Pelabresib With Ruxolitinib in Myelofibrosis

By Patrick Daly - Last Updated: June 10, 2024

In the phase III MANIFEST-2 trial, the combination of pelabresib plus ruxolitinib improved spleen and symptom responses in Janus kinase inhibitor (JAKi)-naïve patients with myelofibrosis, according to a presentation at the European Hematology Association 2024 Hybrid Congress.

Advertisement

Pelabresib plus ruxolitinib also improved the bone marrow microenvironment, “as evidenced by a reduction in fibrosis, a decrease of [CD61-positive megakaryocytes], and a maturation of [CD71-positive erythrocyte progenitor cells] associated with amelioration of anemia,” said lead author, Raajit Rampal, MD, PhD, of Memorial Sloan Kettering Cancer Center.

The MANIFEST-2 trial compared pelabresib plus ruxolitinib (n=46) with placebo plus ruxolitinib (n=37). The primary endpoint was spleen volume reduction of 35% or greater (SVR35) from baseline, and a key secondary endpoint was total symptom score improvement of 50% or greater (TSS50) from baseline.

Pelabresib Plus Ruxolitinib in Myelofibrosis

Mutational burden was assessed via next-generation sequencing in peripheral blood collected prior to treatment initiation and at week 48. Proinflammatory cytokine levels were analyzed via bead-based multiplex assays in plasma samples collected prior to treatment and at week 24. Bone marrow metrics were assessed by digital pathology in tissue samples collected prior to treatment and at week 24.

The authors found that JAK2 variant allele fraction (VAF) was associated with SVR35 (P<.001) at week 24. Overall, 41.3% of patients in the pelabresib group versus 37.8% of those in the placebo group had a 20% or greater JAK2 VAF reduction at week 48, representing a mean change in JAK2 VAF of −26.2% versus 17.0%, respectively.

According to the authors, decreased cytokine levels were associated with both SVR35 (P<.001) and TSS50 (P=.005) at week 24, and patients in the pelabresib group had greater reductions in proinflammatory cytokine levels at week 24 (−33.9%; 95% CI, −36.5 to −31.1) compared with those in the placebo group (−20.8%; 95% CI, −23.7 to −17.9; P<.001).

Additionally, patients in the pelabresib group showed greater reductions of reticulin fiber density and megakaryocytes compared with placebo. Notably, the pelabresib group had increased erythrocyte progenitor cell proportions from baseline while the placebo group had decreased proportions.

Ultimately, “results from patients treated with pelabresib plus ruxolitinib in MANIFEST-2 indicate a potential for pelabresib to enhance clinical responses to ruxolitinib by further reducing mutational burden and decreasing inflammation, which was associated with SVR35 and TSS50 responses,” Dr. Rampal and colleagues reported.

Related: Adding Parsaclisib to Ruxolitinib Improves Myelofibrosis Symptoms, Spleen Volume

 

Reference

Rampal RK, Vannucchi A, Gupta V, et al. Pelabresib plus ruxolitinib combination therapy in JAK inhibitor-naïve patients with myelofibrosis in the MANIFEST-2 study: preliminary evidence of bone marrow recovery. Poster #S220. Presented at the European Hematology Association 2024 Hybrid Congress; June 13-16, 2024; Madrid, Spain.

Advertisement
Advertisement
Advertisement
Editorial Board