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J-C. Ianotto et al.
(Interactive Biosoftware). Only exonic non-synonymous muta-
tions were analyzed.
Statistical analyses
The Student t-test, chi-squared test and Kaplan-Meier curves were applied using the R-project (3.1.2 version, BiostaGV website, hosted by the Institute for Statistics and Mathematics of Wirtschaftuniversität Wien, Austria). Results were considered sta- tistically significant if the P value was less than 0.05, and each value was expressed plus or minus the standard deviation. Overall survival was defined as the period between diagnosis of myelofi- brosis or, when indicated, initiation of pegylated interferon-α2a treatment and last visit or death. Leukemia-free survival was defined as survival without transformation to acute leukemia.
Univariate analyses were performed based on either an exact Fisher test or Wilcoxon rank sum test. Variables that were found to be associated with the outcome at the 10% level were then introduced into a multivariate logistic model.
Results
Patients’ characteristics
Sixty-two patients with primary myelofibrosis (n=29, 46.8%) or secondary myelofibrosis (n=33, 53.2%) were included in this study. The median age of these patients at the time their myelofibrosis was diagnosed was 66 years old (range, 33-81) and the mean interval between the diag- nosis of myelofibrosis and the beginning of pegylated interferon-α2a treatment was 19.1 months. Forty-two patients (68%) had been previously treated and 40 of them (95%) had received hydroxyurea. The patients’ char- acteristics are summarized in Table 1.
At the time of starting treatment with pegylated inter- feron-α2a, the median age of the patients with primary myelofibrosis was 64 years, whereas that of the patients with secondary myelofibrosis was 70.5 years old. The majority of the patients were over 65 years old (35/62, 56.5%). The male/female sex ratio was 1.38. Splenomegaly was present in 43 patients (69.4%), consti- tutional symptoms were documented in 28 (45.2%). More than two-thirds of the patients (44/62, 71%) were in a proliferative phase (leukocytosis and/or thrombocytosis). However, 36 patients were anemic (58.1%) and 13 were transfusion-dependent (36%). Most of the patients were classified in the “Intermediate-2” risk category according to International Prognostic Scoring System (IPSS) or Dynamic IPSS (DIPSS) scores.
The mutational status for driver mutations was identi- fied for all patients: 42 (68%) had JAK2V617F, 14 had CALR exon 9 mutation (9 with type 1, 3 with type 2, and 2 with other mutations), one had MPLW515, four were triple-nega- tive (3NEG) and one had coexisting JAK2 and MPL muta- tions. Karyotype was available for 37 (59.7%) patients, and was normal in 70.3% (Table 1).
Survival and leukemic transformation
The median follow-up after starting treatment with pegylated interferon-α2a was 58 months (range, 9-107), whereas the median follow-up after having been diag- nosed with myelofibrosis was 69.6 months (range, 10- 178). The median duration of pegylated interferon-α2a treatment was 39 months (range, 6-107).
At the time of the analysis, 30 patients (48.4%) were still alive. The median overall survival of the cohort was
7.4 years from the diagnosis of myelofibrosis whereas the median leukemia-free survival had not been reached (Figure 1A,B). The 5-year actuarial survival rate for the whole cohort was 69.4% from diagnosis and 54.8% from the first prescription of pegylated interferon-α2a. The duration of pegylated interferon-α2a therapy had a signif- icant impact on overall survival: the median overall sur- vival was 30 months in patients who received less than 2 years of treatment compared to 70 months for patients who received the drug for more than 2 years (P<0.0001).
As expected, the Lille and DIPSS scores differentiated patients treated with pegylated interferon-α2a in terms of overall survival (Figure 1C,D). However, the median sur- vival observed in this cohort was clearly longer than that
Table 1. Characteristics of the patients and their disease.
Variable
Myelofibrosis subtype, n. Primary myelofibrosis Post-PV myelofibrosis Post-ET myelofibrosis
Value [range]
29 19 14
67 [33-81]
64 [35-81] 70.5 [33-79] 35 (56,5)
19.1
50 / 40.3 / 9.7
14.7 / 27.9 / 36.1 / 21.3 16.1 / 37.1 / 41.9 / 4.9
36/26
42 (68) 1.6 40 (95) 16 (38) 10 (24) 7 (17)
62
42 (67.7) 14 (22.6) 1 (1.6) 1 (1.6) 4 (6.4)
37 (59.7) 26 (70.3) 4 (10.8) 3 (8.1) 2 (5.4) 2 (5.4)
43 (69.4) 28 (45.2)
10.5 [1.3-78.3] 103 [74-160] 378 [23-1396]
Median age at the beginning of interferon (years) All the patients
Primary myelofibrosis
Secondary myelofibrosis
Patients ≥ 65 years, n. (%)
Mean time between diagnosis of myelofibrosis
and start of interferon therapy (months)
Risk category, %
Lille score (Low / Intermediate / High) IPSS score (Low / Int1 / Int2 / High) DIPSS score (Low / Int1 / Int2 / High)
Male / female, n.
Previous therapy, n. (%)
Number of patients
Median number of treatments per patient Hydroxyurea
Pipobroman
Anagrelide
6 Mercaptopurine
Driver mutations, n. (%) JAK2V617F
CALR
MPL
MPL/JAK2 Triple negative
Karyotype, n. (%) Normal Deletion 20q Anomaly 9 Trisomy 21 Monosomy Y
Clinical parameters, n. (%) Splenomegaly Constitutional symptoms
Biological parameters
Median white blood cell count (109/L) Median hemoglobin (g/L)
Median platelet count (10 /L)
440
9
PV: polycythemia vera; ET: essential thrombocythemia; IPSS: International Prognostic Scoring System; DIPSS: Dynamic International Prognostic Scoring System; Int1: inter- mediate-1; Int2: intermediate-2.
haematologica | 2018; 103(3)