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The First-in-Class Anti-CD47 Antibody Magrolimab + Azacitidine Is Well-Tolerated and Effective in Patients with AML

2020 Year in Review - AML - Leukemia

CD47, a macrophage immune checkpoint, signals macrophages to refrain from phagocytosis of cancerous cells. Magrolimab is an antibody that blocks CD47, thus inducing macrophage-mediated tumor phagocytosis and the elimination of leukemia stem cells. Azacitidine works with magrolimab to enhance phagocytosis. This phase 1b study aimed to determine the safety and efficacy of magrolimab plus azacitidine in patients with untreated acute myeloid leukemia (AML), including those with TP53 mutations, who are unfit for intensive chemotherapy.

Patients received magrolimab plus azacitidine. A magrolimab priming/intrapatient dose-escalation regimen (1-30 mg/kg every week, and then every 2 weeks in cycle 3+) was used, and azacitidine was dosed at 75 mg/m2 on days 1 to 7. European Leukemia Net 2017 response criteria were used to assess efficacy.

The median age of the 29 enrolled patients was 74 years (range, 60-89 years). Of the population, 7% had intermediate cytogenetic risk and 72% had poor risk (21% unknown or missing). In terms of subtypes, 66% of patients had AML with myelodysplasia-related changes, 10% had therapy-related AML, and 45% had a TP53 mutation. Safety and tolerability for the combination therapy were similar to those of azacitidine alone. Common treatment-related adverse events (AEs) included anemia (31%), neutropenia (28%), fatigue (24%), thrombocytopenia (17%), and nausea (17%). One patient experienced treatment-related febrile neutropenia; another patient discontinued as a result of an AE. Anemia was mostly mild and transient. The priming dose regimen helped to mitigate anemia, and many patients were able to decrease their red blood cell (RBC) transfusion requirements while on therapy. Hemoglobin decreased by a mean of 0.4 g/dL at the first dose of treatment. In patients who were dependent on RBC transfusions, 64% became transfusion independent. The population evaluable for efficacy included 25 patients, 16 of whom had an objective response. Complete response (CR), CR with incomplete hematologic recovery (CRi), partial response, morphologic leukemia-free state, and stable disease (SD) were achieved by 40%, 16%, 4%, 4%, and 32% of patients, respectively; 4% of patients had progressive disease (PD). It was determined that 50% of patients with CR/CRi also achieved minimal residual disease (MRD)-negative status, and cytogenetic CRs were observed in 50% of evaluable responding patients. With the combination therapy, the time to response was rapid, at a median of 1.9 months; this is faster than is typically achieved with azacitidine alone. Median duration of response and median overall survival (OS) have not been reached.

In the population with mutated TP53, the CR/CRi rate was 75%, with CR, CRi, SD, and PD achieved by 42%, 33%, 17%, and 8% of patients, respectively. Cytogenetic CR was achieved in 50% of patients, with 44% of patients in CR/CRi also achieving MRD negativity. Median duration of response and median OS have not been reached, but 100% of responding patients continued to respond at the 6-month landmark time point. Estimated OS at 6 months was 91%.

In conclusion, adding magrolimab, a novel macrophage-targeting immunotherapy, to azacitidine is well-tolerated and effective for treating patients with AML who are unfit for chemotherapy. Patients with TP53 mutations typically have a poor prognosis and lack effective therapies. Therefore, the efficacy results in this population are particularly encouraging. Enrollment of additional patients continues.

Reference

David S, Al Malki M, Asch A, et al. The First-in-Class Anti-CD47 Antibody Magrolimab Combined with Azacitidine Is Well-Tolerated and Effective in AML Patients: Phase 1B Results. Presented at: 25th European Hematology Association Congress Virtual; June 11-21, 2020. Abstract S144

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