Venetoclax plus intensive chemotherapy with cladribine, idarubicin, and cytarabine in patients with newly diagnosed acute myeloid leukaemia or high-risk myelodysplastic syndrome: a cohort from a single-centre, single-arm, phase 2 trial.

Background: Addition of the BCL2 inhibitor venetoclax to lower intensity therapy has been shown to improve overall survival in older (aged 75 years or older) and unfit patients with newly diagnosed acute myeloid leukaemia. The aim of this study was to investigate the activity of venetoclax combined with intensive chemotherapy in patients aged 65 years or younger with acute myeloid leukaemia.
Methods: This cohort study was done at the MD Anderson Cancer Center in the USA, as part of the single-centre, single arm, phase 2, CLIA trial. Here we report on the independent cohort investigating the safety and activity of venetoclax added to intensive chemotherapy (the CLIA regimen [cladribine, high-dose cytarabine, idarubicin]). Eligible patients were aged 18-65 years with a new diagnosis of acute myeloid leukaemia, mixed phenotype acute leukaemia, or high-risk myelodysplastic syndrome (≥10% blasts or International Prognostic Scoring System ≥2 [intermediate]), who received no previous potentially curative therapy for leukaemia. Patients received cladribine (5 mg/m ² ) and cytarabine (1·5 g/m ² for patients aged <60 years, 1 g/m ² for patients aged ≥60 years) intravenously on days 1-5 and idarubicin (10 mg/m ² ) intravenously on days 1-3. Consolidation was cladribine (5 mg/m ² ) and cytarabine (1 g/m ² for patients aged <60 years and 0·75 g/m ² for patients aged ≥60 years) on days 1-3 and idarubicin (8 mg/m ² ) on days 1-2. Venetoclax (400 mg) was given on days 2-8 with each course. Patients with a known FLT3-ITD or FLT3-TKD mutation received midostaurin or gilteritinib. The primary outcome was composite complete response (complete response plus complete response with incomplete blood count recovery). Secondary outcomes were overall response, duration of response, event-free survival, overall survival, and safety. This trial was registered with ClinicalTrials.gov, NCT02115295.
Findings: Between Feb 25, 2019, and March 23, 2021, 77 patients were assessed for eligibility, 50 of whom were enrolled. Median age was 48 years (IQR 37-56). 47 (94% [95% CI 83-98]) patients had composite complete response, with the same proportion also having an overall response; two (4% [1-14]) patients did not respond, and one (2% [0-11]) patient died during induction. 37 (82% [95% CI 68-92]) of 45 patients had undetectable measurable residual disease (MRD). At a median follow-up of 13·5 months (IQR 6·4-19·5), the median duration of response, event-free survival, and overall survival were not reached. At 12 months, the estimated duration of response was 74% (95% CI 60-92), event-free survival was 68% (54-85), and overall survival was 85% (75-97). The most common adverse events of grade 3 or worse were febrile neutropenia (42 [84%] patients), infection (six [12%]), and alanine aminotransferase elevations (six [12%]). There was one death during induction in a patient treated with CLIA-venetoclax plus a FLT3 inhibitor. Two patients died of infectious complications while in complete response in consolidation cycles, both of whom had FLT3-mutated acute myeloid leukaemia and were receiving combined therapy with a FLT3 inhibitor. No deaths were deemed to be treatment related.
Interpretation: Venetoclax added to CLIA was safe and active in patients with newly diagnosed acute myeloid leukaemia or high-risk myelodysplastic syndrome, producing high rates of durable MRD-negative remissions and encouraging event-free survival and overall survival.
Funding: MD Anderson Cancer Center.
Competing Interests: Declaration of interests TMK reports grants from Amgen, Ascentage, Astellas, AstraZeneca, BMS, Cellenkos, Pulmotech, Cyclacel, Glycomimetics, Incyte, and Genfleet; personal fees from Agios, Cure, Daichi Sankyo, Genzyme, Liberum, Novartis, and Sanofi-Aventis; and grants and personal fees from Abbvie, Genetech, Jazz Pharmaceuticals, and Pfizer. GB reports grants from Oncoceutics, Xbiotech USA, Arvina, Polaris, AstraZeneca, BMS, Cyclacel, GlaxoSmithKline, Janssen, Incyte, and AbbVie; personal fees from Argenx, PTC Therapeutics, BioTheryX, Nkarta, Treadwell Therapeutics, and Curio Science; and grants and personal fees from FTC Therapeutics, BioLine Rx, and Novartis. MY reports research support from Daiichi-Sankyo and Pfizer. CDD reports research support from Calithera, Cleave, Jazz, and Loxo; personal fees from Aprea, Cleave, Novartis, Takeda, and Notable Labs; and grants and personal fees from Abbvie, Agios, ImmuneOnc, Celgene/BMS, and Daiichi Sankyo. ND reports research support from NOHLA, Glycomimetics, Sobi, Hanmi, Forty Seven, Newave, Trovagene, Covance, FATE, and Novimmune; personal fees from Otsuka, Celgene, Incyte, Jazz Pharmaceuticals, Immunogen, Agios, Syndax, and Trillium; and grants and personal fees from Pfizer, BMS, Novartis, Daiichi-Sankyo, Karyopharm, Incyte, Abbvie, Genetech, Immunogen, Astellas, Servier, Gilead, Amgen, and Sunesis. NJ reports grants from Pfizer, Incyte, Aprea Therapeutics, Fate Therapeutics, and Kite; personal fees from Janssen, Beigene, and TG Therapeutics; and grants and personal fees from Pharmacyclics, AbbVie, Genentech, AstraZeneca, BMS, ADC Therapeutics, Cellectis, Adaptive Biotechnologies, Servier, and Precision Biosciences. NP reports grants from Affymetrix, SagerStrong Foundation, Samus Therapeutics, Cellectis, Daiichi Sankyo, and Plexxikon; personal fees from Pacylex Pharmaceuticals, ImmunoGen, BMS, Blueprint Medicines, Incyte, LFB Biotechnologies, Celgene, AbbVie, MustangBio, Roche Diagnostics, DAVA Oncology, Springer Science+Business Media; and grants and personal fees from AbbVie, Stemline Therapeutics, and Novartis. MK reports grants from Ablynx, Agios, Ascentage, AstraZeneca, Rafael Pharmaceutical, and Sanofi; personal fees from Reata Pharmaceutical and Janssen; and grants and personal fees from AbbVie, F Hoffman La-Roche, Stemline Therapeutics, Forty-Seven, and Genetech. In addition, MK has a patent US7795305B2 CDDO-compounds and combination therapies with royalties paid to Reata Pharmaceuticals, a patent combination therapy with a mutant IDH1 Inhibitor and a BCL2 licensed to Eli Lilly, and a patent 62/993166 combination of a MCL1 inhibitor and midostaurin, uses and pharmaceutical compositions thereof pending to Novartis. FR reports grants from AbbVie. HMK reports grants from Ascentage, BMS, Daiichi-Sankyo, Immunogen, Jazz Pharmaceuticals, and Sanofi; personal fees from Actinium, Adaptive Biotechnologies, Apptitude Health, BioAscend, Daiichi-Sankyo, Delta Fly, Janssen Global, Novartis, Oxford Biomedical, and Takeda Oncology; and grants and personal fees from Abbvie, Amgen, and Pfizer. All other authors report no competing interests.
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