ENHANCE-3 Trial: Evaluating Magrolimab Addition to Venetoclax and Azacitidine in Untreated AML Unfit for Intensive Chemotherapy

Highlight

– The ENHANCE-3 study evaluated the addition of magrolimab, a CD47-blocking antibody, to venetoclax and azacitidine in newly diagnosed AML patients unfit for intensive chemotherapy.
– The trial was terminated early due to futility; magrolimab did not improve overall survival or complete remission rates compared to placebo.
– The magrolimab combination was associated with increased fatal adverse events, primarily grade 5 infections and respiratory complications.
– Results underscore the ongoing challenges in improving therapy outcomes for AML patients ineligible for intensive treatment.

Study Background and Disease Burden

Acute myeloid leukemia (AML) is a heterogeneous hematologic malignancy characterized by clonal proliferation of myeloid precursors leading to impaired hematopoiesis. Intensive chemotherapy (IC) remains the standard frontline approach for eligible patients, but a significant subset of individuals—often older adults or those with comorbidities—are deemed unfit for such intensive regimens. This population suffers from poor prognosis due to limited effective therapies and increased vulnerability to treatment-related toxicities.

Venetoclax, a selective BCL-2 inhibitor, combined with hypomethylating agents like azacitidine, has transformed treatment paradigms for older or unfit AML patients by achieving superior response rates and improved survival relative to azacitidine alone. Nonetheless, outcomes remain suboptimal with substantial relapse rates. Magrolimab is a humanized monoclonal antibody targeting CD47, a “don’t eat me” signal overexpressed on AML cells that inhibits macrophage-mediated phagocytosis. Preclinical rationale suggested that disrupting CD47–SIRPα interaction could augment leukemic cell clearance and enhance the efficacy of venetoclax-azacitidine therapy.

The burden of AML among older and fragile patients with restricted therapeutic options creates an unmet need for novel, tolerable, and efficacious combinations. The ENHANCE-3 phase 3 trial was initiated to evaluate whether incorporation of magrolimab into frontline venetoclax and azacitidine improved clinical outcomes in untreated AML patients ineligible for intensive chemotherapy.

Study Design

ENHANCE-3 was a randomized, double-blind, placebo-controlled phase 3 trial enrolling adults with newly diagnosed AML who were considered unfit for IC based on established criteria including age, performance status, and comorbidities. A total of 378 patients were randomized in a 1:1 ratio to receive either the triplet combination of magrolimab plus venetoclax and azacitidine (magrolimab arm) or placebo plus venetoclax and azacitidine (control arm).

Intervention dosing was as follows: magrolimab was administered intravenously at 1 mg/kg on days 1 and 4, 15 mg/kg on day 8, 30 mg/kg on days 11 and 15 during cycle 1, then weekly for 5 weeks, and subsequently every two weeks thereafter. Venetoclax was dosed orally with ramp-up (100 mg day 1, 200 mg day 2) followed by 400 mg daily from day 3, and azacitidine was given subcutaneously or intravenously at 75 mg/m2 on days 1–7 of each 28-day cycle.

The primary endpoint was overall survival (OS). Key secondary endpoints included rates of complete remission (CR) or CR with incomplete hematologic recovery (CRi) within 6 cycles, duration of response, and safety profiles.

Key Findings

At a preplanned interim analysis, the trial was terminated early due to futility in demonstrating survival benefit of magrolimab addition. The final analysis included 378 randomized patients with median follow-ups of 7.6 months for the magrolimab arm and 7.4 months for the control arm.

Median OS was 10.7 months in the magrolimab-containing arm versus 14.1 months in the placebo arm. This translated into a hazard ratio (HR) of 1.178 (95% confidence interval [CI], 0.848–1.637), indicating no statistically significant survival advantage; in fact, the trend nonsignificantly favored control.

Response rates within the first 6 cycles showed slight differences — complete remission rates were 41.3% for magrolimab plus venetoclax and azacitidine compared with 46.0% for the control arm. These differences were not statistically significant, indicating no improvement in remission induction with magrolimab addition.

Importantly, the safety profile revealed higher rates of fatal adverse events in the magrolimab arm (19.0%) compared with controls (11.4%). Fatal events were predominantly from grade 5 infections (11.1% vs 6.5%) and respiratory complications (2.6% vs 0%). Despite this increase in fatal outcomes, incidences of overall infections, febrile neutropenia, and neutropenia were comparable between arms, suggesting heightened severity rather than frequency.

These results suggest that magrolimab’s addition to venetoclax and azacitidine does not confer meaningful clinical benefit but increases risks of severe adverse events in this patient population.

Expert Commentary

The negative outcome of the ENHANCE-3 study illustrates the complexity of improving treatment outcomes in patients with AML unfit for intensive chemotherapy. While the biological rationale for targeting CD47 was compelling, the anticipated synergy with venetoclax and azacitidine did not translate into survival benefit.

Potential explanations include the immunosuppressive and fragile nature of this AML population, which may exacerbate susceptibility to infections when exposed to additional immunomodulation. Furthermore, optimal patient selection and biomarkers predictive of response to magrolimab remain unclear, possibly diluting measurable efficacy in an unselected population.

The increased incidence of fatal infections and respiratory complications underscore the need to carefully evaluate safety profiles when adding novel agents to established regimens, especially in vulnerable patients.

Ongoing and future investigations may focus on identifying subsets of patients who could benefit from CD47 blockade, exploring alternative combination partners, or refining dosing strategies to mitigate toxicity.

Conclusion

In summary, the ENHANCE-3 phase 3 trial demonstrated that adding magrolimab to the current standard of venetoclax and azacitidine therapy does not improve overall survival or remission rates in newly diagnosed AML patients who are ineligible for intensive chemotherapy. Moreover, the combination increases fatal adverse events, particularly infections and respiratory complications.

These findings highlight the persistent challenges in developing effective, safe therapies for this high-risk AML population. The results emphasize the importance of rigorous randomized studies to validate novel treatment concepts and caution against extrapolating positive early-phase signals without definitive efficacy and safety data.

Further research is necessary to explore alternative therapeutic avenues, improve patient stratification, and enhance supportive care to optimize outcomes for AML patients who cannot tolerate intensive chemotherapy.

References

1. Daver N, Vyas P, Huls G, et al. The ENHANCE-3 study: venetoclax and azacitidine plus magrolimab or placebo for untreated AML unfit for intensive therapy. Blood. 2025 Jul 31;146(5):601-611. doi: 10.1182/blood.2024027506. PMID: 40233321.

2. DiNardo CD, Jonas BA, Pullarkat V, et al. Azacitidine and Venetoclax in Previously Untreated Acute Myeloid Leukemia. N Engl J Med. 2020;383(7):617-629.

3. Advani R, Flinn IW, Popplewell L, et al. CD47 Blockade by Hu5F9-G4 and Rituximab in Non-Hodgkin’s Lymphoma. N Engl J Med. 2018;379(18):1711-1721.