First-line Therapy in Highrisk PV: Will JAK2 Inhibitor Treatment Be the Remedy?

Study Title: MITHRIDATE: A Phase III, Randomised, Open-label, Multicenter International Trial Comparing Ruxolitinib With Either Hydroxycarbamide or Interferon Alpha as First-line Therapy for High-risk Polycythemia Vera (PV)

ClinicalTrials.gov Identifier: NCT04116502

Participating Centers: 100 centers across the United Kingdom and France

Accrual Goal: 586 patients over five years

Study Design: The trial is a phase III, randomizedcontrolled, multicenter, international, open-label trial comparing ruxolitinib versus best available therapy (BAT) in patients with high-risk PV and associated leukocytosis. BAT is a choice of interferon alfa (IFN), any formulation permitted, or hydroxycarbamide (HC); the BAT will be elected by the investigator prior to randomization. There will be no crossover either between BAT and the ruxolitinib arms or between therapies on the BAT arm. The primary objective is to compare the time to combined incidence of major thrombosis, major hemorrhage, death, and transformation to myelodysplastic syndrome, secondary acute myeloid leukemia, or post-PV myelofibrosis, with event-free survival as the primary endpoint.

Rationale: First-line therapy for high-risk patients with PV remains suboptimal; patients continue to develop thrombosis, hemorrhage, impaired quality of life, and transformation to more aggressive blood cancers (myelofibrosis, myelodysplastic syndrome, and acute myeloid leukemia). Beyond control of hematocrit and the use of aspirin, optimal first-line therapy is not yet proven, though hydroxycarbamide and IFN are in widespread use. In 2005, a mutation in JAK2 (JAK2 V617F) was identified as the biological basis of PV, which led to the development of targeted therapies for patients with myeloproliferative neoplasms such as PV for the first time. Ruxolitinib is a first-in-class JAK1/2 inhibitor that has already gained approval for second-line use in patients with PV who are resistant or intolerant to HC, and it has proven efficacy when used as first-line treatment in myelofibrosis. As a second-line therapy for PV, in patients who are resistant or intolerant to HC, ruxolitinib has also demonstrated an excellent safety profile and efficacy in terms of blood count control, spleen volume reduction, and symptom control.^1–3  This raises the question as to whether earlier treatment with ruxolitinib in the first-line setting might offer superior disease control to established BAT (both HC or IFN). A positive result from this study could lead to the development of ruxolitinib as a new first-line therapy for patients with PV.

Comment: Randomized studies in the second-line setting have shown evidence of efficacy of ruxolitinib in patients with PV who are resistant or intolerant to HC.^1–3  However, these studies were commercially sponsored and relied on short-term endpoints of efficacy in terms of hematocrit control, spleen volume reduction, and symptom improvement. The design of these studies does not allow for proper assessment of the beneficial effect of ruxolitinib on the “hard” disease endpoints of vascular events, disease transformation, and death, which requires long-term follow-up without crossover between the study arms. MITHRIDATE is an ambitious trial that will address this important question in a large prospective cohort of high-risk patients with PV in the first-line setting. A major outstanding question in the field is also whether JAK2 inhibitor therapy has the potential to alter the natural history of PV in terms of disease progression to more advanced blood cancers. Assessment of disease modification requires longterm follow-up and no crossover between study arms. Furthermore, the extensive biobanking and translational studies associated with this academic-led trial will allow a deeper analysis of the effect of HC, IFN, and ruxolitinib on disease biology over time. Supporting investigatorinitiated studies such as MITHRIDATE is absolutely crucial if we are to make definitive progress in the treatment of patients with myeloproliferative neoplasms. For those of you who wonder about the name “MITHRIDATE,” it is a semimythical remedy and antidote to poisoning dating back to the first century B.C.. Let us hope that the outcome of the trial lives up to the name!