Vol 89, No 7 (2017)
- Year: 2017
- Articles: 17
- URL: https://journals.rcsi.science/0040-3660/issue/view/1826
Editorial
Clinical features of essential thrombocythemia and primary myelofibrosis, depending on the molecular characteristics of disease
Abstract
The aim of the present paper was to evaluate the clinical features and risk of thrombotic events (TE) in patients with essential thrombocythemia (ET) and primary myelofibrosis (PMF), depending on the molecular characteristics of disease. Clinical data and laboratory parameters were analyzed in 50 ET patients and 50 PMF ones who had been followed up at the Department for Standardization of Treatments, National Research Center for Hematology, Ministry of Health of the Russian Federation, from February 2015 to September 2016. The patients with ET and those with PMF were found to have a high risk of TE. The risk for TE in the patients with ET is higher (24% in the entire group) than in those with PMF (14% in the study group). In ET, there is a high thrombosis risk in the detection of JAK2 and CALR gene mutations as compared with triple-negative cases. The PMF patients with JAK2 V617F mutations are at high risk for TE compared to those who are CALR mutation carriers and in triple-negative cases. There was no significant association of TE with high thrombocytosis. A factor, such as age, was found to be of no negative prognostic value in the patients with PMF.
Terapevticheskii arkhiv. 2017;89(7):4-9
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Adult B-cell acute lymphoblastic leukemias: Conclusions of the Russian prospective multicenter study ALL-2009
Abstract
Aim. To analyze the efficiency and reproducibility of the ALL-2009 protocol within the Russian prospective multicenter study based on different principles of cytostatic effects (non-intensive, but continuous cytotoxic treatment and a small number of allogeneic hematopoietic stem cells). Subjects and methods. The ALL-2009 (NCT01193933) study conducted in April 2009 to December 2016 included 194 patients (95 males and 99 females) aged 15 to 55 years (median age 28 years) with Ph-negative B-cell acute lymphoblastic leukemia (ALL). There was early pre-B-cell ALL in 54 patients, common ALL in 101, pre-B ALL in 39, initial leukocytosis in 9.4·109/l (0.4-899.0), lactate dehydrogenase in 901 IU (31-13 059), an initial central nervous system lesion in 17 (8.7%), mediastinal injury in 3 (1.5%), and splenomegaly in 111 (57.2%). The results of standard cytogenetic analysis are known in 113 (60.4%) patients. Normal karyotypes were detected in 49 (54.5%) out of the patients; t(4;11) in 9 (5.4%), t(1;19) in 2 (1.2%), and other karyotypic abnormalities in 53 (46.9%). Thirteen (7.8%) patients underwent allogeneic hematopoietic stem cell transplantation in first complete remission (CR); their proportion did not differ in the federal and regional centers. Results. The frequency of CR achievement was the same in the federal and regional centers and generally amounted to 87.5%. Early (8.8%) and CR (9.6%) mortality rates remained high despite the low aggressiveness of cytotoxic action, necessitating the improvement of auxiliary treatment. The five-year overall survival (OS) rates vary considerably in the federal and regional centers (72.6 and 43.8%), the relapse-free survival (RFS) (70.2 and 53.4%) and recurrence risk (23.1 and 36.5%) are comparable. This suggests that the non-intensive, but continuous exposure principle built in the ALL-2009 protocol makes it possible to reproduce the envisaged treatment program and to achieve satisfactory results. Conclusion. The ALL-2009 protocol allows both the federal and regional centers to obtain the long-term results comparable with those of current foreign studies: OS (54.2%), RFS (56.5%); and relapse risk (35.4%). Multivariate analysis has identified age (over 30 years), initial leukocytosis (30·109/l and more) and t(4;11) among the main clinical prognostic factors. Gene mutation detection evaluated in a small number of patients (8/36) is not a poor prognostic sign. There is a need for further investigations with centralized evaluation of the mutation status of leukemic cells and the clearance of minimal residual disease.
Terapevticheskii arkhiv. 2017;89(7):10-17
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Absolute numbers of peripheral blood CD34+ hematopoietic stem cells prior to a leukapheresis procedure as a parameter predicting the efficiency of stem cell collection
Abstract
Aim. To identify a parameter predicting a collection of at least 2·106 CD34+ hematopoietic stem cells (HSC)/kg body weight per leukapheresis (LA) procedure. Subjects and methods. The investigation included 189 patients with hematological malignancies and 3 HSC donors, who underwent mobilization of stem cells with their subsequent collection by LA. Absolute numbers of peripheral blood leukocytes and CD34+ cells before a LA procedure, as well as a number of CD34+ cells/kg body weight (BW) in the LA product stored on the same day were determined in each patient (donor). Results. There was no correlation between the number of leukocytes and that of stored CD34+ cells/kg BW. There was a close correlation between the count of peripheral blood CD34+ cells prior to LA and that of collected CD34+ cells calculated with reference to kg BW. Conclusion. The optimal absolute blood CD34+ cell count was estimated to 20 per µl, at which a LA procedure makes it possible to collect 2·106 or more CD34+ cells/kg BW.
Terapevticheskii arkhiv. 2017;89(7):18-24
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Multiple myeloma: Maintenance therapy after autologous hematopoietic stem cell transplantation, depending on minimal residual disease
Abstract
Aim. To determine the efficiency of maintenance therapy with bortezomib in patients with multiple myeloma (MM) who have achieved complete remission (CR) after autologous hematopoietic stem cell (auto-HSCT), depending on the presence of minimal residual disease (MRD). Subjects and methods. In January 2014 to February 2016, fifty-two MM patients (19 men and 33 women) aged 24 to 66 years (median 54 years), who had achieved CR after auto-HSCT, were randomized to perform maintenance therapy with bortezomib during a year. On day 100 after auto-HSCT, all the patients underwent immunophenotyping of bone marrow plasma cells by 6-color flow cytometry to detect MRD. Relapse-free survival (RFS) was chosen as a criterion for evaluating the efficiency of maintenance therapy. Results. After auto-HSCT, MRD-negative patients had a statistically significantly higher 2-year RFS rate than MRD-positive patients: 52.9% (95% confidence interval (CI), 35.5 to 70.5%) versus 37.2% (95% CI, 25.4 to 49.3%) (p=0.05). The presence of MRD statistically significantly increased the risk of relapse (odds ratio 1.7; 95% CI, 1.2 to 3.4; p=0.05). Two-year cumulative risk of relapse (using the Kaplan-Meier) after auto-HSCT did not statistically significantly differ in MRD-negative patients receiving (n=15) and not receiving (n=10) maintenance therapy with bortezomib (p=0.58). After completion of maintenance treatment, 42% of the MRD-positive patients achieved a negative status. In the MRD-positive patients who had received maintenance therapy, the average time to recurrence was 5 months longer than that in the naïve patients: 17.3 versus 12.3 months. Conclusion. The MRD status determined in MM patients who have achieved CR after auto-HSCT is an important factor for deciding on the use of maintenance therapy.
Terapevticheskii arkhiv. 2017;89(7):25-31
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Prognostic value of 1q21 amplification in multiple myeloma
Abstract
Aim. To determine the prevalence of amp1q21 and its relationship to the clinical manifestations of multiple myeloma (MM). Subjects and methods. In December 2009 to March 2016, a total 134 patients aged 30 to 81 years (median 57 years) underwent a pretreatment FISH-study of bone marrow (BM) with centromeric and locus-specific DNA probes to identify amp1q21, t(11;14), t(4;14), t(14;16), t(14;20), t(6;14), trisomies of chromosomes 5, 9, 15, del13q14, del17p13/TP53, and t(8q24)/cMYC. Induction therapy with bortezomib-containing cycles was performed. Autologous stem cell transplantation was carried out in 48 patients. The median follow-up of patients was 19.3 months (3.2—77.4 months). Disease progression was diagnosed in 69 (51.5%) patients; 12 patients also underwent FISH study during disease progression. Results. At the onset of MM, amp1q21 was detected in 53 (39.6%) patients. The overall 5-year survival rate in patients with amp1q21 was almost 2 times lower than that in those without amp1q21 (43.5 and 79.4%, respectively; p=0.07). The overall 5-year survival rate in patients with one extra copy of 1q21 (only 3 copies) was 67.3%, that in those with 2 or more extra copies of 1q21 (only 4—7 copies) was 20.9% (p=0.0016). Nine (75%) of the 12 patients examined during disease progression were found to have amp1q21: 2 cases were detected in the period of progression to have amp1q21 in its absence at disease onset; 7 cases had amp1q21 both at MM onset and progression; however, the number of copies of 1q21 was unchanged. Conclusion. Аmp1q21 is one of the most common chromosomal abnormalities in patients with new-onset MM and may appear in the course of disease progression. The presence of аmp1q21 is an important prognostic factor and must have to be included in the diagnostic study both at disease onset and progression.
Terapevticheskii arkhiv. 2017;89(7):32-38
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Analysis of VEGF-A/VEGFR1/VEGFR2 gene expression in patients with myelodysplastic syndrome
Abstract
Aim. To assess the significance of gene expression of the vascular endothelial growth factor-A (VEGF-A) and its interacting receptors VEGFR1 and VEGFR2 as potential diagnostic and prognostic molecular markers in patients with myelodysplastic syndrome (MDS). Materials and methods. A real time polymerase chain reaction (RT-PCR) assay was used to investigate the gene expression of VEGF-A, VEGFR1, and VEGFR2 in the mononuclear cell fractions obtained from 24 patients with MDS. Results. The expression of the 3 genes was identified in all the patients examined. There was the highest expression level of the VEGF-A gene (p<0.0001), whereas the expression of the VEGFR1 gene was higher than that of the VEGFR2 gene (p<0.001). The expression of the VEGF-A gene proved to be higher in patients at a higher risk of acute leukemia and positively correlated with the expression levels of the VEGFR1 gene (p<0.05) rather than that of the VEGFR2 gene. At the same time, patients with higher VEGFR1 gene expression had significantly lower overall survival rates (r=–0.5; p<0.05). Patients with intermediate-2 or high-risk acute leukemia showed an increase in the average expression levels of VEGF-A and VEGFR1 and a reduction in VEGFR2 expression. Conclusion. This investigation revealed correlations between the number of blast cells in patients with MDS and the expression levels of the VEGF-A gene and between the overall survival of patients with MDS and the expression levels of the VEGFR1 gene rather than those of the VEGF-A and VEGFR2 genes.
Terapevticheskii arkhiv. 2017;89(7):39-44
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Leukemization of follicular lymphoma: The features of diagnostic and clinical course of a rare form of the disease
Abstract
Aim. To characterize a group of patients with follicular lymphoma (FL) with leukemization and to evaluate the efficiency of different therapy options (R-CHOP/R-FMC/high-dose chemotherapy (HDCT)). Subjects and methods. 18 (7.2%) out of 250 patients diagnosed with FL, who were examined and treated at the National Research Center for Hematology, Ministry of Health of the Russian Federation, were found to have leukemic FL (tumor cells in the peripheral blood smears were detected by cytology and flow cytofluorometry. Eight of the 18 patients had extranodal foci of involvement: lung, stomach, spleen, lumbar muscles, upper jaw, and vertebrae. Bone marrow was involved in 17 of the 18 patients. Tumor biopsy specimens displayed a morphological pattern of indolent FL in the majority of patients (10 of the 18 patients had cytological grade 1—2 tumors and 14 patients had a nodular or nodular-diffuse tumor growth pattern). The patients underwent R-CHOP/R-FMC) or HDCT cycles as first-line therapy, followed by autologous stem cell transplantation (auto-SCT). Results. The median follow-up was 66 months (range 12—217 months). The 5-year overall survival (OS) and progression-free survival (PFS) rates were 70% (10% SEM) and 35% (15% SEM), respectively. The median OS was not reached; the median PFS was 3 years. Conclusion. Leukemic FL is characterized by low OS and PFS rates. The most effective chemotherapy regimens were R-CHOP, followed by HDCT and auto-SCT in first remission or R-FMC. These cycles can to a greater extent achieve a complete eradication of the bone marrow tumor clone. Due to the relapsing course of FL and the aggressiveness of leukemic FL, it is expedient to carry out auto-SCT in first remission.
Terapevticheskii arkhiv. 2017;89(7):45-50
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Use of crizotinib for refractory ALK-positive lymphomas
Abstract
Aim. To evaluate the safety and efficacy of crizotinib used in pediatric patients with relapsed or refractory ALK-positive anaplastic large-cell lymphoma (ALCL). Subjects and methods. The paper describes the experience with crizotinib used in 8 patients with refractory ALK-ALCL before and after allogeneic hematopoietic stem cell transplantation (HSCT). Results. All the 8 (100%) patients treated with crizotinib were recorded to have complete responses, including complete metabolic ones (tumor disappearance as evidenced by positron emission tomography (PET)/computed tomography. Conclusion. Low and manageable toxicity of crizotinib and complete PET-negative responses in patients with resistant ALK lymphomas favor the need to test the drug as first-line therapy, by possibly decreasing the intensification of chemotherapy.
Terapevticheskii arkhiv. 2017;89(7):51-56
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Efficacy of a bendamustine and rituximab combination in first-line therapy for chronic lymphocytic leukemia: Results of the BEN-001 study
Abstract
Aim. To evaluate the efficacy and safety of the BR regimen containing bendamustine in patients with chronic lymphocytic leukemia (CLL) who have not previously received specific therapy. Subjects and methods. The results of the Russian prospective observational multicenter study BEN-001 (2012—2015) covering 196 CLL patients from 34 centers of the Russian Federation were analyzed. The diagnosis was confirmed by the results of peripheral blood lymphocyte immunophenotyping. A centralized approach was employed to make IGHV gene mutational status analysis, FISH examination, and minimal residual disease according to standardized methods. Quality-of-life (QOL) indicators were estimated using the EQ-5D and FACT-Leu questionnaires. Survival rates were calculated applying by the Kaplan-Meier method. Results. The patients’ median age was 61 years. 41% of patients had a decline in estimated creatinine clearance less than 70 ml/min/1.73 m2. The combination of bendamustine and rituximab could achieve a common response in 83.2% of the patients, including complete remission in 59.7%. Eradication of minimal residual disease was achieved in 23 (27.4%) of 84 patients. Two-year progression-free survival rates were 85.9%. The QOL indicators were noted to be improved during the treatment. Conclusion. The investigation shows the good tolerability of bendamustine when it is used in clinical practice. Due to the high cost of new drugs (ibrutinib, obinutuzumab, ofatumumab, etc.) and toxicity of the FCR regimen, the combination including bendamustine can be the best first-line therapy option for all CLL patients, regardless of their age and comorbidity.
Terapevticheskii arkhiv. 2017;89(7):57-64
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Bone marrow involvement in primary mediastinal B-cell lymphoma
Abstract
Primary mediastinal large B-cell lymphoma (PMBCL) is a distinct type of large B-cell lymphoma. In this type of the disease, the neoplastic process is located in the anterior and superior mediastinum, frequently with compression of the superior vena cava and with tumor invasion into the adjacent organs and tissues: the pericardium, lung, pleura, etc. Despite the fact that in PMBCL progression, there may be involvement of extranodal organs, such as the kidney, adrenal glands, liver, and central nervous system, bone marrow (BM) injury is generally absent. Since BM injury in patients with diffuse large B-cell lymphoma is an independent poor prognostic indicator, there is reason to believe that BM involvement in PMBCL affects the prognosis. These cases may need intensified induction therapy followed by autologous hematopoietic stem cell transplantation; and BM injury should be monitored during the therapy. The paper gives reports of clinical cases of bone marrow involvement in 2 PMBCL patients treated at the National Research Center for Hematology, Ministry of Health of the Russian Federation.
Terapevticheskii arkhiv. 2017;89(7):65-68
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EBV-positive central nervous system lymphoproliferative disease associated with immunosuppression after organ transplantation: Long-term remission without chemotherapy
Abstract
Primary central nervous system (CNS) lymphomas account for 13-20% of the posttransplant lymphoproliferative disorders (PTLD) and rank among the most aggressive conditions. Reduction of immunosuppressive therapy should be mandatory to treat PTLD, but this is rarely used as the only therapy option. Chemotherapy regimens for PTLD involving the CNS most commonly include high-dose rituximab and high-dose methotrexate and/or cytarabine. The efficiency only of discontinuation of immunosuppressive therapy for PTLD does not exceed 5—10%, but there are no literature data on its efficiency for PTLD involving the CNS. The paper describes a clinical case of achieving long-term remission in a female patient with Epstein-Barr virus (EBV)-positive diffuse large B-cell lymphoma involving the central nervous system, associated with immunosuppression after kidney transplantation from a related donor, in the absence of chemotherapy during immunosuppressive therapy discontinuation and transplantectomy.
Terapevticheskii arkhiv. 2017;89(7):69-75
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Thrombotic events in patients with hemophilia
Abstract
The paper describes 4 clinical cases of thrombotic events (pulmonary embolism, deep vein thrombophlebitis, acute myocardial infarction, ischemic stroke) that have occurred in patients with hemophilia. It discusses the possible causes of their development and methods for their prevention and treatment. Controlled natural hypocoagulation, in which the dose of an administered deficient factor decreases to such an extent that in order to maintain the safe level of hypocoagulation (plasma factor activity is 15—20%; activated partial thromboplastin time is 1.5—2 times normal values), is proposed as one of the treatment options.
Terapevticheskii arkhiv. 2017;89(7):76-84
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Diffuse large B-cell lymphoma with concomitant c-MYC and BCL6 gene rearrangements with primary skin involvement: A case report and a review of literature
Abstract
Double-hit lymphoma (DHL) is a rare aggressive B-cell lymphoma with concomitant c-MYC, BCL2 or BCL6 gene rearrangements, which is characterized by the high frequency of extranodal lesions and by resistance to chemotherapy. The median survival does not exceed 18 months in patients with this disease. The majority of DHL is represented by с-MYC/BCL2 cases. The combination of c-MYC/BCL6 occurs rarely (5—8%). The paper describes a case of DHL with concomitant c-MYC and BCL6 gene rearrangements, which mimics diffuse large B-cell lymphoma, leg-type.
Terapevticheskii arkhiv. 2017;89(7):85-92
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Breast implant-associated anaplastic large-cell lymphoma: A case report and a review of literature
Abstract
Breast implant-associated anaplastic large-cell lymphoma will be identified as a separate nosological entity in the 2017 adapted WHO classification due to differences in its clinical presentations, pathogenesis, and prognosis with those of nodal and cutaneous anaplastic large-cell lymphomas. The paper gives a review of the literature and describes the authors’ own clinical case of common breast implant-associated anaplastic large-cell lymphoma involving breast tissue, axillary lymph nodes, anterior chest muscles, and bone marrow. The treatment policy chosen by the authors could achieve complete remission.
Terapevticheskii arkhiv. 2017;89(7):93-98
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Hairy cell leukemia and pregnancy
Abstract
The paper presents experience in following up and treating hairy cell leukemia (HCL) during pregnancy. The combination of HCL and pregnancy was observed in 5 patients. The patients’ median age was 35 years (range, 28—42 years). The diagnosis of HCL was based on a conventional examination protocol: clinical blood analysis with the morphological assessment of lymphocytes, a myelogram and trepanobiopsy, immunophenotypic analysis of lymphocytes or bone marrow (in all the patients), cytochemical determination of tartrate-resistant acid phosphatase in 3 patients, and identification of BRAFV600E mutation in 3 patients. Three pregnant women were treated for HCL in the postpartum period. In one patient with HCL, pregnancy was seen in remission after treatment with cladribine. In one patient with HCL detected at 11 weeks’ gestation, interferon-α therapy during the second trimester of pregnancy was performed for increased cytopenia, which was followed by cladribine therapy after delivery. Pregnancy and delivery were uncomplicated in all the patients; 3 patients had vaginal delivery and 2 patients underwent cesarean section. All infants were healthy, with no developmental abnormalities during a follow-up period of 6—140 months (median 30 months). All the patients with HCL are currently in remission: 4 patients in first remission at a follow-up of 10 to 48 months (median 15 months) and one patient in second remission at a follow-up of 88 months. Possible observational tactics is possible when HCL is detected during pregnancy. Treatment of HCL during pregnancy is necessary in cases of deep or progressive cytopenia and/or splenomegaly. The use of interferon-α or splenectomy is preferable.
Terapevticheskii arkhiv. 2017;89(7):99-104
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Analysis of inpatient care for HIV-positive patients with malignant lymphomas and hepatitis over 5 years (2011—2015) at the A.S.Loginov Moscow Clinical Research Center, Moscow Healthcare Department
Abstract
The authors give their own data in the first Russian publication on 170 patients with lymphomas and hepatitis concurrent with HIV infection, on the distribution of therapy regimens by nosological entities and the number of deaths. Conventional protocols and programs were used for diagnosis and treatment. All the patients received highly active antiretroviral therapy. Lymphoma was treated according to the conventional programs using rituximab in people without hepatitis B. Aggressive lymphomas, such as diffuse large B-cell lymphoma, Burkitt lymphoma, and plasmablastic lymphoma, were identified in most patients. Hodgkin’s lymphoma is the matter of a separate study; it differs in its pathogenesis from other lymphomas. The rate of coinfection with hepatitis was high in the entire group of patients with lymphomas. The major prognostic indicators included low CD4 T-cell counts (less than 50), stage IVB lymphoma, and hepatitis. Complete remissions were achieved in 40% of patients. Forty-one (24%) patients died.
Terapevticheskii arkhiv. 2017;89(7):105-111
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Current approaches to treating of patients with multiple myeloma with renal failure: Questions and proofs
Abstract
Renal failure (RF) is detected in 20-30% of patients at the onset of multiple myeloma (MM), in 50% of patients during its progression. The advent of new, highly effective agents has considerably expanded the possibilities of treatment in MM patients. Unfortunately, patients with RF, especially those with severe RF, were not included in the majority of investigations. The available data are based on the results of treatment in small groups of patients generally without the morphological identification of nephropathies, with varying severity of RF, which explains significant differences in renal response rates. This review analyzes the results of the most important studies and gives recommendations for treatment in accordance with national and international standards.
Terapevticheskii arkhiv. 2017;89(7):112-117
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