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

Abstract

Pegylated interferon α-2a (PEG-IFN-α-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-α-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 wild-type patients. These data demonstrate that PEG-IFN-α-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-α-2a.

Figure 1

Long-term follow-up of response to PEG-IFN-α-2a. (A) Hematologic response in patients with PV or ET. (B) Dynamics of JAK2V617F mutant allele burden in patients with PV or ET over time. Black horizontal lines indicate median values; black bars represent minimum and maximum values; yellow rectangular boxes represent values included between the 25% and the 75% percentiles.

Figure 2

Serial mutational analysis of genes outside of JAK2 during therapy with PEG-IFN-α-2a in patients with PV and ET. Graphical representation of serial mutational analysis in patients based on JAK2V617F allele burden response. (A) Somatic mutations in granulocyte DNA that were acquired (red boxes), retained (orange boxes), or lost (purple boxes) in follow-up samples compared with pretreatment samples. Also displayed are the JAK2V617F mutant allele burden values (determined by JAK2V617F ASP) in peripheral blood granulocyte DNA at the time in which extended mutational profiling was performed. (B) Sanger sequencing electropherograms displaying acquisition and/or loss of mutations from individual patients during the course of PEG-IFN-α-2a therapy.

Figure 3

JAK2V617F allele burden prior to and during PEG-IFN-α-2a therapy based on TET2 mutational status. Patients with JAK2V617F mutations in addition to TET2 mutations (n = 6) had a significantly higher JAK2V617F allele burden at the onset of therapy compared with their TET2 wild-type/JAK2 mutant counterparts (P = .04; Mann-Whitney U test). Moreover, patients with TET2/JAK2 comutations did not experience a significant decrement in JAK2V617F allele burden in contrast with JAK2 mutant/TET2 wild-type patients.