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J-C. Ianotto et al. AB
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Figure 6. Survival according to non-driver mutation status. (A) Overall survival and (B) leukemia-free survival according to the presence of at least one mutation. (C) Overall survival and (B) leukemia-free survival according to the presence of one of the high molecular risk mutations. High molecular risk is defined by the presence of one of the five following mutations: ASXL1, SRSF2, EZH2 or IDH1/2.
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longer than that of patients who stopped (P<10-6). The patients who were identified as resistant to pegylated interferon-α2a had the worst survival, suggesting that resistance to interferon is a marker of aggressive disease. However, these results should be interpreted in the light of subsequent treatment that clearly affected survival. For example, patients who received ruxolitinib after discon- tinuing pegylated interferon-α2a had a median survival of 22 months compared to 14 months for patients treated with other therapies.
All seven patients who underwent ASCT died within a median of 10 months, mainly from GvHD (5/7 patients). Although numbers are small, this is in stark contrast with previous studies of ASCT in myelofibrosis patients report- ing 5-year overall survival rates between 41 and 55%.25,26 There is no available study of the impact of interferon on the outcome of ASCT in Philadelphia chromosome-nega- tive myeloproliferative neoplasms. However, in chronic myeloid leukemia, Pigneux and colleagues showed that interferon therapy increased the incidence of GvHD (65 versus 38%, P=0.01) and decreased disease-free and overall survival rates at 5 years (33 versus 41%, P=0.005% and 41 versus 55%, P=0.002, respectively).27 Collectively, our results suggest that interferon therapy should not be initi- ated in patients with myelofibrosis who have a high prob- ability of undergoing ASCT within a few months.
Interferon has been shown to decrease the mutant allele burden of JAK2 or CALR driver mutations in both poly-
cythemia vera and essential thrombocythemia. Accordingly, we observed a greater than 10% reduction of the JAK2V617F allele burden in 63% of the patients and a greater than 95% reduction in four (15%). This molecular response in myelofibrosis patients is, however, less than the 89.6% JAK2V617F allele burden reduction and 24% com- plete molecular responses reported by Kiladjian et al. in patients with polycythemia vera.28,29 Very good molecular responses were also recently reported by Masarova et al. after long-term follow-up of pegylated interferon-α2a therapy in patients with polycythemia vera or essential thrombocythemia.30 Among 63 JAK2V617F-positive patients, they observed a molecular response rate of 63% (including 16% complete molecular responses), with a reduction of the median mutant allele burden from 41 to 12%. The reduction of the JAK2V617F allele burden did not have any impact on overall survival or leukemia-free survival in our study. Silver et al. also recently reported such an absence of correlation between molecular response and clinical outcomes in a series of 30 myelofibrosis patients treated with interferon.31 Such a level of response seems unique to interferon since in the COMFORT-II study, ruxolitinib achieved a greater than 20% reduction of JAK2V617F burden in only 30% of the patients (compared to 55.6% in our series), and none reached a complete molecular response.22 We were also able to evaluate the CALR molecular response in a few patients and found that only one patient had a significant decrease in CALR mutant allele burden.
haematologica | 2018; 103(3)