Combination Therapy with Ruxolitinib and Interferon in Newly Diagnosed Patients with Polycythemia Vera

Background: In the COMBI-I trial, we have shown that the combination treatment of Interferon-alpha-2a (IFN) and ruxolitinib is safe and efficacious in patients with polycythemia vera (PV) and myelofibrosis, who were mostly intolerant or refractory to IFN monotherapy. Interferon-alpha2 (IFN) has been used successfully for decades in the treatment of Philadelphia-negative chronic myeloproliferative neoplasms. However, 20–30% of patients are intolerant or show limited response to IFN treatment. Ruxolitinib is an anti-inflammatory agent and is used as first-line treatment in patients with myelofibrosis as well as second-line treatment in patients with PV. Combination therapy with the two agents may be more efficacious than monotherapy. Several reports suggest that after achieving a deep hematological and molecular response, treatment pause for several months to years is safe after IFN treatment. Therefore, an initial high-intensity regimen may help to control the disease allowing for treatment pause or low-dose IFN monotherapy. Herein, we report preliminary safety and efficacy data from the COMBI-II trial in patients with newly diagnosed PV.

Aims: To evaluate the safety and efficacy of combination therapy with IFN and ruxolitinib in newly diagnosed patients with PV.

Methods: A preplanned interim analysis after at least one year of treatment. Twenty-five patients with newly diagnosed PV were included. They were pretreated according to normal clinical standard with phlebotomies and, if high risk, hydroxyurea before inclusion and initiation of combination treatment. Hydroxyurea was withheld 1 week before initiation of treatment. Patients with severe kidney-, liver-, or heart disease were excluded. Initial therapy was IFN (Pegasys®) 45 μg sc/week and ruxolitinib (Jakavi®) 10 mg BID. The study duration was planned to be two years. Safety was assessed by registering all adverse events graded according to the CTCAE V 5.0. Efficacy was evaluated using the 2013 ELN and IWG-MRT response criteria. The JAK2V617F allele burden was measured using high-sensitivity real-time qPCR on whole blood with a lower detection limit of below 0.1%. Histological response, QoL data, and bone marrow MRI results will be presented in the final report.

Results: Twenty-five patients with PV were included in 2019–2021. They had a median age of 70 years; 14 were females and 11 were males. Of the 25 patients, 19 patients were high-risk and 6 were low-risk; 5 patients had previous thrombosis. The median time from accepted referral to initiation of treatment was 67 days. The median follow-up time was 21 months. At time of data evaluation, 13 patients had completed 24 months, while 24 patients had completed 12 months of treatment. One patient was withdrawn from the study early due to the development of myelofibrosis 10 months after beginning treatment. One patient was diagnosed with follicular lymphoma 9 months after initiation of treatment. One patient had an acute myocardial infarction. No other thromboembolic events occurred. No grade 3-4 infections were observed. At follow-up, 19 patients were still receiving combination therapy. One patient was receiving concomitant hydroxyurea; 1 ruxolitinib monotherapy; 1 IFN monotherapy; 1 combination of hydroxyurea and IFN; and 1 hydroxyurea monotherapy. Grade 1-2 anemia was frequent and managed with dose reductions. The median doses of ruxolitinib and IFN at follow-up were 5 mg BID and 45 μg sc/2.week, respectively.

High rates of complete hematological response were observed after 1 month of treatment (Figure 1). Three patients required phlebotomy after the first 2 weeks of treatment. The JAK2V617F allele burden was significantly reduced 3 months after the start of treatment, and continued to decline from a median of 47% (95%CI 35–59) at baseline to 6% (95%CI 3–12) after 24 months (figure 2);4 patients had a JAK2V617F allele burden < 1%, and 7 patients had a JAK2V617F allele burden below 5% at the latest measurement. No significant difference in JAK2V617F allele burden was observed between referral and initiation of the combination treatment.

Conclusion: Combination therapy with IFN and ruxolitinib is relatively well tolerated and is highly efficacious in newly diagnosed PV patients with frequent normalization of cell counts and a marked reduction of the JAK2V617F allele burden. This therapy could lead to a subsequent long-term approach with low-dose interferon or treatment pauses.