Magrolimab in Combination With Azacitidine in Patients With Higher-Risk Myelodysplastic Syndromes: Final Results of a Phase Ib Study

Abstract

PURPOSE Magrolimab is a monoclonal antibody that blocks cluster of differentiation 47, a don't-eat-me signal overexpressed on cancer cells. Cluster of differentiation 47 blockade by magrolimab promotes macrophage-mediated phagocytosis of tumor cells and is synergistic with azacitidine, which increases expression of eat-me signals. We report final phase Ib data in patients with untreated higher-risk myelodysplastic syndromes (MDS) treated with magrolimab and azacitidine ( NCT03248479 ). PATIENTS AND METHODS Patients with previously untreated Revised International Prognostic Scoring System intermediate-/high-/very high-risk MDS received magrolimab intravenously as a priming dose (1 mg/kg) followed by ramp-up to a 30 mg/kg once‐weekly or once‐every-2-week maintenance dose. Azacitidine 75 mg/m2 was administered intravenously/subcutaneously once daily on days 1-7 of each 28-day cycle. Primary end points were safety/tolerability and complete remission (CR) rate. RESULTS Ninety-five patients were treated. Revised International Prognostic Scoring System risk was intermediate/high/very high in 27%, 52%, and 21%, respectively. Fifty-nine (62%) had poor-risk cytogenetics and 25 (26%) had TP53 mutation. The most common treatment-emergent adverse effects included constipation (68%), thrombocytopenia (55%), and anemia (52%). Median hemoglobin change from baseline to first postdose assessment was −0.7 g/dL (range: −3.1 to +2.4). CR rate and overall response rate were 33% and 75%, respectively. Median time to response, duration of CR, duration of overall response, and progression-free survival were 1.9, 11.1, 9.8, and 11.6 months, respectively. Median overall survival (OS) was not reached with 17.1-month follow-up. In TP53-mutant patients, 40% achieved CR with median OS of 16.3 months. Thirty-four patients (36%) had allogeneic stem-cell transplant with 77% 2-year OS. CONCLUSION Magrolimab + azacitidine was well tolerated with promising efficacy in patients with untreated higher-risk MDS, including those with TP53 mutations. A phase III trial of magrolimab/placebo + azacitidine is ongoing (ENHANCE: NCT04313881 ).

An Overview of Targeted Therapies in Acute Myeloid Leukemia

“…Sixty-two percent of patients had poor-risk cytogenetics, and 26% had a TP53 mutation. 149 The combination was well-tolerated, the CR rate was 33%, and the duration of the overall response was 9.8 months. Median OS was not reached with a median 17.1-month follow-up.…”

Overview of the Management of Higher-Risk Myelodysplastic Syndromes

“…Thirty-one percent of the evaluable OR patients with abnormal cytogenetics at baseline achieved a cytogenetic CR. Twelve-month OS and 24-month OS have been reported to be 75% and 52%, respectively 40,41 . Molecular remissions were also notable, with all patients with a TP53 mutation having an undetectable whole exome sequencing test by the fifth cycle.…”

“…Twelve-month OS and 24-month OS have been reported to be 75% and 52%, respectively. 40,41 Molecular remissions were also notable, with all patients with a TP53 mutation having an undetectable whole exome sequencing test by the fifth cycle. Survival outcomes have been reported to be favorable for both TP53 mutant and wild subtypes.…”

Myelodysplastic syndromes: 2023 update on diagnosis, risk‐stratification, and management

“…The second combination of significant interest is the combination of azacitidine with an antibody against CD47 known as magrolimab 159 . In recently published study 160 of 95 patients the combination resulted in an ORR of 75% and a CR of 33 and the median survival was not reached. A randomized registration trial known as the Enhance trial has also been completed (NCT0441748).…”