Considerations for Selection and Sequencing in Polycythemia Vera and Myelofibrosis

Ruxolitinib (Jakafi) remains a reliable treatment option for patients with polycythemia vera and myelofibrosis, even with more novel and FDA-approved JAK inhibitors on the rise, according to Naseema Gangat, MBBS.

Of note, studies such as the phase 3 RESPONSE trial (NCT01243944) have demonstrated the long-term efficacy and safety of ruxolitinib for the treatment of patients with polycythemia vera.1 At the 5-year follow-up, the probability of maintaining primary composite response (CR) was 74% (95% CI, 51%-88%), and the probability of maintaining complete hematological remission was 55% (95% CI, 32%-73%). In the intention-to-treat population, the probability of survival at 5 years was 91.9% (95% CI, 84.4%-95.9%) with ruxolitinib compared with 91.0% (95% CI, 82.8%-95.4%) with best available therapy (BAT).

Furthermore, in the myelofibrosis space, momelotinib (Ojjaara) still stands as the most recent JAK inhibitor FDA-approved, gaining the nod in September 2023 for patients with intermediate or high-risk myelofibrosis, including primary myelofibrosis or secondary myelofibrosis, and anemia.2 The regulatory decision was based on findings from the phase 3 MOMENTUM trial (NCT04173494), which demonstrated that 25% of patients treated with momelotinib experienced a Myelofibrosis Symptom Assessment Form 4.0 total symptom score of 50% or more compared with 9% of those treated with danazol, showing a treatment difference of 16% (95% CI, 6%-26%; P < .01).3

However, ruxolitinib continues to demonstrate improved spleen size reduction and tolerability compared with momelotinib, Gangat explained, making individualized treatment selection important in the myelofibrosis space.

“I'm hopeful that there's going to be more ruxolitinib use in clinical practice, despite the availability of the other agents [for myelofibrosis],” Gangat said in an interview with OncLive® following a State of the Science Summit™ on hematologic malignancies, which she chaired. “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 [AE] profiles, particularly gastrointestinal toxicity.”

During the interview, Gangat highlighted the role of ruxolitinib in polycythemia vera and myelofibrosis; what data from the phase 3 RESPONSE, phase 3 RESPONSE-2 (NCT02038036), and phase 2 MAJIC-PV (ISRCTN61925716) trials have provided for the polycythemia vera landscape; and the growing armamentarium of JAK inhibitors in the myelofibrosis space.

Gangat is a professor of medicine and consultant in hematology at Mayo Clinic in Rochester, Minnesota.

OncLive: How does ruxolitinib currently fit into the polycythemia vera treatment paradigm?

Gangat: [Currently], ruxolitinib is an [FDA-]approved therapy for [patients with] polycythemia vera who are refractory or resistant [to hydroxyurea], and it is [mainly] used as a second-line treatment. Typically, [based on factors including] older age, thrombosis history, or hematocrit control, we go with hydroxyurea as a first-line therapy. A close competitor of hydroxyurea is the interferon-based treatments, particularly the long-acting ropeginterferon alfa-2b-njft [Besremi], which is also [FDA-]approved for polycythemia vera. In our practice, ruxolitinib is a second-line treatment, particularly when patients have been intolerant or resistant to hydroxyurea treatment. However, there are emerging data [showing] that ruxolitinib can reduce the JAK2 burdens, and so can ropeginterferon alfa-2b.

The comparisons [in polycythemia vera] have been mainly between the BAT and ruxolitinib, which has been mostly a hydroxyurea-based treatment. 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. Ruxolitinib is a good agent if a patient has splenomegaly, constitutional symptoms, and itching, which can be alleviated. [Ruxolitinib also] leads to good symptom and hematocrit control, compared with the BATs, and in the [phase 3] RESPONSE trial, as well as the [phase 2] MAJIC-PV study, the majority of patients had hydroxyurea use, but a subset of patients would also have had interferon use in the BAT arm. In comparison, ruxolitinib definitely had superior hematocrit control, which is not surprising, since it is a myelosuppressive agent, and it led to better symptom control, which all correlated with reductions in the JAK2 allele burden.

What did data from the RESPONSE and RESPONSE-2 trials reveal?

The RESPONSE and RESPONSE-2 studies [randomly assigned] patients to ruxolitinib vs BAT. [More than] half of the patients had hydroxyurea, BAT, and [6%] had interferon. The primary end point was hematocrit control; two-thirds of patients in the ruxolitinib arm had hematocrit control below 45%, and that was maintained even in long-term follow-up. Symptom control, similarly, was markedly superior in the ruxolitinib arm compared with BAT. Based on that, it was felt that ruxolitinib may be a better option if you need better hematocrit control and better symptom control, especially in patients who are not responding or are intolerant to BAT.

What were the implications of data from the MAJIC-PV trial?

The key efficacy data were the complete response [CR] rate. CR was defined as hematocrit control, not needing phlebotomy within 3 months, having a normal white [blood cell] count, platelet count, and no splenomegaly. The CR rates were higher with ruxolitinib compared with BAT, and the event-free survival was also improved with ruxolitinib, which was a composite of thrombosis, hemorrhage, disease transformation, and death; all those correlated with the changes in the JAK2 [allele] burden.

How did these data help inform treatment decision-making in clinical practice?

Ruxolitinib is currently used as a second-line agent in clinical practice. 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. Although the risk is low, there can be shingles. There [is] a risk for fungal infections because [the agent] suppresses your cell-mediated immunity. You want to use ruxolitinib when it's needed. If hydroxyurea or interferon is [inadequately] controlling symptoms, then perhaps it is not necessarily a good idea to put them on ruxolitinib and needing it long term because of the long-term nature of therapy.

In the myelofibrosis realm, how has ruxolitinib set the stage for other JAK inhibitors?

Ruxolitinib was the first JAK inhibitor on the market [after being] FDA-approved in 2011. It was a breakthrough for patients with myelofibrosis because prior to ruxolitinib, there were no other effective therapies. It is an extremely potent agent in reducing spleen size, improving symptoms, leading to improved appetite, weight gain, itching relief, and bone pain relief. It has changed the treatment paradigm for our patients in terms of quality of life. However, there are a few limitations of ruxolitinib, such as anemia and thrombocytopenia, but over the past decade, we have learned that it is possible to overcome some of the limitations by using combination therapies.

There are also ways to improve the potency of ruxolitinib by adding other agents [that are not yet FDA-approved]. There's still quite a bit of investigation going on combining ruxolitinib with any anti-anemia agents and the new JAK inhibitors have been on the market the last couple of years, specifically momelotinib, which was [FDA-]approved specifically for anemia related to myelofibrosis. [Momelotinib] does have a superior anemia profile compared with ruxolitinib, but regarding spleen and tolerability, it is inferior to ruxolitinib. The net gain of the availability of ruxolitinib is a major advance in the field, and now there are only more and more efforts to improve upon that by overcoming its limitations.

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 AEs. If a patient is anemic, then momelotinib is perhaps a better option because you don't want your patients to start needing transfusions. There are more and more anti-anemia drugs being developed, and in the future, there may be potential to use more and more ruxolitinib in the first line in combination with those drugs.

References

1. Kiladjian JJ, Zachee P, Hino M, et al. Long-term efficacy and safety of ruxolitinib versus best available therapy in polycythaemia vera (RESPONSE): 5-year follow up of a phase 3 study. Lancet Haematol. 2020;7(3):e226-e237. doi:10.1016/S2352-3026(19)30207-8
2. Ojjaara (momelotinib) approved in the US as the first and only treatment indicated for myelofibrosis patients with anemia. News release. GlaxoSmithKline. September 15, 2023. Accessed August 20, 2025. https://www.gsk.com/en-gb/media/press-releases/ojjaara-momelotinib-approved-in-the-us-as-the-first-and-only-treatment-indicated-for-myelofibrosis-patients-with-anaemia
3. Verstovsek S, Gerds AT, Vannucchi AM, et al. Momelotinib versus danazol in symptomatic patients with anaemia and myelofibrosis (MOMENTUM): results from an international, double-blind, randomised, controlled, phase 3 study. Lancet. 2023;401(10373):269-280. doi:10.1016/S0140-6736(22)02036-0