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Single-Arm Salvage Therapy with Pegylated Interferon Alfa-2a for Patients with High-Risk PV or High-Risk Essential Thrombocythemia
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Abdulraheem Yacoub, M.D. presents from ASH 2017 on the final results of a large investigator-initiated trial of pegylated-rIFN-alfa-2a as salvage therapy for high-risk PV/ET patients with hydroxyurea-resistant or intolerance (MPD-RC 111).

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These are the final results of a single-arm salvage therapy with pegylated interferon alfa-2a in patients with high-risk polycythemia vera or high-risk essential thrombocythemia who are either hydroxyurea resistant or intolerant, the final results of the Myeloproliferative Disease Research Consortium Protocol 111 Global Phase II Trial.

Interferons are active agents in achieving cytoreduction and inducing molecular responses in essential thrombocytosis and polycythemia vera with pegylated interferons being more convenient in dosing and have improved tolerance. We carried out a large investigator initiated local trial to investigate the role of pegylated recombinant interferon alfa-2a (brand name: Pegasys) as therapy for ET and PV patients with hydroxyurea resistance or intolerance.

The MPD-RC 111 is an international phase II open label clinical trial conducted at the participating MPD-RC sites. The study was designed to include 84 patients with polycythemia vera and 84 patients with essential thrombocythemia of any disease duration. The patients had to meet the WHO criteria 2008 and they were included if they had hydroxyurea intolerance or resistance as well as high risk features. No prior interferon therapy was allowed and patients were excluded if they had uncontrolled depression or autoimmune disorders.

Study therapy consisted of pegylated recombinant interferon alfa-2a (Pegasys) administered at the dose of 45 mcg subcutaneously weekly and allowed dose titration up to 180 mcg per dose and treatment duration was for 12 months and a maximum of 4 years.  Response assessment was performed at 12 months of all patients enrolled in the study and were included in the intention to treat overall response assessment and safety analysis. Sixty-five patients with ET and 50 patients with polycythemia vera were included. The primary endpoint was overall response assessment at 12 months by central review. Response criteria were followed according to LeukemiaNet criteria with a complete response strictly meeting the combination of complete resolution of disease-worthy symptoms and normalization of the spleen size as well as normalization of the blood counts with a platelet count less than 400,000, white cell count less than 10,000 and hematocrit less than 45%.

In regard to toxicity, adverse events were common and at least 90% of subjects had a grade 1 or higher toxicity and 34% of subjects had a grade 3 or higher toxicity. Toxicities that were reported are consistent with the known adverse events of pegylated interferons. There were no deaths from trial. Despite the high rate of adverse events, discontinuation due to adverse events occurred only in 13.9% of subjects, indicating fair tolerance and manageable toxicity.

In regard to response assessment, the primary endpoint at 12 months overall response was achieved in 69% of patients with ET and 60% of patients with polycythemia vera. Most of those responses were observed in the first year.

In regard to molecular response, there was a heterogeneous response in our patients with only a small group achieving deep molecular responses with 20% of our patients achieving 50% reduction in their JAK2 allele burden of more than 50%.

In conclusion, pegylated interferon alfa has a higher activity in patients with ET and PV with prior hydroxyurea exposure. In this older cohort of patients, safety, adverse events and discontinuation rates were comparable to prior reports. Thrombotic events and progression to high-risk diseases continued to occur on the study. Full model remissions and molecular remissions were rare and we did not identify specific predictors of response in our patients, except for calreticulin mutation.

Thank you.