The combination of ruxolitinib (Jakafi) and low-dose pegylated interferon alfa-2a (Peg-IFN-α2a; Pegasys) has shown promising results in patients with newly diagnosed polycythemia vera (PV). The phase 2 COMBI II trial (EudraCT2018-004150-13), published in Blood Advances, demonstrated that this combination increased cell counts, improved bone marrow cellularity and fibrosis, decreased JAK2 V617F variant allele frequency (VAF), and had acceptable toxicity.
Efficacy Outcomes
The overall remission rate (ORR) in the total PV population (n = 25) at 12 months was 52%, comprising a 12% complete remission (CR) rate and 40% partial remission (PR) rate. At 24 months, these rates were 56%, 12%, and 44%, respectively. The overall molecular response (MR) was 52% and 68% at 12 and 24 months, respectively. Complete MR (CMR), defined as a VAF of less than 0.1%, was not achieved by any patient. Among 22 evaluable patients for PR, with a baseline JAK2 V617F VAF of at least 20, 59% achieved a PR at 12 months and 77% achieved a PR at 24 months. At a cutoff of less than 1%, the overall MR was 52% and 72% at 12 and 24 months, respectively; 4 patients had a CMR at 24 months.
A statistically significant reduction in the JAK2 V617F VAF occurred at all time points (P < .001). The median JAK2 V617F VAF after 2 years decreased from 47% (95% CI, 35%-59%) at baseline to 7% (95% CI, 3%-15%).
Bone marrow histological remission (BMHR) was observed in 20% and 16% of patients at 12 and 24 months, respectively. At 12 months, 22 patients had a peripheral blood cell count remission (PBCR); this increased to 23 patients by 24 months. Only 6 patients had a PBCR at baseline.
Safety and Tolerability
Four percent of patients on the study dropped out within 2 years. Treatment with Peg-IFN-α2a or ruxolitinib was discontinued in 16% of patients each. Adverse events (AEs) were primarily grade 1/2, and no grade 3/4 hematologic AEs were observed. These included anemia (grade 1, 68%; grade 2, 20%); thrombocytopenia (32%; 4%) and leukopenia (48%; 12%).
Insights from Lead Investigator
"The COMBI II study shows a reassuring toxicity profile of combination therapy with ruxolitinib and Peg-IFN-α2a in newly diagnosed patients with PV while supporting results from the [phase 2] COMBI I trial [EudraCT2013-003295-12] showing a very high rate of hematologic response, and a swift reduction in the JAK2 V617F VAF, along with histological responses and even normalization of bone marrow in a subset of patients within 2 years," wrote lead study author Anders Lindholm Sørensen, PhD, of the Department of Hematology at Zealand University Hospital in Roskilde, Denmark, and coauthors, in the paper.
COMBI II Trial Design
COMBI II was an investigator-initiated, single-center, open-label, single-arm phase 2 study enrolling patients at least 18 years of age with newly diagnosed PV according to 2016 World Health Organization criteria. The study’s primary end point was safety, as determined by a recording of adverse effects (AEs) during treatment and changes in quality-of-life (QOL) measurements using the MPN Symptom TSS questionnaire. The key secondary end point was efficacy, based on hematologic parameters and the JAK2 V617F VAF and assessed by both 2013 European LeukemiaNet and International Working Group-Myeloproliferative Neoplasms Research response criteria.
Future Directions
Based on these data, several post-hoc analyses with longer follow-up periods are in development and will assess long-term responses with the combination treatment alongside the rate of treatment discontinuation in patients who have achieved deep MRs.
"This study supports the previously described theory that combination therapy with RUX and Peg-IFN-α2a may be 1 of the most promising treatment options in patients with myeloproliferative neoplasms. Further analysis of this study will show how many patients can achieve stable disease without the need for cytoreductive treatment," the authors concluded.
