What are the unmet needs in the management of myelofibrosis-related anemia?

The MPN Hub was pleased to speak with Jean-Jacques Kiladjian, Université de Paris and Hôpital Saint-Louis, Paris, FR. We asked, What are the unmet needs in the management of myelofibrosis-related anemia?

In this interview, Kiladjian explores the impact and multifactorial causes of myelofibrosis-related anemia, with particular attention to the on-target effects of JAK inhibition. He reviews currently approved JAK inhibitors, emphasizing the anemia benefits seen with momelotinib and pacritinib. Kiladjian also underscores that JAK inhibitors alone do not completely address myelofibrosis-related anemia, highlighting the potential of JAK inhibitor-based combination therapies to address this unmet need.

Key learnings

• Anemia is a frequent complication in myelofibrosis, occurring in approximately 40% of patients at diagnosis, increasing to over 60% of patients beyond 1 year of diagnosis.¹
• Anemia with hemoglobin levels below 10 g/dL significantly worsens the prognosis of patients with myelofibrosis and is a key risk factor incorporated into prognostic scoring systems, highlighting the importance of managing myelofibrosis-related anemia effectively.
• Anemia in myelofibrosis is difficult to address due to the multifactorial causes, including ineffective erythropoiesis, splenomegaly-induced hemodilution, red blood cell sequestration, and elevated inflammation leading to impaired erythropoiesis, increased hepcidin levels, and iron deficiency.
• JAK inhibition may also cause or exacerbate myelofibrosis-related anemia. JAK2 has a key role in the JAK/STAT pathway, where activation of the pathway leads to proliferation, survival, and differentiation of hematopoietic stem cells. Therefore, inhibition of JAK2 can result in the on-target effect of anemia.
• Current approved JAK inhibitors include ruxolitinib, fedratinib, momelotinib (each EMA and FDA approved), and pacritinib (FDA approved only).
• With ruxolitinib, hemoglobin levels often decline at the start of treatment but may return to baseline after several months. In some cases, dose adjustments are needed to manage anemia, though these modifications can compromise the overall efficacy of ruxolitinib.
• In addition to JAK, momelotinib and pacritinib also inhibit ACVR1, a receptor found on hepatocytes that regulates hepcidin production. Inhibition of ACVR1 leads to decreased hepcidin production and therefore increases iron availability for erythropoiesis, resulting in increased production of red blood cells and improved hemoglobin levels.
• The Phase 3 MOMENTUM trial (NCT04173494) compared momelotinib with danazol in patients with JAKi-exposed myelofibrosis and anemia.
  • Transfusion independence at Week 24 was achieved by 30% of patients treated with momelotinib compared with 20% of those treated with danazol (p = 0.0116).²
  • Patients treated with momelotinib experienced a greater increase in hemoglobin that was maintained over time than those in the danazol group.²
• A post hoc analysis of the SIMPLIFY-1 and MOMENTUM trials revealed that, regardless of anemia severity, patients who achieved Hb >10 g/dL by Week 24 with momelotinib had numerically longer OS than those who did not.³
• Anemia remains a complex and frequent complication in myelofibrosis that is not completely addressed by JAK inhibitors alone. Though momelotinib and pacritinib have meaningful impacts on anemia, JAK inhibitor-based combination therapies may further improve myelofibrosis-associated anemia. 

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.