Phase 3 ENHANCE Trial: Magrolimab Adds Toxicity, Not Benefit, in MDS

The phase 3 ENHANCE trial (NCT04313881) has found that adding magrolimab to azacitidine (Vidaza) did not improve complete remission rates or overall survival in patients with untreated higher-risk myelodysplastic syndromes (MDS) and was associated with more frequent severe and fatal adverse events than azacitidine alone, according to results published in the Journal of Clinical Oncology.¹

The randomized, double-blind, multicenter trial enrolled 539 treatment-naive patients with intermediate-, high-, or very-high-risk MDS by Revised International Prognostic Scoring System criteria across 116 sites in 18 countries. Patients were randomly assigned 1:1 to receive magrolimab, an antibody targeting the antiphagocytic signal CD47, plus azacitidine (n = 268), or placebo plus azacitidine (n = 271). Dual primary end points were complete remission (CR) rate and overall survival (OS).

Primary End Point Analysis

At final analysis, CR rates were 21.3% with magrolimab plus azacitidine vs 23.6% with placebo plus azacitidine (OR, 0.876; 95% CI, 0.585-1.312; P =.522). Median OS was 15.9 months vs 18.6 months, respectively (HR, 1.203; 95% CI, 0.947-1.528; P =.130). The study was terminated after a prespecified interim analysis met a nonbinding futility boundary for overall survival.

Secondary end points were consistent with the primary results. Objective response rate was 53.7% with magrolimab vs 58.7% with placebo, and median event-free and progression-free survival did not differ meaningfully between arms. In a subgroup analysis of patients with TP53-mutated disease, CR rates were numerically lower with magrolimab than placebo (17.7% vs 32.8%; OR, 0.441; 95% CI, 0.203-0.960; P =.038), and there was a trend toward inferior OS with magrolimab in this subgroup, particularly among patients who proceeded to allogeneic stem-cell transplantation. Fewer patients in the magrolimab arm underwent transplantation overall (20.5% vs 35.1%), which the authors suggested may reflect reduced treatment tolerability rather than a treatment effect on transplant eligibility.

Safety Findings

Grade 3 or higher treatment-emergent adverse events occurred in 92.8% of patients receiving magrolimab plus azacitidine vs 79.2% receiving placebo plus azacitidine. Serious adverse events (71.9% vs 51.5%), adverse events leading to treatment discontinuation (24.0% vs 12.1%), and fatal adverse events (15.2% v 9.8%) were all more common with magrolimab. The most frequent grade 3 or higher toxicities in both arms were hematologic, including neutropenia, anemia, and thrombocytopenia, with anemia notably more common with magrolimab (42.6% vs 21.2%), consistent with the drug's known on-target effect on aging red blood cells. Infections were the leading cause of fatal adverse events in both arms.

Partway through enrollment, after 388 patients had been randomly assigned, investigators implemented revised anemia management guidance requiring hemoglobin thresholds and monitoring after initial magrolimab or placebo doses. This reduced treatment discontinuations in both arms, though safety differences between arms persisted.

The authors concluded that magrolimab did not improve the efficacy of azacitidine in higher-risk MDS and was associated with a less favorable safety profile, including in patients with TP53-mutated disease, a population with substantial unmet need. They noted that an exploratory, treatment-independent association between complete remission or minimal residual disease–negative response and improved overall survival may inform future MDS trial design.

The findings add to a broader pattern in recent higher-risk MDS trials, including the phase 3 VERONA study of venetoclax (Venclexta) plus azacitidine, which also did not demonstrate a survival or remission benefit over azacitidine alone.² The authors noted that other anti-CD47 strategies currently in development may help address the on-target toxicities observed with magrolimab.

REFERENCES

1. Sallman DA, Garcia-Manero G, Daver N, et al. Magrolimab Plus Azacitidine Versus Placebo Plus Azacitidine in Patients With Untreated Higher-Risk Myelodysplastic Syndromes: The Phase III ENHANCE Study. J Clin Oncol. 0, JCO-25-00617. doi:10.1200/JCO-25-00617

2. Garcia JS, Platzbecker U, Odenike O, et al. Efficacy and safety of venetoclax plus azacitidine for patients with treatment-naive high-risk myelodysplastic syndromes. Blood. 2025 Mar 13;145(11):1126-1135. doi: 10.1182/blood.2024025464. PMID: 39652823; PMCID: PMC11923426.