Pelabresib Plus Jakafi (Ruxolitinib) Sustains Responses in JAK Inhibitor-Naïve Myelofibrosis

BET inhibitor in combination with Jakafi appears promising for the treatment of myelofibrosis

Dr. C H Weaver MD
2–3 minutes
Home » Myeloproliferative Neoplasms » Pelabresib Plus Jakafi (Ruxolitinib) Sustains Responses in JAK Inhibitor-Naïve Myelofibrosis

Results from a phase 3 study, randomized, double-blind study recently presented at the American Society of Hematology annual meeting indicate that JAK inhibitor-Naïve patients with myelofibrosis experienced improvements in spleen volume, total symptom score, anemia, and the bone marrow microenvironment at week 48 when treated with pelabresib plus Jakafi versus Jakafi plus placebo.

The MANIFEST-2 Study

The study included 430 patients who had not previously received a JAK inhibitor. Patients were randomly divided into two groups:

    1. One group received Jakafi plus a new drug called pelabresib.
    2. The other group received Jakafi plus a placebo.
  • The treatment was given in cycles:
  • Jakafi was taken twice a day.
  • Pelabresib (or placebo) was taken once a day for 14 days out of every 21-day cycle.

The study looked at several important things:

  1. How much the spleen size decreased after 24 weeks of treatment.
  2. How much symptoms improved.
  3. How well the treatment worked after 48 weeks.
  4. Whether it helped with anemia (low red blood cell count).
  5. If it reduced scarring in the bone marrow.
  6. How safe the treatment was.

Key Findings

  • Spleen Size Reduction: More patients who received the combination treatment had their enlarged spleens shrink significantly (57% vs 37.5% at 48 weeks)
  • Symptom Improvement: 45.3% of patients on the combination had at least a 50% reduction in symptoms, compared to 39.4% on ruxolitinib alone
  • Anemia: Fewer patients needed blood transfusions with the combination treatment
  • Bone Marrow Fibrosis: 41% of patients on the combination showed improvement in bone marrow scarring, compared to only 15% on ruxolitinib alone

Safety and Side Effects

The combination treatment appeared to be generally well-tolerated:

  • Serious side effects were similar between both groups (57.1% vs 62.1%)
  • The most common non-blood-related side effects included diarrhea, constipation, taste changes, cough, and nausea

About Pelabresib

Pelabresib is a BET inhibitor. Bromodomain and extra-terminal domain (BET) proteins regulate key cancer causing pathways which are important drivers of pro-inflammatory cytokine expression and bone marrow fibrosis implicated in myelofibrosis. BET inhibitors are thought to work by suppressing the cytokine production, promote erythroid (red blood cell) differentiation and normalize megakaryocytic (platelet) differentiation. Preclinical studies suggest that a combination of a BET inhibitor and Jakafi may result in synergistic reduction of splenomegaly and bone marrow fibrosis.

Longer follow-up data from the MANIFEST-2 study will be presented at a future medical conference.

More Reading

BET Inhibitors: Myelofibrosis

Join the Conversation on CancerConnect!

Reference:

Mascarenhas JO, Grosicki S, Chraniuk D, et al. Updated Results from the Phase 3 Manifest-2 Study of Pelabresib in Combination with Ruxolitinib for Janus Kinase Inhibitor-Naïve Patients with Myelofibrosis. Blood. 2024;144(suppl 1):3178. doi:10.1182/blood-2024-193193

You May Be Interested In