Pelabresib (CPI-0610) shows promise as a novel treatment option for patients with myelofibrosis (MF), according to a review article published in Current Hematologic Malignancy Reports.

Previous preclinical and clinical results have been positive for pelabresib and will soon be investigated in combination with ruxolitinib in a global phase 3 clinical trial called MANIFEST-2. In MANIFEST-2, patients with MF who are naïve to treatment with Janus kinase (JAK) inhibitors will receive either pelabresib with ruxolitinib or placebo with ruxolitinib as first-line treatment.

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Pelabresib has already been investigated in 3 phase 1 clinical trials of patients with hematologic malignancies including lymphoma, acute leukemia, myelodysplastic syndrome (MDS), MDS/myeloproliferative neoplasms (MPNs), and multiple myeloma. It is currently being investigated in the phase 2 MANIFEST trial.

Preliminary data from the MANIFEST trial showed that pelabresib in combination with ruxolitinib was well tolerated and showed efficacy in JAK inhibitor-naïve patients (arm 3 of the trial) and in patients who had a suboptimal response to ruxolitinib alone (arm 2 of the trial).

In arm 3, 68% of the 84 patients had achieved a spleen volume reduction of  ≥ 35% (SVR35%) at Week 24. A ≥ 50% reduction in total symptom score (TSS50%) was observed in 56% of patients at Week 24. Both of these numbers increased over time and 80% of patients achieved SVR35% and 83% achieved TSS50% at 1 point during the trial.

In the MF arms of the trial, positive effects on megakaryocyte differentiation, maturation, and erythropoiesis were also observed. Reduced levels of serum proinflammatory cytokines and JAK2 V617F mutant allele fractions (MAF) were also observed along with improvements in bone marrow morphology.

“Pelabresib is a novel and exciting drug for patients with MF, showing promising results and mounting evidence, placing it as a valuable therapeutic option in the treatment landscape of this complex disease,” the authors wrote.

As opposed to currently approved MF treatments that inhibit JAK, pelabresib targets the bromodomain and extra-terminal domain (BET) proteins. It is an oral small-molecule therapy that selectively targets all 4 BET proteins (BRD2, BRD3, BRD4, and BRDT) and causes the disruption of chromatin remodeling and gene expression. This disruption ultimately inhibits megakaryocyte differentiation and proliferation and suppresses the transcription and release of inflammatory cytokines.


Ferreira Gomes G, Harrison C. Pelabresib (CPI-0610): an exciting novel drug for the treatment of myelofibrosis. Curr Hematol Malig Rep. Published online May 17, 2023. doi:10.1007/s11899-023-00696-6