Pegylated interferon (PEG-IFN) alpha was equally effective as hydroxyurea at normalizing blood counts and reducing thrombotic events in patients with high-risk essential thrombocythemia (ET) or polycythemia vera (PV), according to study results published in Blood. Researchers led by John Mascarenhas, MD, of Icahn School of Medicine at Mount Sinai in New York, suggested that given the similar efficacy between these agents, the choice of treatment for high-risk ET and PV should be tailored to the individual patient.
“These results are important as they confirm that patients with ET or PV can benefit from either drug option as it relates to thrombosis risk reduction, and the treatment plan for each patient must be personalized,” explained Dr. Mascarenhas. For instance, interferon-alpha may be particularly appealing in younger patients with ET or PV who are at high-risk for thrombosis, “as the potential for progressive events over their lifetime is greater and this option may provide additional benefit beyond the more immediate thrombosis risk reduction, which appears to be equivalent with both treatments.”
In the study, the Myeloproliferative Disorders Research Consortium (MPD-RC) performed an investigator-initiated phase III trial to assess the efficacy and safety of hydroxyurea or PEG-IFN alpha in treatment-naïve patients with high-risk ET or PV. The primary endpoint was the 12-month complete response (CR) rate.
The overall cohort included a total of 168 patients, 81 with ET and 87 with PV, who received treatment for a median of 81.0 weeks. Eighty-six patients received hydroxyurea and 82 patients received PEG-IFN alpha. High-risk disease was defined by one of the following: history of thrombosis, age greater than 60 years, history of bleeding (ET only), platelet count >1,500 × 109/L in ET and >1,000 × 109/L in PV, vasomotor symptoms (e.g., erythromelalgia, severe migraine headaches), significant or symptomatic splenomegaly, and the presence of diabetes or hypertension requiring pharmacologic intervention. The most frequent myeloproliferative neoplasm (MPN) driver mutation was JAK2 V617F (91%). At baseline, the median JAK2 V617F allelic burden was 13% in patients with ET and 35% in patients with PV.
At 12 months, there was no significant difference between the hydroxyurea and PEG-IFN alpha groups in terms of complete hematologic response (37% vs. 35%, respectively; p=0.8). After a two-year treatment period, the CR was 20% in the hydroxyurea group and 29% in the PEG-IFN alpha group. Additionally, the two-year overall response rate (ORR) was 41% with hydroxyurea and 60% with PEG-IFN alpha (p=0.045).
In patients with ET, driver mutation status did not predict hematologic response. Approximately 21% of hydroxyurea-treated patients and 38% of PEG-IFN alpha–treated patients lost a baseline cytogenetic abnormality during treatment.
Additionally, treatment with hydroxyurea was associated with a greater likelihood of patients achieving bone marrow histomorphologic remission, as determined by blinded central expert hematopathology review.
While the type of driver mutation was not significantly associated with response achievement in the study, an ASXL1 mutation did correlate with lower odds of achieving hematologic CR status, according to a multivariable analysis (p=0.055).
In the 162 patients (96%) assessed for adverse events (AEs), grade 3 or higher AEs were reported in 37% of patients (n=60). By assigned treatment group, grade 3 or higher AEs were observed in 28% of patients (n=22) in the hydroxyurea arm and 46% of patients (n=38) in the PEG-IFN alpha group. The investigators stated that PEG-IFN alpha–related AEs, such as flu-like symptoms, blurred vision, and injection site reaction, were common during the study. Anorexia and mucositis were observed at a significantly higher frequency in the hydroxyurea arm, while treatment with PEG-IFN alpha was more often associated with leukopenia, aspartate aminotransferase (AST) elevations, and depression.
A limitation of the study was the closure of enrollment following the accrual of 168 patients, as there was a lack of PEG-IFN alpha availability. As such, this limitation, coupled with the limited follow-up period, may affect the ability to draw conclusions on longer-term outcomes with hydroxyurea and PEG-IFN alpha in patients with ET or PV.
Dr. Mascarenhas noted that the significance of “attaining a complete molecular response in the absence of bone marrow pathologic remission,” as observed in the study, remains “unclear and deserves further investigation, particularly given the robust laboratory evidence that [PEG-IFN alpha] depletes the MPN hematopoietic stem and progenitor cell pool.”
Any conflicts of interest declared by the authors can be found in the original article.
Reference
Mascarenhas J, Kosiorek HE, Prchal JT, et al. A randomized, phase 3, trial of interferon-α versus hydroxyurea in polycythemia vera and essential thrombocythemia [published online ahead of print, 2022 Jan 10]. Blood. doi: 10.1182/blood.2021012743.