Impact of genomic alterations on outcomes in myelofibrosis patients undergoing JAK1/2 inhibitor therapy

Abstract

Key Points ASXL1/EZH2, transfusion dependence, and a high prognostic risk score predict shorter TTF in MF patients on JAK1/2 inhibitors. These clinical and genetic factors were also associated with decreased overall survival.

Mutation landscape in patients with myelofibrosis receiving ruxolitinib or hydroxyurea

“…Results of current study confirm and extend previous reports on the impact of driver 39 , 40 and non-driver 24 , 26 , 27 baseline mutations, and of mutations acquired while on treatment (clonal progression) 16 , on response to treatment and response duration in patients with myelofibrosis receiving ruxolitinib. For the first time, our study included a control group of matched patients treated with hydroxyurea, that highlighted that MF is hallmarked by highly dynamic mutation landscape that is largely treatment-independent, since modifications of mutation profile during follow-up were substantially similar in patients receiving ruxolitinib or hydroxyurea.…”

“…On the other hand, in a series of a long-term treated patients included in a phase 1/2 trial and analyzed by NGS panel of 28 non-driver recurrently mutated genes, the number of non-driver mutations at baseline had an impact on SVR; patients with 2 or less mutations had nine-fold higher odds of achieving SVR than those with 3 or more mutations, who also had shorter time to discontinuation of therapy 26 . A shorter time to treatment failure was also noticed in a study of 100 patients, including 23 treated with momelotinib, in association with an HMR profile and presence of ASXL1 and EZH2 mutations 27 . More recently, among 86 patients receiving ruxolitinib for a median of 79 months, clonal evolution, hallmarked by acquisition of new mutations under treatment, was associated with significantly shorter survival after therapy discontinuation compared to patients without clonal evolution 16 .…”

“…Overall, findings from this study add novel information on the impact of baseline and on-treatment acquired genomic alterations on the clinical response in patients with MF receiving ruxolitinib, further highlighting the complexity of genomic landscape of these patients. The ultimate goal of this kind of studies is to identify a molecular profile at baseline that might guide decision regarding initiation of therapy with ruxolitinib; 50 although presence of some molecular assets at baseline argue against a long-term likelihood to maintain SVR (current study and 16 , 24 , 26 , 27 ), the large majority of patients obtain rapid clinical improvements, that are not otherwise achieved with other agents, making use of ruxolitinib a reasonable upfront strategy in symptomatic patients. Conversely, detection of specific molecular assets might be useful in counseling for an earlier shift from ruxolitinib to experimental therapies and/or stem cell transplantation.…”

Ruksolitynib w terapii chorych na mielofibrozę — pytania i odpowiedzi

“…Spiegel i wsp. [33] Wyniki przedstawionych analiz wskazują, że obecność mutacji "z grupy HMR" istotnie skraca czas trwania odpowiedzi na leczenie ruksolitynibem. Z tego względu w grupie chorych z obecnością mutacji kwalifikujących się do allo-HSCT nie należy odraczać decyzji o transplantacji, a leczenie ruksolitynibem powinno być jedynie terapią przygotowującą do zabiegu.…”

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

“…Additionally, patients in the HMR group were characterised by a shorter TTD and OS. Spiegel et al [33] evaluated correlation between mutations and similar parameters in a cohort of 100 patients with MF treated with ruxolitinib (77 patients) or momelotinib (23 patients). Unlike the observation of Patel et al [32], this analysis showed no correlation between the presence of mutations and splenic response.…”