In a phase III trial (MPD-RC 112) reported in the journal Blood, John Mascarenhas, MD, and colleagues found no difference in 12-month complete response rates between treatment with pegylated interferon-alfa vs hydroxyurea in previously untreated patients with high-risk polycythemia vera or essential thrombocythemia. 

John Mascarenhas, MD

Study Details

In the trial, 168 patients (87 with polycythemia vera and 81 with essential thrombocytopenia) from sites in North America and Europe were randomly assigned between September 2011 and June 2016 to receive hydroxyurea (n = 86; 44 with polycythemia vera and 42 with essential thrombocytopenia) or pegylated interferon-alfa (n = 82; 43 with polycythemia vera and 39 with essential thrombocythemia). Pegylated interferon-alfa was self-administered via subcutaneous injection at 45 µg weekly and titrated in 45 µg increments monthly to a maximum of 180 µg weekly; hydroxyurea was initiated at 500 mg twice daily. The JAK2 V617F driver mutation was present in 91% of patients. The primary endpoint was complete response rate at 12 months on blinded central review committee assessment.

Complete Response Rates

At 12 months, complete response was achieved in 37% of patients in the hydroxyurea group vs 35% of the pegylated interferon-alfa group (P = .80), including complete response in 30% vs 28% of patients with polycythemia vera and 45% vs 44% of patients with essential thrombocythemia. The overall response rate at 12 months was 70% in the hydroxyurea group vs 78% in the pegylated interferon-alfa group (P = .22). Complete response rates were 20% vs 29% at 24 months and 17% vs 33% at 36 months.

The median greatest change from baseline in JAK2 V617F variant allele frequency (VAF) was –5.3% in the hydroxyurea group vs –10.7% in the pegylated interferon-alfa group. Median JAK2 V617F VAF decreased consistently from baseline through month 24 in the pegylated interferon-alfa group, but increased in the hydroxyurea group after month 12, with a significantly greater reduction with pegylated interferon-alfa at 24 months (P = .002).

Among 109 evaluable patients (with pre- and posttreatment biopsy), histopathologic response was observed in 12 (23%) of 52 in the hydroxyurea group vs 3 (5%) of 57 in the pegylated interferon-alfa group (P = .01).

A total of five complication-free survival events were observed, including three in the hydroxyurea group and two in the pegylated interferon-alfa group. The cumulative incidence of thrombotic events at 24 months was 2.0% in each group.

Adverse Events

Grade ≥ 3 adverse events occurred in 28% of patients in the hydroxyurea group vs 46% of the pegylated interferon-alfa group (P = .01); the most common were neutropenia, peripheral sensory neuropathy, and urinary tract infection (4% each) in the hydroxyurea group, and fatigue and hypertension (7% each) in the pegylated interferon-alfa group. Adverse events of any grade that were more common in the hydroxyurea group included mucositis and anorexia; those more common in the pegylated interferon-alfa group included leukopenia, flu-like symptoms, injection site reactions, aspartate transaminase elevation, depression (grade 1–2 in 15% vs 3%, no grade ≥ 3), hypertension, fatigue, and lymphopenia.

The authors concluded, “At 12 months of treatment, there was no significant difference in complete response rates between hydroxyurea and pegylated [interferon-alfa]. This study indicates that pegylated [interferon-alfa] and hydroxyurea are both effective treatments for polycythemia vera and essential thrombocythemia. With longer treatment, pegylated [interferon-alfa] was more effective in normalizing blood counts and reducing driver mutation burden, while hydroxyurea produced more histopathologic responses. Despite these differences, both agents did not differ in limiting thrombotic events and disease progression in [patients with] high-risk essential thrombocythemia/polycythemia vera.”

Dr. Mascarenhas, of the Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, is the corresponding author for the Blood article.

Disclosure: The study was funded by the National Cancer Institute and by Roche Genentech. For full disclosures of the study authors, visit ashpublications.org/blood.