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

70th Anniversary of Hematology Clinic of Russian Scientific Research Institute of Hematology and Transfusiology

This report describes major events of the 70-year history of the Hematology Clinic of the Russian Scientific Research Institute of Hematology and Transfusiology founded in 1945. It covers activities related to studies of etiology, pathogenesis, diagnosis, and therapy of hematological disorders, as well as training of the personnel and development of methods for improvement of the system of specialized medical care for hematological patients in the Russian Federation. Much attention is paid to personnel’s faultless work. The article emphasizes that recent scientific discoveries are successfully implemented in the everyday clinical practice and are published in leading domestic and foreign periodicals. It makes a special emphasis on modern therapeutic and diagnostic equipment that allows to apply all modern methods of diagnosis and therapy of hematological disorders

Chronic Lymphocytic Leukemia: Prognostic Significance of Minimal Residual Disease and Potential of Modern Methods of Its Diagnosis and Therapy (Literature Review)

Achieving a complete remission (CR) in patients with chronic lymphocytic leukemia (CLL) has become a feasible goal directly correlating with a prolonged survival. However, a certain number of tumor cells may be present in the patient’s body even when CR has been achieved, and this phenomenon is called a minimal residual disease (MRD). A lot of data confirming the necessity of MRD diagnosing and monitoring has emerged recently, since the MRD has a significant impact on the prognosis of CLL. Achieving MRD-negative remission is an independent predictor of long-term progression-free survival and overall survival. The occurrence of new diagnostic techniques has allowed to define the MRD and to develop standards for its assessment. This paper presents an overview of literature data about MRD, methods of its evaluation, prognostic significance, as well as the methods of eradication

Low Dose Cytarabine and Cladribine for Treatment of Relapsed or Refractory Acute Myeloid Leukemia: Clinical Experience

Aim. The aim of this paper is to evaluate the effectiveness of low dose cytarabine (Ara-C) combined with cladribine for the treatment of relapsed or refractory acute myeloid leukemia (AML) and to determine clinical and lab factors associated with response to the therapy. Methods. Data of 10 patients aged 26–58 years (median 48 years) were analyzed. The diagnoses were de novo AML (7 patients), secondary AML (sAML) (2 patients) and refractory anemia with excess of blasts (RAEB-2) (1 patient). Four patients had primary refractory AML. Relapse was diagnosed in 3 patients. The induction scheme 7+3 was ineffective in patient with RAEB-2. There was no response to any kind of therapy in sAML patients. The treatment scheme under trial consisted of Ara-C 10–15 mg/m2 subcutaneously twice a day for 1–14 days and cladribine 5 mg/m2 intravenously once a day for 1–5 days. The course was repeated in case of at least two-fold decrease in bone marrow blasts level in a punctate versus baseline. Medical examination and maintenance therapy were performed in accordance with protocols approved by the clinic. Results. According to the protocol, the patients received 1–2 courses. Response was achieved in 5 patients: 2 patients achieved complete response (CR) and 3 achieved partial response (PR). The most common complication was hematologic toxicity. All patients received transfusions of blood components. No lethal outcomes were observed within 8 weeks. The duration of the response was 2 to 3 months. During this period of time, allogeneic stem cell transplantation was performed in 2 patients with CR; however, in one patient, the conditioning regimen began at the same time with the increase in blast cell count in the bone marrow. The search for unrelated donors of hematopoietic stem cells for 2 patients with CR was begun. The distinct features of all patients with CR and PR were the following factors: de novo AML, absence of FLT3 or c-KIT mutations and the course duration was not less than 10 days. Conclusion. Low dose Ara-C in combination with cladribine may be considered a treatment option for some patients with relapsed or refractory de novo AML

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

Bortezomib plus melphalan and prednisone for initial treatment of multiple myeloma.

BACKGROUND: The standard treatment for patients with multiple myeloma who are not candidates for high-dose therapy is melphalan and prednisone. This phase 3 study compared the use of melphalan and prednisone with or without bortezomib in previously untreated patients with multiple myeloma who were ineligible for high-dose therapy. ETHODS: We randomly assigned 682 patients to receive nine 6-week cycles of melphalan (at a dose of 9 mg per square meter of body-surface area) and prednisone (at a dose of 60 mg per square meter) on days 1 to 4, either alone or with bortezomib (at a dose of 1.3 mg per square meter) on days 1, 4, 8, 11, 22, 25, 29, and 32 during cycles 1 to 4 and on days 1, 8, 22, and 29 during cycles 5 to 9. The primary end point was the time to disease progression. RESULTS: The time to progression among patients receiving bortezomib plus melphalan-prednisone (bortezomib group) was 24.0 months, as compared with 16.6 months among those receiving melphalan-prednisone alone (control group) (hazard ratio for the bortezomib group, 0.48; P<0.001). The proportions of patients with a partial response or better were 71% in the bortezomib group and 35% in the control group; complete-response rates were 30% and 4%, respectively (P<0.001). The median duration of the response was 19.9 months in the bortezomib group and 13.1 months in the control group. The hazard ratio for overall survival was 0.61 for the bortezomib group (P=0.008). Adverse events were consistent with established profiles of toxic events associated with bortezomib and melphalan-prednisone. Grade 3 events occurred in a higher proportion of patients in the bortezomib group than in the control group (53% vs. 44%, P=0.02), but there were no significant differences in grade 4 events (28% and 27%, respectively) or treatment-related deaths (1% and 2%). CONCLUSIONS: Bortezomib plus melphalan-prednisone was superior to melphalan-prednisone alone in patients with newly diagnosed myeloma who were ineligible for high-dose therapy. (ClinicalTrials.gov number, NCT00111319.