NCCN Guidelines Update Adds Momelotinib Below Ruxolitinib for High-, Low-Risk Myelofibrosis

Updated January 23, 2024.

In 2 updates to the National Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines in Oncology for Myeloproliferative Neoplasms momelotinib was added for the treatment of patients with high- and low-risk myelofibrosis (MF) and myelofibrosis with anemia, below ruxolitinib, which has been given category 1 status for higher risk MF, and updates were made to the treatment selection of management of MF-associated anemia and high-risk polycythemia vera (PV).

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MF is part of a group of heterogeneous disorders of the hematopoietic system collectively knowns as Philadelphia chromosome–negative myeloproliferative neoplasms (MPNs). MPNs are considered a rare disease, with the prevalence of MF in the United States estimated to be approximately 13,000, respectively.

Furthermore, MPNs are associated with symptom burdens that result in worse quality of life, functional status, and activities of daily living. Patients with MF are more likely to report symptoms such as fever, night sweats, and weight loss compared with patients with PV or essential thrombocythemia (ET).

Momelotinib is an oral Janus kinase (JAK) 1, JAK2, and activin A receptor type 1 (ACVR1) inhibitor with a recommended dosage of 200 mg orally once daily with or without food. Special considerations for the use of momelotinib also includes risk of major adverse cardiovascular events, thrombosis, and development of malignancies, especially in patients who currently smoke or previously smoked.

The treatment approach for MF is currently identical for primary MF (PMF), post-PV MF, or post-ET MF.

Treatment for lower-risk MF includes momelotinib as a category 2B drug in symptomatic patients. Symptomatic patients may be treated with category 2A drugs, including ruxolitinib, peginterferon alfa-2a, or hydroxyurea, or category 2B momelotinib.

The treatment pathway requires monitoring the response and signs/symptoms of disease progression every 3 to 6 months. For those who respond to the treatment, the guidelines recommend continuing treatment and monitoring. For those with no response or loss of response, the guidelines recommend an alternative option not used for initial treatment, such as momelotinib. The guidelines recommend that patients with disease progression are moved to a higher-risk and accelerated/blast phase MF status.

In patients with high-risk MF, momelotinib was given category 2A status for those with higher platelets (≥ 50 x 10⁹/L) who were not a transplant candidate; other drugs include ruxolitinib (category 1), fedratinib (category 1), or pacritinib (category 2B). Similarly, the guidelines recommend monitoring patients every 3 to 6 months, continuing treatment for those with a response, recommending a clinical trial or alternative JAK inhibitor not used before for those with no response or loss of response, and accelerated/blast phase MF status for those with disease progression.

For the management of MF-associated anemia, the guideline recommends ruling out coexisting causes, such as bleeding; iron, vitamin B₁₂, or folate deficiency; and hemolysis. After treating coexisting causes, the guidelines segment the treatment selection:

• In the presence of symptomatic splenomegaly and/or constitutional symptoms, the preferred regimen for patients currently controlled on a JAK inhibitor is a clinical trial, with other recommended regimens being ruxolitinib in combination with luspatercept-aamt, erythropoiesis-stimulating agents (ESAs; if serum erythropoetin [EPO] ≤ 500 mU/mL), or danazol.
  • Ruxolitinib in combination with luspatercept-aamt or ESAs were category 2A
  • Ruxolitinib with danazol was category 2B
  • Momelotinib and pacritinib were listed as useful in certain circumstances
• In the presence of symptomatic splenomegaly and/or constitutional symptoms, the preferred regimen for patients currently not controlled is either a clinical trial or momelotinib, while pacritinib, and ruxolitinib in combination with luspatercept-aamt, ESAs (if serum EPO ≤ 500 mU/mL), or danazol were listed as other recommended regimens
  • Ruxolitinib in combination with luspatercept-aamt and pacritinib were both category 2A
  • Ruxolitinib with ESAs and danazol were both category 2B
• For patients with anemia and symptomatic splenomegaly and/or constitutional symptoms, the preferred regimen is a clinical trial, with other recommended regimens being luspatercept-aamt, ESAs, (if serum EPO ≤ 500 mU/mL), and danazol all category 2A, in addition to momelotinib and pacritinib, both category 2B
  • Lenalidomide plus prednisone for del(5q) was listed as useful in certain circumstances (category 2B)

For treatment of high-risk PV, ruxolitinib was added as a treatment considered useful in certain circumstances as a front-line treatment. After treatment, patients should be monitored for new thrombosis or bleeding, and their response monitored for signs or symptoms of disease progression. For patients who have inadequate response or loss of response and hydroxyurea resistance or tolerance, ruxolitinib is a category 1 preferred regimen.

Reference

NCCN. Clinical Practice Guidelines in Oncology. Myeloproliferative neoplasms, version 3.2023. Accessed November 21, 2023. https://www.nccn.org/professionals/physician_gls/pdf/mpn.pdf