Magrolimab Plus Azacitidine Fails to Improve Outcomes in Higher-Risk Myelodysplastic Syndromes

Clinical Summary:

• Design/Population: The phase 3 ENHANCE trial compared magrolimab plus azacitidine with azacitidine alone in treatment-naïve patients with intermediate-, high-, or very high-risk myelodysplastic syndromes. 
• Key Outcomes: Magrolimab plus azacitidine did not improve complete remission rates or overall survival compared with azacitidine alone. The combination was also associated with higher rates of grade ≥3 adverse events, serious adverse events, treatment discontinuations, and fatal adverse events.
• Clinical Relevance: These findings do not support the addition of magrolimab to azacitidine as first-line therapy for higher-risk myelodysplastic syndromes and underscore the need for alternative strategies targeting CD47 in this patient population.

Results from the phase 3 ENHANCE trial demonstrated that adding the CD47-targeted antibody magrolimab to azacitidine did not improve efficacy and increased toxicity compared with azacitidine alone in patients with previously untreated higher-risk myelodysplastic syndromes. 

“Without treatment, patients with higher-risk myelodysplastic syndromes have a median overall survival (OS) of <2 years and a high risk of progression to [acute myeloid leukemia],” stated David Sallman, MD, Moffitt Cancer Center, Tampa, Florida, and coauthors. “In a phase Ib study, magrolimab plus azacitidine was well tolerated with promising efficacy in untreated [high-risk myelodysplastic syndromes], and excellent long-term survival in patients who underwent [stem cell transplantation].”

In this double-blind, placebo-controlled trial, 539 patients with treatment-naïve intermediate-, high-, or very high-risk myelodysplastic syndromes were randomized to receive either magrolimab (n = 268) or placebo (n = 271) plus azacitidine. Magrolimab was administered at 1 mg/kg on days 1 and 4, 15 mg/kg on day 8, and 30 mg/kg on days 11 and 15, followed by weekly dosing for 5 doses and maintenance dosing every 2 weeks. Azacitidine was administered at 75 mg/m² daily on days 1 through 7 or days 1 through 5 and 8 through 9 of each 28-day cycle. Dual primary end points were complete remission rate and OS. A key secondary end point was safety. 

At analysis, the complete remission rate was 21.3% in the magrolimab plus azacitidine arm and 23.6% in the placebo plus azacitidine arm (odds ratio, 0.876; 95% confidence interval [CI], 0.585 to 1.312; P = .5218). Median OS was 15.9 months and 18.6 months, respectively (hazard ratio, 1.203; 95% CI, 0.947 to 1.528; P = .1299). 

Grade ≥3 adverse events occurred in 92.8% of patients receiving magrolimab plus azacitidine compared with 79.2% of patients receiving placebo plus azacitidine. Adverse events leading to treatment discontinuation were reported in 24% and 12.1% of patients, respectively. Serious adverse events occurred in 71.9% versus 51.5% of patients, while fatal adverse events were reported in 15.2% and 9.8% of patients, respectively.

“ENHANCE did not meet the primary end points…and showed more frequent severe [adverse events] in patients treated in the [magrolimab plus azacitidine] arm,” concluded Dr Sallman et al. “On-target toxicities, a major challenge, could potentially be mitigated with other anti-CD47 strategies under assessment.”

“The development of therapeutic strategies with the ability to improve outcomes in high-risk [myelodysplastic syndromes] remains a major unmet need,” added Journal of Clinical Oncology associate editor Charles Craddock, MD, University of Warwick, England, United Kingdom. 

Source: 

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. Published online: July 9, 2026. doi: 10.1200/JCO-25-00617