Clinical outcomes and safety of CD47-targeted immunotherapies across hematologic malignancies: a systematic review of monoclonal antibodies and fusion proteins in combination strategies.

[BACKGROUND] The CD47-SIRPα axis is a key innate immune checkpoint that enables tumor cells to evade macrophage-mediated clearance. CD47 is overexpressed in a spectrum of hematologic malignancies, contributing to poor outcomes, particularly in high-risk biological subgroups. While early clinical trials of CD47 blockade demonstrated limited efficacy as monotherapy, combination strategies have emerged as promising approaches. This systematic review synthesizes the current clinical evidence on the outcomes and safety of CD47-targeted monoclonal antibodies and fusion proteins administered in combination with regimens for hematologic malignancies.

[METHODS] A comprehensive search of PubMed/MEDLINE, Embase, Cochrane Library, and clinical trial registries was conducted until May 2025. Prospective interventional trials evaluating CD47-targeted agents in combination with systemic therapies for hematologic malignancies were included. The outcomes of interest were response rate, survival, and safety. The methodological quality was assessed using the MINORS. The protocol for this review was prospectively registered in the PROSPERO International Prospective Register of Systematic Reviews (registration number: CRD420251071435).

[RESULTS] Nine prospective clinical trials enrolling over 800 patients were included in this study. In patients with higher-risk myelodysplastic syndromes (MDS), the combination of magrolimab and azacitidine achieved an overall response rate (ORR) of 63%, with a complete remission (CR) rate exceeding 30%, including in patients with TP53-mutant disease. In untreated AML, the ORR reached 65%, with durable responses observed in patients with adverse cytogenetic mutations. In relapsed/refractory diffuse large B-cell lymphoma (DLBCL), combinations of CD47 blockade with anti-CD20 antibodies ± chemotherapy or novel immunotherapeutics achieved an ORR of 33-52%, with CR rates of up to 33%. In indolent non-Hodgkin lymphoma, magrolimab plus rituximab produced an ORR of 74% and a CR of 39%, including in rituximab-refractory patients. Preliminary data on multiple myeloma have demonstrated encouraging activity in triple-class refractory diseases. Across malignancies, CD47-targeted combinations were well tolerated, with manageable anemia and no unexpected toxicity.

[CONCLUSIONS] CD47-targeted combinations demonstrate encouraging early phase efficacy and manageable safety in hematologic malignancies, with signals of benefit in higher-risk MDS, TP53-mutant AML, relapsed/refractory DLBCL, and rituximab-refractory iNHL. However, recent Phase III trials in newly diagnosed AML Daver et al. [27], and Zeidner et al. [26] did not confirm this benefit, underscoring that CD47 blockade remains investigational and requires validation in rigorously designed randomized studies.