Mutation landscape in patients with myelofibrosis receiving ruxolitinib or hydroxyurea

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.

Tracing the decision-making process for myelofibrosis: diagnosis, stratification, and management of ruxolitinib therapy in real-word practice

“…Third, physicians interviewed complained about the absence of uniform criteria for treatment failure. While the outcome of patients after ruxolitinib discontinuation has been reported to be poor [32][33][34], the definition of resistance was unclear. A recent Italian retrospective analysis of 218 MF patients who received and discontinued ruxolitinib therapy in routine clinical practice found that greater burden of disease at baseline is significantly associated with a higher discontinuation rate [35].…”

<p>Impact of Mutational Profile on the Management of Myeloproliferative Neoplasms: A Short Review of the Emerging Data</p>

“… 86 A subsequent study which included 25 MF patients treated with hydroxyurea as a control group confirmed these data but also demonstrated that clonal progression is independent of the treatment. 87 However, acquisition of new mutations under ruxolitinib has important clinical correlates, since it is associated with a higher rate of discontinuation due to resistance to treatment and death.…”

Next Generation Sequencing in MPNs. Lessons from the Past and Prospects for Use as Predictors of Prognosis and Treatment Responses

“…Of note, SRSF2 was not included in their targeted NGS panel [64]. Likewise, Pacilli et al found in their study of 46 MF patients that HMR status or mutations in ASXL1 at baseline resulted in loss of spleen response or shorter duration of spleen response, respectively after 3 years of ruxolitinib treatment, although the symptom response rate to ruxolitinib was not affected by baseline HMR mutations [163]. Furthermore, Spiegel et al found a shorter time to treatment failure in MF patients with a HMR profile or with mutations in ASXL1 or EZH2, however, they found no impact of mutations in IDH1/2 or SRSF2, and no individual mutations or HMR mutations were associated with spleen response [82].…”

“…Contradictory, among 46 ruxolitinib treated MF patients in the study by Pacilli and colleagues, all patients with acquisition of ≥1 mutation experienced loss of spleen response compared with 21% of patients without clonal evolution. Furthermore, acquisition of ≥1 non-driver mutation correlated with treatment discontinuation [163]. Whether the appearance of new clones are attributed to selective pressure by ruxolitinib or disease progression are a matter of debate and needs to be tested in larger studies.…”