Abdulraheem Yacoub, MD
About two-thirds of patients with hydroxyurea (Hydrea)-resistant/intolerant polycythemia vera (PV) or high-risk essential thrombocytopenia (ET) had objective responses to pegylated interferon alfa-2a, according to findings from a phase II study of salvage therapy presented at the 2017 ASH Annual Meeting.
Sixty-nine percent of patients with ET and 60% of patients with PV had achieved objective responses at 12 months. The overall response rates (ORR) included complete responses (CRs) in 43% of the ET group and 22% of the PV group. No new safety or toxicity signals emerged from the MPD-RC 111 study.
“Pegylated interferon alfa-2a is a reasonable second-line treatment option for patients with high-risk essential thrombocytopenia or polycythemia vera and hydroxyurea resistance or intolerance,” lead study author Abdulraheem Yacoub, MD, an associate professor of medicine at the University of Kansas Medical Center, said at ASH.
“Thrombotic events, progression of bone marrow fibrosis, as well as transformations occurred during the study follow-up. Bone marrow histologic remissions and deep molecular responses occurred in a minority of patients,” added Yacoub.
Yacoub also noted that the response rate was lower than in previous studies, probably due to the intention-to-treat (ITT) study design, advanced disease state of the patients, and adherence to strict response criteria.
Historically, interferons have long demonstrated effectiveness in ET and PV, achieving cytoreduction and inducing molecular responses in both conditions. Pegylated interferon offers more convenient dosing and better tolerance.
The investigator-initiated prospective trial by Yacoub et al evaluated pegylated interferon alfa-2a in ET/PV patients who were intolerant to hydroxyurea or whose disease had developed resistance. The study included patients with any disease duration and with high-risk features, such as older age, history of thrombosis, erythromelalgia/migraine, significant or symptomatic splenomegaly, elevated platelet count, and diabetes or hypertension.
Treatment continued for 12 months, and the primary endpoint was ORR at 12 months. Key secondary endpoints included toxicity and tolerability of pegylated interferon alfa-2a, impact of therapy on biomarkers, incidence of disease transformation, incidence of major cardiovascular events, bone marrow response, and quality of life.
There were 115 patients (65 with ET, 50 with PV) included in the data analysis and the median age was 64. Yacoub reported that 19% of the ET patients and 56% of those with PV had splenomegaly. Median disease duration was 37.3 months for patients with ET and 54.8 months for those with PV. Two-thirds of patients had ongoing therapy with hydroxyurea at enrollment.
More than 70% of the study population remained on treatment for 12 months. About 40% of patients had grade 3/4 adverse events (AEs), and 14% of patients discontinued because of AEs. The most common grade ≥3 AEs were hematologic (9%), gastrointestinal and liver-enzyme abnormalities (9%), cutaneous manifestations (5%), respiratory AEs (5%), musculoskeletal events (5%), pruritus (5%), abnormal blood pressure (4%), and hyperglycemia (4%).
The best ORRs by ITT analysis were 70.8% for ET and 64.0% for PV. Yacoub said that 96.2% of the clinical responses occurred within 12 months.
There was a significant association between objective response and shorter disease duration (33.8 vs 68.1 months; P
= .05), but objective response was not associated with mean dose of pegylated interferon alfa-2a. Age <50 was not associated with an increased likelihood of response.
Complete responses occurred more often in patients with a CALR mutation (56.3% vs 28.6%; P
= .02). Five patients had a TP53 mutation, but none achieved a CR. Three of 10 patients with ASXL1 mutations achieved CRs.
During the study, no major bleeding events occurred. Three patients had major cardiovascular events. One patient with ET had transformation to acute myeloid leukemia, and 1 patient with PV had transformation to myelofibrosis. Patients with splenomegaly at baseline (n = 40) did not have significant splenic responses.
Among 68 patients evaluable for bone marrow response, 8 patients met International Working Group criteria for CR, 7 of whom also had complete clinical responses. Seven patients had progression to grade 2+ reticulin fibrosis.
One patient developed acquired clonal cytogenetic abnormalities during the trial. Three patients with PV had disappearance of baseline clonal abnormalities, and all 3 achieved CRs.
Yacoub A, Mascarnhas J, Kosiorek HE, et al. Single-arm salvage therapy with pegylated interferon alfa-2a for patients with high-risk polycythemia vera or high-risk essential thrombocythemia who are either hydroxyurea-resistant or intolerant: final results of the myeloproliferative disorders-research consortium (MPD-RC) protocol 111 global phase II trial. Presented at: 2017 ASH Annual Meeting; December 9-12, 2017; Atlanta, GA. Abstract 321.