Bexmarilimab and azacitidine: promise for immunotherapy in myelodysplastic syndrome?

The results of the phase 1 dose escalation portion of the phase 1/2 BEXMAB trial evaluating the use of bexmarilimab plus azacitidine for high-risk myelodysplastic syndrome (HR-MDS) and relapsed or refractory (R/R) acute myeloid leukemia (AML) were published by Kontro et al. in The Lancet Hematology in May, 2025 (1). The authors report the safety and preliminary efficacy of the combination and conclude that the combination showed a manageable safety profile and promising clinical activity, particularly in patients with HR-MDS. Phase 2 of the study is a dose expansion to further evaluate the recommended phase 2 dose and is currently ongoing. While numbers are small and further studies are needed, promising results were seen in patients with myelodysplastic syndrome (MDS), particularly those who were refractory to prior treatment with hypomethylating agents (HMA).

HR-MDS is a devastating hematologic malignancy with a median age of onset of 73 years (according to the MDS foundation website) and characterized by cytopenias—which are often severe—and propensity to transform to AML. Overall survival and leukemia-free survival are estimated by the Revised International Prognostic Scoring System (IPSS-R) (2) and, more recently, the Molecular International Prognostic Scoring System (IPSS-M) (3), which includes molecular profiling. High risk patients are generally considered to have an IPSS-R score of 3.5 or greater, which encompasses very high, high and some intermediate risk patients, or an IPSS-M risk assessment of very high, high or moderately high. For the highest risk patients, survival is less than one year. HMA treatment has been the standard of care for HR-MDS patients since the AZA-001 trial (4) established the overall survival benefit of the HMA azacitidine over conventional care; however, nearly two decades after enrollment completed in the AZA-001 trial, the further development of effective treatments for MDS has been plagued by therapies which fail to demonstrate benefit in a randomized comparison after initial promise (5-12). Specifically with regard to immunotherapies, some examples include the CD47-targeting antibody, magrolimab, where a combination of increased treatment-emergent adverse events and early drug discontinuation in the experimental arm may have negated any additional benefit of the agent (6), and the T-cell immunoglobulin and mucin domain 3 (TIM3)-targeting antibody, sabatolimab, which failed to show improvement in complete responses (CRs) or progression-free survival in combination with azacitidine compared to azacitidine alone (11).

In the AZA-001 trial, despite a meager 16% of high-risk patients, as assessed by IPSS, achieving a CR and an objective response rate (ORR) of 50%, the median overall survival in the azacitidine group was 24.5 vs. 15 months for those treated with conventional care. For HMA non-responders, survival is a dismal 4–6 months (13,14). Allogeneic hematopoietic stem cell transplantation (HSCT) remains the only curative option for patients with HR-MDS. Despite successes in other hematologic malignancies, including acute lymphoblastic leukemia and non-Hodgkin lymphoma, development of tolerable and effective immunotherapies for patients with myeloid malignancies has been limited, with development plagued by a number of factors, including identification of appropriate targets which allow for eradication of tumor cells and limited “on-target/off-tumor” activity on hematopoietic stem and progenitor cells (15,16) and the immunosuppressive/immunologically “cold” bone marrow microenvironment (17).

In the BEXMAB trial, Kontro et al. evaluated the use of bexmarilimab, a novel, fully-humanized IgG4 monoclonal antibody targeting common lymphatic endothelial and vascular endothelial receptor-1 (Clever-1, also known as Stabilin-1). The authors postulated that since Clever-1 is expressed on immunosuppressive monocytes and macrophage and highly expressed on AML blasts, activates macrophage antigen presentation on T cells, inhibition of Clever-1 with bexmarilimab may work synergistically with the immunomodulatory effects HMA treatment to improve clinical activity. The BEXMAB trial is a multicenter, single-arm phase 1/2 dose escalation and expansion study evaluating the safety of bexmarilimab in combination with azacitidine in patients with myeloid malignancies, including both newly diagnosed (ND) and R/R patients with HR-MDS (IPSS-R ≥3.5 in USA and 3.0 in Europe), chronic myelomonocytic leukemia (CMML) with 10–19% blasts or AML. No ND-AML patients or CMML patients were enrolled and patients with proliferative CMML, active central nervous system involvement and autoimmune disease were excluded. R/R MDS was defined as failure to achieve CR or modified CR [as per International Working Group (IWG) 2006 criteria] after 4 cycles of HMA and R/R AML was defined as having received at least 1 prior line of therapy. Phase 1 evaluated the safety of 3 dose levels of bexmarilimab in combination with azacitidine and the phase 2 dose expansion is ongoing.

In this mixed group of 33 patients with ND-HR-MDS, R/R-MDS and R/R-AML, no dose limiting toxicities (DLTs) were observed and the most common treatment emergent adverse events were consistent with azacitidine therapy, including febrile neutropenia and cytopenias. Treatment related adverse events occurred in 39% of patients, a small proportion of which were serious—including one each of grade 3 rash, grade 3 capillary leak syndrome and grade 3 cryptogenic organizing pneumonia which all resolved with treatment delay and steroids and one treatment-related death due to hemophagocytic lymphohistiocytosis—and all of which occurred after completion of the DLT period. It is worth noting that each of these events were immune-related. Overall, patients with ND-HR-MDS (n=5), R/R-MDS (n=9) and R/R-AML (n=19) were able to receive a median of 8, 5 and 2 cycles, respectively, with the primary reason for treatment discontinuation being disease progression in 13 (44%) of 27 patients. The remainder of patients discontinued for patient or physician decision (n=6), adverse events (n=5), HSCT (n=2) and death (n=1) and 6 patients remained on treatment after 6 cycles.

Regarding efficacy, the ORR for the phase 1 cohort was 45% with the majority of benefit seen in MDS patients, including a remarkable ORR of 100% (5/5) of ND-HR-MDS and 89% (8/9) of R/R MDS patients with 5/6 TP53-mutated MDS patients responding. It is worth noting that ORR was defined by IWG 2006 criteria, which included marrow CR and that marrow CR has been removed from the more recent 2023 criteria (18); however, overall survival of the admittedly small numbers of ND-HR-MDS and R/R-MDS patients was 13.8 months [95% confidence interval (CI): 11.7–not estimable] and 13.4 months (95% CI: 3.8–not estimable), respectively, the latter being more than double the historical survival after failure of HMA. Two R/R-MDS patients underwent allogeneic HSCT. It is of particular interest that the majority of TP53-mutated MDS patients (5/6) achieved response. TP53-mutated MDS is a particularly difficult population to treat as responses and survival are often shorter in duration in this particularly high-risk group (19). Conversely, only 10% of R/R-AML patients achieved an objective response, 74% of which were stable disease.

Based on results of phase 1, 6.0 mg/kg of bexmarilimab was selected as the recommended dose for expansion for R/R-MDS, and it is currently being evaluated in the phase 2 dose expansion in combination with azacitidine. This evaluation is critical to understand if these encouraging results are maintained in a larger patient cohort. Further, as the authors note, responses should be graded based on the most recent response criteria. Additionally, the authors plan to evaluate the triplet combination of bexmarilimab, azacitidine and venetoclax in patients with ND-AML based on pre-clinical evidence that knockdown of STAB1 (the mRNA encoding Clever-1) sensitizes blasts to Bcl-2 inhibition.

While further studies are needed to characterize the potential clinical benefit of bexmarilimab in addition to azacitidine (and/or other therapies) in myeloid diseases, bexmarilimab is unique in targeting the bone marrow microenvironment. The bone marrow microenvironment in MDS has been shown to inhibit T cell function, specifically via inhibitory myeloid-derived suppressor cells and M2 macrophage-mediated release of inhibitory growth factors, including transforming growth factor beta and vascular endothelial growth factor (20). Kontro et al. showed that human leukocyte antigen-DR (HLA-DR) of monocytes was up-regulated after treatment with bexmarilimab and that this increase was significantly higher in responding patients, especially those with MDS and including those who had previously failed HMA therapy. By modulating the tumor microenvironment, bexmarilimab may have the potential to overcome factors which have plagued development of more effective immunotherapeutic in MDS. The implications of success in increasing the immunogenicity of immunologically cold tumors, as has been shown in pre-clinical studies of bexmarilimab (21,22), extends well beyond the myeloid diseases. Early results of the phase 1/2 MATINS trial of bexmarilimab demonstrated activation of circulating monocytes and CD8⁺ T cells and early efficacy in patients with advanced solid tumors (23). Further clinical studies of bexmarilimab are ongoing and results are anxiously awaited.

Acknowledgments

None.

Footnote

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