Highlights
- Bexmarilimab, a novel Clever-1 inhibitor, combined with azacitidine, demonstrated a manageable safety profile with no dose-limiting toxicities in high-risk myelodysplastic syndrome (MDS) and relapsed/refractory acute myeloid leukaemia (AML).
- The recommended phase 2 expansion dose of bexmarilimab was determined as 6.0 mg/kg weekly, with promising objective response rates (45%).
- Adverse event rates were consistent with known profiles of azacitidine, and no new safety signals emerged.
Study Background and Disease Burden
Myelodysplastic syndromes and acute myeloid leukaemia are aggressive hematologic malignancies characterized by ineffective hematopoiesis and a high risk of progression to fatal outcomes. Despite advances in therapy, particularly with hypomethylating agents (HMAs) such as azacitidine, a substantial proportion of patients experience refractory disease or relapse, facing poor prognosis and limited treatment options. The pathobiology of both MDS and AML is increasingly understood to involve not only malignant blasts but also an immunosuppressive tumor microenvironment. Clever-1 (also known as Stabilin-1), a scavenger receptor expressed on macrophages and myeloid leukemia cells, modulates antigen presentation and T cell activation, making it a compelling target for immunomodulatory strategies. Bexmarilimab is a monoclonal antibody designed to block Clever-1, potentially enhancing anti-tumor immune responses and improving outcomes when combined with standard therapies like azacitidine.
Study Design
This phase 1/2, multicenter, single-arm clinical trial evaluated the safety, tolerability, and preliminary efficacy of bexmarilimab in combination with azacitidine in adults with high-risk MDS, relapsed/refractory AML, or HMA-refractory chronic myelomonocytic leukaemia (CMML).
The phase 1 dose-escalation component was conducted at six centers in Finland and the USA. Eligible patients were 18 years or older with:
– MDS (2016 WHO criteria) and a high Revised International Prognostic Scoring System (IPSS-R) score (≥3.5 USA, ≥3.0 EU);
– CMML with 10–19% marrow blasts;
– MDS or CMML unresponsive to or progressing during HMA therapy;
– Relapsed or refractory AML (2016 WHO criteria).
Patients received intravenous bexmarilimab at escalating doses (1.0, 3.0, and 6.0 mg/kg; once weekly, 28-day cycles) plus azacitidine per label. Safety (dose-limiting toxicities, adverse events, maximum tolerated dose) was the primary endpoint, with secondary endpoints including objective response rate (ORR) and determination of the recommended phase 2 dose (RP2D). Bayesian optimal interval design guided dose escalation. All patients receiving ≥1 dose of bexmarilimab were included in safety analyses; those with post-baseline assessments contributed to efficacy analyses.
Key Findings
Between June 2, 2022, and December 7, 2023, 33 patients (14 MDS, 19 relapsed/refractory AML) enrolled; no eligible CMML patients were identified. The median follow-up was 6.2 months (IQR 3.5–10.7). The cohort was predominantly male (58%) and non-Hispanic (73%), with 24% White ethnicity.
Safety Outcomes:
– No maximum tolerated dose was reached across the three bexmarilimab dose levels.
– No dose-limiting toxicities were observed.
– The most frequent grade 3–4 treatment-emergent adverse events (TEAEs) included febrile neutropenia (24%), anemia (21%), and thrombocytopenia (15%), consistent with expected myelosuppressive effects.
– Serious treatment-related adverse events occurred in four patients: grade 3 rash, grade 3 capillary leak syndrome, grade 3 cryptogenic organizing pneumonia, and grade 5 haemophagocytic lymphohistiocytosis (HLH), the latter resulting in one death.
– Three treatment-emergent deaths were recorded—one each from sepsis, neutropenic infection, and HLH.
Efficacy Outcomes:
– Across all doses and indications, the objective response rate was 45% (15/33; 95% CI 28–62%), which is notable given the high-risk, heavily pretreated population.
– The RP2D for phase 2 was established as 6.0 mg/kg weekly for patients with HMA-refractory MDS.
Expert Commentary
These phase 1 results support the biological rationale for dual targeting of the leukemic clone and the immune microenvironment in MDS and AML. The absence of dose-limiting toxicities, coupled with the manageable and predictable safety profile, is encouraging for further development. The observed response rate compares favorably to historical data for HMA-refractory MDS and relapsed/refractory AML, where response rates with salvage therapies are typically below 20–30%.
Nevertheless, interpretation must consider the study’s limitations: the single-arm design, small sample size, and short follow-up preclude definitive efficacy conclusions. Additionally, the occurrence of HLH—a rare but potentially fatal immune complication—warrants careful monitoring in future trials. The lack of CMML participants in this phase limits generalizability to that subgroup. Further mechanistic studies may clarify whether Clever-1 blockade modifies the immunosuppressive microenvironment, potentially synergizing with other immune-modulatory or cytotoxic therapies.
Conclusion
Bexmarilimab combined with azacitidine exhibits a manageable safety profile and promising early signals of efficacy in patients with high-risk MDS and relapsed/refractory AML, particularly those with HMA-refractory disease. These findings justify progression to phase 2 trials, where efficacy, durability of response, and optimal patient selection can be further elucidated. As the therapeutic landscape for MDS and AML continues to evolve, targeting the tumor microenvironment through macrophage modulation represents a novel strategy with potential to improve outcomes in these challenging hematologic malignancies.
References
1. Kontro M, Stein AS, Pyörälä M, et al. Bexmarilimab plus azacitidine for high-risk myelodysplastic syndrome and relapsed or refractory acute myeloid leukaemia: results from the dose-escalation part of a multicentre, single-arm, phase 1/2 trial. Lancet Haematol. 2025 Jul;12(7):e516-e528. doi: 10.1016/S2352-3026(25)00103-6. Epub 2025 May 28. PMID: 40449509.
2. Fenaux P, et al. Azacitidine prolongs overall survival in higher-risk myelodysplastic syndromes: a phase III international study. Lancet Oncol. 2009;10(3):223-232.
3. Sallman DA, Komrokji R. Myelodysplastic syndromes: pathogenesis, diagnosis, and clinical advances. Oncologist. 2020;25(5):e123-e134.