Ruxolitinib Plus Pegylated Interferon Alfa-2a Is Safe and Effective in Newly-Diagnosed PV

The combination of ruxolitinib (Jakafi) and low-dose pegylated interferon alfa-2a (Peg-IFN-α2a; Pegasys) increased cell counts, bone marrow cellularity, and fibrosis; decreased JAK2 V617F variant allele frequency (VAF); and had acceptable toxicity in patients with newly diagnosed polycythemia vera (PV), according to 2-year end-of-study results from the phase 2 COMBI II trial (EudraCT2018-004150-13) published in Blood Advances.¹

In the efficacy analysis, 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 medianJAK2 V617F VAF after 2 years decreased from 47% (95% CI, 35%-59%) at baseline to 7% (95% CI, 3%-15%). The majority of patients who achieved a CR also had an MR, excepting 1 patient with a JAK2 V617F VAF that decreased from 8.3% at baseline to 0.51% at 24 months.

Bone marrow histological remission (BMHR) was observed in 20% and 16% of patients at 12 and 24 months, respectively. Among 2 patients who achieved BMHR at 12 months, and an additional patient who achieved BMHR at 24 months, complete peripheral blood cell count remission (PBCR) was achieved; however, these patients did not fulfill the criteria for symptom remission. Partial responses at 24 months with a technically unsuccessful bone marrow biopsy were observed in 3 patients, 1 of whom had a BMHR at 12 months. At 12 months, 22 patients had a PBCR; this increased to 23 patients by 24 months. Only 6 patients had a PBCR at baseline.

Computed tomography–verified splenomegaly was present at baseline in 3 patients, 2 of whom had a normal spleen after 12 months. All patients displayed a normal spleen after 24 months. Notably, 1 patient who progressed to post-PV myelofibrosis developed splenomegaly during the study.

“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 JAK2V617F VAF, along with histological responses and even normalization of bone marrow in a subset of patients within 2 years,” lead study author Anders Lindholm Sørensen, PhD, of the Department of Hematology at Zealand University Hospital in Roskilde, Denmark, and coauthors, wrote in the paper.

Data From COMBI I Study Support Initiation of COMBI II

Previously reported data from the COMBI I trial established the safety and efficacy of Peg-IFN-α2a plus ruxolitinib in patients with PV and myelofibrosis. According to final 2-year data, 31% of patients with PV (n = 32) achieved remission with the combination, 9% of which were complete remissions.2 The cumulative incidence of peripheral blood count remission was 0.85 in this patient population. After 2 years, the Myeloproliferative Neoplasm Symptom Assessment Form total symptom score (TSS) decreased from 22 (95% CI, 16-29) at baseline to 15 (95% CI, 10-22), and the median JAK2 V617F allele burden decreased from 47% (95% CI, 33%-61%) to 12% (95% CI, 6%-22%).

Notably, 36 patients in the COMBI I study were intolerant or refractory to Peg-IFN-α2a monotherapy, as well as hydroxyurea. Of these patients, 86% completed the study and 67% received Peg-IFN-α2a during the study. The majority of patients also required ruxolitinib dose reductions from 20 mg twice daily to 10 mg twice daily.

Accordingly, the COMBI II study was designed to validate the safety and efficacy of this regimen in newly diagnosed patients with PV at this reduced dose of ruxolitinib.¹

COMBI II: Study Overview

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. Eligibility was also contingent on evidence of active disease, defined as 1 or more of the following: need for phlebotomy; white blood cell and platelet counts of 10 × 10⁹ per liter or greater and 400 × 10⁹/L or greater; constitutional symptoms; pruritus; symptomatic splenomegaly; or previous thrombosis.

Exclusion criteria included pregnancy; allergic hypersensitivity to study medications; an ECOG performance status of 3 or greater; other active malignancy within 5 years (except nonmelanoma skin cancer and prostate cancer without the need for treatment); and white blood cell and platelet counts of less than 1.5 × 10⁹/L and 100 × 10⁹/L, respectively. Patients who withdrew consent or did not receive any study medication for 6 months were unenrolled from the study.

Investigators noted that, “The inclusion criteria used in this trial do not directly reflect the European LeukemiaNet guidelines for the initiation of cytoreductive treatment. Indeed, both high- and low-risk patients with PV were included. This is similar to most contemporary clinical trials in patients with PV where criteria like splenomegaly, need for frequent phlebotomies, vasomotor symptoms, diabetes or hypertension have been considered high-risk factors.”

Prior to treatment initiation, patients underwent pretreated with phlebotomies in accordance with normal practice. Notably, high-risk patients, defined as patient aged 60 years or older or those with prior thromboembolic events, were treated with hydroxyurea per investigator’s discretion; this ceased 1 week before protocol treatment initiation.

Study treatment was self-administered and consisted of 45 μg of Peg-IFN-α2a per week and 10 mg of oral ruxolitinib twice daily. Dosing was adjusted according to toxicity and efficacy. Moreover, all patients with no evidence of bleeding received 75 mg of acetylsalicylic acid per day, unless treated with another platelet inhibitor or anticoagulant. Study visits occurred at baseline, 2 weeks, 1 month 3 months, and every third month after that until 2 years of treatment. Importantly, an amendment has been filed to follow-up patients until 2043 without further intervention.

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.

“A strength of our study is the investigation of bone marrow remissions, which is essential in assessing a possible disease-modifying effect of new treatments,” study authors stated.

A total of 25 patients were enrolled onto the study between 2019 to 2023. The median age of patients in the overall population was 70 years (range, 58-75). The majority of patients were male (56%) and had high-risk disease (76%). Prior thrombosis and splenomegaly were present in 20% and 12% of patients, respectively. Half of patients (IQR, 35-65) displayed JAK2 V617F VAF at diagnosis; 54 patients (IQR, 21-66) displayed this at baseline. The median hemoglobin and hematocrit levels were 13.8 g/dL (IQR, 13.4-15.3) and 0.44 ((QR, 0.41-0.48), respectively. Median white blood cell counts were 9.9 x 10⁹/L (IQR, 7.3-11.4); median platelet counts were 415 x 10⁹/L (IQR, 275-570).

Discontinuation and Safety Data

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. One patient discontinued both drugs; 2 patients discontinued Peg-IFN-α2a; and 2 patients discontinued ruxolitinib and continued monotherapy with the other agent. Reasons for treatment discontinuation included anemia and other AEs; a tumor in the parotid gland; increased liver enzymes; or unclear neurological symptoms that may have been exacerbated during Peg-IFN-α2a treatment.

“Similar, or higher, rates of Peg-IFN-α2a discontinuation were reported in previous studies on Peg-IFN-α2a treatment. The discontinuation rate of Peg-IFN-α2a was higher in COMBI I; however, this was expected since all but 1 patient in COMBI I had previously been exposed to Peg-IFN-α2a,” investigators noted.

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%). Among the AEs observed, 1 patient had a grade 3 infection with pneumonia and an upper airway infection. Grade 1 and 2 depressive symptoms were reported in 36% and 16%) of patient, respectively. However, no clinical depression was diagnosed, no psychiatric treatment was needed, and no patients had to discontinue treatment due to psychiatric symptoms. Notably 1 thromboembolic AE, a non-ST elevation myocardial infarction, was reported. Grade 1/2 sensory neuropathy at any time point was observed in 68% of patients, 9 of whom reported the symptom at 3 or fewer time points without symptoms at the final evaluation.

“There was a difference in the frequencies of grade 1 to 2 AEs compared with COMBI I,” the study authors clarified. “In this study, in which safety was the primary objective, we routinely asked the patient to grade several AEs; this was not done in COMBI I study. This will inadvertently result in more AEs not necessarily related to the study drugs. Taken together, we do not believe that the toxicity profile of this treatment should raise concern.”

Patient-Reported QOL Outcomes

Although an overall reduction in TSS from baseline was observed during the 2 years of treatment, this was only significant at 2 of the visits: 14 days and 21 months. Abdominal discomfort (P < .001), night sweats (P < .001), itching (P < .05), and bone pain (P < .001) were all significantly reduced at more than half of the time points vs baseline. No TSS items were significantly reduced during the study.

“In our study, the TSS was reduced during treatment but not statistically significant like in COMBI I study. This may be due to the lower baseline symptom burden TSS 14 vs 21 or the fewer patients,” investigators stated.

Future Research Directions

Although the study was planned for 2 years, hematologic and histologic responses have been observed after several years of treatment with an interferon. Accordingly, investigators stress that responses after 2 years may underestimate the long-term clinical effect of this therapy. 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.

References

1. Sørensen AL, Skov V, Kjær L, et al. Combination therapy with ruxolitinib and pegylated interferon alfa-2a in newly diagnosed patients with polycythemia vera. Blood Adv. 2024;8(20):5416-5425. doi:10.1182/bloodadvances.2024013170
2. Sørensen AL, Mikkelsen SU, Knudsen TA, et al. Ruxolitinib and interferon-α2 combination therapy for patients with polycythemia vera or myelofibrosis: a phase II study. Haematologica. 2020;105(9):2262-2272. Published 2020 Sep 1. doi:10.3324/haematol.2019.235648