Abstract
Refractoriness to ruxolitinib in patients with myelofibrosis (MF) was associated with clonal evolution; however, whether genetic instability is promoted by ruxolitinib remains unsettled. We evaluated the mutation landscape in 71 MF patients receiving ruxolitinib (n = 46) and hydroxyurea (n = 25) and correlated with response. A spleen volume response (SVR) was obtained in 57% and 12%, respectively. Highly heterogenous patterns of mutation acquisition/loss and/or changes of variant allele frequency (VAF) were observed in the 2 patient groups without remarkable differences. In patients receiving ruxolitinib, driver mutation type and high-molecular risk profile (HMR) at baseline did not impact on response rate, while HMR and sole ASXL1 mutations predicted for SVR loss at 3 years. In patients with SVR, a decrease of ≥ 20% of JAK2V617F VAF predicted for SVR duration. VAF increase of non-driver mutations and clonal progression at follow-up correlated with SVR loss and treatment discontinuation, and clonal progression also predicted for shorter survival. These data indicate that (i) ruxolitinib does not appreciably promote clonal evolution compared with hydroxyurea, (ii) VAF increase of pre-existing and/or (ii) acquisition of new mutations while on treatment correlated with higher rate of discontinuation and/or death, and (iv) reduction of JAK2V617F VAF associated with SVR duration.
Highlights
Introduction Ruxolitinib is aJAK1 and JAK2 inhibitor approved for the treatment of intermediate and high-risk patients with primary (PMF) and post-polycythemia vera (PPV-MF) and post-essential thrombocythemia (PET-MF) myelofibrosis[1,2]
The purpose of our study was to analyze first, whether attainment and duration of clinical responses in patients with MF receiving ruxolitinib in a real-life setting was associated with unique mutation landscape at baseline and/or changes of mutation profile and variant allele frequency (VAF) at follow-up, and whether clonal evolution might be attributed directly to selective pressure induced by ruxolitinib on preexisting clones and/or through the facilitation of emergence of new mutated clones, in comparison with standard therapy represented by hydroxyurea
We found no difference in the proportion of patients with JAK2V617F mutation vs. patients with CALR mutation who achieved either a spleen or symptom response, confirming previous reports; a spleen volume response (SVR) and/or a symptom response was obtained by 54.1% and 86.0% of JAK2V617F mutated patients compared to 66.7% and 60.0% of CALR mutated patients
Summary
Introduction Ruxolitinib is aJAK1 and JAK2 inhibitor approved for the treatment of intermediate and high-risk patients with primary (PMF) and post-polycythemia vera (PPV-MF) and post-essential thrombocythemia (PET-MF) myelofibrosis[1,2]. Sometimes dramatic, clinical benefits, at least 50% of the patients become overtly refractory to ruxolitinib or experience progressively increase of spleen volume or reappearance of symptoms, necessitating soon or later discontinuation of therapy. In the COMFORT-I and COMFORT-II phase 3 trials, discontinuation due to loss of response, disease progression and treatment-related adverse events involved ≈50% of the patients at 3 years and 75% at 5 years[12,13,14,15]. Discontinuation of ruxolitinib because of loss of response was associated with dismal outcome among 107 patients enrolled in a phase 1/2 study, with median survival after discontinuation of only 14 months[16]. Managing patients who fail ruxolitinib therapy may be challenging especially when stem cell transplantation is not feasible, and Pacilli et al Blood Cancer Journal (2018)8:122 options include alternative JAK inhibitor therapy, alone or in combination, in the setting of clinical trials, novel agents, splenectomy, other palliative approaches[17]
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