Role of glutathione-S-transferase M1 (GSTM1) and T1 (GSTT1) genes in the development and progress of chronic myeloid leukemia and in the formation of response to imatinib therapy.

The effects of GSTM1 and GSTT1 gene deletion ("zero") polymorphisms on the risk of chronic myeloid leukemia development and progress and on response to imatinib monotherapy were studied in the representatives of the Russian nationality in the Vyatka region of Russia. Homozygotic carriership of GSTT1 "zero" allele was associated with a 3.66 times higher risk of chronic myeloid leukemia development in residents of the Vyatka region (OR=3.66, 95% CI=2.12-6.30; p<0.0001). Combinations of the "zero" GSTM1 and GSTT1 genotypes were risk factors indicating the probable disease progress and failure of high cytogenetic response after 12 months of imatinib therapy (400 mg daily).

[The diagnostic of defects of inborn immunity under B-cell tumors of lymphatic system].

The genetic characteristics are key risk factors of development of many human neoplasms including B-cell tumors of lymphatic system. The relationship between polymorphic variants of genes FCGR2A (His 1 66Agr), CD14 (C-159T). IL1ß (T-31C), IL2 (7:330G) and 7LR2 (Arg753Ghn) and development of various forms of B-cell tumors of lymphatic system in 80 patients was investigated. The statistically significant differences of rates of particiular genotypes of single nucleotid polymorphisms of genes FCGR2A, CD14. IL1ß, IL2 and TLR2 in patients with indolent and aggressive types of course of non-Hodgkin lymphoma and also multiple myeloma. The results prove hypothesis that genetic variants of genes of inborn immune response effect the origin and character of course of different types of lymphoproliferative diseases. The markers can become additional prognostic characteristics of benign and aggressive course of tumors.

[The interpretation of immunophenotyping results during diagnostics of lymphatic proliferative disease using immunophenotyping count].

The article considers immune phenotyping heterogeneity of chronic lymphatic leukemia detected using basic diagnostic markers ofcell. The results of analysis of immune phenotypes of 108 patients with B-cell lymphatic proliferative diseases made it possible to establish that the atypical is related most rarely to indicators of expression of monotypic immunoglobulines and CD5 and most frequently to CD23, FMC7, CD22 and CS79b. During the present observation, the immune phenotyping count made up "3" or "2"points and the atypical alternative was registered among 10% of all examined patients with chronic lymphatic leukemia. It is demonstrated that patients with chronic lymphatic leukemia and with lower immune phenotyping count are characterized by major intensity of tumor substrate.

[The first results of treatment for adult acute myeloid leukemia according to the AML-01.10 protocol of the Research Group of the Hematology Centers of Russia].

AIM: To give the preliminary results of the AML-01.10 Russian multicenter randomized trial to treat adult acute myeloid leukemia (AML), the basic principle of which is to use high-dose anthracycline antibiotics in induction/consolidation. SUBJECTS AND METHODS: By December 2011, 145 patients with AML had been randomized from 18 hematology centers of 15 cities and towns of the Russian Federation; the median age of all the patients was 44 years. Seventy-one patients were analyzed in August 2011 (a 1.5-year follow-up). RESULTS: The efficiency of 2 courses 7+3 using high-dose daunorubicin (60 mg/m2 per administration) and continuous infusion of cytarabine during the second course was high and comparable with that in the use of a high-dose HAM protocol as a second induction course and can achieve a complete remission in 74.6%. The protocol toxicity evaluated from its early mortality (11.3%) and its death in complete remission (16.6%) was permissible, particularly by taking into consideration the multicenter pattern of the trial. At the completion of analysis, 53 (68.8%) out of the 77 patients on whom the data on their vital status were available were alive. In this follow-up period, the frequency of recurrences was 19.2% (10/52). Only 3 (4.2%) patients out of the 71 patients in whom the efficiency of the protocol had been completely evaluated underwent allogeneic bone marrow transplantation. CONCLUSION: The total high dose (720 mg/m2) of anthracycline antibiotics, which is used in the period of induction and consolidation, determines the long periods of myelosuppression and intercourse intervals. Protocol deviations (no course of consolidation therapy, lower-dose idarubicin during consolidation therapy, a course of low-dose cytarabine, between the courses of induction and consolidation chemotherapy, and very long intercourse intervals) were recorded in a total of 20 (28%) patients.

[Toxicity of different treatment protocols for acute myeloid leukemias in adults: the results of four Russian multicenter studies].

AIM: To comparatively analyze the toxicity of 4 treatment protocols in patients with acute myeloid leukemia (AML), which were used in the Russian multicenter center in 1992 to 2009. MATERIALS AND METHODS: The information obtained in 4 Russian multicenter studies conducted in 33 hematology departments of 26 cities and towns of the Russian Federation in 1992 to 2009 was analyzed. Randomization was made in 243 patients with AML (median age 38 years) in 1992-1995, 396 patients (median age 39 years) in 1995-1999, 392 patients (median age 39 years) in 2001-2006, and 137 patients (median age 40 years) in 2006-2009. The analysis excluded patients with acute promyelocytic leukemias who were recruited in the AML-92 and AML-95 studies. These patients' statutory forms adequately filled in were 60-70% therefore toxicity was analyzed on the basis of the data of 631 patients. RESULTS: The baseline clinical and laboratory parameters in the patients enrolled in the studies in different years slightly differ in the count of leukocytes at the onset of the disease and in the level of lactate dehydrogenase (LDH): the recent studies revealed a larger number of high-risk group patients (leukocytes more than 30 10(9)(/l; LDH more than 500 units) possibly due to the later diagnosis of AML. During the studies, the number of complete remissions remained as before (55%) after the first course and increased from 65 to 78% after the second course using cytosine arabinoside in high doses. Despite treatment intensification, mortality in the induction period remained as before (19-21%). Remission mortality decreased from 18 to 10-13%. The long-term results of using the aggressive therapy did not differ from those obtained during the standard treatment protocols. The duration of leucopenia after standard induction courses during the all studies remained equal (17-19 days); the exclusion was a HAM course as the second induction course after which the duration of neutropenia was much more than that of the standard course (17 and 10 days, respectively). During the study years, there was an increase in platelet transfusion volumes (from 20 to 53 doses during the first course and from 7 to 28 doses during the second course) and a reduction in the percentage of severe hemorrhagic complications. The incidence of pneumonias remained at the same level (40-50%) during the induction courses and that of septic complications and necrotic enteropathy considerably decreased from 40-46 to 17-19%. The incidence of invasive aspergillosis during the current programs from AML treatment was 10% (two induction courses), that of invasive candidiasis was 4.7% (two induction courses). CONCLUSION; The long-term results of treatment for AML were virtually unchanged regardless significant therapy intensification. Mortality remained high during induction treatment and in the postremission period. Its cause is severe infectious complications developing during myelotoxic agranulocytosis. The results of the analysis provide the basis for developing a new AML treatment protocol that should take into account all the merits and demerits of the previous protocols and provide a toxicity-treatment efficiency balance.

[Evaluation of fludarabine-containing regimens versus immunochemotherapy for chronic lymphocytic leukemia].

AIM: to analyze the efficacy of RFC (rituximab, fludarabine, and cyclophosphan), FCM (fludarabine, cyclophosphan, and mitoxantrone), and FC (fludarabine and cyclophosphan) treatment programs in patients with chronic lymphocytic leukemia (CLL) in an open-labeled comparative controlled investigation. MATERIALS AND METHODS: The paper presents the authors' results of treatment in patients with progressive CLL in 2002 to 2007. The study included 229 patients, of them 78 patients received the RFC program, 72 had the FCM program, and 79 had the FC one. RESULTS: With the use of RFC, a clinically significant therapeutic effect was obtained in 96% of the patients, a complete remission (CR) was in 80% of the primary patients and in 53% of the pretreated patients. When the FCM program was applied, a positive response was noted in 93% of the patients, CR was seen in 75 and 42% of the primary and pretreated patients, respectively. In the treatment of FC, the total effect was 80%, CR was in 41 and 14% of the primary and pretreated patients, respectively. CONCLUSION: Comparative analysis of an objective response to therapy has indicated that the effectiveness of the RFC significantly exceeds that of the FCM and FC programs, without enhancing toxicity, which allows he RFC regimen to be regarded as the program of choice in therapy for CLL.

[Results of the treatment of adult acute lymphoblastic leukemia according to ALL-2005 protocol as a basis for new trials].

AIM: To analyse the results of the treatment according to ALL-2005 protocol for adult patients with acute lymphoblastic leukemia (ALL); on the basis of the summarized evidence on ALL treatment to propose principles for development of a new program of ALL treatment in 15-55-year-old patients. MATERIAL AND METHODS: Five hematological centers (in Moscow, Saransk, Volgograd, Tambov, Kirov) participated in ALL-2005 protocol trial initiated in 2005. A total of 71 adult patients with ALL (age median 27 years) were treated. The results of the MB-2002 study with participation of 16 patients aged 16-23 years performed in the State Hematological Research Center (SHRC) were reviewed RESULTS: The results of the induction therapy according to ALL-2005 protocol conducted in Moscow SHRC were good: a complete remission was achieved in 90% patients, early lethality was 6%, resistance was observed in 4%. In regional centers lethality in remission was higher, 5-year overall survival was 28% (in SHRC it was 56%), recurrence-free survival in regional center was 22% versus 51%, respectively. Long-term response by ALL-2005 and MB-2002 in patients aged 19-23 was the same, but toxicity of ALL-2005 treatment was higher (no lethality and 5, 4% in induction and remission, respectively). CONCLUSION: The decision was made on design of a new protocol of treatment of Ph-negative ALL for patients aged from 15 to 55 years the main principles of which are the following: continuous treatment with modification of cytostatic drugs doses depending on myelosuppression severity; assessment of tumor cells sensitivity to prednisolone and its replacement for dexametasone throughout the treatment; prolongation of L-asparaginase treatment with elevation of its total dose; monitoring of minimal residual disease (MRD) for decision on late intensification in patients with MRD at late treatment stages (5 months).

[The results of a multicenter randomized trial on the treatment of acute myeloid leukemia of adults].

AIM: Systematization of the results of 20-year multicenter randomized trial of the efficacy of treatment of acute myeloid leukemia (AML) of adults; presentation of the design of the study of the strategy of consolidation and maintenance therapy after high-dose consolidation initiated in 2007. MATERIAL AND METHODS: Treatment outcomes on the protocol AML-01.01 are presented for 354 AML patients from 29 hematological centers located in 22 towns of Russia and 2 towns of Ukraine. The patients were randomized into 3 groups by variant of therapy: 124 patients (62 males and 62 females; age median 42 years) received 4 courses of 7+3+VP-16 and 5 courses of maintenance therapy (7+3 with thioguanin); 130 patients (65 males and 65 females, age median 41 year) received 2 courses of 7+3+VP-16, 2 courses 7+3, maintenance--5 courses 7+3 with thioguanin; 126 patients (57 males and 68 females, age median 40 years) were given 2 courses of 7+3+VP-16, 2 HAD courses, treatment discontinuation. RESULTS: A complete remission after the first course of 7+3+VP-16 was achieved in 55% patients, after the second course--in 30% after the course 7+3+VP-16 or 7+3 with mitoxantron, in 70%--after NAM. Overall and recurrence-free survival were 18 and 35%; 30 and 20%; 36 and 30%, respectively. There was no significant difference in efficacy of the treatment scheme. CONCLUSION: The multivariate analysis has shown that a leading factor having impact on treatment results was the number of randomized patients: the less patients were randomized, the worse were the results.

[Preliminary results of a multicenter randomized study on the treatment of acute promyelocytic leukemias]. / Predvaritel'nye rezul'taty mnogotsentrovogo randomizirovannogo issledovaniia po lecheniiu ostrykh promielotsitarnykh leikozov.

AIM: To study efficacy of maintenance therapy of patients with acute promyelocytic leukemia (APL) in the APL treatment Russian multicenter trial. MATERIAL AND METHODS: The trial was made with participation of 18 hematological departments of clinics in Russia. A total of 68 APL patients entered the trial. The maintenance therapy consisted of 5-day courses of cytostatic drugs which alternated or did not alternate with 5-day courses of ATRA. Cytogenetic tests were made in 31 patients, t(15;17) was detected in 26 of them. Molecular examination conducted in 28 patients discovered chimeric transcript PML/RARa in 26 of them. Of 20 patients examined in Hematological Research Center, 7 (35%) had a bcr 1/2 variant of the transcript PML/RARa, 13 (65%)--bcr 3 variant. RESULTS: 65 patients were eligible for assessment. A complete remission was achieved in 90% cases. No resistance was observed. In follow-up within 30 months the recurrence rate was similar on both treatments. The results of the induction therapy and survival in patients with different variants of the transcripts were also similar. Overall 2.5 year survival for all the patients was 77%, recurrence-free--80%. The survival analysis in patients with leukocytosis higher and lower 10 x 10(9)/l found no statistical differences by the survival. Patients with hyperleukocytosis had higher early lethality than patients with leukocytes under 10 x 10(9)/l (25% vs 5.3%, p = 0.03). CONCLUSION: The APL 06.01 protocol showed high efficacy of the relevant maintenance which provides a complete molecular remission in the majority of patients with probable recurrence-free 2.5 year survival 80%.