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 × 10/L at the start of therapy or <100 × 10/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 ). 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.

Life after ruxolitinib: Reasons for discontinuation, impact of disease phase, and outcomes in 218 patients with myelofibrosis

“…Outcomes were particularly poor in patients who had molecular clonal evolution and thrombocytopenia. 13 A second study of 64 patients treated in a real-life comparison confirmed that responses to salvage treatments are rare. 14 Understanding that the outcome after ruxolitinib is important for identifying patients who may benefit from specific interventions, such as allogeneic stem cell transplantation, 15 second-generation JAK inhibitors, [16][17][18] drugs with alternative mechanisms of action, 19,20 or investigational agents in combination with ruxolitinib.…”

“…The outcome of patients who failed ruxolitinib within the phase 1/2 trial reportedly was poor (median survival, 14 months). Outcomes were particularly poor in patients who had molecular clonal evolution and thrombocytopenia . A second study of 64 patients treated in a real‐life comparison confirmed that responses to salvage treatments are rare .…”

Impact of ruxolitinib pretreatment on outcomes after allogeneic stem cell transplantation in patients with myelofibrosis

“…6 Furthermore, ruxolitinib discontinuation is associated with a short survival of approximately 14 months. [9][10][11] At present allogeneic stem cell transplantation (ASCT) is the only potentially curative therapy. 12,13 However, morbidity and mortality are high from conditioning regimen toxicity, acute and chronic graft vs host disease (GVHD), infection and relapse.…”

Ruxolitinib in the treatment of patients with myelofibrosis — questions and answers

“…Long-term observations indicate that ruxolitinib needs to be stopped in 55% of patients after three-year follow-up (data from COMFORT-I and -II trials) [46]. Median OS after stopping ruxolitinib is 14 months [47].…”