Treatment options in patients with myelofibrosis

Patients diagnosed with myelofibrosis (MF) predominantly experience a cytogenetic abnormality within the JAK/STAT signaling pathway, which leads to marrow fibrosis, myleoproliferation, and abnormal inflammatory cytokine signaling.

The risk of leukemic transformation and vascular complications in this patient population is relatively high. In contrast, the JAK/STAT signaling pathway represents a highly suitable therapeutic target, which has given rise to a number of successfully approved janus kinase inhibitor (JAKi) therapies, shown to have a significant impact on symptom response and survival. To learn more about JAKi treatments, take a look at our dedicated section on the MPN Hub here.

During the Society of Hematologic Oncology (SOHO) Annual Congress 2023, Anthony Hunter gave a presentation on how to choose and properly use a JAKi for the treatment of MF.¹ We summarize the key points from his presentation below.

JAK inhibitors for MF

Ruxolitinib

• Ruxolitinib (Rux) was the first successfully approved JAKi therapy that showed clinical activity against JAK-1 and JAK-2 receptors.
• The approval was based on the results collected in the COMFORT-1 (NCT00952289) and COMFORT-2 (NCT00934544) trials, which have previously been reported on the MPN Hub.
  • The results showed significant improvements in total symptom score and spleen volume reduction.
  • Subsequent real-world analysis has further highlighted long-term overall survival benefits.
• Currently, Rux is the standard of care for patients with symptomatic, high-risk patients with MF.
• More recent analysis has also shown clinical benefit in symptomatic, low-risk patients.
• Dose titration has been shown to impact response, with greater symptom response and spleen volume reduction observed at higher dose intensities.
  • However, disease modification appears to be minimal.

Fedratinib

• Fedratinib was the second JAKi therapy to be approved and showed selective JAK-2 receptor inhibition.
  • Approval was based on the results from the JAKARTA (NCT01437787) and JAKARTA2 (NCT01523171) trials, previously reported on the MPN Hub.
• While significant improvements in spleen and symptom response were observed, a higher proportion of gastrointestinal adverse events were observed compared with Rux.
  • However, these were manageable with antiemetics and antidiarrheals.
• Fedratinib is primarily used in the second-line treatment setting if a patient is  refractory or intolerant to Rux.

Pacritinib

• Pacritinib is the most recently approved JAKi therapy.
  • It’s approval was based on the results from the PERSIST-1 (NCT01773187) and PERSIST-2 (NCT02055781) phase III trials, previously reported by the MPN Hub.
• Pacritinib is specifically used in thrombocytopenic patients with MF with a platelet count <50 × 10⁹/L.
  • Continuous treatment with pacritinib was associated with stable platelet levels.
• Similar to fedratinib, an increased proportion of patients experienced gastrointestinal adverse events.
• Pacritinib is also used in the second-line treatment setting if a patient becomes refractory or intolerant to Rux.
• Pacritinib has demonstrated clinical activity against ACVR1, which may confer a benefit in improving anemia, potentially more potently than the effects of momelotinib therapy.

Momelotinib

• Momelotinib is currently under review by the United States Food and Drug Administration with approval expected in September 2023.
• Results from the SIMPLIFY-1 (NCT01969838) and SIMPLIFY-2 (NCT02101268) phase III trials are being used as the basis for potential approval and have been reported by the MPN Hub.
• Therapeutic activity is the inhibition of ACVR1, and therefore, is particularly effective in patients with pre-existing anemia.

• If approval is successful, momelotinib is expected to be used as a second-line therapy option for patients who are refractory or intolerant to Rux.

Challenges with JAK inhibitors

• One of the main challenges associated with JAKI treatment is the development of cytopenias leading to early treatment discontinuation.
  • If discontinuation is required, patients should reduce treatment over several weeks to avoid withdrawal syndrome.
• Both Rux and fedratinib have high rates of hematologic toxicity, including Grade 3 and 4 anemias.
• While baseline anemia has been found to impact survival with Rux, treatment emergent anemia regardless of a pre-existing condition, does not appear to worsen survival.
• Patient survival outcomes after becoming refractory or intolerant to Rux are poor.
  • The real-world data shows that median Rux treatment duration was 1–1.5 years.

Conclusion

While not all patients with MF require JAKi therapy at diagnosis, Rux remains the standard of care for a large proportion of patients. The more recently approved JAKi are generally reserved for second-line treatment, when patients become intolerant or refractory to Rux. However, pacritinib is an exception and is used as a first-line therapy for thrombocytopenic patients with MF. Although the treatment landscape for JAKi has rapidly improved over the last decade, clinical trials and allogeneic-hematopoietic stem cell transplantation should also be considered whenever possible.