Patients with acute myeloid leukemia (AML) ineligible for intensive chemotherapy (IC) have limited treatment options. The phase 3 ENHANCE-3 study aimed to determine whether magrolimab (magrolimab arm) was superior to placebo (control arm) when either was combined with venetoclax and azacitidine. Adults with previously untreated AML who were ineligible for IC were randomized to receive magrolimab (1 mg/kg on days 1 and 4, 15 mg/kg on day 8, 30 mg/kg on days 11 and 15, then weekly for 5 weeks, and then every 2 weeks) or placebo, venetoclax (100 mg on day 1, 200 mg on day 2, and 400 mg daily thereafter), and azacitidine (75 mg/m2 days 1-7) in 28-day cycles. The primary end point was overall survival (OS); key secondary end points included complete remission (CR) rate and safety. After randomization of 378 patients, the trial was stopped at a prespecified interim analysis owing to futility. At final analysis, with median follow-up of 7.6 months (magrolimab arm) vs 7.4 months (control arm), median OS was 10.7 vs 14.1 months (hazard ratio, 1.178; 95% confidence interval, 0.848-1.637). The CR rate within 6 cycles was 41.3% vs 46.0%. Addition of magrolimab to venetoclax and azacitidine resulted in more fatal adverse events (19.0% vs 11.4%), primarily driven by grade 5 infections (11.1% vs 6.5%) and respiratory events (2.6% vs 0%). There were similar incidences of any-grade infections, febrile neutropenia, and neutropenia between arms. These results highlight the difficulty in improving outcomes for patients with AML who were ineligible for IC. This trial was registered at www.clinicaltrials.gov as #NCT05079230.

Department of Hematology Erasmus MC Cancer Institute Rotterdam The Netherlands

Department of Hematology Fakultní Nemocnice Královské Vinohrady Prague Czech Republic

Department of Hematology Hôpital Saint Louis Paris France

Department of Hematology Hospital Clinic de Barcelona Barcelona Spain

Department of Hematology Hospital Universitario La Fe Valencia Spain

Department of Hematology Universitair Medisch Centrum Groningen Groningen The Netherlands

Department of Internal Medicine 3 Ulm University Hospital Ulm Germany

Department of Internal Medicine Hematology and Oncology Faculty Hospital Brno and Masaryk University Brno Czech Republic

Department of Internal Medicine National Taiwan University Hospital Taipei Taiwan

Department of Leukemia MD Anderson Cancer Center Houston TX

Department of Medicine Centre Hospitalier Universitaire de Liège Site Sart Tilman Liège Belgium

Division of Hematology and Oncology Froedtert and Medical College of Wisconsin Milwaukee WI

Division of Hematology Oncology Rhode Island Hospital Providence RI

Gilead Sciences Inc Foster City CA

Hematology Department Hôpitaux Universitaires Henri Mondor Créteil France

Hematology Department Hospital Universitario Quirónsalud Madrid and Universidad Europea de Madrid Madrid Spain

IRCCS Azienda Ospedaliero Universitaria di Bologna Istituto di Ematologia Seràgnoli Bologna Italy

MRC Molecular Haematology Unit Weatherall Institute of Molecular Medicine Radcliffe Department of Medicine Oxford University Hospitals NHS Foundation Trust Oxford United Kingdom

Blood. 2025 Jul 31;146(5):527-528. doi: 10.1182/blood.2025029850. PubMed

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ClinicalTrials.gov
NCT05079230