Molecular Genetic Markers and Clinical Characteristics of Essential Thrombocythemia

Background & Aims. The presence of different molecular genetic markers of clonality (mutations in JAK2, MPL, CALR) or their absence (triple negative status, TN) in essential thrombocythemia (ET) indicates a biological heterogeneity of the disease and can determine its clinical forms. The aim was to evaluate the association of molecular genetic markers with the clinical form and the prognosis of ET. Materials & Methods. We analyzed the data of 240 patients with ET at the age of 20–91 years (median age 58.7 years), who were observed in the Russian Research Institute of Hematology and Transfusiology from 1999 to 2016 (median observation period 37.2 months). Results. The JAK2V617F (JAK2+) mutation was found in 182 (75.9 %) of 240 patients. CALR (CALR+) mutations were found in 30 (12.5 %): type 1 (CALR1+) mutations in 13/30 (43.3 %) and type 2 (CALR2+) in 17/30 (56.7 %). MPL (MPL+) mutations were found in only 2 (0.8 %) of 240 patients. None of the mutations were detected in 26 (10.8 %) of 240 patients (TN status). Significantly higher platelet counts were observed in CALR1+ and CALR2+ subgroups during the primary diagnosis of ET compared with JAK2+ and TN groups. The mean platelet counts were 1252 × 109/L for CALR2+ and 1079 × 109/L for CALR1+ vs 841 × 109/L (p < 0.001; p = 0.06) and 775 × 109/L (p < 0.001; p = 0.04) for JAK2+ and TN, respectively. Thrombosis was diagnosed in 50 (27.4 %) of 182 patients of the JAK2+ subgroup, in 8 (30.7 %) of the 26 patients of the TN subgroup, and in 2 (18.2 %) of 11 patients of the CALR1+ subgroup. No thrombosis was found in the CALR2+ and MPL+ subgroups (p < 0.001). In general, the CALR1+ status was characterized as the most favorable in terms of prognosis (5-year overall survival rate of 100 %), compared to the least favorable TN status (5-year overall survival rate of 85 %). Conclusion. Mutations in the CALR gene were characterized by a more favorable prognosis in comparison with JAK2+ and TN, as well as a decrease in the risk and frequency of thrombosis, despite higher platelet counts. TN-status of ET was associated with unfavorable prognosis

Genetic Markers of Hereditary Thrombophilia and Risk of Thrombotic Complications in Patients with Polycythemia Vera

Background. Thrombotic complications are one of the main problems of polycythemia vera (PV) treatment. They significantly impair the quality of life of these patients and may lead to the lethal outcome. A thrombotic event often precedes the diagnosis of this hematological disease. The pathogenesis of thrombosis in myeloproliferative neoplasms, PV, in particular, is a complex one. Prescription of antiaggregants in the absence of thrombosis and anticoagulants after a thrombotic event requires special attention and development of corresponding recommendations. The prescription of anticoagulants is impossible without taking into account the risks of hemorrhagic complications, which are also typical for myeloproliferative neoplasms. Aim. Assessment of the impact of hereditary thrombophilia genetic markers on the risk of thrombotic complications in patients with PV. Methods. The study examined 116 patients with PV, who were screened for markers of hereditary thrombophilia: factor V (G1691A, FV Leiden), prothrombin, methylenetetrahydrofolate reductase (MTHFR), fibrinogen (FI), plasminogen activator inhibitor (PAI-1), and platelet fibrinogen receptor type IIIA (GPIIIA). The incidence of these markers and their role in thrombosis in such patients was investigated. Results. The study provided data on the incidence of hereditary thrombophilia markers in patients with PV. Statistically significant differences in the incidence of these markers and homocysteine level were found between patients with thrombosis and without them. Conclusion. The information about the hereditary thrombophilia markers presence may be useful for the prescription of adequate antiaggregant and anticoagulant therapy for PV patients. Further research in this field is justified and it will probably demonstrate the relevance of hereditary thrombophilia markers as prognostic factors for thrombotic complications risk assessment

Chronic Myeloid Leukemia: Long-Term Experience of Target Therapy

Background & Aims. Interpretation of key aspects of pathogenesis of chronic myeloid leukemia (CML) and development and introduction of target therapy have changed the prognosis of this once fatal disease dramatically. Results of numerous clinical trials demonstrated substantial superiority of tyrosine kinase inhibitors over previous therapy techniques. At the same time, clinical trials had limitations in patient enrollment, as well as treatment conditions and duration. The analysis of our clinical experience in CML target therapy (over the period from 2003 till 2015) is an important argument for introduction of novel drugs into routine clinical practice. The aim of the study is to analyze our own experience in CML target therapy and to compare our results with clinical trials data. Methods. Outpatient’s cards and case histories of CML patients treated in the Russian Scientific Research Institute of Hematology and Transfusiology over last 12 years were analyzed in this work. Published results of multi-center clinical trials evaluating the use of tyrosine kinase inhibitors in CML were used for a comparative analysis. The primary morbidity rate and the prevalence of CML, results of first and subsequent treatment lines were studied with assessment of survival rates, adverse events, and the nature of the response (hematologic, cytogenetic and molecular). Results. The experience in treatment of 208 CML patients was analyzed. The use of imatinib led to clinical and hematological remission (complete hematologic response) was achieved in 95 % of patients. The frequency of complete cytogenetic responses (CCyR) was 69 %, and that of major molecular responses (MMR) was 58 %. The overall 5-year survival (OS) was 86.4 %, the 10-years OS was 67.5 %. The use of nilotinib during the second line permitted to achieve CCyR in 61 % of patients, and the MMR in 55 % of cases. The two-year OS was 96 % and the 5-year OS was 68 %. CCyR and MMR were achieved in 50 % patients treated with dasatinib during the second line. As for the third line, CCyR was achieved in 50 % of patients and MMR in 25 %. In case of previous imatinib and nilotinib resistance, CCyR was observed only in 36 % of patients and MMR in 18 % of cases. During second-line dasatinib treatment, the 2-year OS was 85 %, and the 5-year OS was 51 %; as for the third line, the results were 75 % and 50 %, respectively. The range and rates of adverse events of the therapy, in general, corresponded to results of clinical trials. Conclusion. The use of tyrosine kinase inhibitors in treatment of CML permits to prolong patient’s life span and quality of life significantly. The use of nilotinib and dazatinib (in case of nilotinib intolerance and/or resistance) could be effective in most patients