Type: Oral
Session: 615. Acute Myeloid Leukemias: Commercially Available Therapies, Excluding Transplantation and Cellular Immunotherapies: New Approaches to Combination Chemotherapy and Venetoclax Plus Hypomethylating Agent Therapy in AML
Hematology Disease Topics & Pathways:
Research, clinical trials, Clinical Research
Methods: Pts >18 years of age with R/R AML, defined as lack of response after at least 1 cycle of induction or relapsed disease with any prior number of treatments but without prior receipt of venetoclax, with sustained organ function were eligible. Induction consisted of fludarabine (30mg/m2, D2-6), cytarabine (1.5g/m2 D2-6), idarubicin (6mg/m2, D4-5), and Filgrastim(D1-7). Venetoclax was administered D1-14 during induction and D1-7 for consolidation (100mg D1, 200mg D2, 400mg onwards for induction). Consolidation consisted of fludarabine(30mg/m2) and cytarabine (1.5g/m2) for D2-4. The primary objective was evaluation of ORR. Secondary objectives included overall survival (OS), CRc, and duration of response (DOR). Mutation analysis was performed using next-generation sequencing and measurable residual disease (MRD) detection was performed using flow cytometry (sensitivity 10-3-10-4).
Results: Thirty-three R/R pts have been treated. Baseline characteristics are shown in Table 1. The median age was 47 (range 18 to 68). For 70% of pts, this regimen was Salvage 1. Thirty percent of pts underwent prior SCT. The majority of pts had ELN 2017 adverse risk disease (67%).Complex karyotype and TP53 mutations occurred in 19% and 21% of pts respectively.
Among the 33 pts, 1 patient remains too early for response assessment. The ORR of the remaining 32 pts was 60% (19 pts), with CRc rate of 53% and 12 pts (71% of responders) achieving MRD negativity. ORR and CRc rates in salvage 1 pt were 65% and 61%. By ELN risk, ORR and CRc rates were 100% and 85% in favorable risk, 50%and 50% in intermediate risk, and 48% and 43% in adverse risk. ORR and CRc rates for TP53 wild-type vs TP53 mutant was 68% and 14%, vs 64% and 14%.
The median number of cycles received was 2 (range 1-4) with a median number of cycles to best response of 1 (range 1-2). Among responding pts, 13 (68%) proceeded to allogeneic transplant, including two pts who transitioned to HMA + VEN and sorafenib maintenance, respectively prior to transplant.
At a median follow up of 15.8 months, the OS and DOR were 27 (95% CI 22.3-26.3) months and NR (95% CI 22.4-NR) respectively. Six-month and 12-month survival was 69% and 60%, respectively. Of the 13 pts that proceeding with transplant, median DOR post-transplant has not been reached. OS in TP53 wild-type vs TP53 mutant was NR and 5.4 months with a 12-month OS of 68% and 17% respectively.
Thirty-day and 60 day- mortality was 0% and 12%. Two deaths occurred within 60 days in pts with persistent leukemia (secondary to hemoptysis from known fungal pneumonia and disease).
Conclusion: In a cohort of pts with R/R AML enriched for fit pts with adverse-risk disease, this intensive combination resulted in an ORR of 60% with a CRc of 53%. Seventy-one percent of CRc pts attained an MRD negative remission and 68% of responding pts proceeded to transplant. In conclusion, this regimen is associated with deep remissions and a high rate of transition to transplant inpatients with R/R AML, particularly in TP53 wild-type.
Disclosures: Konopleva: Forty-Seven; F. Hoffman LaRoche: Honoraria; Reata Pharmaceuticals, Novartis and Eli Lilly: Patents & Royalties; Stocks, Reata Pharmaceuticals: Current equity holder in publicly-traded company; AbbVie, Genentech, F. Hoffman La-Roche, Stemline Therapeutics, Amgen, Forty-Seven, Kisoji; Janssen: Consultancy; 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. Takahashi: Symbio Pharmaceuticals: Consultancy; GSK: Consultancy; Novartis: Consultancy; Celgene/BMS: Consultancy; Agios: Consultancy; Mission Bio: Honoraria; Ostuka Pharmaceuticals: Honoraria; Illumina: Honoraria. Loghavi: Astellas: Research Funding; PeerView: Honoraria; GLG: Consultancy; Amgen: Research Funding; Abbvie: Consultancy, Current equity holder in publicly-traded company; QualWorld: Consultancy; Guidepoint: Consultancy; Caris: Consultancy; BluePrint Medicine: Consultancy; Daiichi Sankyo: Consultancy. Kadia: Glycomimetics: Research Funding; PinotBio: Consultancy; Ascentage: Research Funding; JAZZ: Consultancy, Research Funding; Amgen: Research Funding; AstraZeneca: Research Funding; Astellas: Research Funding; Iterion: Research Funding; Astex: Honoraria; Delta-Fly: Research Funding; cyclacel: Research Funding; Novartis: Consultancy; Abbvie: Consultancy, Research Funding; Servier: Consultancy; cellenkos: Research Funding; Pfizer: Research Funding; Genfleet: Research Funding; Genentech: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Agios: Consultancy; Regeneron: Research Funding. Daver: Kartos and Jazz Pharmaceuticals: Other: Data monitoring committee member; Agios, Celgene, SOBI and STAR Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees; 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. Short: Stemline Therapeutics: Research Funding; AstraZeneca: Consultancy; Astellas: Research Funding; Takeda Oncology: Consultancy, Research Funding; Amgen: Consultancy, Honoraria; Novartis: Consultancy; Pfizer: Consultancy. Sasaki: Daiichi-Sankyo: Membership on an entity's Board of Directors or advisory committees; Otsuka Pharmaceuticals: Honoraria; Pfizer: Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Borthakur: Pacylex, Novartis, Cytomx, Bio Ascend: Membership on an entity's Board of Directors or advisory committees; Catamaran Bio, Abbvie, PPD Development, Protagonist Therapeutics, Janssen: Consultancy; Astex Pharmaceuticals, Ryvu, PTC Therapeutics: Research Funding. Issa: Novartis, Kura Oncology, Nuprobe: Consultancy; Celgene, Kura Oncology, Syndax, Merck, Cullinan and Novartis: Research Funding. Alvarado: Sun Pharma: Research Funding; FibroGen: Research Funding; Jazz Pharmaceuticals: Research Funding; Daiichi-Sankyo/Lilly: Research Funding; Astex Pharmaceuticals: Research Funding; BerGenBio: Research Funding. Yilmaz: Pfizer: Research Funding; Daiichi-Sankyo: Research Funding. Andreeff: NCI: Membership on an entity's Board of Directors or advisory committees; Glycomimetics: Consultancy; AstraZeneca: Research Funding; German Research Council: Membership on an entity's Board of Directors or advisory committees; CLL Foundation: Membership on an entity's Board of Directors or advisory committees; Daiichi-Sankyo Inc.: Consultancy, Research Funding; Brooklyn ITX: Research Funding; Breast Cancer Research Foundation: Research Funding; Medicxi: Consultancy; Cancer UK: 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; Oxford Biomedical UK: Research Funding; Pinot Bio: Research Funding; Senti Bio: Consultancy, Research Funding; Syndax: Consultancy, Research Funding; Aptose: Consultancy, Membership on an entity's Board of Directors or advisory committees; Oncolyze: Current holder of stock options in a privately-held company; Reata: Current holder of stock options in a privately-held company; Chimerix: Current holder of stock options in a privately-held company; Kintor Pharmaceutical: Research Funding. Jabbour: Bristol Myers Squibb: Other: Advisory Role, Research Funding; Adaptive Biotechnologies: Other: Advisory Role, Research Funding; Amgen: Other: Advisory Role, Research Funding; Spectrum: Research Funding; Takeda: Other: Advisory Role, Research Funding; Pfizer: Other: Advisory Role, Research Funding; Genentech: Other: Advisory Role, Research Funding; AbbVie: Other: Advisory Role, Research Funding. Garcia-Manero: AbbVie: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; BMS: Consultancy, Honoraria, Research Funding; Astex: Consultancy, Honoraria, Research Funding; Acceleron Pharma: Consultancy; Genentech: Honoraria, Research Funding; Curis: Honoraria, Research Funding; Gilead Sciences: Research Funding; Aprea: Honoraria. Ravandi: Astellas: Consultancy, Honoraria, Research Funding; Syos: Consultancy, Honoraria, Research Funding; Novartis: Consultancy; Xencor: Research Funding; Astex/Taiho: Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Honoraria, Research Funding; AstraZeneca: Consultancy; BMS/Celgene: Consultancy, Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Biomea Fusion, Inc.: Research Funding; Prelude: Research Funding; Abbvie: Consultancy, Honoraria, Research Funding. Kantarjian: Astellas Health: Honoraria, Membership on an entity's Board of Directors or advisory committees; NOVA Research: Honoraria; AbbVie: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Ipsen Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees; ImmunoGen: Research Funding; Daiichi-Sankyo: Consultancy, Research Funding; KAHR Medical Ltd: Honoraria, Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceuticals: Research Funding; Ascentage: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding; Takeda: Honoraria. DiNardo: Cleave: Research Funding; AbbVie: Consultancy, Research Funding; GenMab: Membership on an entity's Board of Directors or advisory committees; LOXO: Research Funding; Astex: Research Funding; ImmuneOnc: Honoraria, Research Funding; Takeda: Honoraria; Servier: Consultancy, Honoraria, Research Funding; Astellas: Honoraria; Kura: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Honoraria, Research Funding; Foghorn: Honoraria, Research Funding; Forma: Research Funding; Bluebird Bio: Honoraria; Notable Labs: Current holder of stock options in a privately-held company, Membership on an entity's Board of Directors or advisory committees; GlaxoSmithKline: Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria; Jazz: Honoraria; Gilead: Honoraria.