Magrolimab plus azacitidine vs physician’s choice for untreated TP53 -mutated acute myeloid leukemia: the ENHANCE-2 study
Open accessAbstract
Patients with TP53-mutated acute myeloid leukemia (AML) have an extremely poor prognosis, necessitating new treatments. The global, randomized, phase 3 ENHANCE-2 trial evaluated the anti-CD47 monoclonal antibody magrolimab plus azacitidine (Magro/Aza) for previously untreated TP53-mutated AML. Patients determined ineligible for intensive therapy were randomized to receive Magro/Aza or venetoclax plus Aza (Ven/Aza); those eligible for intensive therapy were randomized to receive Magro/Aza or 7+3 induction chemotherapy. The primary end point was overall survival (OS) in the nonintensive arm. At interim analysis, nonintensive-arm OS hazard ratio (HR) between treatment groups was 1.191 (95% confidence interval [CI], 0.744-1.906), meeting the study’s definition for futility and resulting in study termination. At final analysis, median OS was 4.4 vs 6.6 months (HR, 1.132; 95% CI, 0.783-1.637; P = .5070) in the nonintensive arm (n = 205) and 7.3 vs 11.1 months (HR, 1.434; 95% CI, 0.635-3.239; P = .3798) in the intensive arm (n = 52) between Magro/Aza and control groups, respectively. Incidences of grade ≥3 adverse events were similar across Magro/Aza and control groups (nonintensive, n = 194: 96.9% and 95.9%; intensive, n = 50: 92.6% and 95.7%), including grade ≥3 anemia (nonintensive: 27.1% and 23.5%; intensive: 25.9% and 21.7%). Grade ≥3 infections were observed in 50.0% and 53.1% of patients in the nonintensive arm and 44.4% and 65.2% of intensive-arm patients. ENHANCE-2 did not meet its primary end point of OS in TP53-mutated AML but provides important data informing future studies in this challenging population. This trial was registered at www.clinicaltrials.gov as #NCT04778397.
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Phase 3 ENHANCE and ENHANCE-2 studies were closed for futility with lower OS in combination cohorts.
“However, Phase 3 ENHANCE (HR‐MDS) and ENHANCE‐2 studies (mTP53 AML) were closed for futility with lower OS observed in the combination cohorts.”
From Long‐term follow‐up and combined Phase 2 results of eprenetapopt and azacitidine in patients with <i>TP53</i> mutant MDS/AML (2025) · cites this paper as [41]
The Results > Efficacy section reports that ENHANCE-2 was terminated after an interim futility analysis and that median overall survival was lower with magrolimab plus azacitidine than with the comparator. The cited paper does not establish that the separate ENHANCE study in high-risk MDS was also closed for futility with lower overall survival in its combination cohort; searches for that study found no passage addressing its outcome. Page numbers were not provided in our copy. (LLM, conf=0.86)
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“40,41 In m TP53 mutant MDS with HMA, the CR rate is ~20% with a median OS of less than 12 months.”
Self-citation
- Authors
- Zeidner, J. F., Sallman, D. A., Récher, C., Daver, N. G., Leung, A. Y. H., Hiwase, D. K., Subklewe, M., Pabst, T., Montesinos, P., Larson, R. A., Wilde, L., Enjeti, A. K., Kawashima, I., Papayannidis, C., O’Nions, J., Johnson, L., Dong, M., Huang, J., Bagheri, T., Hacohen Kleiman, G., Lee, C., & Vyas, P.
- Affiliations
- University of North Carolina at Chapel Hill (US)
- Moffitt Cancer Center (US)
- Université Toulouse III - Paul Sabatier (FR)
- The University of Texas MD Anderson Cancer Center (US)
- Queen Mary Hospital (CN)
- Royal Adelaide Hospital (AU)
- LMU Klinikum (DE)
- University Hospital of Bern (CH)
- Universitat de València (ES)
- University of Chicago (US)
- Thomas Jefferson University (US)
- Calvary Mater Newcastle Hospital (AU)
- University of Yamanashi Hospital (JP)
- Istituto di Ematologia di Bologna (IT)
- National Health Service (GB)
- Gilead Sciences (United States) (US)
- 17Gilead Sciences, Inc, Foster City, CA
- John Radcliffe Hospital (GB)
- Corresponding author
- Zeidner, Joshua F.
- ORCID
- Venue
- Blood
- Publisher
- American Society of Hematology
- Published
- 2025-07-31
- Volume
- 146
- Issue
- 5
- Pages
- 590-600
- ISSN
- 0006-4971 (ISSN-L)
- 1528-0020
- PMC
- PMC12824667
- OpenAlex
- W4407953944
- Cited by
- 76
- References
- 19
- Citations by year
- 2026: 48 · 2025: 28
- FWCI
- 56.16
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- cc-by-nc-nd
- Locations
- Blood (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- PubMed Central (publishedVersion, cc-by-nc-nd)
- Open Access CRIS of the University of Bern
- Topics
- Health Sciences › Medicine › Hematology › Acute Myeloid Leukemia Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Retinoids in leukemia and cellular processes
- Health Sciences › Medicine › Pharmacology › Flavonoids in Medical Research
- Keywords
- magrolimab, azacitidine, anti-CD47 monoclonal antibody, venetoclax, 7+3 induction chemotherapy, overall survival, treatment-related adverse events, anemia, infection, allogeneic stem cell transplantation
- MeSH terms
- Adult, Aged, Aged, 80 and over, Antineoplastic Combined Chemotherapy Protocols, Azacitidine, Female, Humans, Male, Middle Aged, Mutation, Sulfonamides, Leukemia, Myeloid, Acute, Tumor Suppressor Protein p53, Bridged Bicyclo Compounds, Heterocyclic, Antibodies, Monoclonal, Humanized
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