Dr Mascarenhas on the Background of the MANIFEST-2 Trial in Myelofibrosis

John Mascarenhas, MD, professor of medicine, the Icahn School of Medicine, Mount Sinai, director, the Center of Excellence for Blood Cancers and Myeloid Disorders, member, the Tisch Cancer Institute, Mount Sinai, discusses the background of the phase 3 MANIFEST-2 trial (NCT04603495) investigating the combination of pelabresib (CPI-0610) and ruxolitinib (Jakafi) vs ruxolitinib plus placebo in patients with myelofibrosis who have not been previously treated with a JAK inhibitor.

Previously, the phase 1/2 MANIFEST trial (NCT02158858) evaluated pelabresib alone and in combination with ruxolitinib. In patients who previously received ruxolitinib, the combination produced suboptimal responses, including a spleen volume reduction of at least 35% (SVR35) at week 24 in 20% of patients, Mascarenhas begins. However, in JAK inhibitor–naïve patients, the combination produced a SVR35 at week 24 of 68%, showing that significantly more spleen volume reduction can be obtained with the combination than one would expect with single-agent ruxolitinib, Mascarenhas notes. In addition to improved SVR35 at week 24, the combination led to significant symptom burden improvement in patients who were not treated with a prior JAK inhibitor, Mascarenhas explains.

Additional correlative study data suggested that pelabresib plus ruxolitinib elicited changes in the bone marrow that may be indicative of a more pronounced effect on the level of the disease within the marrow. For example, a hallmark of myelofibrosis is the clustering of atypical megakaryocytes in a tight formation in the bone marrow; however, with the combination therapy, the distance between megakaryocytes increased, which also correlated with spleen volume reduction and symptom improvement, Mascarenhas says. Changes within the bone marrow suggest disease modification stemming from treatment with pelabresib plus ruxolitinib, Mascarenhas emphasizes.

The goal of MANIFEST-2 is to determine the true benefit of pelabresib plus ruxolitinib combination therapy over ruxolitinib monotherapy with a randomized, placebo-controlled study. The phase 3 trial is an ongoing in patients with intermediate- and high-risk myelofibrosis who are naïve to a JAK inhibitor. The results of this study are anticipated because they have the potential to shift the treatment paradigm of myelofibrosis, Mascarenhas concludes.