Magrolimab Plus Azacitidine Elicits Manageable Anemia in HR-MDS

James Y. Chen

Magrolimab plus azacitidine (Vidaza), at priming and maintenance doses, enables manageable anemia in patients with higher-risk myelodysplastic syndrome (HR-MDS) and acute myeloid leukemia (AML), according to results from a prospective phase 1 study (NCT03248479) that were presented at the 2022 ASCO Annual Meeting.

“Combination treatment of magrolimab with azacitidine resulted in a manageable anemia that correlated with rapid, near-complete loss of CD47 from [red blood cells (RBCs)], but not [white blood cells (WBCs)],” lead study author James Y. Chen, a clinical fellow in Oncology at Stanford University School of Medicine, and colleagues, wrote in the poster.

An initial priming dose of magrolimab sufficiently mitigated magrolimab-induced anemia, effects which persisted with subsequent magrolimab maintenance dosing.

Preclinical studies have demonstrated that CD47 is crucial for RBC homeostasis, and that CD47 deficiency decreases RBC half-life. CD47 inhibitors and Fc-mediated opsonization have the potential to cause on-target anemia, creating a potential area of concern when using agents that inhibit CD47 via multiple mechanisms.

However, previous clinical trials have shown that magrolimab, a monoclonal immunoglobulin G4 antibody and CD47 inhibitor that blocks cancer cells from escaping immune surveillance and macrophage-mediated clearance, is safe when administered as a monotherapy with a lower initial dose. The priming dose yields transient anemia with compensatory reticulocytosis, with no anemia observed at subsequent higher maintenance doses.

This multicenter, prospective study sought to define the underlying mechanisms of manageable anemia in patients with treatment-naïve/unfit HR-MDS and AML who were treated with magrolimab plus azacitidine.

A total of 95 patients with HR-MDS and 87 patients with AML were treated with a combination of magrolimab and azacitidine. A 1 mg/kg priming dose of magrolimab was administered intravenously on days 1 and 4, followed by increased weekly maintenance dosing of 30 mg/kg, which transitioned to maintenance dosing every 2 weeks. Azacitidine was administered at 75 mg/m2 on days 1 through 7 of each 28-day cycle.

Throughout the study, peripheral blood, bone marrow, and complete blood counts were collected to analyze CD47 expression and hemoglobin levels. CD47 expression on RBCs and WBCs was analyzed through flow cytometry, and magrolimab binding was performed with IgG4 and CD45 inhibitors. RBCs were defined as those that were CD45 negative, and WBCs were defined as those that were CD45 positive.

Additionally, preclinical mouse models were used to further investigate how CD47 decreases in RBCs through this regimen. These preclinical data were studied in murine models with Fc-deficient and intact anti-mouse and anti-human CD47 antibodies. The mouse model strains C57BL/6J, C57BL/6J B-hSIRPA/hCD47, FcG1, 3 knockout, and FcG2 knockout were used, with the CD47 inhibitors magrolimab and MIAP410, the IgG4 inhibitor G17-4, the IgG1 inhibitor RMG1-1, and the CD45 antibody 2D1.

These preclinical studies showed that CD47 removal through treatment with magrolimab plus azacitidine uses a mechanism that is independent from cellular compartments and RBC antigen modulation mechanisms. Instead, the CD47 loss exhibited through the combination requires cross-linking of CD47 inhibition between RBCs and non-RBCs.

Additional results indicated that CD47 loss from this combination is not mediated by splenic function or Fc.

The findings of this prospective study align with prior clinical observations regarding magrolimab monotherapy in patients with solid tumors and magrolimab plus rituximab (Rituxan) in patients with lymphoma.

“Overall, these results support that on-target magrolimab-mediated anemia is manageable in patients with HR-MDS and AML who are treated with magrolimab in combination with azacitidine,” the study authors concluded.

Reference

Chen JY, Johnson L, McKenna KM, et al. Impact of magrolimab treatment in combination with azacitidine on red blood cells in patients with higher-risk myelodysplastic syndrome (HR-MDS). J Clin Oncol. 2022;40(suppl 16)7054. doi:10.1200/JCO.2022.40.16_suppl.7054