What is on the horizon for the treatment of myelofibrosis-related anemia?

The MPN Hub was pleased to speak with John Mascarenhas, Icahn School of Medicine at Mount Sinai, New York, US. We asked, What is on the horizon for the treatment of myelofibrosis-related anemia?

In this interview, Mascarenhas explores the emerging strategies for myelofibrosis-associated anemia, with a focus on agents targeting the transforming growth factor-beta (TGF-β) superfamily members and hepcidin modulation, including luspatercept, elritercept, and DISC-0974. Mascarenhas notes that whether these approaches are most effective as single agents, in combination, or at specific stages of anemia progression remains to be determined.

Key learnings

• Current therapies for myelofibrosis-associated anemia include recombinant erythropoietin, danazol, and JAK inhibitors (JAKi) including momelotinib and pacritinib.
• Advances in managing myelofibrosis-associated anemia focus on inhibition of TGF-β superfamily members, including agents such as luspatercept.
• Luspatercept was tested in the phase III INDEPENDENCE study (NCT04717414). The INDEPENDENCE study did not meet its primary endpoint of red blood cell (RBC) transfusion independence during any consecutive 12-week period, starting within the first 24 weeks of treatment compared with placebo.
• In phase II studies and in clinical practice, luspatercept is well tolerated, improves hemoglobin levels, and reduces RBC transfusion requirements in patients with myelofibrosis-related anemia, and is currently recommended by the National Comprehensive Cancer Network (NCCN).²
  • Luspatercept is also being studied in combination with other therapies, including momelotinib in patients with transfusion-dependent myelofibrosis in the phase II ODYSSEY study (NCT06517875).
• Elritercept is an activin receptor type IIA ligand trap designed to bind and inhibit activin A and other select TGF-β superfamily ligands and is currently under investigation as a monotherapy and in combination with ruxolitinib in the phase II RESTORE study (NCT05037760).
  • Early data suggest that elritercept improves hemoglobin levels, transfusion burden, and symptomatology, and may also address thrombocytopenia and splenomegaly.¹
• DISC-0974 is a monoclonal antibody that blocks hemojuvelin, therefore reducing hepcidin expression, and has shown anemia benefits in patients with myelofibrosis in a phase Ib/II study (NCT05320198).³
  • Initial efficacy data suggest that DISC-0974 results in hematologic responses in patients who are transfusion-dependent or non-transfusion dependent, regardless of concomitant JAKi use.
• Ongoing development focuses on targeting the TGF-β/SMAD pathway and hepcidin modulation, offering several potential therapeutic avenues. Whether these approaches are most effective through use of single agents, combination regimens, or at specific stages of anemia progression remains to be determined.

This educational resource is independently supported by GSK. All content was developed by SES in collaboration with an expert steering committee. Funders were allowed no influence on the content of this resource.