V617F JAK2 Mutation and Bone Marrow Fibrosis Define Subgroups Of Patients With Polycythemia Vera and Essential Thrombocythemia With Shared Clinicobiological Profiles

The JAK2 V617F mutation is of high diagnostic value in the evaluation of myeloproliferative neoplasms (MPN) as it helps to document clonality; in addition, it may also predict for response to hydroxyurea treatment. According to recent studies, the presence of bone marrow (BM) fibrosis at diagnosis may be associated with the clinical evolution of MPNs, in particular development of secondary acute myeloid leukemia (AML) or transformation to myelofibrosis (MF), however the underlying mechanisms remain unknown. In this study we characterized in detail subgroups of patients with Polycythemia Vera (PV) and Essential Thrombocythemia (ET) carrying the JAK2 V617F mutation (M-JAK2) or displaying BM fibrosis at diagnosis with the ultimate aim of identifying potential associations and/or overlapping phenotypes. The present single-institution patient cohort included 118 cases diagnosed according to WHO 2008 criteria. Patient characteristics were as follows: (i) Diagnosis: PV/ET, 37/82; (ii) Gender: male/female, 58/60; (iii) median age at diagnosis: 59.8 years (range, 25-90). M-JAK2 was detected in 86/118 (72.9%) cases [PV: 32/37 (86.5%) - ΕΤ: 54/82 (65%)]. BM fibrosis was observed in 28/112 (25%) cases [PV: 10/34 (29.4%), ΕΤ: 18/78 (23%)], grade I in 24/28 (85%) cases and grade II in 4 cases (all with ΕΤ). Thirteen patients without BM fibrosis at diagnosis underwent a second BM biopsy at a median time of 4.7 years (range, 1-10): BM fibrosis was observed in 5/13 (38.4%), 4 carrying M-JAK2, of whom only one had received anagrelide before the second BM biopsy. With a median follow up of 6 years (range 1-10), one of these five patients developed AML. There was no statistically significant association between M-JAK2 and BM fibrosis at diagnosis, neither in the entire cohort, nor in each MPN (ET or PV) separately. In PV: (i) M-JAK2 was significantly (p<0.05) associated with advanced age at diagnosis, increased hemoglobin levels (Hb) and white blood cell (WBC) count at diagnosis; (ii) the presence of BM fibrosis demonstrated a strong trend for correlation with increased platelet counts at diagnosis (p=0.08). In ΕΤ: (i) M-JAK2 was significantly (p<0.05) associated with advanced age at diagnosis, splenomegaly, increased WBC count and Hb levels at diagnosis, and increased incidence of thrombotic events (12/54 versus 1/28); (ii) BM fibrosis was correlated with increased WBC and platelet count at diagnosis. Neither M-JAK2 nor BM fibrosis were correlated with increased incidence of hemorrhagic events, development of secondary AML or the presence of other concurrent malignancy. Furthermore, neither of these two parameters had any impact on overall survival, it has to be noted though that patients were not treated uniformly. In conclusion, the present analysis did not document a statistically significant correlation between M-JAK2 and BM fibrosis. Nonetheless, the clinicobiological similarities of patient subgroups defined by either of these parameters, as well as the increased incidence of BM fibrosis in sequential BM samples amongst M-JAK2 patients are suggestive of common pathogenetic mechanisms.