Long-Term Outcomes of Acute Myeloid Leukemia Following Allogeneic Stem-Cell Transplantation after Decitabine and Venetoclax: Subgroup Analysis of a Phase II Trial

Introduction: Venetoclax (VEN)-based lower intensity regimens are the current standard for older/unfit patients with newly diagnosed acute myeloid (AML). Such regimens are increasingly used in the salvage setting as well. Allogeneic stem-cell transplantation (SCT) following VEN-based regimens has been shown to be safe and feasible in pts with AML (Mukherjee et al. J Clin Oncol 2019; Pratz et al. Blood 2019). We herein describe long-term outcomes after SCT following treatment on a prospective clinical trial of 10-day decitabine and venetoclax (DEC10-VEN) for treatment-naïve and previously treated AML (NCT03404193).

Methods: In this phase II trial, pts received decitabine 20 mg/m² for 10 days during induction and 5 days during consolidation. VEN was administered 400 mg daily on D1-28 during cycle 1 but was held on day 21 if bone marrow evaluation showed blasts ≤5%. During subsequent cycles VEN duration could be reduced in pts with myelosuppression. This trial enrolled pts with ECOG PS ≤3 with adequate organ function. Pts with favorable risk cytogenetics were excluded. Pts with newly diagnosed AML were either unfit for intensive therapy, or older than 60 yrs. Pts in relapsed/refractory cohort were ineligible if they had received prior BCL2 inhibitor. Eligible pts with an available donor could proceed to SCT at any time following achievement of response. Response, overall survival (OS) and relapse-free survival were defined per ELN2017. Survival outcomes were not censored at SCT. Data cut-off date was July 26, 2022.

Results: Between January 2018 and June 2022 we enrolled 230 pts with AML, high-risk or relapsed/refractory myelodysplastic syndrome or chronic myelomonocytic leukemia, and blastic plasmacytoid dendritic cell neoplasm. Among 201 pts with AML, CR/CRi/MLFS response was achieved in 146 pts (73%) and 40 pts (20%) were able to proceed to SCT; including 21 pts with treatment-naïve AML and 19 pts with either R/R AML or AML following treatment for antecedent hematological disorder (AHD) including MDS-EB (n=2) and CMML (n=1), considered "previously treated AML". The median age of pts undergoing SCT was 66 yrs (range 18-77); 10 pts (25%) were older than 70 yrs, 16 pts (40%) pts had R/R AML, 19 pts (45%) had ELN adverse risk disease and 4 pts had received prior SCT (Table 1).

Fourteen pts in each group received additional concomitant therapy with FLT3 inhibitors including gilteritinib and sorafenib (Table 1). All pts proceeding to SCT were in CR/CRi except in the previously treated group where 4 pts had non-CR/CRi responses including MLFS/aplasia. 28 pts (70%) had achieved negative measurable residual disease (MRD) by flow cytometry (sensitivity 0.1-0.01%) prior to proceeding to SCT while 8/40 pts (20%) had persistent MRD. Remaining 4 pts either had inadequate sample or were not evaluated for MRD. Conditioning regimens and donor types are summarized in Table 1.

Median no. of cycles of DEC10-VEN administered was 2 (range 1-12) and the median time to SCT was 3.5 mo from start of DEC10-VEN (range 1.1-16.2). The median follow-up duration was 29.1 mo. Among pts with AML who proceeded to SCT, the 100-day post-SCT mortality was 8% (n=3). The median OS for treatment-naïve pts was 35.1 mo and for previously treated pts was 16.7 mo. Median RFS for treatment naïve pts was 23.5 mo and for previously treated pts was 12.9 mo. Landmark analysis of pts achieving CR/CRi/MLFS and alive at 3.5 mo showed that pts with treatment-naïve AML who were eligible to proceed to SCT (n=21) derived significant benefit in OS with median OS 35.1 vs 15.7 mo in pts who did not / were ineligible (n=60) (HR 0.47, 95% CI 0.24, 0.76, p=.01, Fig. 1). Similarly, pts with previously treated AML who proceeded to SCT in CR/CRi/MLFS (n=18) had median OS of 19.3 vs 12.0 mo for pts who could not (n=36) (HR 0.53, 95% CI 0.28, 1.01, p=.07). Both analyses were limited by confounding factors. At data cut-off, 19 pts (48%) are alive, 8 pts (20%) died in remission, and 13 pts (33%) pts died after disease progression (Table 1).

Conclusion: In this prospective trial of DEC10-VEN enrolling older/unfit pts with newly diagnosed AML, secondary AML, and younger or older pts with R/R AML, 20% of pts were able to proceed to SCT. DEC10-VEN served as bridge to SCT for responding pts with newly diagnosed as well as previously treated AML, with low 100-day post-SCT mortality.

Maiti:Biosight: Research Funding; Sanofi: Research Funding. DiNardo:Bluebird Bio: Honoraria; Bristol Myers Squibb: Honoraria, Research Funding; GenMab: Membership on an entity's Board of Directors or advisory committees; GlaxoSmithKline: Membership on an entity's Board of Directors or advisory committees; Kura: Honoraria, Membership on an entity's Board of Directors or advisory committees; Foghorn: Honoraria, Research Funding; Takeda: Honoraria; Cleave: Research Funding; Forma: Research Funding; Gilead: Honoraria; LOXO: Research Funding; Novartis: Honoraria; ImmuneOnc: Honoraria, Research Funding; Astex: Research Funding; Astellas: Honoraria; Servier: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Research Funding; Jazz: Honoraria; Notable Labs: Current holder of stock options in a privately-held company, Membership on an entity's Board of Directors or advisory committees. Pemmaraju:stemline: Consultancy; abbvie: Consultancy; immunogen: Consultancy; mustangbio: Research Funding; incyte: Consultancy; novartis: Research Funding; pacylex: Consultancy, Research Funding; samus: Research Funding; daiichi sankyo: Research Funding; cellectis: Research Funding; cellularity: Research Funding. Daver:Agios, Celgene, SOBI and STAR Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees; Kartos and Jazz Pharmaceuticals: Other: Data monitoring committee member; Karyopham Therapeutics and Newave Pharmaceutical: Research Funding; Astellas, AbbVie, Genentech, Daiichi-Sankyo, Novartis, Jazz, Amgen, Servier, Karyopharm, Trovagene, Trillium, Syndax, Gilead, Pfizer, Bristol Myers Squibb, Kite, Actinium, Arog, Immunogen, Arcellx, and Shattuck: Consultancy, Other: Advisory Role; Astellas, AbbVie, Genentech, Daiichi-Sankyo, Gilead, Immunogen, Pfizer, Bristol Myers Squibb, Trovagene, Servier, Novimmune, Incyte, Hanmi, Fate, Amgen, Kite, Novartis, Astex, KAHR, Shattuck, Sobi, Glycomimetics, Trillium: Research Funding. Borthakur:Catamaran Bio, Abbvie, PPD Development, Protagonist Therapeutics, Janssen: Consultancy; Pacylex, Novartis, Cytomx, Bio Ascend: Membership on an entity's Board of Directors or advisory committees; Astex Pharmaceuticals, Ryvu, PTC Therapeutics: Research Funding. Ravandi:Amgen: Honoraria, Research Funding; Syos: Consultancy, Honoraria, Research Funding; Xencor: Research Funding; Astellas: Consultancy, Honoraria, Research Funding; Abbvie: Consultancy, Honoraria, Research Funding; BMS/Celgene: Consultancy, Honoraria, Research Funding; Astex/Taiho: Membership on an entity's Board of Directors or advisory committees, Research Funding; AstraZeneca: Consultancy; Prelude: Research Funding; Novartis: Consultancy; Biomea Fusion, Inc.: Research Funding; Amgen: Honoraria, Research Funding. Issa:Celgene, Kura Oncology, Syndax, Merck, Cullinan and Novartis: Research Funding; Novartis, Kura Oncology, Nuprobe: Consultancy. Garcia-Manero:Acceleron Pharma: Consultancy; BMS: Consultancy, Honoraria, Research Funding; Genentech: Honoraria, Research Funding; Astex: Consultancy, Honoraria, Research Funding; Novartis: Honoraria, Research Funding; AbbVie: Honoraria, Research Funding; Gilead Sciences: Research Funding; Curis: Honoraria, Research Funding; Aprea: Honoraria. Jain:Loxo Oncology: Research Funding; Adaptive Biotechnologies: Consultancy, Honoraria, Other: Travel Support, Research Funding; Newave: Research Funding; Beigene: Honoraria; Medisix: Research Funding; Dialectic Therapeutics: Research Funding; BMS: Consultancy, Honoraria, Other: Travel Support, Research Funding; MEI Pharma: Honoraria; TG Therapeutics: Honoraria; AstraZeneca: Consultancy, Honoraria, Other: Travel Support, Research Funding; Precision Biosciences: Consultancy, Honoraria, Other: Travel Support, Research Funding; Janssen Pharmaceuticals, Inc.: Consultancy, Honoraria, Other: Travel Support; Pharmacyclics, Inc.: Consultancy, Honoraria, Other: Travel Support, Research Funding; Servier Pharmaceuticals LLC: Research Funding; Cellectis: Honoraria, Research Funding; Incyte Corporation: Research Funding; Mingsight: Research Funding; AbbVie: Consultancy, Honoraria, Other: Travel Support, Research Funding; Takeda: Research Funding; Kite, a Gilead Company: Consultancy, Honoraria, Research Funding; Cellectis: Honoraria, Research Funding; TransThera Sciences: Research Funding; Fate Therapeutics: Research Funding; Genentech, Inc.: Consultancy, Honoraria, Other: Travel Support, Research Funding; Ipsen: Honoraria; Pfizer: Research Funding; Aprea Therapeutics: Research Funding; Novalgen: Research Funding; ADC Therapeutics: Research Funding; CareDx: Honoraria. Kadia:AstraZeneca: Research Funding; Regeneron: Research Funding; Ascentage: Research Funding; cyclacel: Research Funding; Amgen: Research Funding; Glycomimetics: Research Funding; Astex: Honoraria; JAZZ: Consultancy, Research Funding; Novartis: Consultancy; Pfizer: Research Funding; cellenkos: Research Funding; Servier: Consultancy; Delta-Fly: Research Funding; Iterion: Research Funding; PinotBio: Consultancy; Genentech: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Genfleet: Research Funding; Astellas: Research Funding; Agios: Consultancy; Abbvie: Consultancy, Research Funding. Wierda:AstraZeneca/Acerta Pharma. Inc.: Research Funding; AbbVie: Research Funding; Cyclacel: Research Funding; Miragen: Research Funding; Oncternal Therapeutics, Inc.: Research Funding; Pharmacyclics LLC: Research Funding; Janssen: Research Funding; Gilead Sciences: Research Funding; GSK/Novartis: Research Funding; Karyopharm: Research Funding; Juno: Research Funding; Genentech: Research Funding; Loxo Oncology, Inc./Lilly: Research Funding; Sunesis: Research Funding; Xencor: Research Funding; Kite, a Gilead Company: Research Funding; Bristol Meyers Squibb (Juno and Celgene): Research Funding; Genzyme: Consultancy; Sanofi: Consultancy. Yilmaz:Pfizer: Research Funding; Daiichi-Sankyo: Research Funding. Alvarado:Sun Pharma: Research Funding; FibroGen: Research Funding; BerGenBio: Research Funding; Jazz Pharmaceuticals: Research Funding; Daiichi-Sankyo/Lilly: Research Funding; Astex Pharmaceuticals: Research Funding. Jabbour:Pfizer: Other: Advisory Role, Research Funding; Spectrum: Research Funding; Bristol Myers Squibb: Other: Advisory Role, Research Funding; Genentech: Other: Advisory Role, Research Funding; Amgen: Other: Advisory Role, Research Funding; Adaptive Biotechnologies: Other: Advisory Role, Research Funding; AbbVie: Other: Advisory Role, Research Funding; Takeda: Other: Advisory Role, Research Funding. Short:Takeda Oncology: Consultancy, Research Funding; Pfizer: Consultancy; Novartis: Consultancy; Amgen: Consultancy, Honoraria; AstraZeneca: Consultancy; Stemline Therapeutics: Research Funding; Astellas: Research Funding. Takahashi:Ostuka Pharmaceuticals: Honoraria; GSK: Consultancy; Novartis: Consultancy; Symbio Pharmaceuticals: Consultancy; Agios: Consultancy; Mission Bio: Honoraria; Celgene/BMS: Consultancy; Illumina: Honoraria. Loghavi:Amgen: Research Funding; Abbvie: Consultancy, Current equity holder in publicly-traded company; GLG: Consultancy; QualWorld: Consultancy; PeerView: Honoraria; Astellas: Research Funding. Mehta:Syndax: Research Funding; Orca Bio: Research Funding. Popat:Iovance: Consultancy; Novartis: Research Funding; Abbvie: Research Funding; Incyte: Research Funding; Bayer: Research Funding. Kebriaei:Pfizer: Consultancy; Amgen: Research Funding; Ziopharm: Research Funding; Kite: Consultancy; Jazz: Consultancy. Oran:ASTEX: Research Funding; AROG: Research Funding. Shpall:Fibroblasts and FibroBiologics: Consultancy; axio: Consultancy; adaptimmune: Consultancy; Bayer: Honoraria; NY blood center: Consultancy; Navan: Consultancy; Takeda: Patents & Royalties; Affimed: Other: License agreement. Champlin:Johnson &Johnson: Consultancy; Bluebird: Other: Data Safety Monitoring Board; General Oncology: Other: Data Safety Monitoring Board; Kadmon: Consultancy; Actinium: Consultancy; Cell Source Inc.: Research Funding; Omeros: Consultancy. Kantarjian:Astellas Health: Honoraria, Membership on an entity's Board of Directors or advisory committees; Daiichi-Sankyo: Consultancy, Research Funding; KAHR Medical Ltd: Honoraria, Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceuticals: Research Funding; Ipsen Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees; ImmunoGen: Research Funding; NOVA Research: Honoraria; Ascentage: Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Honoraria, Research Funding; AbbVie: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding; Takeda: Honoraria. Konopleva:Reata Pharmaceuticals, Novartis and Eli Lilly: Patents & Royalties; AbbVie, Genentech, F. Hoffman La-Roche, Stemline Therapeutics, Amgen, Forty-Seven, Kisoji; Janssen: Consultancy; Forty-Seven; F. Hoffman LaRoche: Honoraria; Stocks, Reata Pharmaceuticals: Current equity holder in publicly-traded company; AbbVie, Genentech, F. Hoffman La-Roche, Eli Lilly, Cellectis, Calithera, Ablynx, Stemline Therapeutics, Agios, Ascentage, Astra Zeneca; Rafael Pharmaceutical; Sanofi, Forty-Seven: Research Funding; Stemline Therapeutics, F. Hoffman La-Roche; Janssen: Membership on an entity's Board of Directors or advisory committees.

Use of venetoclax in slavage setting