Pathways to Improve Overall Survival in Myelofibrosis: Finding Alternate Trial End Points

Myelofibrosis (MF) is a neoplasm presenting with constitutional symptoms (non-specific symptoms affecting the overall well-being of an individual), bone marrow fibrosis, and pathological features such as anemia and thrombocytopenia. Currently, the only curative treatment is allogenic stem cell transplantation for which very few patients are eligible.

Clinical trial research | Image credit: Cavan | stock.adobe.com

Janus kinase (JAK) inhibitors such as ruxolitinib (Jakafi; Incyte) reduce symptom burden and splenomegaly in MF. Current clinical trials primarily measure the benefits of JAK inhibitors using changes in symptom burden and splenomegaly as data points. However, a recent review of MF clinical trials published in Blood proposes that revising the focus of end points may enhance the development of new agents for MF.

Surrogate end points are used to predict an outcome or when it is not clinically feasible to wait for a measurable outcome. Reviewing available data and surveying actual trials can reveal end points that provide a better assessment of overall disease modifying ability.

Current randomized clinical trials of JAK inhibitors evaluate end points such as Total Symptom Score (TSS), which is derived from a symptom assessment form, and spleen volume reduction (SVR). Symptomatic improvement and quality of life enhancements are benefits shown in JAK inhibitor trials.

The review authors posit that measuring end points such as molecular response, cytokines, and histomorphometry would show a greater range of benefits. Relying on SVR measurements can exclude patients without splenomegaly from some clinical trials. Developing new agents that have a mechanism of action that differs from JAK inhibitors may require different surrogate end points.

The authors recommend that future clinical trials examine either mitigating potential or disease modifying potential. They stress the importance of finding surrogate end points that will allow researchers to place emphasis on those possible agents that show promise of disease modifying potential early.

Evaluating data such as molecular response, cytokine levels, and histology profiles will help identify end points that align with more desirable clinical outcomes such as overall survival. Ultimately, the goal is to better serve patients with MF with agents that alter the natural history of MF and improve outcomes.

REFERENCE

Ross DM, Lane SW, Harrison CN. Identifying disease-modifying potential in myelofibrosis clinical trials. Blood. 2024;144(16):1679-1688. doi:10.1182/blood.2024024220