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Pegylated interferon-α in myelofibrosis
carrying no (median not reached), one (median not reached) or several additional mutations (median 6.7 years) (P=0.026). A similar trend was observed for overall survival (not reached, 7 years and 6 years, respectively), but the difference did not reach statistical significance.
Nine patients (18% of the tested patients, 32% of those with non-driver mutations) carried at least one of the mutations belonging to the high molecular risk (HMR) group: six patients had one mutation and three had two or more mutations. Carrying a mutation in these HMR genes was associated with reduced overall and leukemia-free survival but, surprisingly, HMR mutations did not have a stronger impact than any other additional mutations (Figure 6C,D).
HMR mutations were found in five (24%) JAK2-mutat- ed patients, three (50%) CALR-mutated patients, and one triple-negative patient (P=0.32). Mutations in ASXL1 were identified in three (14%) JAK2–mutated and three (50%) CALR-mutated patients (P=0.1). The presence of ASXL1 mutations had no impact on either the leukemia- free survival or the overall survival of CALR-positive patients, and it was not relevant whether the mutation pattern was CALR-positive/ASXL1-negative or CALR- negative/ASXL1-positive.
Discussion
This study reports long-term outcomes of the largest cohort of interferon-treated myelofibrosis patients to our knowledge. The first finding is an unexpectedly long median overall survival of 89 months after myelofibrosis diagnosis in this population of patients, of whom the majority had intermediate or high-risk disease according to the DIPSS (84%) and Lille (50%) scoring systems. For these categories, the observed overall survival in this study was clearly longer than that expected according to the DIPSS (6.9 versus 4 years for intermediate-2 risk patients and 4.58 versus 1.5 years for high-risk patients) and the Lille (5.42 versus 2.17 years for intermediate-risk and 4.46 versus 1.08 years for high-risk) score categories.20,21 The 5-
AB
year actuarial survival rate was 69.4% from diagnosis for
the whole cohort, and 60% for patients with intermedi-
ate-2 or high risk according to the IPSS. These findings
suggest a positive impact of interferon therapy on both
overall and leukemia-free survivals in addition to the high
rate of clinical and hematologic responses that we previ-
ously reported.17,18 By comparison, two prospective trials
(COMFORT-I and II) have reported the results of the use
of ruxolitinib in myelofibrosis patients with IPSS interme-
diate-2 or high-risk score.8,9 In a recent actualization after
5 years of the COMFORT-II study,22 Harrison et al.
observed an overall survival of 59.4% (median not
reached). However, the study was not originally designed
to assess survival, and these results have been debat- ed.12,23,24
At the time of the analysis, 16 patients (25.8%) were still being treated with pegylated interferon-α2a whereas 45 (72.6%) had stopped treatment, 25 (55.6%) due to resistance and 20 (44.4%) due to intolerance. The overall survival of patients who continued their therapy was
Figure 4. Variations of the JAK2V617F allele burden during the follow-up. Relative variation of the JAK2V617F allele burden for each of the 27 patients for whom sequential testing was done.
Figure 5. Non-driver mutations identified by next-generation sequencing among 49 tested patients. The black color indicates high molecular risk (HMR) mutations. (A) Number of patients with each mutation; (B) number of additional mutations identified per patient. The percentages correspond to the proportion of HMR muta- tions among additional mutations.
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