What the EHA data showed, and how it may shape the future of HR-MDS

In June, we presented updated data from the BEXMAB Phase 1/2 trial at the European Haematology Association Congress in Stockholm. Our Chief Medical Officer, Petri Bono, set out last week why higher-risk MDS (HR-MDS) has proved so resistant to treatment, and why we believe we have been asking a different and more useful question than what the field has asked before. This post focuses on evidence — what the data showed at EHA, and why the translational findings within the bone marrow are, in my opinion, a crucial part of the story.

Of course, we should appreciate from the outset that BEXMAB is a Phase 1/2 study. The efficacy data are from an uncontrolled, single-arm trial, and therefore need to be interpreted accordingly. What it gives us is signal, mechanism and direction. Together with what the field has learned before, it is what allows us to design a trial that can provide proof, which is why the randomised, placebo-controlled BEXERA trial is now in preparation.

With that context in place, the signal is worth examining carefully.

In the treatment-naïve cohort, 85% of patients responded to bexmarilimab plus azacitidine, with a complete remission (CR) rate of 45%. Among those who achieved complete remission, the median duration of CR has now extended to 16.1 months with longer follow-up; up from 12.1 months at the previous data cut. That extension matters with the safety profile remaining tolerable in a vulnerable older population: no grade 5 bexmarilimab-related adverse events were reported in HR-MDS patients and bexmarilimab did not increase the rates of severe side effects commonly associated with azacitidine, such as neutropenia and anaemia.

Consequently, what I found most scientifically informative at EHA was the translational data from bone marrow samples collected before and after treatment.

Using single-cell RNA sequencing and spectral flow cytometry on samples from BEXMAB patients, we were able to show consistent changes in the bone marrow microenvironment across treatment. In the treatment-naïve patients, we observed increases in erythroid progenitor and haematopoietic progenitor cells alongside activation of cytotoxic CD8 T cells. These are the precursors of healthy blood cells, and the immune cells whose function is to kill cancer respectively. Seeing both types of cells increase during bexmarilimab and azacitidine treatment provides a biologically coherent signal. The combination may help restore, at least in part, the conditions for normal haematopoiesis while simultaneously promoting immune activity consistent with an anti-tumour response, although the clinical significance of these findings remains to be confirmed in a prospective randomised setting.

In the relapsed/refractory cohort, patients who had already progressed on or become refractory to azacitidine, the translational picture is particularly coherent. Target engagement, measured as reduction of soluble Clever-1 in the bone marrow, correlated significantly with depth of clinical response. HLA-DR activation, a marker associated with a shift towards a more immunostimulatory macrophage phenotype, increased in 65% of evaluable patients. Cytotoxic T cell engagement occurred in 64%, and regulatory T cells decreased in 68%. In patients with HMA-refractory disease, at least two of these three immune changes were present in every patient with available data. In this same cohort, 64% of patients responded to treatment. We must remember that these are patients with very limited treatment options and a historically poor prognosis. This response data, supported by the mechanistic evidence above, provides a meaningful signal for this setting.

It is also worth noting that the BEXMAB population includes a significant proportion of patients with complex cytogenetics and high-risk mutations, including biallelic TP53 mutations; a subgroup with historically poor outcomes regardless of treatment. That context matters for interpreting the survival data as it matures.

Why does this matter? Because one of the central challenges in HR-MDS drug development has been the gap between single-arm signal and randomised outcome. Programs that looked encouraging in Phase 1/2 have repeatedly failed to demonstrate benefit when randomised against azacitidine. The translational data give us a biological account of mechanism that is independent of the efficacy readout. The response rates themselves do not prove the biology works; however, the biology observed directly in bone marrow tissue corroborates, and to a certain degree, explains the demonstrated response rates. The clinical and translational observations point in the same direction, supporting further evaluation of the hypothesis in a randomised trial.

I should also note what the data does not yet tell us. Importantly, the overall survival (OS) data in the treatment-naïve cohort are immature: at the current follow-up of 14.9 months, the median has not been reached in the full cohort, and the only subgroup to have hit a median OS is the biallelic TP53-mutated population at the June data cut. That subgroup has historically very poor outcomes, and a median OS of 8.8 months in that context is in line with historical data rather than a signal of concern. It is a reminder, however, that the full OS story in treatment-naïve patients will take more time and more data to tell.

The BEXERA trial is the next step. It is the trial that will tell us whether these signals hold in a randomised controlled setting against single agent azacitidine. Until then, what EHA gave us is a biologically coherent and clinically encouraging dataset, interpreted with appropriate caution. That is a sound foundation to build on.

In the coming weeks, we will look at how this work extends beyond HR-MDS, and at the investigator-initiated trials taking bexmarilimab into new indications.

— Aneel Nimba, Medical Director

Forward-looking statements: This post contains forward-looking statements regarding the development of bexmarilimab. Bexmarilimab is investigational and has not been approved by any regulatory authority.