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Very young patients with ET and PV
Biological characteristics
The results of the full blood count at diagnosis are pre- sented in Table 1. For ET patients, the median leukocyte count was 10.6 109/L, the hemoglobin concentration was 131 g/L and the platelet count was 1192x109/L (maximum 4500x109/L). For PV patients, the median leukocyte count was 13.2x109/L, the hemoglobin concentration was 180 g/L (maximum level, 189 g/L), the maximum hematocrit was 72.5% and the platelet count was 799x109/L. It is dif- ficult to understand how hereditary thrombocytosis and erythrocytosis were excluded for these patients.
To assess the diagnosis of MPN, many authors wrote in the “Patients and methods” section that their patients ful- filled the diagnostic criteria according to the 2001, 2008 or 2016 World Health Organization classification. However, bone marrow results were described for less than 52% of the ET and 44% of the PV cases. Generally, the descrip- tions were short with a conclusion expressed as “compat- ible with MPN”.
Molecular analyses
Considering the entire cohort of PV patients, we noted that only 37% and 2.5% were positive for JAK2 exon 14 and exon 12 mutations, respectively. Three studies com- prehensively assessed the presence of both types of JAK2 mutations: the percentage of JAK2 exon 14 cases decreased to 24% whereas, the rate of JAK2 exon 12 mutations remained stable at 3% (Figure 1A).9,13,24 According to these results, the percentage of patients pos- itive for the V617F mutation in exon 14 is far less than in adults, whereas that of exon 12 is identical. Consequently, the percentage of patients who do not harbor one of these two mutations is also high: 73%. Information on JAK2V617F allele burden was available in a small number of studies and the mean value was 43.5%. This finding of much lower rates of JAK2 mutation in young patients with PV is also unexpected and requires a prospective evaluation, including, for example, the role of red cell isotopic studies to confirm the diagnosis.
The analysis in ET patients is more complex because of
the number of mutations to test. Notwithstanding, in a global analysis, the percentages of positivity were 31.7% for JAK2V617F, 5.6% for CALR and 1% for MPL mutations Analyzing the eight cohorts of ET patients in whom all driver mutations were tested, the proportions of positivity became 31% for JAK2V617F, 10% for CALR, and 2% for MPL and so 57% of the cases were triple-negative (Figure 1B).12,14,16,17,19,20,22,33 These percentages are quite different from those in adults, among whom there is a much higher frequency of triple-negative cases and lower percentages of JAK2- or CALR-positive cases.64 As for PV patients, the number of studies reporting JAK2V617F allele burden was small and the mean value was 24.1%. As discussed earlier the exclusion of hereditary cases is critical here.
Interestingly, two groups have reported the results of next-generation sequencing analyses in this population.12,16 Among 68 patients tested the authors found that 35% did not carry any of the tested non-driver mutations. Most of the patients carried only one additional mutation. The description and the proportions of non-driver mutations are shown in Figure 2. In one study, patients with ET seemed to have more mutations than PV patients.16 The presence of mutations belonging to the high molecular risk group and inducing worse prognosis in primary myelofi- brosis is uncommon in this population (ASXL1 in 4 cases and IDH1/2 in 1 case).65,66 As far as concerns young patients with ET or PV, the real clinical significance of these non- driver mutations cannot be assessed from the studies.
Outcomes and survival
Thrombotic events
As noted above, some very young patients were diag- nosed with MPN because of the occurrence of a thrombotic event. The exact incidence of thrombosis at diagnosis was 14.7% and 4% in PV and ET patients, respectively. So, these events seemed quite infrequent compared to their frequency in adults.67-68 Importantly, the incidence of thrombosis after the diagnosis of MPN decreased in the PV cohort (9.3%), but remained stable in the ET patients (3.8%) (Table 2).
Figure 2. Description and numbers of non-driver mutations identified by next-generation sequencing in two studies (68 patients).12,16 mut: mutations.
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