<i>JAK2</i> exon 12 mutated polycythemia vera: Mayo‐Careggi MPN Alliance study of 33 consecutive cases and comparison with <i>JAK2</i>V617F mutated disease
Authors: Ayalew Tefferi, Sravanthi Lavu, Mythri Mudireddy, Terra L. Lasho, Christy M. Finke, Naseema Gangat, Animesh Pardanani, Curtis A. Hanson, Carmela Mannarelli, Paola Guglielmelli, Alessandro M. Vannucchi
Journal: American Journal of Hematology (2017)

To the Editor:Janus kinase 2 (JAK2) is located on chromosome 9p24 and includes 25 exons and its protein 1132 amino acids. JAK2 mutations almost always accompany World Health Organization (WHO)-defined polycythemia vera (PV); about 97% of such mutations are represented by JAK2V617F, which results from a somatic G to T mutation involving JAK2 exon 14, leading to a nucleotide change at position 1849 and the substitution of valine to phenylalanine at codon 617.1 JAK2V617F-negative PV occurs in 1%-3% of patients and mostly involves JAK2 exon 12.2 Conversely, over a quarter of patients with otherwise unexplained idiopathic erythrocytosis and low serum erythropoietin level might harbor such mutations.3 Mouse models and clinical studies have both revealed phenotypic differences between JAK2 exon 12 and JAK2V617F mutated PV; the former was characterized by erythroid-dominant myeloproliferation, more subtle tri-lineage hyperplasia in the bone marrow and younger age.4, 5 The main objective of the current study was to identify consecutive cases of JAK2 exon 12 mutated PV from two centers of excellence in myeloproliferative neoplasms and compare their natural history with their JAK2V617F mutated counterparts. Diagnoses of PV and leukemic or fibrotic disease transformation were according to WHO criteria.6 JAK2 exon 12 mutation analyses were performed by Sanger sequencing of exons 12–15 or next generation sequencing. Statistical analyses considered clinical and laboratory data collected at the time of initial diagnosis. A separate Mayo Clinic cohort of PV patients with JAK2V617F mutation, controlled for time of diagnosis (1989–2016), was used for comparison of phenotype, overall, leukemia-free, myelofibrosis-free, and thrombosis-free survival data. Standard statistical methods were used to determine significance of differences among groups in the distribution of continuous or nominal variables. Survival data were prepared by the Kaplan–Meier method and compared by the log-rank test. Cox proportional hazard regression model was applied for multivariable analysis. P-value of <.05 was considered significant. The Stat View (SAS Institute, Cary, NC) statistical package was used for all calculations. The study population included 33 consecutive cases of JAK2 exon 12 mutated PV, seen at either the Mayo Clinic (n = 21) or the University of Florence, Careggi Hospital (n = 12). The JAK2 exon 12 mutation variants included H538-K539delins (n = 8; 24%), F537-K539delins (n = 6; 18%), N542-E543delins (n = 5; 15%), E543-D544del (n = 5; 15%), K539L (n = 4; 12%), R541-E543delins (n = 2; 6%), and one each of E543delinsMK, H538-I540del, and F537IK539I. Comparison between JAK2 exon 12 (n = 33) and JAK2V617F mutated (n = 364) PV patients disclosed significant differences in median age (54 vs. 62 years; P = 0.02), platelet count (281 vs. 434 × 109/L; P = .0003), and leukocyte count (8.4 vs. 11.4 × 109/L; P = .0008) levels, respectively (Table 1). We observed no difference in median hemoglobin level (17.2 vs. 18.1 g/dL; P = .08), prevalence of palpable splenomegaly (27% vs. 24%; P = .66), or abnormal karyotype (17% vs. 20%; P = .8); similarly, no differences were noted in regards to rate of thrombotic events after diagnosis (12% vs. 20%; P = .3) or at any time before or after diagnosis (27% vs. 42%; P = .1), between the JAK2 exon 12 and V617F mutated cases, respectively (Table 1). Consistent with the study design that required the comparator cohort (JAK2V617F mutated PV) be selected based on similar time range for initial diagnosis, there was no significant difference (P = .3) in median follow-up for JAK2 exon 12 (6 years) versus JAK2V617F mutated patients (7.4 years). During this period, the number (%) of deaths, leukemic transformations, fibrotic progressions, and post-diagnosis thrombotic events, among JAK2 exon 12 versus JAK2V617F mutated patients were 2 (6%) versus 121 (33%), 0 versus 12 (3%), 6 (18%) versus 43 (12%), and 4 (12%) versus 72 (20% of evaluable cases), respectively (Table 1); of note, the 6 fibrotic progressions in JAK2 exon 12 mutated PV occurred in 2 (40%) of 5 patients with E543-D544del, 2 (33%) of 6 patients with F537-K539delins, and 2 (25%) of 8 patients with H538-K539delins variants. In univariate analysis, comparison of JAK2 exon 12 versus V617F mutated PV revealed significant difference in overall survival (P = .02; Figure 1A), favoring the former, but significance was lost during multivariable analysis that accounted for age (P = .1), leukocyte count (P = .08) or both (P = .23); in contrast both age (P < .0001) and leukocyte count (P < .0001) were independently predictive of shortened survival. Similarly, no significant difference was noted, in univariate analysis, in regards to myelofibrosis-free (P = .25; Figure 1B) or thrombosis-free (P = .32) survivals; the number of leukemic events (n = 12) was too low to allow valid statistical comparisons, although such an event was yet to be documented in any one of the JAK2 exon 12 mutated cases. A, Overall survival data of 387 patients with polycythemia vera (PV) stratified by JAK2V617F VS JAK2 exon 12 mutational status; B, Myelofibrosis-free survival data of 397 patients with PV, stratified by JAK2V617F VS JAK2 exon 12 mutational status. Observations from the current study and those of a previous multicenter report on 106 patients were similar in regards to the association between JAK2 exon 12 mutated PV and lower leukocyte and platelet counts, compared to JAK2V617F mutated PV.5 On the other hand, the two studies were different in their suggestion of an association between JAK2 exon 12 mutated PV and younger age (current study) or higher hemoglobin level (previous study).5 Both studies reported similar outcome data in terms of survival and disease complications; median follow-up in the aforementioned study of 106 JAK2 exon 12 mutated patients was 3.9 years, during which time 9 deaths, 5 cases of leukemic transformation, 2 cases of fibrotic transformation, and 11 cases of thrombotic events were reported.5 In summary, the current study provides long-term outcome data on JAK2 exon 12 mutated PV, which appear to be similar to those of JAK2V617F mutated disease. Nothing to report.