[Carfilzomib, lenalidomide and dexamethasone in relapsed/refractory multiple myeloma patients: the real-life experience].

BACKGROUND: Carfilzomib, lenalidomide, and dexamethasone (KRd) have been approved for the treatment of relapsed and refractory multiple myeloma (RRMM) based on ASPIRE clinical trial. AIM: Analysis of efficacy and safety of KRd in routine clinical practice. MATERIALS AND METHODS: The prospective analysis included patients with MM who received at least one line of previous therapy. The inclusion criteria were relapse/progression; refractoriness; lack of very good partial response (VGPR) and more after the first line of therapy. Since February 2016, we used KRd like in ASPIRE trial, since October 2019, carfilzomib has been used at a dose of 56 mg/m2 on days 1, 8 and 15. Autologous hematopoietic stem cell transplantation (autoHSCT), consolidation (KRd) and maintenance therapy (Rd) were regarded as one line of therapy. RESULTS AND DISCUSSION: We evaluated 77 patients with median age at the time of diagnosis is 55 (3072) years. For 56% (n=43) of patients KRd was applied as the second line (group 1), for 44% (n=34) as the third and more (group 2). In 23/43 patients from group 1, an early change in therapy was made due to insufficient effectiveness (after 24 courses of VCD or PAD). KRd served as a "bridge" to autoHSCT in 25 (32%) patients (21 of 25 in group 1). Another 7 patients underwent collection of autoHSC (all from group 1). The overall response rate (ORR) was 80.5%, with 33.8% complete response (CR) and 26% VGPR. ORR in group 1 was 98% versus 65.6% in group 2; 24-month overall survival (OS) was 70%, progression free survival (PFS) 49.8%. In group 1, 24-month OS was 85.6% versus 50.0% in group 2, 24-month PFS was 67.8% versus 25.5% (p=0.01). CONCLUSION: Our analysis confirmed the high efficiency of KRd in the treatment of RRMM in real-life practice. Early correction of therapy with insufficient effectiveness of the first line made it possible to implement the strategy of high-dose consolidation and autoHSCT in a larger percentage of patients with MM.

[Efficiency of interferon therapy in patients with essential thrombocythemia or polycythemia vera]. / Effektivnost' interferonoterapii u bol'nykh essentsial'noi trombotsitemiei i istinnoi politsitemiei.

AIM: To evaluate the efficiency of interferon (IFN) therapy in patients with essential thrombocythemia (ET) and polycythemia vera (PV). SUBJECTS AND METHODS: A total of 61 patients (41 with ET and 20 with PV) were examined. Prior to study enrolment, 44 (72%) patients with ET or PV received one or other therapy (aspirin was not taken into account). The mean Jak2V617F mutant allele at baseline was 23% (6-54%) in the patients with ET and 40% (11-88%) in those with PV. The median time from diagnosis to enrollment was 49 months. RESULTS: The paper presents the clinical and molecular findings of long-term INF-α therapy in patients with ET or PV. The median follow-up was 52 months. Recombinant IFN-α2 showed its ability to induce complete hematologic remission (ET (76%), PV (70%)) and a complete molecular response. 22 (69%) out of 32 patients were noted to have a smaller number of cells with the Jak2V617F mutation. In the patients with PV and in those with ET, the relative reduction in the proportion of cells with the Jak2V617F mutant gene averaged 85% and 56% of the baseline values, respectively. There was a reduction in the proportion of cells expressing the Jak2V617F mutation in both the ET (from 12 to 2.2%; p=0.001) and PV (from 32.7% to 3.2%) groups (р=0.001). Ten (31%) patients achieved a deep molecular remission (≤2% Jak2V617F allele); among them, 5 patients were not found to have Jak2V617F mutation. The obtained molecular response remained in 7 of the 10 patients untreated for 11 to 86 months. The long-term treatment with IFN-α led to normalization of the morphological pattern of bone marrow in 5 of the 7 PV or ET patients. CONCLUSION: Significant molecular remissions achieved by therapy with recombinant interferon-α2 confirm the appropriateness of this treatment option in in the majority of patients with ET or PV.

[Clinical and epidemiological characteristics of acute myeloid leukemias in adults according to the data of municipal hematology departments in Moscow].

AIM: To estimate the incidence of acute myeloid leukemias (AML) in Moscow adults and to evaluate the efficiency of their treatment. SUBJECTS AND METHODS: Data on Moscow residents who were first diagnosed with AML in 2010 were retrospectively collected. The efficiency of their treatment was evaluated from the rates of complete remissions (CR), recurrences, deaths, and 4-year overall (OS) and relapse-free survival (RFS). The data as of September 1, 2013, were analyzed. RESULTS: According to the 2010 pooled materials of the city's municipal hematology departments, AML (non-M3 types) was diagnosed in 286 patients whose median age at diagnosis was 64.9 years (range, 18.2-92.0 years). The notified incidence rate was 2.9 (3.3 for men and 2.6 for women) cases per 100,000 population. 118 (41%) patients received intensive chemotherapy (ICT); 119 (42%) had chemotherapy with low-dose cytarabine (LDC); 7 (2%) had that with hypomethylating agents (HA); and 42 (15%) had palliative therapy (PT). During first-line therapy, none of the patients underwent allogeneic hematopoietic stem cell transplantation (allo-HSCT). In the entire group, the early (within the first 60 days) mortality rates were 42% (119 deaths); that of patients with primary refractory disease was 32% (90 deaths). CR was achieved in 77 (27%) patients: 57 (48%) on ICT, 17 (14%) on LDC, and 3 (43%) on HA. Recurrences occurred in 37 (48%) of the 77 patients who had achieved CR at a median follow-up of 43.9 months. Four-year OS in all the patients receiving PT was 9.8±1.9% (18.2±3.9% in the patients on ICT versus 4.5±2% in those of LDC; p=0.028); 4-year RFS was 36.1±5.7% (39.6±6.7% inthe patients on ICT versus 31.3±11 .6% in those on LDC; p=0.8). CONCLUSION: High mortality rates in the induction, which are caused by the limited resources of accompanying therapy, poor sanitary conditions, and no own opportunities to perform allo-HSCT, remain a key problem of AML therapy in adults.

[The detection of minimal residual disease in patients with chronic B-cell lymphatic leukemia using patient-specified polymerase chain reaction].

The new effective protocols of treatment of chronic B-cell lymphatic leukemia, including purine analogs and monoclonal antibodies, provide robust remissions under this disease. Accordingly, the requirements to remission quality assessment are changed too. In particular the assessment of minimal residual disease is obligatory. To assess minimal residual disease in terms of quantity in case of chronic B-cell lymphatic leukemia the technique of polymerase chain reaction was applied in real time with patient-specific primers from the area of V-D-J combinations of genes of heavy chain of immunoglobulin. The study included samples from 60 patients suffering of chronic B-cell lymphatic leukemia. In 15 of them (25%), it was impossible to apply neither the sequence analysis of genes of heavy chain of immunoglobulin nor the fitting of patient-specific primer. The results of quantitative determination of minimal residual disease were obtained in 45 patients (55 tests). The minimal residual disease was detected in 30 of 55 samples (54.5%) and was not detected in 25 of 55 samples (45.5%). At the same time, the quantitative determination of minimal residual disease was implemented in regard to the initial level of neoplastic cells. The method sensitivity qualified by serial dilutions, consisted 10(-5) or 1 neoplastic cell to 100 000 normal cells. The comparative analysis was applied to the results of determination of minimal residual disease using two methods -polymerase chain reaction in real time using patient-specified primers and four-color flow cytofluometry. The determination of minimal residual disease with both methods was implemented in 37 patients (45 tests). The results of both methods matched in 93.3% (42 tests out of 45) with maximal disparity of one degree. Then Spearman factor consisted 0.87 (p < 0.0001). In 3 out of 45 tests (6.7%) neoplastic cells were detected with only one method. In the first case, it was the method of four-color flow cytofluometry and in other two cases it was polymerase chain reaction in real time. Therefore, the detection of minimal residual disease under chronic B-cell lymphatic leukemia using the method of polymerase chain reaction in real time is rather sensitive and specific and correlates with the results received with the method of four-color flow cytofluometry. The results are the same in the case of using anti-CD20 monoclonal antibodies under treatment.

[Prognosis factors in imatinib mesilate therapy in patients with a chronic phase of Ph-positive chronic myeloid leukemia: data from a multicenter non-randomized trial in Russia].

AIM: To reveal prognostically significant factors affecting efficacy of glivek therapy in untreated (duration of the disease < or = 6 months) and pretreated (duration of the disease > 6 months) patients with chronic myeloid leukemia (CML) in a chronic phase. MATERIAL AND METHODS: A total of 338 patients (64 untreated and 274 pretreated) with a chronic-phase CML on glivek therapy entered the trial. RESULTS: Five-year survival on glivek was high (89, 98 and 88% in untreated and pretreated patients, respectively). Incidence of transformation in the acceleration phase and blast crisis was low both in untreated and pretreated patients (1.6 and 11%, respectively) and correlated with the rate of a complete cytogenetic response (CCR). Untreated patients had no factors affecting treatment efficacy negatively, CCR probability was 96%. Blastemia, thrombocytosis and splenomegaly reduced CCR probability significantly in pretreated patients. Slow reduction of the tumor mass, late achievement of a complete hematological response and a cytogenetic response decreased probability of CCR. CONCLUSION: Glivek is a drug of choice for patients with chronic-phase CML. High probability of CCR both in untreated and pretreated patients lowers the risk of the disease transformation into the phase of acceleration/blast crisis and raises overall survival in both groups.

Application of PRV-1 mRNA expression level and JAK2V617F mutation for the differentiating between polycytemia vera and secondary erythrocytosis and assessment of treatment by interferon or hydroxyurea.

Increased PRV-1 mRNA expression and the presence of Jak2(V617F) mutation in peripheral blood granulocytes are specific markers for chronic myeloproliferative disorders (MPD), which facilitate the differential diagnosis between polycythemia vera (PV) and secondary erythrocytosis (SE) and may be helpful for monitoring treatment efficacy in MPD patients. We evaluated the presence of the Jak2V617F mutation and increased PRV-1 mRNA expression along with previously established markers - erythropoietin (EPO) independent colony formation (EEC) and erythropoietin level for diagnosis of PV and assessment of treatment efficiency. Increased PRV-1 expression was found in 37 out of 46 patients diagnosed with PV (80%), in 4 out of 15 patients diagnosed with essential thrombocythemia (ET) (27%) and in 4 out of 8 patients with chronic idiopathic myelofibrosis (CIMF) (50%), and increased PRV-1 expression plus EEC formation was observed in 19 of 36 examined MPD patients indicating the superiority of PVSG and WHO bone marrow criteria for the diagnosis of ET, PV and CIMF. We could confirm a very high sensitivity, specificity and utility of the Jak2(V617F) mutation for differential diagnosis between PV and SE. Spontaneous EEC, serum EPO levels, PRV-1 expression was evaluated in 22 PV patients who carried the Jak2(V617F) mutation. A concordance of increased PRV-1 expression and presence of Jak2(V617F) mutation in 19/22 (85%); of increased PRV-1/Jak2/EEC in 14/22 (63%); and of Jak2/PRV-1/EEC/low Epo level in 10/22 (45%) patients was found indicating the superiority of the presence of Jak2(V617F) mutation for the diagnosis of PV. IFN-alpha therapy in patients with PV was more effective then hydroxyurea treatment and significantly reduced increased PRV-1 expression together with higher levels of Jak2(V617F) mutation (50-100%) in PV patients treated with hydroxy urea (HU) and lower levels of Jak2(V617F) mutation (35-90%) in PV patients treated with IFN-alpha. Normal PRV-1 expression level was observed in 44% of PV patients who achieved clinical remission and only in 3% of patient who did not. These preliminary observations indicate that the Jak2(V617F) mutation in particular and PRV-1 overexpression appear to be suitable markers for monitoring treatment efficiency in prospective randomised clinical studies comparing pegylated interferon and hydroxyurea in well defined PV patients with a clear indication for cytoreductive therapy.

[Chronic myeloproliferative diseases and pregnancy].

AIM: To analyse the course of pregnancy in chronic myeloproliferative diseases (CMPD) with hyperthrombocytosis, primarily, essential thrombocytemia. MATERIAL AND METHODS: The analysis of thrombogenic risk factors covered literature data and 8 cases observed by the authors. RESULTS: Six pregnant women received long-term treatment with preparations of interferon-alpha in a dose 9-20 million IU a week (both before and during pregnancy). Rapid reduction of hyperthrombocytosis (1100-4000 x 10(9) l) and the absence of a negative effect on development of the fetus were seen in all the cases. Normal delivery on week 37-39 was in 4 patients, spontaneous abortion on week 24 was provoked by a car accident. Three gravidas (gestational week 28, 33 and 34) are still under observation. Lupus anticoagulant or elevation of anticardiolipin antibodies level was detected in 4 of 8 patients, 2 patients had heterozygous mutation of methylentetrahydrofolatereductase genes and factor V (Leiden). These patients were given lannacher, faxiparine, folic acid and discrete plasmapheresis (in 2 cases). CONCLUSION: Gravidas with hyperthrombocytosis, if not contraindicated, must be treated with aspirin and interferon-alpha preparations at any gestational term. Moreover, it is necessary to exclude additional most prevalent causes of thrombophilia for adequate prevention of thromboses.

[Bloodsucking mosquitoes on the irrigated lands of Kara-Kalpakia. 2. The annual cycle of Anopheles pulcherrimus]. / Krovososushchie komary na oroshaemykh zemliakh Karakalpakii. Soobshchenie 2. Godovoi tsikl Anopheles pulcherrimus.

The authors characterize the annual cycle of An. pulcherrimus population, distinguish the stages of this cycle that differ by the population composition and number and by the size of its area. The spatial structure of the population depends on the site of water bodies for wintering and the conditions at different territories. High numbers of mosquitoes were found in the southern part of the oasis at villages of rice-growing farmers. Mosquito population densities in the central parts of the oasis are much lower and are increased nearby sandy islets.

[Bloodsucking mosquitoes on the irrigated lands of Kara-Kalpakia. I. The species composition and distribution of mass species]. / Krovososushchie koary na oroshaemykh zemliakh Karakalpakii. I. Vidovoi sostav i raspredelenie massovykh vidov.

Data on fauna of bloodsucking mosquitos (Culicidae), obtained during the survey in the irrigated part of Takhta-Kupyr District of Kara-Kalpakia in 1988-1989, are presented. The density of mosquito populations of mass species in different parts of the oasis is, to a great extent, caused by the presence of reservoirs of different types and also by the features of anthropogenic landscapes.

[The seasonal changes in the resistance and irritability to insecticides in malarial mosquitoes in Karakalpakia]. / Sezonnye izmeneniia rezistentnosti i razdrazhimosti k insektitsidam u maliariinykh komarov v Karakalpakii.

Primary observations on insecticide resistance and irritability in Anopheles martinius and An. pulcherrimus were carried out in Karakalpakia. Both the species were completely susceptible to malathion and fenitrothion, and An. pulcherrimus was also susceptible to propoxur and DDT. An. martinius had a moderate resistance to DDT, which decreased by the autumn, and initial stage of resistance to propoxur probably based on knockdown mechanism. In both the species irritability was to DDT high, and was lower to malathion, propoxur and especially fenitrothion. During the season, irritability to the four insecticides was decreasing in An. pulcherrimus, and in An. martinius; it was high in April but became moderate or low in July and then began to grow again reaching the initial high level in November. No relation between the seasonal changes of irritability and rounds of insecticide spraying was noticed. It is supposed that a genetically and physiologically stipulated mechanism of the seasonal variability of irritability exists in mosquito populations.

Effect of estradiol on RNA synthesis and nuclear protein phosphorylation in rat liver.

Experiments were made to study the effect of 17, beta-estradiol on the RNA synthesis and nuclear protein phosphorylation in the liver of sexually mature female albino rats: sham-operated, ovariectomized and hormone-treated after the ovariectomy (20 micrograms estradioldipropionate/100 g body mass). The rate of RNA synthesis is determined in vivo by the 3H-uridine incorporation in the acid-insoluble fraction, whereas the nuclear protein phosphorylation is determined in vitro by the incorporation of gamma-32 P-ATP in isolated cell nuclei. Increased RNA synthesis is found to occur under the effect of the hormone, which corresponds to the hormone's effect on the uterine cells. The hormone stimulates the nuclear protein phosphorylation--an effect which could be associated with the gene expression.

Effect of estradiol on the phosphorylation of rat liver ribosome proteins.

The effect of estradiol on phosphorylation with gamma-32P-ATP of ribosome proteins from polyribosome fraction, isolated from female rat liver is found out. Rats (180 g) used were: sham-operated, ovariectomized and treated after ovariectomy for 11 days with 20 micrograms 17 beta-estradiol-dipropionate per 100 g body weight. The estradiol deficiency after ovariectomy decreased phosphorylation, but the estrogenization of ovariectomized rats increases it twice. In vitro the hormone (1-2 mumol/l) [corrected] also stimulated ribosome protein phosphorylation. It is supposed that the hormone may take part in the regulation of protein synthesis in the translational region of the process.

[Effect of estradiol on the synthesis of DNA in the female rat liver]. / Vliianie éstradiola na sintez DNK v pecheni samok krys.

The effect of estradiol on DNA synthesis in hepatocytes was investigated for a study of the functional importance and mechanism of action of sex steroids in the liver. After administration of 17, beta-estradiol dipropionate at a dose of 20 micrograms per 100 g of body mass to ovariectomized albino female rats for 11 days the kinetics of incorporation of 3H-thymidine triphosphate in liver cell nuclei and chromatin was determined. A stimulating effect of the hormone on the tracer incorporation in the nuclei and chromatin was established. A similar tendency was noted in immature female rats. The tracer incorporation depends on the cytosol presence in the system. The rate of incorporation has been shown to increase under the influence of the liver cytosol of intact rats. In can be assumed that estradiol is involved in the regulation of liver DNA synthesis raising matrix activity and modulating cytosol factor activity.

Effect of estradiol on the protein synthesis in the female rat liver in vitro.

The incorporation of 14C-leucine in protein, as well as in aminoacyl adenylate and aminoacyl-tRNA (AA-tRNA) from the liver of mature female rats (controls, ovariectomized and treated after the ovariectomy with daily doses of 20 micrograms 17, beta-estradiol-dipropionate/100 g body weight for 11 days), was investigated under conditions of a cell-free protein-synthesizing system containing isolated microsomes and cytosol. The ovariectomy causes reduced incorporation of the label in protein and in AA-tRNA, while hormonal treatment compensates this decrease either partially or completely. Data are presented which suggest that the hormone probably increases the supply of macroergic components and free amino acids to the hepatocytes, and that it also increases the sensitivity to cycloheximide and tetracycline. It is assumed that estradiol participates in the regulation of the protein synthesis in the hepatocytes at the level of AA-tRNA synthesis.

Binding of cytosol 3H-17, beta-estradiol to cytosol receptors in the liver of female rats.

The article is a study of the specific binding of 3H-17, beta-estradiol to cytosol receptors in the liver of female, sexually mature albino rats: sham-operated, ovariectomized and treated after the ovariectomy with 17-beta-estradiol (in doses of 20 micrograms/100 g body weight for 11 days). The binding of the labelled hormone in the liver cytosol isolated from ovariectomized rats is considerably reduced compared with the sham-operated animals. In the cytosol from the liver of the estradiol-treated rats the formation of a hormone-receptor complex is substantially increased compared with the ovariectomized animals. It is assumed that the formation of estradiol-receptor complexes in the liver depends on the concentration of the cytosol receptors, which is determined by the concentration of oestrogens in the blood.

Effect of estradiol on DNA and protein synthesis in rat liver in vivo.

The article studies the effect of 17, beta-estradiol on the binding of cytosol estradiol-receptor complex with chromatin isolated from the liver of female albino rats (sham-operated, ovariectomized and treated after the ovariectomy with 20 micron hormone/100 g body weight for 11 days) and sexually mature male albino rats. Higher binding of the complex is found for the female animals compared with the males. Parallel experiments are made to study the incorporation of 3H-thymidine and 14C-glycine in vivo, in acid-soluble and acid-insoluble liver fractions of female rats, respectively, which is used as a basis for assessing the rate of DNA and protein synthesis. Ovariectomy induces considerable reduction of the binding of the estradiol-receptor complex with chromatin, as well as of the DNA and protein synthesis. Hormonal treatment of the ovariectomized rats is followed by substantial increase in the parameters investigated above the level measured in intact animals. The observed effects of the hormone on the liver correspond to the accepted view concerning the action of steroid sex hormones on their target organs.

[Epidemiological analysis of the influenza virus A carrier state in healthy children]. / Epidemiologicheskii analiz nositel'stva virusa grippa A u zdorovykh detei.

Clinical and laboratory examinations in two permanently observed children's institutions were carried out in 1968--1978. Altogether, 241 children were examined virologically 759 times, of them 181 children were found to be truly healthy. In the epidemic period the latter yielded virus in 3.7%, in the interepidemic period in 1%. Unlike asymptomatic infection, transitory virus carrier state was not accompanied by antibody production, and in a number of such cases subsequently led to an overt clinical disease.