December 2023

Leah Lawrence

Patients with previously untreated acute myeloid leukemia (AML) who were not candidates for intensive chemotherapy experienced disease response when treated with a combination of azacitidine and magrolimab, a first-in-class humanized monoclonal antibody against cluster of differentiation 47, according to the results of a phase Ib study published in Journal of Clinical Oncology (JCO).¹

About one-third of patients overall and about one-third of those with TP53-mutated disease experienced disease response.

“Efficacy data from this phase Ib study support the magrolimab/azacitidine synergy observed in preclinical studies,” wrote researchers, led by Naval G. Daver, MD, of the University of Texas MD Anderson Cancer Center. “Magrolimab/azacitidine showed encouraging efficacy in TP53-mutant AML and preliminary activity in a small subset of patients with TP53 wild-type AML who were enrolled during the initial study period.”

The study enrolled 87 patients with previously untreated AML; 82.8% of these patients had TP53-mutant AML. Of the patients with TP53-mutant disease, the majority (79.2%) had European Leukemia Net 2017 adverse-risk cytogenetics.

All patients received intravenous magrolimab 1 mg/kg on days one and four, followed by 15 mg/kg on day eight and 30 mg/kg once weekly or every two weeks as maintenance. Azacitidine 75 mg/m² was given either intravenously or subcutaneously once daily on days one to seven of each 28-day cycle.

Among patients with TP53-mutant disease, the overall response rate was 47.2% (95% CI 35.3-59.3). The complete response (CR) rate was 31.9% (95% CI 21.4-44.0). Additionally, 40.3% of patients had CR/CR with incomplete blood count recovery (95% CI 28.9-52.5), and 5.6% of patients had partial response. The median duration of CR was 7.6 months. Median event-free survival was 3.7 months, and overall survival (OS) was 9.8 months.

For patients with TP53 wild-type disease, the CR rate was 33.3%, with a median duration of CR of 31.3 months. Median OS was 18.9 months. Four of the five patients who achieved CR were negative for measurable residual disease.

Patients received a median of four cycles of treatment. Gastrointestinal toxicity occurred in about half of patients; these included constipation (49.4%), nausea (49.4%), and diarrhea (48.3%). About one-third (34.5%) of patients experienced anemia, which the researchers said was a known side effect of magrolimab because of its mechanism of action. The median hemoglobin (Hb) change from baseline to first post-dose assessment was -0.9 g/dL.

“A requirement for adequate pretreatment Hb value and a repeat Hb check after initial infusions of magrolimab have been incorporated into current magrolimab trials to help mitigate observed initial drops in Hb,” the researchers wrote.

Overall dose reductions occurred in 1.1% of patients for magrolimab and 10.3% of patients for azacitidine, “suggesting that the regimen may be easier to deliver in continuous cycles without need for frequent dose/duration modifications.”

Limitations of the study include that it was a single-arm, non-randomized study conducted at larger academic centers, the lack of centralized serial TP53 assessments via next-generation sequencing, and the inability of the small sample size to delineate efficacy and impact in individual molecular and cytogenetic subgroups. Researchers also noted that their findings were limited by the study’s inclusion of predominately white patients (86.2%).

In the relevance section of the study, JCO Associate Editor Charles F. Craddock, MD, commented, “It will be important to confirm this promising early-phase data relating to tolerability and efficacy of the novel magrolimab/azacitidine combination in adults with de novo AML deemed ineligible for intensive chemotherapy, and the results of ongoing randomized trials are awaited with interest.”

The two ongoing phase-III studies are ENHANCE-2, which will look at magrolimab/azacitidine compared with physician’s choice of venetoclax in combination with azacitidine or intensive chemotherapy in patients with untreated TP53-mutant AML, and ENHANCE-3, which will study magrolimab versus placebo in combination with venetoclax and azacitidine in untreated AML. Recently, Gilead announced discontinuation of the ENHANCE-2 study in AML with TP53 mutations.² Based on an ad hoc analysis and following review by an independent data monitoring committee, Gilead concluded that magrolimab is unlikely to demonstrate a survival benefit in AML with TP53 mutations compared with standard of care. There were no new safety signals identified, and the safety profile was comparable between treatment arms.