The effect of long-term ruxolitinib treatment on JAK2p.V617F allele burden in patients with myelofibrosis

Abstract

The JAK2 c.1849G>T (p.V617F) mutation leads to constitutive activation of Janus kinase (JAK)2 and contributes to dysregulated JAK signaling in myelofibrosis (MF), polycythemia vera (PV), and essential thrombocythemia (ET). In the phase 3 Controlled Myelofibrosis Study with Oral JAK Inhibitor Treatment-I trial, patients with MF, post-PV MF, or post-ET MF achieved significant reductions in splenomegaly and improvements in symptoms with ruxolitinib vs placebo at week 24. This long-term follow-up analysis was performed to determine whether ruxolitinib therapy altered the JAK2p.V617F allele burden in JAK2p.V617F-positive patients. Assessments at baseline and weeks 24, 48, 120, 144, 168, and 216 demonstrated reductions in allele burden from baseline with ruxolitinib treatment that correlated with spleen volume reductions. Of 236 JAK2p.V617F-positive patients analyzed, 20 achieved partial and 6 achieved complete molecular responses, with median times to response of 22.2 and 27.5 months, respectively. Allele burden reductions were greater in patients with shorter disease duration, which suggests a potential benefit of earlier treatment. This trial was registered at www.clinicaltrials.gov as #NCT00952289.

Figure 1

JAK2p.V617F allele burden reductions and correlations with spleen volume reductions in patients with myelofibrosis. (A) Mean percent change (±SE) in allele burden from baseline. (B) Best molecular response in individual patients randomized to ruxolitinib and in patients receiving ruxolitinib after crossover from placebo. (Inset) Change from baseline at week 24 for individuals randomized to ruxolitinib and placebo. (C) Allele burden change over time for patients achieving CMR (<2% with confirmation). Solid green lines, patients randomized to ruxolitinib; dashed green line, patient initially randomized to placebo who crossed over to ruxolitinib, with time 0 marking the start of ruxolitinib treatment. (D) Mean percent change in spleen volume stratified by tertile of maximum allele burden reduction. SE, standard error. *Patients on placebo who did not cross over to ruxolitinib. ^†All patients randomized to placebo; shading of the line in this group represents crossover of patients from placebo to ruxolitinib.