Dr Kuykendall on the Relevance of QOL End Points in Myelofibrosis Clinical Trials

"For all the criticism [QOL] end points receive, they are still reasonable, as they reflect clinically relevant aspects of [myelofibrosis]."

Andrew Kuykendall, MD, an assistant member in the Department of Malignant Hematology at Moffitt Cancer Center, discussed the limitations of quality of life (QOL)– and symptom-related end points in clinical trials investigating therapies for patients with myelofibrosis.

Kuykendall asserted that QOL end points remain reasonable to use in myelofibrosis therapy research despite criticism because they reflect clinically relevant aspects of myelofibrosis. Patients with myelofibrosis often present with inflammatory symptoms and splenomegaly, he said. He explained that a therapy with true anticlonal activity or disease-modifying potential would logically be expected to reduce spleen size and improve symptoms, although the timelines for these effects may differ.

Kuykendall stated that the major challenge of using these end points lies in how they are applied in trial design, potentially setting too high a bar for new therapies. He noted the phase 3 MANIFEST-2 trial (NCT04603495) as an example. This trial randomly assigned patients with higher-risk myelofibrosis to receive ruxolitinib (Jakafi) monotherapy or a combination of ruxolitinib plus pelabresib (CPI-0610). He stated that although the combination regimen significantly improved spleen volume reduction (SVR) rates compared with ruxolitinib alone, the trial failed to meet the statistical threshold for superiority concerning the symptom end point, which was a 50% or greater reduction in total symptom burden.

Kuykendall explained that this outcome reflects the complexity of demonstrating additive benefit when comparing a combination against an already effective monotherapy. He added that increased toxicity from dual therapy may counteract symptomatic gains, and high expectations likely influenced the regulatory outlook and development pace for pelabresib.

Kuykendall emphasized that the myelofibrosis field needs to better understand how these end points are weighted and validated. He asserted that demonstrating that greater SVR or longer duration of spleen response correlates with improved survival or long-term outcomes would strengthen the utility of these end points in therapeutic development. Heconcluded that many trials to date have limited follow-up and lack robust data on the durability or depth of response. Therefore, he stressed that it is necessary for researchers and industry sponsors to generate these necessary long-term data.