Clonal evolution and outcomes in myelofibrosis after ruxolitinib discontinuation

Abstract

Despite significant improvements in the signs and symptoms of myelofibrosis (MF), and possible prolongation of patients' survival, some have disease that is refractory to ruxolitinib and many lose their response over time. Furthermore, patients with ≥3 mutations are less likely to respond to ruxolitinib. Here we describe outcomes after ruxolitinib discontinuation in MF patients enrolled in a phase 1/2 study at our center. After a median follow-up of 79 months, 86 patients had discontinued ruxolitinib (30 of whom died while on therapy). The median follow-up after ruxolitinib discontinuation for the remaining 56 patients was 32 months, with median survival after discontinuation of 14 months. Platelets <260 × 10⁹/L at the start of therapy or <100 × 10⁹/L at the time of discontinuation were associated with shorter survival after discontinuation. Of 62 patients with molecular data at baseline and follow-up, 22 (35%) acquired a new mutation while receiving ruxolitinib (14 [61%] in ASXL1). Patients showing clonal evolution had significantly shorter survival after discontinuation (6 vs 16 months). Transfusion dependency was the only clinical variable associated with clonal evolution. These findings underscore the need for novel therapies and suggest that clonal evolution or decreasing platelet counts while on ruxolitinib therapy may be markers of poor prognosis.

Figure 1.

CONSORT diagram. Patient enrollment, discontinuation, and analysis schema are shown.

Figure 2.

Kaplan-Meier survival curves showing survival after ruxolitinib discontinuation. Comparison of survival after discontinuation by platelet counts at (A) baseline and (B) follow-up. (C) Comparison of survival after ruxolitinib discontinuation in those with and without clonal evolution. Cum, cumulative; FU, follow-up; HR, hazard ratio.

Figure 3.

Correlation between clonal evolution and disease status. (A) Mutations at baseline and follow-up in patients who acquired a mutation while receiving ruxolitinib. Red squares denote an acquired mutation. Red/blue squares denote the acquisition of a second, different mutation in the same gene. Note that at the time of follow-up, patient (Pt) 3 had lost the GATA2 and KRAS mutations present at baseline. (B) Bar graph depicting disease status at the time of ruxolitinib discontinuation in patients with (CE) and without (No) clonal evolution. Bars are colored according to karyotype: gray, sample was not available; light blue, noncomplex karyotype; red, complex karyotype. (C) Bar graph depicting spleen size at baseline (light green) and at the time of ruxolitinib discontinuation (purple). Asterisks indicate patients who acquired a new mutation while on therapy. ND, mutation status at discontinuation not determined. PD, progressive disease; SD, stable disease.