The frequency of JAK2 exon 12 mutations in idiopathic erythrocytosis patients with low serum erythropoietin levels.

BACKGROUND AND OBJECTIVES: Idiopathic erythrocytosis (IE) is characterized by erythrocytosis in the absence of megakaryocytic or granulocytic hyperplasia, and is associated with variable serum erythropoietin (Epo) levels. Most patients with IE lack the JAK2 V617F mutation that occurs in the majority of polycythemia vera patients. Four novel JAK2 mutant alleles have recently been described in patients with V617F-negative myeloproliferative disorders presenting with erythrocytosis. The aims of this study were to assess the prevalence of JAK2 exon 12 mutations in IE patients, and to determine the associated clinicopathological features. DESIGN AND METHODS: A cohort of 58 IE patients with low to normal serum Epo levels and no known causative mutation were identified from 181 individuals diagnosed with IE. Patients' DNA samples were screened for the presence of a JAK2 exon 12 mutation by allele-specific polymerase chain reaction and sequencing. Bone marrow trephines were examined for morphological abnormalities and the erythroid activity assessed immunohistochemically. RESULTS: Eight mutation-positive cases were identified, including one with a previously undescribed mutant JAK2 exon 12 allele and another with biallelic involvement. The hematologic features of mutation-positive and mutation-negative patients were similar, although Epo-hypersensitive erythroid progenitors occurred exclusively in patients with an exon 12 mutation (p=0.0002; n=15). Patients' bone marrows were moderately hypercellular, as the result of erythroid hyperplasia, and several had mild megakaryocyte atypia. INTERPRETATION AND CONCLUSIONS: JAK2 exon 12 mutations were detected in 27% of patients with low serum Epo levels, all of whom had Epo-independent erythroid progenitors. Consequently, IE patients presenting with either of these features should be tested for the presence of a JAK2 mutation.

The incidence of the JAK2 V617F mutation in patients with idiopathic erythrocytosis.

Sixty-three patients with erythrocytosis exhibiting a range of erythropoietin levels were screened for the JAK2 V617F mutation. One patient (1.6%) was found to have this mutation, and has remained stable for 9 years, suggesting that the JAK2 V617F mutation is rare in patients with idiopathic erythrocytosis.

Novel uses for recombinant erythropoietin therapy in unlicensed indications.

Clinical uses for recombinant human erythropoietin (rHuEPO) therapy continue to expand. Initial use was in anaemia associated with end-stage renal disease, but more recently there have been many reports of the benefits of erythropoietin in other clinical situations such as cancer-related anaemia. Recombinant erythropoietin reduces the need for blood transfusion and hence exposure to donor blood products as well as improving quality of life. We report four patients who were transfusion dependent, none of whom had licensed indications for the use of recombinant erythropoietin. Two patients had microangiopathic haemolytic anaemia secondary to mechanical valve haemolysis and were unsuitable for any further cardiac intervention. One patient had anaemia of chronic disease and anti-Vel red cell antibodies, making compatible blood transfusions difficult to obtain. The fourth patient had primary thrombocythaemia and developed transfusion-dependent anaemia secondary to myelosuppressive agents. All four patients had a relative deficiency in endogenous erythropoietin levels ranging between 7 and 41 IU/l. After commencing recombinant erythropoietin therapy, all had a response in haemoglobin of at least 1 g/dl with an overall improvement in their quality of life. We conclude that rHuEPO is a very convenient and useful form of treatment in transfusion-dependent anaemia and in some cases beyond the licensed indications.