The phase III ENHANCE trial, published in the Journal of Clinical Oncology, found that adding the anti-CD47 antibody magrolimab to azacitidine did not improve complete remission or overall survival in 539 previously untreated patients with higher-risk myelodysplastic neoplasms (MDS). The combination caused more toxicity and treatment discontinuations, and fewer patients reached allogeneic stem cell transplantation. Earlier phase Ib results, particularly in TP53-mutated disease, were not confirmed.
Background: Why CD47 Blockade Was Tested
Allogeneic transplantation is the only established potentially curative option in higher-risk MDS, but many patients are ineligible because of age or comorbidities. For them, hypomethylating agents such as azacitidine remain standard, yet CR occurs in a minority and responses are often short. In TP53-mutated MDS, median survival with azacitidine-based treatment is generally about one year or less.
Magrolimab targets CD47, which binds SIRPα on macrophages and signals against phagocytosis, allowing malignant cells to evade immune clearance. Preclinical work suggested azacitidine could enhance CD47 blockade. In a phase Ib study of untreated higher-risk MDS, magrolimab plus azacitidine produced a CR rate of 33% and a transplantation rate of 36%.
Trial Design
ENHANCE (NCT04313881) was a randomized, double-blind, placebo-controlled study at 116 centers in 18 countries. It enrolled patients with intermediate-, high- or very-high-risk MDS by the Revised International Prognostic Scoring System who were not immediately eligible for transplantation. Patients received magrolimab plus azacitidine (268) or placebo plus azacitidine (271).
Azacitidine was given at 75 mg/m² for seven days per 28-day cycle, with a planned minimum of six cycles. The dual primary endpoints were CR rate by 2006 International Working Group criteria and OS. Median age was 70 years. The magrolimab group had numerically more patients with TP53 mutations, baseline transfusion dependence and transplantation ineligibility.
Efficacy: No Benefit on Any Major Endpoint
The trial stopped after the second interim analysis crossed the prespecified futility boundary for OS. At final analysis, the CR rate was 21.3% with magrolimab versus 23.6% with azacitidine alone. Median OS was 15.9 versus 18.6 months (hazard ratio 1.20). The trial did not show that magrolimab increased mortality.
Secondary endpoints matched the primary results:
- Overall response: 53.7% versus 58.7%.
- Median progression-free survival: about nine months in both groups.
- Eight-week transfusion independence among patients transfusion-dependent at baseline: 27.9% versus 35.2%.
- Progression to AML: no significant reduction.
TP53-Mutated MDS
Among patients with locally assessed TP53 mutations, CR occurred in 17.7% with magrolimab versus 32.8% with azacitidine alone, and median OS was 10.1 versus 10.4 months. These subgroup analyses were not adjusted for multiple comparisons. Central assessment confirmed the adverse prognosis of TP53 mutation: median OS was about 10-12 months with mutation versus 30-31 months without.
The investigators saw a trend toward inferior survival with magrolimab in TP53-mutated patients, particularly those who proceeded to transplantation. The study wasn’t designed to test treatment effect in this subgroup, and baseline imbalances limit interpretation.
Safety: More Severe Toxicity and Discontinuations
Adverse events were more frequent with magrolimab plus azacitidine than with azacitidine alone:
- Grade 3 or higher adverse events: 92.8% versus 79.2%
- Serious adverse events: 71.9% versus 51.5%
- Fatal treatment-emergent adverse events: 15.2% versus 9.8%
- Discontinuation for adverse events: 24.0% versus 12.1%
Hematologic toxicity drove much of the difference. Grade 3 or higher anemia occurred in 42.6% versus 21.2%, and severe neutropenia and thrombocytopenia were also more frequent. Pneumonia and sepsis were more common with the combination, and fatal infections occurred in 8.0% versus 4.5%.
Anemia is an on-target effect, since CD47 is also expressed on normal red blood cells. Events grouped as anemia and transient extravascular hemolysis occurred in 58.6% with magrolimab versus 34.5% with placebo, and these aren’t confirmed hemolysis in every patient. About two years into the trial, the protocol required hemoglobin of at least 9 g/dL before the first two doses, with transfusion support and postinfusion monitoring when needed.
The changes reduced adverse event-related discontinuations but not the between-group difference in anemia. The numerical OS gap narrowed afterward, but this exploratory observation comes from a smaller population with limited follow-up, and no significant survival advantage emerged.
Transplantation: 20.5% Versus 35.1%
Only 20.5% of patients on magrolimab plus azacitidine underwent allogeneic transplantation, versus 35.1% on azacitidine alone. The investigators suggested that cytopenias, infections and discontinuations left fewer patients fit enough to proceed.
Transplantation eligibility and TP53 status were not fully balanced and transplantation was not a randomized endpoint. Exploratory analyses linked transplantation to improved OS, but transplanted patients are a selected group.
MRD: Negative Response Tracked With Survival
MRD-negative response rates were nearly identical: 21.6% with magrolimab versus 22.5% with azacitidine alone. Within both arms, patients with MRD-negative response lived longer. In time-dependent analysis, MRD-negative response was associated with an HR for death of 0.46, and CR with an HR of 0.39. The authors describe these as among the first randomized phase III data supporting the prognostic value of MRD-negative response in higher-risk MDS.
MRD negativity here marks favorable outcome in both arms and does not indicate a magrolimab effect. Assay standardization, thresholds and the link between MRD clearance and treatment decisions remain unsettled in MDS, so the data support MRD assessment in future trials but not MRD-guided treatment.
Why Phase III Differed From Phase Ib
The phase Ib study was smaller and uncontrolled, so treatment effect couldn’t be separated from patient selection. ENHANCE enrolled a larger, more heterogeneous population with many TP53-mutated patients. TP53 status was not a stratification factor, and the magrolimab group carried more adverse baseline features.
These imbalances may affect subgroup comparisons but don’t account for the null primary endpoints or the consistent excess toxicity. The investigators also point to on-target toxicity limiting treatment delivery, a particular problem when several azacitidine cycles are often needed before response.
Implications for Future Trials
ENHANCE adds to a series of failed phase III azacitidine combinations in higher-risk MDS. The investigators cite VERONA, in which venetoclax plus azacitidine did not significantly improve OS or CR rates. Future studies may need finer molecular stratification, particularly in TP53-mutated disease, and endpoints that capture dose intensity and transplantation access, which response rates alone miss. The investigators suggest pivotal trials add early stopping rules for excess toxicity or mortality alongside futility monitoring.
The results don’t invalidate CD47 as a target, but they provide no evidence that magrolimab plus azacitidine benefits untreated higher-risk MDS. Effective treatment for TP53-mutated disease remains an unmet need.
