Dr Shammo on Future Research Investigating Combination Regimens in Myelofibrosis

“[The results of this case study speak] to how we should be thinking about combination therapies in the future. If you [administer the agents] sequentially, then you [must be] comfortable with the adverse effect profile of one drug, [so when] you add the second drug, [the toxicities] becomes a bit easier [to manage].”

Jamile M. Shammo, MD, a professor of medicine (hematology and oncology), as well as the Dr. Marjorie C. Barnett – Dr. Hau C. Kwaan Professor at Northwestern University’s Feinberg School of Medicine, discussed the evolving use of JAK inhibitor–based combination regimens for patients with transfusion-dependent myelofibrosis.

Shammo coauthored a case study that involved an older patient with heavily pretreated, intermediate-2–risk primary myelofibrosis. This patient had previously responded to ruxolitinib (Jakafi) but later became transfusion dependent and subsequently achieved transfusion independence with fedratinib (Inrebic) plus luspatercept-aamt (Reblozyl). The decision to use luspatercept was partially influenced by the agent’s FDA approval for the first-line treatment of anemia in patients with lower-risk myelodysplastic syndrome, where it demonstrated efficacy in reducing transfusion dependence, Shammo began. Given luspatercept’s mechanism of action, which involves the modulation of cytokine signaling and erythropoiesis, the study authors hypothesized that the agent would synergize with fedratinib’s spleen-reducing activity, she said. The patient experienced clinical benefit with this combination, although there were periods during which luspatercept was withheld due to hemoglobin levels exceeding the 11 g/dL threshold required for administering the next dose, she explained.

This case study underscores the potential for sequentially administering these agents to manage toxicities and optimize responses, Shammo emphasized. Notably, this patient began receiving fedratinib monotherapy before receiving luspatercept, which allowed for better monitoring of adverse effects and treatment tolerance, she noted. Evidence from the phase 2 ACE-536-MF-001 trial (NCT03194542) supports this strategy. The study showed that patients with myeloproliferative neoplasm–associated myelofibrosis and transfusion-dependent anemia who received stable ruxolitinib dosing derived benefit from the addition of luspatercept to their treatment regimen, she reported.

Overall, the myelofibrosis treatment paradigm is undergoing a broad shift toward the use of combination regimens, according to Shammo. Although the addition of agents like navitoclax and pelabresib to ruxolitinib has improved spleen volume reduction rates compared with ruxolitinib monotherapy, these combinations have not consistently improved symptom scores in clinical trials, raising concerns about their effects on quality of life (QOL), she stated. Enhancing clinical responses during treatment is critical but maintaining a manageable toxicity profile and preserving patient QOL are also important goals that influence treatment selection, she said.

Ongoing trials, including the phase 3 INDEPENDENCE trial (NCT04717414), will be important for further defining the role of luspatercept in myelofibrosis combination regimens, Shammo explained. Additionally, emerging combination approaches with selinexor (Xpovio), MDM2 inhibitors, and interferons could provide more personalized and effective regimens for patients with myelofibrosis in the future, she concluded.