Ruxolitinib (Jakafi) continues to demonstrate robust long-term efficacy and maintains its position as a cornerstone therapy for patients with polycythemia vera and myelofibrosis, even as newer JAK inhibitors enter the market, according to hematology expert Naseema Gangat, MBBS, from Mayo Clinic.
Sustained Long-Term Efficacy in Polycythemia Vera
The phase 3 RESPONSE trial (NCT01243944) has provided compelling evidence for ruxolitinib's durability in polycythemia vera treatment. At the 5-year follow-up, the probability of maintaining primary composite response was 74% (95% CI, 51%-88%), while the probability of maintaining complete hematological remission reached 55% (95% CI, 32%-73%). Notably, the intention-to-treat population showed a probability of survival at 5 years of 91.9% (95% CI, 84.4%-95.9%) with ruxolitinib compared with 91.0% (95% CI, 82.8%-95.4%) with best available therapy.
"Ruxolitinib is a good agent if a patient has splenomegaly, constitutional symptoms, and itching, which can be alleviated," Gangat explained. "It leads to good symptom and hematocrit control, compared with the best available therapies."
Current Treatment Positioning
Ruxolitinib currently serves as an FDA-approved second-line therapy for patients with polycythemia vera who are refractory or resistant to hydroxyurea. The treatment selection process considers multiple factors including older age, thrombosis history, and hematocrit control requirements. Hydroxyurea remains the primary first-line option, with ropeginterferon alfa-2b-njft (Besremi) serving as a close competitor in the first-line setting.
The RESPONSE and RESPONSE-2 studies demonstrated ruxolitinib's superiority over best available therapy, with more than half of patients achieving hematocrit control below 45% in the ruxolitinib arm, a benefit that was maintained during long-term follow-up. Symptom control was markedly superior in the ruxolitinib arm compared with best available therapy.
Evolving Myelofibrosis Landscape
In myelofibrosis treatment, ruxolitinib faces competition from newer agents, particularly momelotinib (Ojjaara), which gained FDA approval in September 2023 for patients with intermediate or high-risk myelofibrosis and anemia. The phase 3 MOMENTUM trial (NCT04173494) showed that 25% of patients treated with momelotinib experienced a Myelofibrosis Symptom Assessment Form 4.0 total symptom score reduction of 50% or more compared with 9% of those treated with danazol, demonstrating a treatment difference of 16% (95% CI, 6%-26%; P < .01).
However, ruxolitinib maintains distinct advantages. "Ruxolitinib continues to demonstrate improved spleen size reduction and tolerability compared with momelotinib," Gangat noted. "Fedratinib (Inrebic) and pacritinib (Vonjo) are the other 2 JAK inhibitors on the market, but they are not utilized very commonly because of their adverse effect profiles, particularly gastrointestinal toxicity."
Treatment Selection Strategy
Gangat advocates for individualized treatment selection based on patient characteristics. "I usually go with ruxolitinib if the patient is not anemic at baseline, because it is the most tolerable JAK inhibitor. In terms of tolerability, there is no question that it has the fewest adverse effects," she explained. "If a patient is anemic, then momelotinib is perhaps a better option because you don't want your patients to start needing transfusions."
JAK2 Allele Burden Reduction
Emerging data suggest both ruxolitinib and ropeginterferon alfa-2b can reduce JAK2 burden in polycythemia vera patients. "It will be interesting to compare the reduction in JAK2 allele burdens with ruxolitinib vs ropeginterferon alfa-2b and see which one may be better," Gangat stated. The phase 2 MAJIC-PV study (ISRCTN61925716) demonstrated that ruxolitinib's superior symptom and hematocrit control correlated with reductions in JAK2 allele burden.
Future Considerations
While ruxolitinib has transformed treatment paradigms since its 2011 FDA approval, long-term use considerations remain important, particularly for younger patients. "The concern with long-term ruxolitinib use, especially for younger patients if they're going to be on treatment for a very long time, is the risk of opportunistic infections," Gangat cautioned, noting potential risks for shingles and fungal infections due to cell-mediated immunity suppression.
Despite these considerations, Gangat remains optimistic about ruxolitinib's continued role. "I'm hopeful that there's going to be more ruxolitinib use in clinical practice, despite the availability of the other agents for myelofibrosis," she concluded, emphasizing the importance of individualized treatment approaches in both polycythemia vera and myelofibrosis management.
