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About 50% of patients with myelofibrosis lose clinical response after three years of treatment with ruxolitinib. Driver and non-driver mutation lack predictive power for the short term response. Also the patients with more than three mutations are less likely to respond to ruxolitinib and recently a shorter survival after discontinuation has been associated with a clonal evolution in the patient treated with ruxolitinib. So the aim of the study was to describe the modification in parent allele frequency of driver and non-driver mutation, a changing pattern of mutational profile, and to correlate these with the clinical response in patients with myelofibrosis treated with ruxolitinib and compared with the cells of patients selected according to clinical and hematological characteristics of patients treated with ruxolitinib but receiving hydroxyurea. We enrolled 25 patients in hydroxyurea group with a medium follow-up from start of treatment of 2.9 years and 46 patients treated with ruxolitinib with a medium follow-up from start of treatment of 3.4 years. Clinical hematological characteristics and mutational profiles at the base were similar in both the groups.
At the last follow-up the mean percentage changed from base range of two visits on 7F allele burden was plus 11% in the hydroxyurea group versus was minus 9% in the ruxolitinib group. In particular we observed just two allele burden increases in 25% of patients treated with hydroxyurea and 16% of patients treated with ruxolitinib, and decreased in 12% in the hydroxyurea group and in 24% in the ruxolitinib group. However, the allele frequency of CALR and MPL at baseline and follow-up were not significantly different in both the groups. About the non-driver mutation, we observed that an allele burden increase was observed in 32% of patients treated with hydroxyurea compared with 24% of patients treated with ruxolitinib and decreased in 12% in hydroxyurea group versus 24% of ruxolitinib group. Acquisition of new mutation occurred in 90% of patients treated with hydroxyurea and in 70% of patients treated with ruxolitinib.
We also observed a correlation between molecular changes during ruxolitinib treatment and clinical response. No mutation individually or allele burden change is predicted for symptoms response. Conversely the probability of maintaining a spleen volume reduction response at two years of treatment in patients with clonal progression was significantly lower, 43%, compared with patients without acquisition of additional mutation, 86%. The spleen volume reduction response was significantly shorter in patients with clonal progression, in particular in those defined in the high molecular risk in comparison with those without clonal progression. Patients with JAK2 V617F allele burden reduction maintain for a longer time spleen volume reduction response.
The acquisition of at least one mutation was also associated with a higher rate of discontinuation and of death. In particular, overall survival was found significantly shortened in patients with clonal progression with a median overall survival of less than four years in comparison with about eight years of patients without clonal progression.
So in conclusion, allele burden changes of driver and non-driver mutation as well as loss and acquisition of new non-driver mutation occurred in comparable rates with similar pattern in patients treated with hydroxyurea and ruxolitinib, and acquisition of new mutation while on ruxolitinib correlated with a higher rate of discontinuation and death with a shorter spleen volume reduction response.