Validation of JAK2 and New Clinical Criteria for the Diagnosis of Polycythemia Vera (PV).

Although the pervasive presence of JAK2 in patients (pts) with PV has been noted in at least 7 published studies, its frequency has ranged from 66 to 97%. Although part of the reason for this wide range is false negative results due to the low sensitivity of sequence analysis, varying criteria used for the clinical diagnosis of PV are also likely to be an important factor. In more than 300 studies, the criteria of the Polycythemia Vera Study Group has been used, although many authors, including ourselves, have commented on their inadequacy. Alternative classifications have been the subject of debate mostly centered about using the rbc-Cr⁵¹ mass. Our criteria included the use of CR⁵¹ labeled red cells to establish first, an increase in red blood cell volume and second, I¹²⁵ to establish an increase in plasma volume. Exception was made for men with a HCT ≥60%, and women ≥56%. If hypervolemic, the major causes of secondary polycythemia were excluded: congenital polycythemias and those secondary to impaired oxygenation, or benign or malignant tumors. This implied a serum erythropoietin level of ≤5u/ml. The aforementioned and 3 of the following 5 were required: splenomegaly, WBC, ≥12,000/ul, platelet count ≥600,000/ul, abnormal marrow histology. We used them to clinically diagnose 61 patients subsequently undergoing therapeutic trials whose blood was analyzed for the JAK2 V617F mutation by allele specific PCR from 679 patients with myeloproliferative diseases, including normal controls. Of 61 patients, with the phenotypic characteristics of p. vera, 59 (97%) were positive for the JAK2 mutation. The 2 remaining patients, although phenotypically characteristic of PV, were negative on repeat examinations. One pt was newly diagnosed and untreated and the other had a 6 year remission after rIFNα followed by a 1 year remission on imatinib. We conclude that determination of JAK2 is consistent with PV in virtually all cases clinically diagnosed appropriately. Our data, to be presented, indicate that the combination of increased red cell mass, demonstration of JAK2 and increased platelet count establish the diagnosis of PV in virtually all cases.