Dr Zhou on the Evaluation of Combination Therapies With Ruxolitinib in Myelofibrosis

Amy W. Zhou, MD, assistant professor, Department of Medicine, Division of Hematology, Washington University School of Medicine in St. Louis, discusses the investigation of ruxolitinib (Jakafi) given in conjunction with novel or emerging agents such as pacritinib (Vonjo) and momelotinib (Ojjaara), highlighting these agents’ potential at contributing to the treatment paradigm in myelofibrosis.

Combination therapies involving ruxolitinib are demonstrating the potential for anemia improvement in patients with myelofibrosis, Zhou begins. Although the superiority of these JAK inhibitor combinations when compared with single-agent ruxolitinib has not yet been conclusively determined, data from phase 2 investigations indicates that pelabresib (CPI-0610) may be an effective option for patients who are refractory or lose response to ruxolitinib, she says.

The addition of pelabresib to ruxolitinib was evaluated as an upfront therapy in the phase 2 MANIFEST trial (NCT02158858), Zhou details. This global, open-label, nonrandomized, multicohort study was designed to ascertain whether this JAK inhibitor combination therapy was more effective than ruxolitinib monotherapy for patients with JAK inhibitor-pretreated or JAK inhibitor-naïve myelofibrosis.

Initial findings from the JAK inhibitor-naïve cohort demonstrated that pelebresib and ruxolitinib elicited a reduction of spleen volume by 35% in 68% of individuals. This was accompanied by a decrease in the total symptom score by at least 50% in 56% of participants at the 24-week mark.

The augmented spleen and symptom responses achieved with pelabresib and ruxolitinib indicate that JAK inhibitor combination therapies may be a viable option for patients who have not yet achieved an optimal response with JAK inhibitor monotherapy, Zhou states. However, the eventual integration of these combination therapies into the frontline setting hinges on the results of phase 3 trials such as the MANIFEST-2 trial (NCT04603495), she notes. This study is evaluating the use of upfront pelabresib and ruxolitinib vs ruxolitinib alone in a larger cohort of patients with JAK inhibitor-naïve myelofibrosis.

Trials like MANIFEST-2 will provide essential comparisons through rigorous, randomized, controlled investigations, thereby more definitively determining whether the combination approach surpasses the efficacy of a single-agent JAK inhibitor in the management of patients with myelofibrosis, Zhou concludes.