusions The addition of VEN to standard treatment regimens did not improve outcomes in younger or older patients who had TP53mut AML. These data highlight the need for novel therapies beyond VEN to improve the outcome of patients with TP53mut AML.