The Role of JAK Inhibitors for Treating Myelofibrosis

Myelofibrosis (MF) is categorized by progressive bone marrow fibrosis, inefficient hematopoiesis, and reduced survival, and the etiology of the condition is unknown. Clinical presentation includes anemia, splenomegaly, fever, weight loss, night sweats, abdominal pain, early satiety, hepatomegaly, and pruritus. Goals of treatment for MF include symptom control, alleviating anemia, reducing the risk of thrombotic events, and increasing survival.

During a presentation at the Asembia 2020 Summit, Julianne O. Darling, PharmD, BCOP, outpatient oncology clinical pharmacist at the Indiana University Simon Cancer Center

In Indianapolis, IN, and Jeff Reichard, PharmD, MS, BCOP, director of pharmacy at University of North Carolina Health in Durham, NC, discussed the use of Janus kinase (JAK) inhibitors for the treatment of MF, as well as the specialty pharmacist’s role in patient care.

Guideline-directed therapy for MF includes hematopoietic cell transplantation, chemotherapy, and anemia treatment, including immunomodulators, corticosteroids, and erythropoiesis-stimulating agents. “Typically, in MF, we are focused on reducing the spleen size since this has been directly linked to overall survival (OS) benefit,” said Dr. Darling. “We also want to ensure that we are adequately controlling the patient’s symptom burden … and alleviating anemia while also trying to reduce the need for red blood cell transfusions.”

Dr. Darling discussed clinical trial data for JAK inhibitors, which have changed the treatment landscape for myeloproliferative neoplasms, including MF. Ruxolitinib is a JAK1 and JAK2 inhibitor approved by the Food and Drug Administration (FDA) for intermediate- or high-risk MF. The average wholesale price (AWP) is $270.08 per tablet. The randomized, double-blind, phase III COMFORT trial assessed oral ruxolitinib twice daily (n=155) versus placebo (n=154) in patients with MF. The proportion of patients with a ≥35% reduction in spleen volume at week 24 was 41.9% in the ruxolitinib arm and 0.7% in the placebo arm (P<0.001). There was a mean reduction in spleen volume of 31.6% and 8.1%, respectively. Common adverse events (AEs) associated with ruxolitinib are anemia, thrombocytopenia, fatigue, and diarrhea.

In the open-label, randomized, phase III COMFORT II trial, ruxolitinib (n=146) was assessed versus best available therapy (n=73). The proportion of patients with a ≥35% reduction in spleen volume at week 48 was 28% in the ruxolitinib arm and 0% in the best available therapy arm (P<0.001). Change in spleen volume at week 48 was –30.1% and 7.3%, respectively (P<0.001). Median OS was 5.3 years for patients treated with ruxolitinib versus 3.8 years in the best available therapy group (P=0.0065).

Fedratinib is a selective JAK2 inhibitor that is FDA-approved to treat intermediate-2 or high-risk primary or secondary MF. AWP is $210 per capsule. The randomized, double-blind, phase III JAKARTA study compared oral fedratinib 400 mg (n=96) or 500 mg (n=97) once daily versus placebo (n=96). The proportion of patients with a ≥35% reduction in spleen volume at week 24 was 36% in the fedratinib 400 mg arm, 40% in the fedratinib 500 mg arm, and 1% in the placebo arm (P<0.001). Response rates at 24 weeks were 47%, 49%, and 1%, respectively (P<0.001). Common AEs associated with fedratinib include anemia, diarrhea, thrombocytopenia, nausea, lymphopenia, and leukopenia.

Dr. Darling then discussed drugs in the pipeline for MF. Momelotinib is a JAK1, JAK2, and ACVR1 inhibitor. The multicenter, randomized, double-blind, phase III SIMPLIFY I trial comparing momelotinib 200 mg once daily versus ruxolitinib 20 mg twice daily found that the proportion of patients with a ≥35% reduction in spleen volume at week 24 was 26.5% versus 29%, respectively (P<0.011). Pacritinib is a kinase inhibitor with specificity for JAK2, FLT3, IRAK1, and CSF1R. In the randomized, open-label, phase III PERSIST II study, pacritinib 400 mg (n=75) and 200 mg (n=74) was compared to best available choice (n=72). The proportion of patients with a ≥35% reduction in spleen volume at week 24 was 15% in the pacritinib 400 mg arm, 22% in the pacritinib 200 mg arm, and 3% in the best available choice group (P<0.001).

“JAK inhibitors are not the only area of interest” for MF, said Dr. Darling, noting that other investigational agents include bromodomain and extraterminal domain inhibitor CPI-0610, luspatercept in combination with ruxolitinib, lysine-specific demethylase inhibitor bomedemstat, and recombinant human pentraxin-2 molecular PRM-151.

Then, Dr. Reichard discussed various stakeholder considerations for MF specialty medication. Manufacturers must consider medication distribution nuances, pharmacy provider selection, regulatory requirements, clinical care coordination, outcomes and quality data reporting, and patient assistance programs and financial support. Payers must consider formulary options, therapy escalation strategies, drug class management, outcomes and quality data reporting, and specifics of rare disease management. Pharmacy providers must consider care coordination requirements, formulary options, channel strategies, reporting requirements, patient treatment goals, and financial assistance programs.

Treatment should be personalized, and symptoms and thrombotic events must be controlled. The clinical care team must consider implications of disease progression toward the individualized treatment of patients with MF. A multidisciplinary team is best positioned to ensure success of patient goals, and the specialty pharmacist is an important support role for patients with MF—involved with clinical and observational onboarding, as well as financial support. “The role of the pharmacy team is integral for patients adhering to their treatments, especially in MF where symptom management and quality of life are some of the key driver to patient outcomes,” said Dr. Reichard. The specialty pharmacy team is also involved with care coordination, monitoring symptoms and disease progression, assessing treatment dose for modification or interruption needs, and supportive care medications, such as antiemetics and antidiarrheals.

Presentation: Updates in Myelofibrosis: The Significance of JAK Inhibitors in Therapy. Asembia 2020 Specialty Pharmacy Summit Virtual Experience, May 18, 2020.