Identifying disease-modifying potential in myelofibrosis clinical trials

The ultimate goal of bringing most new drugs to the clinic in hematologic malignancy is to improve overall survival. However, the use of surrogate end points for overall survival is increasingly considered standard practice, because a well validated surrogate end point can accelerate the outcome assessment and facilitate better clinical trial design. Established examples include monitoring minimal residual disease in chronic myeloid leukemia and acute leukemia, and metabolic response assessment in lymphoma. However, what happens when a clinical trial end point that is not a good surrogate for disease-modifying potential becomes ingrained as an expected outcome, and new agents are expected or required to meet this end point to demonstrate "efficacy"? Janus kinase (JAK) inhibitors for myelofibrosis (MF) have a specific impact on reducing symptom burden and splenomegaly but limited impact on the natural history of the disease. Since the introduction of ruxolitinib more than a decade ago there has been modest incremental success in clinical trials for MF but no major leap forward to alter the natural history of the disease. We argue that the clinical development of novel agents for MF will be accelerated by moving away from using end points that are specifically tailored to measure the beneficial effects of JAK inhibitors. We propose that specific measures of relevant disease burden, such as reduction in mutation burden as determined by molecular end points, should replace established end points. Careful reanalysis of existing data and trials in progress is needed to identify the most useful surrogate end points for future MF trials and better serve patient interest.