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

Abstract

Myeloproliferative neoplasmsare clonal disorders characterized by the presence of several gene mutations associated with particular hematologic parameters, clinical evolution, and prognosis.Few therapeutic options are available, among which interferon α (IFNα)presents interesting properties like the ability to induce hematologic responses (HRs) andmolecular responses (MRS) inpatients with JAK2 mutation.We reportonthe response to IFNatherapy in a cohort of 31 essential thrombocythemia (ET) patients with CALR mutations (mean follow-up of 11.8 years).HRwas achievedin all patients.MedianCALRmutant allelicburden (%CALR) significantly decreased from 41% at base line to 26%after treatment, and 2patients even achieved complete MR. 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 MR on CALR mutant clones, withonlyminorornoMRS in this subsetofpatients.Analysisof theevolutionof 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 IFNa induces high rates of HRs and MRS in CALR-mutated ET, and that the presence of additional nondriver mutations may influence the MR to therapy.