ENHANCE

Background

Phase 1b, single-arm, open-label study. 95 patients with previously untreated IPSS-R Intermediate (27%), High (52%), or Very High (21%) risk MDS. 62% had poor-risk cytogenetics; 26% had TP53 mutations. Magrolimab is a monoclonal antibody blocking CD47 (the "don't-eat-me" signal), promoting macrophage-mediated phagocytosis of tumor cells; azacitidine synergizes by upregulating "eat-me" signals. Note: the subsequent phase 3 ENHANCE trial (NCT04313881) was terminated in July 2023 without meeting its primary endpoint.

Interventions and follow up

Regimen: Magrolimab 1 mg/kg IV priming dose then escalation to 30 mg/kg weekly × 8 weeks, then q2wk + azacitidine 75 mg/m² SC/IV days 1–7 of each 28-day cycle
Primary endpoint: CR rate (IWG 2006) and safety in untreated higher-risk MDS
mFollow up: 17.1 months

Results

CR rate: 33%
ORR (CR + PR + marrow CR + HI): 75%
Median time to response: 1.9 months
Median duration of CR: 11.1 months
Median duration of overall response: 9.8 months
Median PFS: 11.6 months
Median OS: Not reached at 17.1-month follow-up
TP53-mutant patients — CR rate: 40%; median OS 16.3 months
Allo-SCT rate: 36%; 2-year OS post-transplant 77%

Adverse events

Hematologic: thrombocytopenia 55%, anemia 52% (any grade); median Hgb change from baseline to first post-dose assessment –0.7 g/dL (range –3.1 to +2.4)
Other: constipation 68% (most common any-grade AE); anemia from anti-CD47 opsonization of RBCs was a mechanistic concern, manageable with the priming dosing strategy

Conclusions

Magrolimab + azacitidine demonstrated promising efficacy in untreated HR-MDS, with a 33% CR rate and 75% ORR including encouraging activity in TP53-mutant disease — a high-risk subset with poor outcomes on HMA monotherapy. The safety profile was manageable, supporting progression to phase 3.

Key Limitations

Single-arm, non-randomized phase 1b design without a control arm precludes comparison to HMA monotherapy. Modest sample size (n=95) and limited follow-up (17.1 months) constrain durability and OS estimates. The encouraging TP53-mutant signal was not confirmed: the confirmatory phase 3 ENHANCE trial was terminated early in 2023 for futility, illustrating the limits of single-arm efficacy signals. Anti-CD47 anemia requires the priming/maintenance dosing strategy.

Clinical Context

This phase 1b study generated the rationale for the phase 3 ENHANCE program in frontline HR-MDS. Despite promising early signals, the phase 3 trial was halted for futility in 2023 and magrolimab development in MDS/AML was subsequently discontinued. Azacitidine monotherapy remains the standard HMA backbone in transplant-ineligible HR-MDS per ELN/ESMO guidance; CD47-targeting therapy is not approved for MDS. The trajectory underscores the need for randomized confirmation of single-arm CR-rate signals.

References