Molecular analysis of patients with polycythemia vera or essential thrombocythemia receiving pegylated interferon α-2a

Abstract

Key Points• Treatment with PEG- in PV and ET results in a high rate of complete hematologic and molecular responses.• Patients failing to achieve complete molecular remission tended to have higher frequencies of mutations in genes other than JAK2.Pegylated interferon a-2a (PEG-IFN-a-2a) has previously been shown to induce hematologic and molecular responses in patients with polycythemia vera (PV) or essential thrombocythemia (ET). Here we present a follow-up of a phase 2 trial with PEG-IFN-a-2a treatment in 43 PV and 40 ET patients with detailed molecular analysis. After a median follow-up of 42 months, complete hematologic response was achieved in 76% of patients with PV and 77% of those with ET. This was accompanied by complete molecular response (CMR) (ie, undetectable JAK2V617F) in 18% and 17%, of PV and ET patients, respectively. Serial sequencing of TET2, ASXL1, EZH2, DNMT3A, and IDH1/2 revealed that patients failing to achieve CMR had a higher frequency of mutations outside the Janus kinase-signal transducer and activator of transcription pathway and were more likely to acquire new mutations during therapy. Patients with both JAK2V617F and TET2 mutations at therapy onset had a higher JAK2V617F mutant allele burden and a less significant reduction in JAK2V617F allele burden compared with JAK2 mutant/TET2 wildtype patients. These data demonstrate that PEG-IFN-a-2a induces sustained CMR in a subset of PV or ET patients, and that genotypic context may influence clinical and molecular response to PEG-IFN-a-2a. (Blood. 2013;122(6):893-901)

Safety and efficacy of combination therapy of interferon‐α2 and ruxolitinib in polycythemia vera and myelofibrosis

“…Furthermore, international consensus‐based remission definitions were applied, with remission criteria not only encompassing improvement in or normalization of peripheral blood counts and spleen size, as used in multiple prior studies,9, 10, 13 but also of marrow morphology and disease‐related symptoms. The 2013 revised response criteria were published after the preparation of the study protocol; however, for the evaluation of efficacy in this interim analysis, we chose to adopt these.…”

“…Pegylated forms of IFNα2 (PEG‐IFNα2) allow administration once weekly and have proven efficacious in ET9, 10, 11, 12 and PV9, 10, 11, 12, 13, 14, 15. Patients in the early phase of MF, defined by low‐ or intermediate‐risk disease on the Dynamic International Prognostic Scoring System (DIPSS) scale,16 have also been shown to benefit from treatment with IFNα2 9, 17, 18.…”

“…Patients in the early phase of MF, defined by low‐ or intermediate‐risk disease on the Dynamic International Prognostic Scoring System (DIPSS) scale,16 have also been shown to benefit from treatment with IFNα2 9, 17, 18. Of note, in a subset of patients, long‐term treatment with IFNα2 induces deep molecular remission sustained even years after cessation of therapy 9, 10, 11, 13, 14, 15. However, the use of IFNα2 is limited by toxicity with an average discontinuation rate of 10‐30% 10, 12, 19.…”

“…Of note, in a subset of patients, long‐term treatment with IFNα2 induces deep molecular remission sustained even years after cessation of therapy 9, 10, 11, 13, 14, 15. However, the use of IFNα2 is limited by toxicity with an average discontinuation rate of 10‐30% 10, 12, 19. Moreover, in a subset of MPN patients molecular responses are absent, which is in part attributed to additional non‐driver mutations and, possibly, concurrent inflammation and oxidative stress 10, 20…”

“…However, the use of IFNα2 is limited by toxicity with an average discontinuation rate of 10‐30% 10, 12, 19. Moreover, in a subset of MPN patients molecular responses are absent, which is in part attributed to additional non‐driver mutations and, possibly, concurrent inflammation and oxidative stress 10, 20…”