Mickos:
Baseline T-cell states and hematopoietic remodeling predict response to bexmarilimab plus azacitidine in high-risk Myelodysplastic Syndromes
Jesper Mickos, MS,
Disclosure: Please see Session Details (link below).
Background:
High-risk myelodysplastic syndromes (MDS) are clonal hematopoietic malignancies with limited treatment options, particularly after failure of hypomethylating agents (HMAs). Clever-1 is an immunosuppressive scavenger receptor expressed on monocytes, macrophages, endothelial cells, and malignant myeloid blasts. Bexmarilimab, a humanized anti-Clever-1 antibody, promotes myeloid immune activation, neutralizes soluble Clever-1-mediated immunosuppression, and enhances hematopoietic regeneration in preclinical models. In the ongoing BEXMAB trial (NCT05428969), bexmarilimab combined with azacitidine has demonstrated encouraging efficacy in both frontline high-risk and relapsed/refractory (r/r) MDS. However, the immune mechanisms underlying clinical responses remain incompletely defined.
Aims:
To identify immune and hematopoietic changes associated with clinical response to bexmarilimab plus azacitidine and define baseline biomarkers predictive of treatment benefit.
Methods:
Multiparameter flow cytometry was performed on bone marrow mononuclear cells from 16 frontline and 15 r/r MDS patients enrolled in the BEXMAB trial. Longitudinal immune profiling was correlated with clinical response. In parallel, single-cell RNA sequencing will be expanded to 32 patients, including serial samples from 12 patients, to validate and extend these findings.
Results:
Responding patients demonstrated evidence of hematopoietic remodeling during therapy. Erythroid cells expanded after one treatment cycle (median increase 38.9%, P=0.022), while basophil-lineage cells increased after three cycles (median increase 87.8%, P=0.026). Conversely, granulocyte-monocyte progenitor-like cells (median decrease 38%, P=0.011), monocytes (median decrease 63%, P=0.005), and total Clever-1+ cells (median decrease 19.7%, p=0.013) declined after three cycles, consistent with a shift away from myeloid-biased hematopoiesis.
Baseline T-cell composition was strongly associated with complete remission among frontline patients. Complete responders exhibited higher frequencies of CD4+ central memory T cells (median 38.6% vs. 23.6% in other responders, P=0.03) and CCR7+ CD8+ T cells, including naïve and central memory subsets (median 68.9% vs. 15.4% in non-responders, P=0.0055), together with lower frequencies of CD8+ TEMRA cells (median 16.4% vs. 44.8%, P=0.045), including Granzyme B high TEMRA cells. During treatment, responding patients showed reduced TIM-3 expression on CD4+ T cells (median decrease 41.1%, P=0.003) and increased frequencies of CD226+ CD4+ T cells (median increase 10.5%, P=0.003), consistent with enhanced T-cell activation.
Conclusions:
Bexmarilimab plus azacitidine induces coordinated remodeling of hematopoiesis and adaptive immunity in responding MDS patients. A baseline immune landscape enriched for central memory T cells and depleted of terminally differentiated CD8+ TEMRA cells is associated with complete remission, suggesting that pre-existing immune fitness influences therapeutic efficacy. Ongoing single-cell analyses provide mechanistic insight into response and may support biomarker-driven patient selection.