Zeidanin ASH-absrakti:
Bexmarilimab combined with azacitidine in higher-risk MDS: Overall survival results of the bexmab phase 1/2 study
Amer M. Zeidan, MD,
Disclosure: Please see Session Details (link below).
Introduction
Hypomethylating (HMA) agents, including azacitidine (AZA) are the standard of care for higher-risk myelodysplastic syndrome (HR MDS), including the very high risk subgroup of TP53 mutated (mTP53) disease. Frontline AZA treatment results in complete remission (CR) rate of 15-20% regardless of TP53 status, but mTP53 HR MDS and especially biallelic mTP53 disease is associated with shorter responses and inferior outcomes. Median event-free survival (EFS) and overall survival (OS) in treatment-naïve (TN) mTP53 HR MDS have been reported to be 4-5.5mo (wtTP53 8-11mo) and 8-10mo (wtTP53 15-24mo), respectively (Murthy et al. EHA2026, Urrutia et al. 2026, Sallman et al. 2026). To date, novel combinations, such as venetoclax+AZA, have failed to improve outcomes in HR MDS including mTP53 disease. Bexmarilimab (BEX) is a macrophage checkpoint inhibitor targeting Clever-1, promoting haematopoiesis, enhancing antigen presentation, and stimulating cytotoxic T cell activity within the BM. By reprogramming the dysregulated BM immune microenvironment, BEX may enhance the efficacy of HMA therapy and improve the outcomes in HR MDS, including mTP53 disease.
Aims
The Phase 1/2 (Ph1/2) BEXMAB study investigated safety, tolerability and efficacy of BEX in combination with standard-of-care AZA in HR MDS, including mTP53 disease in TN and HMA relapsed/refractory (r/r) populations.
Methods
Twenty-one TN and 34 HMA r/r MDS patients have been recruited in the BEXMAB study. Key inclusion criteria include indication for AZA treatment with IPSS-R risk score >3, and for r/r population, failure to achieve response after 4 cycles or disease progression during treatment with HMA or HMA containing regimens. BEX (1, 3 or 6mg/kg) was administrated weekly in 28-day cycles, in combination with a standard regimen of azacitidine (75 mg/m2 D1-7 each cycle). BM responses were assessed per IWG2006 (investigator assessment) and IWG2023 (central assessment) criteria. Mutations were assessed locally and IPSS-M risk scores derived centrally based on available data. From the TN patients, 48% (10/21) had mTP53 of whom 60% had a biallelic mutation. Whereas per IPSS-R 38% of patients were in the Very High risk group, the proportion increased to 57% of Very High risk when evaluated by IPSS-M. From the r/r MDS populations, 44% (15/34) were Very High risk (IPSS-R) and 41% were mTP53, of which 57% had a biallelic mutation. MRD negativity was assessed locally by available method(s). Response rates, EFS (progression, leukemic transformation or death), and OS data are reported here.
Results
The safety profile of BEX added to the standard regimen of AZA in HR MDS appeared comparable to AZA monotherapy, with 59% of Gr3 or above treatment-emergent adverse events (TEAE) being haematological. None of the four observed Gr5 TEAEs were BEX-related (per investigator assessment). Rates of neutropenia and febrile neutropenia were 47.3% and 32.7%, respectively, with no prophylactic antibiotics administrated. 21.3% of patients had a TEAE leading to AZA withdrawal. BEX+AZA shows encouraging preliminary efficacy among the 20 evaluable TN HR MDS patients, with 85% (17/20) overall response rate (ORR), 45% (9/20) CR rate (IWG2006), 41% (7/17) CR+CReq rate (17 pts evaluable per IWG2023), median duration of CR of 16.1mo and 67% MRD negativity among CR responders (by local flow cytometry). CR rate among mTP53 was 70% with median duration of CR of 8.1mo. 71% of the mTP53 CRs were MRD negative and the median duration of CR was not reached in these patients. Median EFS was 9.4mo and 14.5mo in TN mTP53 and wtTP53 patients, respectively. After a median follow-up of 15 mo, the 12-month OS rate was 40% in mTP53 and 70% in wtTP53. In subgroup analysis, median OS has not been reached in wt and monoallelic mTP53 cohorts. For patients with biallelic mTP53, the median OS was 8.8 months with the median OS of the total population being 12.1 mo.
In the 33 evaluable r/r MDS with previous failure to HMA, BEX+AZA shows promising efficacy with an ORR of 64% (CR+PR 12%, IWG2006). Median OS was 18.7mo for wtTP53, 10.9 mo for monoallelic and 7.5 mo for biallelic mTP53 r/r MDS patients with the mOS of the total population being 11.2 mo.
Conclusion
BEX+AZA demonstrates good safety profile and promising efficacy in treatment-naïve and r/r HR MDS, including molecularly high-risk patients, supporting further the planned BEXERA Phase 2b randomized trial. Full data from November 2026 data-cut will be presented.