The Janus kinase (JAK) 1 and 2 inhibitor ruxolitinib and the JAK2 inhibitor fedratinib, both approved by the U.S. Food and Drug Administration (FDA), are effective at reducing constitutional symptoms and spleen size in patients with myelofibrosis (MF) but often worsen anemia and increase transfusion needs. A study published in Blood Advances highlights a potential role for pacritinib among patients with MF and anemia.1
Aaron Gerds, MD, MS, associate professor at Cleveland Clinic Taussig Cancer Institute, editor-in-chief of ASH Clinical News, and a coauthor of the recent paper, pointed out that the myeloproliferative neoplasm community has become increasingly interested in the hepcidin pathway in the treatment of anemia. Anemia in MF is multifactorial but seems to be partially driven by inflammatory cytokines and disease-related inflammation. This leads to increased production of the acute phase reactant hepcidin, which reduces iron transport out of cells and decreases serum iron levels, impairing erythropoiesis.
Momelotinib is a JAK1/JAK2 inhibitor that also inhibits activin A receptor, type 1 (ACVR1), which works upstream of the hepcidin gene. On September 15, the FDA approved momelotinib for the treatment of intermediate- or high-risk MF with anemia, regardless of prior therapy, making it the first therapy specifically for MF with anemia.
Researchers wanted to explore the potential role of pacritinib in patients with MF and anemia. Pacritinib is a JAK1 sparing inhibitor of JAK2 and IRAK1 (part of the toll-like receptor signaling pathway), as well as ACVR1; it is currently FDA-approved for patients with intermediate- or high-risk MF with a platelet count below 50,000/mcL. “Pacritinib works in a very similar manner to treat anemia as momelotinib, a drug specifically developed to ameliorate anemia in MF,” Dr. Gerds said.
In the phase III PERSIST-2 study of more than 300 patients with MF and thrombocytopenia, pacritinib demonstrated benefits for anemia. Patients on pacritinib experienced higher rates of clinical improvement in hemoglobin at week 24 compared to those treated with current best available therapy (which included ruxolitinib in some patients).2
The recent study retrospectively analyzed additional data from the PERSIST-2 trial. The researchers found that of patients who still required transfusion at baseline, a significantly greater proportion of those who received pacritinib (200 mg BID) became transfusion independent compared to those on best available therapy (37% vs. 7%, respectively; p=0.001). Moreover, significantly more patients on pacritinib had a greater than 50% reduction in transfusion burden (49% vs. 9%, respectively; p<0.0001).1
The authors also performed additional in vitro data to assess the ACVR1 pathway and compare potency of other JAK2 inhibitors. They found the half-maximal inhibitory concentration (IC50) using serial dilutions and used the maximum plasma concentration at the clinically recommended dose (Cmax) to calculate inhibitory potency (Cmax:IC50). Pacritinib displayed the greater potency compared to momelotinib, fedratinib, or ruxolitinib (12.7 vs. 3.2, 1, and <0.01, respectively). Moreover, they demonstrated in further assays that pacritinib and momelotinib most potently reduced the expression of hepcidin in liver culture cells.1
Partly based on these data, the most recent National Comprehensive Cancer Network guideline recommends pacritinib as a frontline agent for patients below 100,000 platelets/mcL and as a second-line agent regardless of platelet count.3
Dr. Gerds said the retrospective nature of the study is a key limitation. He also noted that differences between baseline characteristics of patients in this and other trials with JAK inhibitors make it difficult to compare agents, and in an ideal world, a prospective trial could assess the best approach to anemia in patients with MF.
“Pacritinib led to significant numbers of patients having improvement in their hemoglobin levels in a manner that’s like the way momelotinib works,” Dr. Gerds said. “To me, the take-home point is that in patients who have MF and anemia, you want to think about pacritinib as a possible treatment for their anemia.”
Any conflicts of interest declared by the authors can be found in the original article.
References
- Oh ST, Mesa RA, Harrison CN, et al. Pacritinib is a potent ACVR1 inhibitor with significant anemia benefit in patients with myelofibrosis. Blood Adv. 2023;7(19):5835-5842.
- Mascarenhas J, Hoffman R, Talpaz M, et al. Pacritinib vs best available therapy, including ruxolitinib, in patients with myelofibrosis: a randomized clinical trial. JAMA Oncol. 2018;4(5):652-659.
- Gerds AT, Gotlib J, Abdelmessieh P, et al. Myeloproliferative neoplasms. Version 2.2023. NCCN Clinical Practice Guidelines in Oncology. https://www.nccn.org/guidelines/recently-published-guidelines.