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Interferon alpha confers hematological, molecular benefits in essential thrombocytopenia
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Treatment with interferon alpha led to strong hematological and molecular responses in patients with essential thrombocytopenia and CALR mutations, according to study results published in Blood.
Further, additional non-driver mutations may influence molecular response to interferon alpha, according to researchers.
Few therapeutic options exists for patients with myeloproliferative neoplasms — including essential thrombocytopenia — or clonal disorders characterized by the presence of gene mutations associated with hematological parameters, clinical evolution and prognosis, according to study background.
Jean-Jacques Kiladjian, MD, PhD, of Saint-Louis Hospital in Paris, and colleagues observed favorable results in a preliminary study of interferon alpha in patients with essential thrombocytopenia and CALR mutations. Thus, they sought to validate their initial findings in a larger cohort of patients.
The study included data from 31 patients (mean age at diagnosis, 39.6 years; 65% women).
The researchers assigned patients to a mean starting dose of 496 µg per month, reduced to 230 µg per month during maintenance.
Mean follow-up was 142 months (range, 23-407) and mean treatment duration was 34.5 months (range, 5-97).
All patients achieved a hematological response, with the median CALR mutant allelic burden decreasing from 41% at baseline to 26% after treatment.
Further, two patients achieved complete molecular response.
In contrast, the median CALR mutant allelic burden remained stable over time in a series of 12 patients with essential thrombocytopenia treated with aspirin only and in a series of 14 patients treated with hydroxyurea only.
Sixty-one percent of patients (n = 19) remained on treatment with interferon alpha at time of reporting. Of the 12 patients who discontinued treatment, six ceased treatment due to toxicity and six discontinued due to achievement of complete clinical and hematological response.
The most commonly observed adverse events included positive autoantibodies (n = 3), mood changes (n = 3), asthenia (n = 3), muscle pain (n = 2), headache (n = 2) and peripheral neuropathy (n = 2).
Using next-generation sequencing, Kiladjian and colleagues identified additional mutations in six patients. The mutations affected TET2, ASXL1, IDH2 and TP53 genes. The presence of these mutations appeared associated with poorer molecular response on CALR mutant clones.
In an analysis of the evaluation of the different variant allele frequencies, mutated clones appeared to have a different sensitivity to interferon alpha in a given patient. However, no new mutation emerged during treatment.
“In conclusion, our study is the first to report on clonal evolution of CALR mutated essential thrombocytopenia patients treated with interferon alpha, showing the possible co-evolution of several subclones,” Kiladjian and colleagues wrote. “The presence of additional non-driver mutations affects the response to interferon alpha therapy, a finding that deserves further investigation to understand the underlying molecular mechanisms and possible impact on clinical outcome.” – by Cameron Kelsall
Disclosure: The researchers report no relevant financial disclosures.
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