CMML Drug Development Experts: Progress Requires Clear Differentiation From MDS

In September 2023, the US Food and Drug Administration (FDA) convened a symposium where physician-experts in chronic myelomonocytic leukemia (CMML) clinical drug development met with FDA regulators. They discussed reasons for the slow pace of advances in treatments for this disease and proposed remedies, which were summarized in a special report published in Blood.

The empaneled experts named several factors as hampering clinical trial work for new CMML agents. The disease itself is clinically rare yet heterogeneous in presentation, and its pathobiology is not well understood. These make optimal trial design in CMML more difficult, such as in risk stratification of patients and choosing relevant end points.

An overarching institutional issue the experts stressed is that CMML has only recently begun to be distinguished as clinically distinct from myelodysplastic syndromes (MDS). They describe that in how clinicians regard this disease in their practices, the drug development models used, and even clinical guidelines, “CMML has been difficult to ‘detach’ from MDS and is still viewed by many as analogous to MDS.” They note that no phase III study designed specifically for CMML has yet been conducted in the US.

To overcome these impediments to CMML drug development, the experts emphasized launching trials specific to this disease and that patient enrollment be strongly encouraged. This would involve consulting with the FDA early in the trial design process, increasing preclinical research, and conducting prospective studies to establish trial end points. The panel stressed that pathobiological differences between CMML and MDS must be appreciated, and “[t]he historical dogma of simply extrapolating work from MDS to CMML needs to be minimized unless a clear biologic rationale for investigating a drug in CMML exists.”

Given recent early phase studies investigating agents’ use specifically in CMML, along with clearer clinical differentiation of this disease from MDS, the panel is optimistic that changes to improve CMML drug development can be applied.

They add that in this process, “[c]ross-center academic, FDA, patient advocate, and industry collaboration, as well as a commitment to treating patients in clinical trials, will be vital to success.”

Reference

Hunter AM, Patnaik MM, Itzykson R, et al. Perspectives on drug development in chronic myelomonocytic leukemia: Changing the paradigm. Blood. 2024;144(19):1987-1992. doi:10.1182/blood.2024025648