Ruxolitinib reduces JAK2 p.V617F allele burden in patients with polycythemia vera enrolled in the RESPONSE study

Abstract

In patients with polycythemia vera (PV), an elevated JAK2 p.V617F allele burden is associated with indicators of more severe disease (e.g., leukocytosis, splenomegaly, and increased thrombosis risk); however, correlations between allele burden reductions and clinical benefit in patients with PV have not been extensively evaluated in a randomized trial. This exploratory analysis from the multicenter, open-label, phase 3 Randomized Study of Efficacy and Safety in Polycythemia Vera With JAK Inhibitor INCB018424 Versus Best Supportive Care trial evaluated the long-term effect of ruxolitinib treatment on JAK2 p.V617F allele burden in patients with PV. Evaluable JAK2 p.V617F-positive patients randomized to ruxolitinib (n = 107) or best available therapy (BAT) who crossed over to ruxolitinib at week 32 (n = 97) had consistent JAK2 p.V617F allele burden reductions throughout the study. At all time points measured (up to weeks 208 [ruxolitinib-randomized] and 176 [ruxolitinib crossover]), mean changes from baseline over time in JAK2 p.V617F allele burden ranged from −12.2 to −40.0% (ruxolitinib-randomized) and −6.3 to −17.8% (ruxolitinib crossover). Complete or partial molecular response was observed in 3 patients (ruxolitinib-randomized, n = 2; ruxolitinib crossover, n = 1) and 54 patients (ruxolitinib-randomized, n = 33; ruxolitinib crossover, n = 20; BAT, n = 1), respectively. Among patients treated with interferon as BAT (n = 13), the mean maximal reduction in allele burden from baseline was 25.6% after crossover to ruxolitinib versus 6.6% before crossover. Collectively, the data from this exploratory analysis suggest that ruxolitinib treatment for up to 4 years provides progressive reductions in JAK2 p.V617F allele burden in patients with PV who are resistant to or intolerant of hydroxyurea. The relationship between allele burden changes and clinical outcomes in patients with PV remains unclear.Electronic supplementary materialThe online version of this article (doi:10.1007/s00277-017-2994-x) contains supplementary material, which is available to authorized users.

A guideline for the diagnosis and management of polycythaemia vera. A British Society for Haematology Guideline

“…Thromboembolic events were more frequent in the BAT arm but this was not a pre‐determined outcome. Data published from this study also suggested that molecular responses can occur, perhaps to the same extent as with IFN (Pieri et al , ; Vannucchi et al , ) and that even profoundly iron deficient patients can normalise their iron parameters with ruxolitinib therapy (Verstovsek et al , ). Disease transformation occurred and there is no information to suggest that ruxolitinib therapy impacts these events.…”

Investigational histone deacetylase inhibitors (HDACi) in myeloproliferative neoplasms

“…(44) Longer term follow-up of the RESPONSE trial has shown a steady decrease in the JAK2 V617F allele burden among patients originally randomized to ruxolitinib (22% mean reduction at weak 80, 40% by week 208). (96, 97) While the significance of JAK2 V617F allele burden reduction in MPN remains unknown, these findings underscore the fact that this action is not unique to HDACI. Finally, given the success of pegylated interferon alfa-2a in PV,(98, 99) a longer acting interferon, ropeginterferon alfa-2b, which allows administration every 2 weeks, has been developed.…”

Developmental Therapeutics in Myeloproliferative Neoplasms

“…29 The mean percent change from baseline JAK2 V617F allele burden among the 104 patients randomized to ruxolitinib was −40% at week 208. 30 …”