Evaluating Efficacy and Safety of Pelabresib Among Patients With MDS/MPN

Eytan M Stein, MD, Memorial Sloan Kettering Cancer Center, New York, New York, discusses findings from the MANIFEST trial which evaluated the efficacy and safety of pelabresib, a bromodomain and extra-terminal (BET) protein inhibitor, among patients with acute leukemia, high-risk myelodysplastic syndrome (MDS), or MDS/myeloproliferative neoplasms (MPNs). 

Dr Stein noted that the promising safety profile of pelabresib supports the pivotal study of this drug among patients with myelofibrosis (MF) using the recommended phase 2 dose, which was presented at the 65th American Society of Hematology (ASH) Annual Meeting in San Diego, California. 

Oncology Learning Network: What was the purpose of the phase 1 MANIFEST trial?

The MANIFEST clinical trial is a trial that [evaluated] the safety and tolerability of a drug called pelabresib, which is a bromodomain inhibitor in patients with myeloid malignancies. 

This was a phase 1 study that we actually started a number of years ago that enrolled patients with acute leukemia, high-risk myelodysplastic syndrome, or MDS/MPN overlap syndromes with relapsed and refractory disease, and gave them pelabresib at escalating doses to assess the safety and tolerability and efficacy of this agent. 

How was pelabresib administered to the patients?

The doses that were given were between 24 and 400 milligrams in cycles that were either 14 days on, 14 days off, or 7 days on and 7 days off.

What were the results of this study, regarding the efficacy and safety of pelabresib? 

This drug had relatively limited efficacy, with only 1 patient with chronic myelomonocytic leukemia (CMML) having a partial remission, while the other patients, both with acute myeloid leukemia and high-risk myelodysplastic syndrome, had stable disease. The rest of the patients had progressive disease. The most frequent drug-related adverse events given this agent were nausea, decreased appetite, and fatigue, and the maximum tolerated dose ended up being 225 milligrams daily. 

Are there any additional factors to note about the potential value of pelabresib for myelofibrosis? 

I think the reason this agent is important is because many of you may know that after this trial that was fully accrued for AML/MDS and MDS/MPN overlap syndromes, this drug has also been investigated subsequently in patients with myelofibrosis and shown very, very interesting efficacy that was presented this past year at the American Society of Hematology annual meeting. 

Source: 

Stein EM, Fathi AT, Harb WA, Results from phase 1 of the MANIFEST clinical trial to evaluate the safety and tolerability of pelabresib in patients with myeloid malignancies. Leuk & Lymph. Published online: January 23, 2024. doi: 10.1080/10428194.2023.2300710