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Clinical and molecular response to interferon alpha therapy in essential thrombocythemia patients with CALR mutations

Emmanuelle Verger, Bruno Cassinat, Aurélie Chauveau, Christine Dosquet, Stephane Giraudier, Marie-Hélène Schlageter, Jean-Christophe Ianotto, Mohammed A. Yassin, Nader Al-Dewik, Serge Carillo, Eric Legouffe, Valerie Ugo, Christine Chomienne and Jean-Jacques Kiladjian

Key points

  • Pegylated interferon alpha induces hematological and molecular remission in CALR mutated essential thrombocythemia patients.

  • The analysis of additional mutations highlights the presence of subclones with variable evolutions during Interferon alpha therapy.

Abstract

Myeloproliferative Neoplasms (MPNs) are clonal disorders characterized by the presence of several gene mutations associated with particular hematological parameters, clinical evolution and prognosis. Few therapeutic options are available, among which Interferon alpha (IFNα) presents interesting properties like the ability to induce hematological and molecular responses in patients with JAK2 mutation. We report on the response to IFNα therapy in a cohort of 31 essential thrombocythemia (ET) patients with CALR mutations (mean follow-up of 11.8 years). Hematological response was achieved in all patients. Median CALR mutant allelic burden (%CALR) significantly decreased from 41% at baseline to 26% after treatment, and two patients even achieved complete molecular response. In contrast, %CALR was not significantly modified in ET patients treated with hydroxyurea or aspirin only. Next generation sequencing identified additional mutations in 6 patients (affecting TET2, ASXL1, IDH2 and TP53 genes). The presence of additional mutations was associated with poorer molecular response on CALR mutant clones, with only minor or no molecular responses in this subset of patients. Analysis of the evolution of the different variant allele frequencies showed that the mutated clones had a differential sensitivity to IFNα in a given patient but no new mutation emerged during treatment. In all, this study shows that IFNα induces high rates of hematological and molecular responses in CALR-mutated ET, and that the presence of additional non-driver mutations may influence the molecular response to therapy.

  • Submitted July 20, 2015.
  • Accepted October 10, 2015.