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Mutations in JAK2V617F, calreticulin (CALR), and thrombopoietin receptor (MPL) genes are three main driver mutations associated with the pathogenesis of myeloproliferative neoplasms (MPN), where abnormality in hematopoietic stem cells (HSC) results in hyperplasia of myeloid lineages. Interferon alpha (IFNα) has been associated with complete hematological response rate (> 70%) and substantial molecular response (> 50%) in patients with MPN, however, low rate of complete molecular response remains a concern. Amandine Tisserand et al.1 have investigated the long-term efficacy of IFNα therapy by observing allele burden in HSC and mature cells of patients with JAK2V617F and CALR mutations to identify the pattern of response in an observational, prospective study. The results were presented by Tisserand during the Virtual Edition of the 25th European Hematology Association (EHA) Annual Congress.
The median follow-up for patients with a JAK2V617F mutation and patients with CALR mutations was 53 months and 42 months, respectively. The proportions of patients achieving molecular responses to IFNα in granulocytes and different progenitors are shown in Figure 1.
Figure 1. Molecular responses to IFNα in granulocytes and different progenitors1
A Molecular response in patients with a JAK2V617F mutation B Molecular response in patients with a CALR mutation. Complete molecular response is expressed in bold.
The analysis of kinetics of JAK2V617F- and CALR-mutated cells showed the following:
Based on the mathematical model incorporated to define mechanism of action, IFNα is likely to show action by exhaustion of JAK2V617F homozygous HSC via differentiation into progenitors and then mature cells, which may explain the increase in the first year and the slow decrease thereafter.
It has been found that even low doses of IFNα were effective in targeting homozygous JAK2V617F HSCs, however, high doses (> 100 µg/week) were needed for heterozygous JAK2V617F HSCs. IFNα was least effective in targeting heterozygous CALR-mutated HSCs.
The study results suggest that IFNα can be effective in eliminating mutated HSCs and may be associated with better responses in patients with a homozygous JAK2V617F mutation, compared with heterozygous JAK2V617F or CALR mutations, when used in high doses. The increase in hematopoietic compartment during the first year may be predictive of efficacy. The authors believe that this study could be helpful to identify patients with MPN who may benefit from IFNα therapy.
Further investigation is planned to predict the IFNα response in patients based on allele burden prior to treatment, to explain the impact of other parameters, including related mutations, age, allele burden prior to treatment on the evaluation of long-term efficacy, and to discover the mechanism of action of IFNα therapy.
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