Transfusion independence, hematological improvement and associated safety outcomes with bexmarilimab and azacitidine in HR-MDS: Results of the bexmab Phase 1/2 study

Abstract Introduction Hypomethylating (HMA) agents, including azacitidine, are standard frontline agents for HR MDS patients with complete remission (CR) rates approximately 16% (Hasegawa et al., 2023). In those with primary refractory or relapsed (r/r) disease after HMAs, outcomes are dismal with median overall survival (mOS) <6 months (Bewersdorf et al., 2020). Early efficacy data from bexmarilimab plus azacitidine combination in HR MDS has shown promising overall response rates (ORR) (85% in frontline; 63 % in r/r, per IWG2006 criteria) and a mOS of 13.4 months in r/r MDS. Bexmarilimab blocks Common lymphatic and vascular endothelial receptor-1 (Clever-1), a scavenger receptor expressed on malignant blasts and monocytes in MDS BM. By inhibiting Clever-1, bexmarilimab activates the immune system but also hampers the energy production of the malignant cells (Mickos et al., 2025; Ylitalo et al., 2025). In addition, pre-clinical data from Clever-1 knock-out and anti-Clever-1 treated mice suggests improved hematopoiesis and hematological recovery after 5-fluorouracil based chemotherapy. Altogether, bexmarilimab may alter the BM immune microenvironment and make the blasts susceptible to other cytotoxic agents, such as HMAs, thereby enhancing their effectiveness in HR MDS patients, simultaneously supporting hematopoietic recovery. Methods Treatment-naive HR (IPSS-R >3; n=21) and HMA r/r (n=32) MDS patients were recruited in the Phase 1/2 BEXMAB study. Bexmarilimab (1-6mg/kg in Ph1; 3 or 6mg/kg in Ph2) was administrated once weekly in 28-day cycles, in combination with a standard regimen of azacitidine (75 mg/m2 D1-7 each cycle). Transfusion independence (TI) status was collected as part of response assessment at the end of cycles 1-6 and then every 3rd cycle. TI was defined as absence of red blood cell (RBC) and/or platelet transfusions for ≥56 days during treatment. Selected pre- and post-treatment (Cycle 1 and 3) BM samples from 2 treatment-naïve and 3 r/r MDS patients were analyzed with single-cell RNA sequencing (scRNAseq) to study BM cell quantities and phenotypes in more detail. Results At baseline, 29% of the treatment-naïve HR MDS patients were transfusion dependent (TD), with 67% dependent on both RBC and platelet transfusions, and 33% dependent on RBC transfusions only. From the r/r MDS patients, 69% were TD at baseline, of which the majority (68%) were both RBC and platelet TD. Including patients from both cohorts (treatment-naive and r/r MDS patients) who were TD at baseline, 18% (17% in treatment-naive and 18% in r/r) achieved TI during bexmarilimab plus azacitidine treatment. The majority (60%) showed conversion of both RBC and platelet status. Of the frontline and r/r MDS patients who were TI before the study, 60% and 70%, respectively, maintained TI during bexmarilimab plus azacitidine treatment for ≥56 days. Safety analysis comparing baseline TI (n=25) and TD (n=28) patients showed lower number of treatment emergent adverse events (TEAE) (341 vs 409) and especially, treatment-related adverse events (TRAE) (26 vs 52) in TI vs. TD patients, respectively. Comparison of neutropenia and leukopenia events during TI and TD periods in the patients who converted from TD to TI, showed less events (2 vs 14) during TI, including ≥Gr3 events. scRNAseq analysis showed increased populations of several progenitor cells producing platelets and erythrocytes; namely multipotent progenitors, megakaryocyte-erythroid progenitors and megakaryocyte-erythroid cells after 3 cycles compared to pre-treatment. Precursor cells producing granulocytes (eosinophils, basophils) and mast cells were also increased. These translational data support the pre-clinical findings showing increased counts of lymphocytes, platelets and neutrophils in Clever-1 knock-out and anti-Clever-1 treated mice, compared to control mice, 12-14 days after 5-FU treatment. Altogether these data suggest that Clever-1 inhibition with the bexmarilimab combination enables hematopoietic recovery in MDS patients. Conclusion Maintenance of baseline TI status, increased TI rate and increased number of BM progenitor cells producing platelets and RBCs, support bexmarilimab's unique mechanism of action in HR MDS, improving the efficacy of HMAs and supporting hematopoietic recovery, associated with lower rate of adverse events.