Abstract
The JAK2V617F mutation is variably found in the Ph’-negative chronic myeloproliferative disorders (MPD); in about 25% of polycythemia vera (PV) or idiopathic myelofibrosis (IM) and in 1–3% of essential thrombocythemia (ET) patients (pts), mitotic recombination causes the mutation to be harboured in the homozygous status. While it has been suggested that homozygosity influences some cellular functions, its clinical significance has not been elucidated yet due to the low number of homozygotes in published series. To this end, a retrospective, multicentric study, that enrolled 1306 pts, was designed within the Myeloproliferative Working Group of the Italian GIMEMA association; all pts who had been typed for JAK2 mutation using the BsaXI digestion assay (Baxter et al, Lancet, 2005) were included. There were 397 PV (30.4%), 639 ET (48.9%), 270 IM (20.7%) pts. JAK2V617F was found in 878 (67.3%), accounting for 82%, 60%, and 64%, respectively, of PV, ET, or IM pts. The homozygotes (Ho) were 183 (20.8%), with a frequency of 26.3% in PV, 2.2% in ET, and 24.1% in IM. Ho pts, irrespectively of the underlying diagnosis, presented higher leukocyte count and hematocrit, while platelet count was lower, as compared to heterozygous (He) or wild-type (WT). The frequency of splenomegaly rose from 26% to 41% to 52% in WT, He and Ho PV pts; from 19% to 22% to 62% in ET; and from 61% to 67% to 89% in IM. Acquagenic pruritus was referred by 12%, 28% and 42% of WT, He, and Ho PV pts, while the corresponding figures were 4%, 12%, and 26% in IM; no difference was noted among ET pts. Also the frequency of systemic symptoms was significantly higher among Ho pts in all three disease groups. 195 pts (14.9% of total) presented major thromboses at diagnosis (71 PV, 114 ET, 10 IM, accounting for 18%, 18%, and 4% in each group, respectively), while 144 events were recorded in the follow-up (15%, 12%, 4% in PV, ET, or IM). The incidence of thrombosis at diagnosis was 12%, 21% and 15% in WT, He or Ho PV pts, while the corresponding figures were 11%, 22% and 50% in ET, and 1%, 7% and 3% in IM. The relative risk (RR) for major thrombosis after diagnosis (adjusted for gender, age, and previous thrombosis) was significantly higher in Ho than in He pts both in ET (RR 4.6 and 1.5, respectively, by taking as 1 the WT pts) and IM (RR 3.2 and 1.6) pts, unlike in PV (RR 0.8 and 0.9, respectively). Ho pts evolved more frequently into myeloid metaplasia than He or WT in both PV (12% vs 0% and 1%, respectively) and ET (14% vs 5%, and 2%). These data support the contention that the JAK2V617F homozygous mutational status associates with a more symptomatic disease across the MPD clinical entities, and identify the unfrequent Ho ET patients as a specific subgroup with a particularly aggressive disease.
JAK2V617F mutational status as determined by semiquantitative sequence-specific primer-single molecule fluorescence detection assay is linked to clinical features in chronic myeloproliferative disorders
