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Aim: To analyze the effectiveness of allogeneic hematopoietic stem cell transplantation (allo-HSCT) from a related HLA-identical donor in patients with multiple myeloma (MM)., Materials and Methods: From 2013 to 2018, the study included 8 patients (6 men, 2 women) aged from 27 to 55 years (median 39 years) with MM who underwent allo-HSCT from a related HLA-identical donor (7 patients after auto-HSCT, in 1 case without previous auto-transplantation). All patients required 2 or more lines of induction therapy, while the achieved antitumor effect was unstable. Before allo-HSCT, complete and very good partial remission was determined in isolated cases, in 4 patients the response was regarded as partial remission, stabilization in 1 observation, progression in 1 patient. All patients underwent reduced intensity conditioning (fludarabine 30 mg/m2 6 days + busulfan 4 mg/kg 2 days). Immunosuppressive therapy included the administration of antithymocyte globulin and post-transplant cyclophosphamide., Results: Severe acute GVHD (grade 34) was observed in 3 (37.5%) cases, which resulted in death in 1 case. A stable antitumor response was achieved in 5 (62.5%) patients, complete remission lasts for 2986 months after allo-HSCT. Specific therapy for these patients is not carried out. The 7-year progression-free survival rate was 75%, the 7-year overall survival rate was 84%, with a median follow-up of 65 months. The transplant-related mortality was 12.5%., Conclusion: Allo-HSCT is considered as an alternative method of therapy for young patients with aggressive MM. Allo-HSCT in MM in some cases leads to long-term immunological control of the tumor. more...

Background: LiFraumeni syndrome (LFS) is a rare, autosomal dominant, hereditary disorder that is characterized by an increased risk for certain types of cancer, acute lymphoblastic leukemia (ALL), particularly. Germline TP53 mutations are associated with LFS. Genetic counseling and follow-up is essential for patients with LFS and their relatives. Special therapeutic approaches are needed for treatment of oncological disease in these patients. The article presents a series of clinical cases of patients with ALL and SLF, considers general issues of diagnosis and treatment of adult patients with this hereditary genetic syndrome., Aim: Describe clinical observations of patients with acute lymphoblastic leukemia (ALL) and LFS and consider general issues of diagnosis and treatment of adult patients with LFS and ALL., Materials and Methods: TP53 gene mutations were screened using Sanger sequencing in 180 de novo patients with Ph-negative (B- and T-cell) and Ph-positive ALL treated by Russian multicenter protocols (ALL-2009, ALL-2012, ALL-2016) at the National Research Center for Hematology, Moscow, Russia, and at the hematology departments of regional clinics of Russia (multicenter study participants)., Results: TP53 gene mutations were found in 7.8% (n=14) of de novo ALL patients. In patients, whose biological material was available TP53 gene mutational status was determined in non-tumor cells (bone marrow and peripheral blood during remission, bone marrow samples after allogeneic hematopoietic stem cells transplantation and in tissue of non-hematopoietic origin) for discriminating germline mutations. The analysis included 5 patients (out of 14 with TP53 mutations), whose non-tumor biological material was available for research. Germline status was confirmed in 4 out of 5 B-cell ALL (n=3), T-cell ALL (n=1) investigated patients., Conclusion: Practical value of the research is the observation that the greater part of TP53 gene mutations in patients with Ph-negative B-cell ALL are germinal and associated with LFS. more...

Aim: To analyze the results of treatment in patients with acute myeloid leukemia (AML) within protocols AML-17 and modified AML-17 (mOML-17) as part of two consecutive pilot studies in order to develop the best treatment strategy for AML patients aged below 60 years., Materials and Methods: The study included 89 AML patients who were aged below 60 years and received treatment within the AML-17 and mOML-17 protocols. Cytogenetic and molecular genetic studies were performed in all patients. The presence of mutations in the FLT3, NPM1, CEBPa genes was assessed by fragment analysis. 35 patients underwent a study for mutTP53, mutRUNX1 using next generation sequencing (NGS). The minimum residual population of tumor cells was evaluated by multicolor flow cytometry. Statistical analysis was performed using the procedures of the SAS 9.3 package., Results: Complete remission (CR) was achieved in 89.7% of patients treated with intensive chemotherapy (CT) courses and in 52.4% of patients treated with low-dose CT courses. 8.8% of intensively treated patients were refractory to therapy, and 38% did not respond to low-dose exposure. The early mortality rate was 3%. The overall survival and disease-free 3-year survival for patients included in 2 consecutive studies was were 60% and 67%, respectively. The level of minimal residual disease (MRD) after the first course of induction CT was an important prognostic indicator. The three-year relapse-free survival for patients in whom CR was achieved after the first course of induction CT and in whom MRD was not detected (MRD-negative status was obtained) was 90% compared to 43% for patients who were MRD positive after the first course of induction CT (p=0.00001)., Conclusion: The key factor that significantly affects the long-term results of therapy is the rate of MRD after the first course of induction CT. more...

The prevalence of multiple primary tumors has significantly increased last time. The question of choosing the optimal tactics of therapy today not fully resolved. Particular interest is the simultaneous detection of two neoplasms of similar origin in one study biopsy material. This publication presents a case of simultaneous diagnosis of myeloid sarcoma and mantle cell lymphoma in a 65-year-old patient, which required use of two different chemotherapy protocols. This example shows the need to use an extended diagnostic approach at all stages of the therapy, which allows choosing right tactics of therapy and achieving complete remission of two neoplasms. more...

Сytokine release syndrome is the common complication of CAR-T therapy. We report a case of patient with B-cell acute lymphoblastic leukemia developing сytokine release syndrome with shock and multiple organ failure and requiring cytokine removal and hemodiafiltration. Remission of the disease was achieved after CAR-T therapy. more...

Indications of allogeneic hematopoietic stem cell transplantation (allo-HSCT) in patients with primary myelofibrosis are intermediate-2 and high-risk group of DIPSS (Dynamic International Prognostic Scoring System), beginning of the disease in childhood. The other adverse factors affect engraftment and survival after allo-HSCT, example partialy matched donor. But the result of allo-HSCT from matched related donors and result of allo-HSCT from haploidentical donors are comparable. The method for haploidentical hematopoietic stem cell transplantation is T-cell-depletion. This is clinical case of T-cell-depleted haploidentical hematopoietic stem cell transplantation in patient with primary myelofibrosis, the diagnosis was established in childhood. more...

Treatment programs for patients with acquired aplastic anemia include two main therapeutic options: allogeneic bone marrow transplantation and combined immunosuppressive therapy (IST). However, combined IST remains the method of choice for most adult AA patients. This study included 120 AA patients who received IST at the National Research Center for Hematology in 20072016. The analysis was applied to 120 patients. Median age was 25 (1765) years, M/F: 66/54, SAA/NSAA: 66%/34%. Effectiveness of IST was carried out in 120 patients with AA. This group did not include 8 SAA patients who died during the first 3 months from the start of treatment from severe infectious complications (early deaths 6.2%) and 2 AA patients who dropped out of surveillance. The observation time was 55 (6120) months. Paroxysmal nocturnal hemoglobinuria (PNH clone) was detected in 67% of AA patients. The median PNH clone size (granulocytes) was 2.5 (0.0199.5)%. The treatment was according to the classical protocol of combined IST: horse antithymocytic globulin and cyclosporin A. Most of patients (87%) responded to combined immunosuppressive therapy. To achieve a positive response, it was sufficient to conduct one course of ATG to 64% of patients, two courses of ATG 24% of patients and 2% of patients responded only after the third course of ATG. A positive response after the first course was obtained in 64% of patients included in the analysis. Most of the responding patients (93%) achieve a positive response after 36 months from the start of treatment. Therefore, the 3rd6th months after the first course of ATG in the absence of an answer to the first line of therapy can be considered the optimal time for the second course of ATG. This tactic allows to get an answer in another 58% of patients who did not respond to the first course of ATG. The probability of an overall 10-year survival rate was 90% (95% confidence interval 83.696.2). more...

Issue: The study of activating mutations (NRAS,KRAS,FLT3,JAK2,CRLF2genes) of RAS/RAF/MEK/ERK and JAK/STAT signaling pathways in B-cell acute lymphoblastic leukemia (B-ALL) in adult patients which are included in Russian multicenter clinical trials., Materials and Methods: Within the multicenter study there were 119 adult patients included withde novoB-ALL. The study was considered as prospective and retrospective. The group withBCR-ABL1-negative B-ALL consisted of up to 93 patients (45 male and 48 female, at the age of 17 to 59, the median age 31), they were treated according to the protocols ALL-2009, ALL-2016. The median follow-up lasted for 19 months (1119). The group withBCR-ABL1-positive B-ALL with up to 26 patients (10 male and 16 female, at the age of 23 to 78, the median age 34 years) was included in the study as well. The treatment was carried out according to the protocols ALL-2009 and ALL-2012 in combination with tyrosine kinase inhibitors. The median follow-up lasted for 23 months (4120). The molecular analysis of activating mutations inNRAS,KRASgenes (RAS/RAF/MEK/ERK signaling pathway) andJAK2,CRLF2genes (JAK/STAT signaling cascade) was performed via Sanger sequencing. The internal tandem duplications (ITDs) inFLT3gene were studied by fragment analysis. The evaluation of CRLF2 expression was fulfilled via flow cytometry., Results: Activating mutations inNRAS,KRAS,FLT3genes were found in 22 (23.6%) patients withBCR-ABL1-negative B-ALL. In total, 23 mutations were revealed in theNRAS(n=9),KRAS(n=12), andFLT3(n=2) genes, according to statistics that was significantly more frequent than withBCR-ABL1-positive B-ALL, these genes mutations were not identified in patients (p=0.007). The frequency of mutations detection inKRASandNRASgenes in patients withBCR-ABL1-negative B-ALL was comparable as 12.9% (12 of 93) to 9.7% (9 of 93), respectively (p=0.488). One patient was simultaneously revealed 2 mutations in theKRASgene (in codons 13 and 61).FLT3-ITD mutations were detected in 3.5% (2 of 57) cases ofBCR-ABL1-negative B-ALL. In patients withBCR-ABL1-positive B-ALLFLT3-ITD mutations were not assessed. Violations in the JAK/STAT signaling cascade were detected in 4 (4.3%) patients withBCR-ABL1-negative B-ALL. They were represented by the missense mutations ofJAK2gene (n=3) and the overexpression of CRLF2 (n=2); in one patient were detected the overexpression of CRLF2 and a mutation inJAK2gene simultaneously. No mutations were found inCRLF2gene. In patients withBCR-ABL1-positive B-ALL noJAK2mutations were detected. As long as analyzing demographic and clinical laboratory parameters between groups of patients with and without mutations, there were no statistically significant differences obtained. In the analyzed groups of patients, long-term therapy results did not differentiate according to the mutations presence inNRAS,KRAS,FLT3,JAK2genes. Also, substantive differences were not shown in the rate of the negative status achievement of the minimum residual disease between patients with and without activating mutations in the control points of the protocol (on the 70th, 133rd and 190th days)., Conclusion: NRAS,KRAS,FLT3,JAK2activating mutations do not affect the long-term results of the therapy and the rate of the negative status achievement of the minimum residual disease in patients withBCR-ABL1-negative B-ALL treated by the Russian multicenter clinical trials. more...

Aim: Analysis of the effectiveness of the MSCs aministration as the second- or third-line therapy of acute GVHD (aGVHD) resistant to glucocorticosteroid treatment., Materials and Methods: The study included 35 patients who received MSCs obtained from the bone marrow of healthy donors as a treatment of steroid-resistant aGVHD. The clinical parameters of patients, MSCs cultural characteristics, the MSC expression profile for various genes including those involved in immunomodulation, expression of cells surface markers, the source of MSCs, as well as the frequency and number of MSC administrations were analyzed., Results: Response to therapy was achieved in 74% of cases, a complete response was reached in 13 (37%) patients, partial response/clinical improvement was demonstrated in 13 (37%). This treatment was ineffective in 9 patients. The prediction of a group of patients with good response to MSC therapy turned to be impossible. The differences between the effective and ineffective for the GVHD treatment MSCs samples were found. The effective ones were characterized with a decreased total MSCs production and an increase in the main histocompatibility complex and PDL-1 antigens expression., Conclusion: These data allow to select optimal samples for aGVHD treatment that can improve clinical results. aGVHD treatment with MSCs has shown efficacy comparable to other treatment approaches. Given the low percentage of complications and the absence of significant adverse effects, MSC therapy seems to be one of the optimal approaches to the treatment of resistant forms of GVHD. more...

Aim: To assess the safety and efficacy of autologous haematopoietic stem cell transplantation (auto-HSCT) in multiple myeloma (MM) patients with dialysis-dependent renal failure., Materials and Methods: During a period from May 2010 to December 2016 fourteen MM patients with dialysis-dependent renal failure aged 48 to 65 years underwent auto-HSCT. After the induction therapy complete response, very good partial response, partial response were documented in 64, 29, 7% of patients, respectively. In no case was a renal response achieved. Haematopoietic stem cell mobilization in most patients (13/14) was performed according to the scheme: G-CSF 10 g/kg. Melphalan in 3 dosages was used as pre-transplant conditioning: 100, 140 and 200 mg/m2; 13 patients underwent a single and in one case underwent a tandem auto-HSCT against the background of hemodialysis. Evaluation of the antitumor and renal response was assessed on the 100th day after auto-HSCT. Subsequently, against the background of programmed hemodialysis and in the setting of high-dosed melphalan (100200 mg/m2), 13 patients underwent a single and one patient underwent a tandem auto-HSCT. At +100 days after auto-HSCT, an antitumor response and renal response were assessed., Results: The period of agranulocytosis after auto-HSCT was from 5 to 12 days (median 8,5) and was accompanied by infectious complications, cardiac and neurological dysfunctions. At +100 days after auto-HSCT, the complete response was confirmed in 71% patients and very good partial response was confirmed in 29% patients. The minimal renal response was registered in 2 patients (14%), hemodialysis was stopped. The transplant-related mortality was absent. After a median follow-up of 53 months 5-year progression-free survival was 59%, and overall survival was 93%., Conclusion: Carrying out auto-HSCT in patients with dialysis-dependent renal failure contributed to the achievement of a minimal renal response in 14% of cases, which allowed these patients to stop hemodialysis. Patients whose conditioning regimen was performed using melphalan at a dose of 200 mg/m2showed more frequent complications in the early post-transplant period compared to patients who received a lower dose of melphalan (100140 mg/m2). Auto-HSCT in MM patients with dialysis-dependent renal failure is a feasible and effective treatment method, which in some cases contributes to independence from hemodialysis. more...

Aim: To study the risk factors, symptoms and outcomes of candidemia caused by C. albicans and C. non - albicans in patients with hematological malignancies., Materials and Methods: The study included patients with hematological malignancies and candidemia. The diagnosis of candidemia was established according to the single isolation of Candida spp. from blood culture and the presence of symptoms of infection., Results and Discussion: Over 12 years (2006-2017), candidemia was diagnosed in 75 patients aged 17 to 77 years (median 48 years). The causative agents of candidemia were C. albicans in 34.7% of patients, C. non - albicans - in 65.3%. Candidemia caused by C. albicans prevailed in patients of the older age group (median 56.5 years, p=0.04) and in patients with lymphoma (61.5%, p=0.01) with colonization of the gut by the same species of Candida (88.5%, p=0.002). Isolation of C. non - albicans from blood culture was more common in patients with acute leukemia (51%, p=0.01) and in recipients of allogeneic hematopoietic stem cells (22.5%, p=0.01). The ability to form biofilms was observed more frequently among C. non - albicans (59.2%) than C. albicans (19.2%, p=0.001). The clinical symptoms of candidemia were non - specific (fever was in 97%). Septic shock developed in 25 (33%) patients with comparable frequency in both groups. Concomitant infections was also comparable (73% vs. 73.5%). Overall 30-day survival in patients with candidemia caused by C. albicans and C. non - albicans was 61.2% and 61.5%. Treatment with echinocandin was associated with increase of survival compared to other antifungal agents among patients with C. albicans candidaemia (88.9% versus 40%, p=0.02) and among C. non - albicans (77.3% versus 47.8%)., Conclusion: C. non - albicans constituted a high proportion among causative agents of candidemia. High mortality rate was observed in both groups. Initial therapy with echinocandin was associated with increase of survival. more...

Aim: Remission induction can be associate, with the life threatening complications and transfer to ICU of de novo acute myeloid leukemia (AML) patients (pts). We evaluate influence of transfer to ICU and life threatening complication on early mortality and long - tram survival of de novo AML pts., Materials and Methods: Retrospective study. All de novo AML pts younger than 60 years old admitted in the National Research Center for Hematology from 2013 to 2016 years were enrolled in the study. Patients were divided into 2 groups: pts who were required ICU admission during remission induction (ICU-pts) and pts who did not require ICU admission and received chemotherapy only in hematology ward (non-ICU pts). The reasons for ICU admissions and results of life support were analyzed. Overall survival (OS) were assessed by the Kaplan-Meier method, long rank value p. more...

Aim: to compare the results of tumor visualization when using 18F-FDG and 11C-methionine PET/CT after auto-HSCT in MM patients., Materials and Methods: A prospective study included 27 MM patients subjected to 18F-FDG and 11C-methionine PET/CT on day 100 after auto-HSCT. Obtained images were visually and semi - quantitatively analyzed. Focal areas of increased uptake for every radiopharmaceutical agent (hypermetabolic foci) not associated with its physiological distribution were registered. Maximum Standardized Uptake Values (SUVmax) in pathological foci were automatically calculated for every radiopharmaceutical agent separately. PET/CT findings were compared to antitumor response achieved after auto-HSCT according to International MM Working Group criteria., Results: After auto-HSCT, the majority of patients (16/60%) achieved a complete response. Abnormal 18F-FDG uptake was registered in 37% (n=10) of patients, negative PET findings were obtained in 63% (n=17) of patients. 11C-methionine PET/CT revealed hypermetabolic foci in 67% (n=18) of patients, and there was no 11C-methionine uptake in 33% (n=9). Pathological foci of radiopharmaceutical agent uptake were 1.8 times more frequently revealed using PET/CT with 11C-methionine (p. more...

The paper describes the results of 15 consecutive Russian clinical trials in the treatment of different types of acute leukemias, conducted by Russian cooperative group within the last 27-years and included more than 25 hundred patients. It was shown that the 5-years overall survival in AML younger than 60 years patients improved from 20 to 33%, in ALL - from 38 to 65%, in APL - from 0 to 95%. The cooperative work resulted in balanced clinical recommendations and protocols, reproducible in regional hospitals. Though till now there is a big difference in the long term outcome in acute leukemias patients treated in coordinating or regional centers mostly due to much higher early death rate: 7.5-9.5% vs 18-25%. This parameter should be used as criteria of the total efficacy of hematological service in each region of Russia. It became possible within the last years to integrate the minimal residual disease monitoring into clinical trials thus providing a clue parameter for choosing the further therapy - allogeneic stem cell transplantation. Non - chemotherapeutic approach with arsenic trioxide and all - trans retinoid acid had dramatically changed the toxicity and duration of treatment with very high efficacy. The Russian cooperative group was the first that started to include pregnant women with acute leukemias into clinical trials. This prospective and prolonged experience has shown that pregnancy in acute myeloid leukemia is an extremely poor prognostic factor, but it does not influence the outcome in acute lymphoblastic leukemia. more...

Mediastinal gray-zone lymphoma (MGZL, lymphoma with features intermediate between classical Hodgkin lymphoma and diffuse large B-cell lymphoma) was declared as a separate entity in WHO classification of Tumors of Haematopoetic and Lymphoid Tissues in 2008 and 2017 years. Despite of similar pathomorphological characteristics between primary mediastinal B-cell lymphoma and Hodgkin lymphoma, clinical features and optimal therapeutic approach to MGZL are not clearly defined. Usually MGZL manifests with mediastinal lymphadenopathy, although extranodal lesions often occur (grey-zone lymphoma, GZL). Patients with MGZL have unfavorable prognosis, taking into account high rate of relapse. This article describes two cases of MGZL. First case manifested by arrhythmias due to primary heart involvement. In spite of cardiac failure antracycline-containing chemotherapy (6 courses of R-DA-EPOCH) it allowed to achieve a complete remission and resolving of arrhythmias. Second case was represented by metachronous tumors: primary mediastinal B-cell lymphoma at the time of disease onset and classical Hodgkin lymphoma, NS II, diagnosed after disease progression. Thus, we demonstrated two examples of MGZL that differ by clinical manifestation, response to chemotherapy, which emphasizes an importance of pathogenesis studying, and using of new therapeutic approaches. more...

Aim: To evaluate occurrence, variety, structural peculiarities and prognostic meaning of cytogenetic abnormalities in adult patients with Ph-negative acute lymphoblastic leukemia (ALL) receiving therapy according to ALL-2009 protocol., Materials and Methods: The study included 115 adult patients with firstly diagnosed Ph-negative ALL: 58 male and 57 female aged from 15 to 61 years (mean age 26.5 years), who underwent treatment from September 2009 to September 2015 in National Medical Research Center for Hematology MH RF (n=101) and in hematology departments of regional hospitals (n=14). All patients received therapy of ALL-2009 protocol (ClinicalTrials.gov, NCT01193933). The median follow-up was 24.5 months (0.2-94.4 months). As a part of the study results of a standard cytogenetic assay (SCA) were analyzed and fluorescence hybridization in situ (FISH) with the use of DNA-probes was performed on archived biological material for structural changes in gene locuses MLL/t(11q23), с-MYC/t(8q24), TP53/ deletion 17p13, CDKN2A/ deletion 9p21, translocation t(1;19)/E2A-PBX1 и t(12;21)/ETV6-RUNX1; iAMP21 identification., Results: Karyotype was defined using SCA in 86% of patients. Normal karyotype was found in 48.5% of them, chromosome aberrations in 51.5% (structural changes were found in 19.2%, hyperploidy in 27.2%, and hypoploidy in 5.1%). In 17.2% of patients complex karyotype abnormalities were found. With the use of FISH technique aberrations were found in 67% of patients: 9p21/CDKN2A deletion in 24.3%, MLL/t(11q23) gene abnormalities in 7.8%, 17p13/TP53 deletion in 5.2%, abnormalities of c-MYC/t(8q24) in 1.7%, t(1;19)/E2A-PBX1 in 0.8%, and iAMP21 in 0.8%, other abnormalities (additional signals/absence of signals from gene locuses) in 26.4%, t(12;21)/ETV6-RUNX1 was not found. FISH technique use in addition to SCA allows to increase aberrant karyotype location from 51.5 to 67%. A statistically significant correlation of 9p21/CDKN2A deletion with high serum lactate dehydrogenase activity (p=0.02); MLL/t(11q23) gene abnormalities - with leucocytosis and high blast cells level in blood (p=0.0016), hyperploidy - with normal leukocyte count (p=0.02) was shown. In groups with different cytogenetic abnormalities no statistically significant differences of treatment with ALL-2009 protocol were found (in terms of complete remission, early mortality and treatment resistance). When connection of cytogenetic abnormalities and their combinations with long-term results were analyzed according to ALL-2009 protocol, only two characteristics - MLL/t(11q23) and c MYC/t(8q24) gene abnormalities had a statistically significant influence on disease-free survival (HR - 176.9; p<0.0001) and chance of recurrence (HR - 6.4; p=0.02)., Conclusion: Adverse prognostic factors in terms of therapeutic management provided in ALL-2009 protocol were MLL/t(11q23) and с-MYC/t(8q24) genes abnormalities. CDKN2A/9p21 and TP53/17p13 genes deletions, quantative and complex karyotype abnormalities were not prognostic factors in adult patients with Ph-negative ALL in ALL-2009 protocol use. more...

Aim: A comparative evaluation of the effectiveness of different therapeutic strategies in patients with polycythemia vera (PV) and essential thrombocythemia (ET)., Materials and Methods: Patients with PV or ET, diagnosed according to the criteria WHO 2016 were included in the study. The primary endpoint - 6 months of therapy (clinical-hematological and molecular responses). The secondary endpoint - 12 months of therapy (clinico-hematologic, molecular, histological responses). Sixty three patients were included in the analysis: the first group consisted of 33 patients who received the therapy with ce-pegiterferone alpha-2b (ce-pegalpha-INF-α-2b), 10 of them received previous treatment; the second group - 23 patients btained hydroxycarbamide; the third group - 7 patients were treated with recombinant interferon alpha therapy (rINFα). In comparison groups, differences in age were revealed: patients receiving hydroxycarbamide therapy were older. Phlebotomy occurred in 36% of patients in the first group, 9% in the second group, and 14% in the third group., Results: By the 6th month of therapy, 43% of the patients receiving the ce-pegalpha-INF-α-2b had complete clinical-hematologic response, 36% had partial clinical-hematologic remission and stabilization of the disease was established in 21% cases. No disease progression occured. By the 12th month of therapy, statistically significant differences in terms of efficacy between the different therapeutic groups (p = 0.2462, Fisher's exact test). In all three groups, the allelic load of JAK2V617F decreased: from 50 to 19%, from 22.3 to 15.8%, from 50 to 7.19%, respectively. The lower the allele load positively correlated with better response to therapy, which was observed in all analyzed groups. Hematologic adverse events (AEs) were more frequently observed in patients receiving ce-pegalpha-INF-α-2b therapy. Local reactions developed on 3-7 days of therapy as a hyperemic macula at the injection site. Both these reactions and hair loss did not influence on patient's condition. In the second group (patients with hydroxycarbamide therapy) there were changes in the skin and mucous membranes: dry skin, stomatitis, and in older patients new keratomas appeared. The flu-like syndrome was the most common adverse event associated with the therapy of ce-pegalpha-INF-α-2b, which fully relived during the first month of therapy. There was only one case with the flu-like syndrome we observed at the 11th month of therapy. As a rule, the biochemical blood test changes did not influence on patient's condition, were mostly associated with dietary violations, had a tendency to self-resolution and did not require medical interventions. Serious AEs were reported in one case - pulmonary embolism in a patient treated with rINFα. The reasons for the therapy discontinue in group 1: toxic hepatitis, intolerance, by the request of the patient, inadequate efficacy of therapy; in group 2: skin toxicity, in group 3: thromboses., Conclusion: Treatment of ce-pegalpha-INF-α-2b in patients with PV and ET is highly effective - the most patients pbtained clinical and hematological responses. There were no statistically significant differences in these parameters in comparison with hydroxycarbamide and rINFα. The use of the ce-pegalpha-INF-α-2b had an acceptable safety profile. The estimated therapeutic dose should be calculated according to body weight. To reduce the frequency of hematologic AE, titration of the drug dose is required. more...

Aim: The aim of the study was to characterize quantitative and qualitative immunoglobulinopathies in patients with AITL at the onset of the disease., Materials and Methods: 55 patients with newly diagnosed AITL were enrolled in the study, the male/female ratio was 30/25; median age was 61 (29-81) years. Diagnosis was based on standard WHO criteria. Immunochemical studies of blood serum included serum protein electrophoresis/immunofixation, nephelometric quantification of total immunoglobulins, serum free light chain assay., Results: Quantitative and qualitative immunoglobulinopathies were determined in 49 (89,1%) of 55 pts. Quantitative immunoglobulinopathies were revealed in 47 (85.5%) of 55 cases, qualitative - in 14 (25,5%). Combination quantitative and qualitative immunoglobulinopathies was observed in 12 (21,8%) of 55 pts. The detected immunoglobulinopathies were divided into 4 groups: polyclonal hypergammaglobulinaemia, hypogammaglobulinaemia, oligoclonal gammapathy, and monoclonal gammapathy. Polyclonal hypergammaglobulinaemia was marked in 41 (74.5%) of 55 pts, elevated level of IgG was determined in 27 (49,15%) of 55 cases, IgM - in 18 (32,7%) and IgA - in 21 (38.2%). Interestingly, polyclonal IgE hypergammaglobulinaemia was detected in 12 (48,0%) of 25 cases of performed studies. Hypogammaglobulinaemia was detected in 8 (14,5%) of 55 cases. Oligoclonal gammapathy was determined in 4 (7.3%) of 55 pts. Monoclonal gammapathy was revealed in 11 (20,0%) of 55 cases. The amount of monoclonal immunoglobulin varied from 2.6 to 14.1 g/l. Monoclonal immunoglobulin Gk was detected in 5 of 11 pts, Gλ - in 2, Mλ - in 2, Mk - in 2. Monoclonal gammapathy was accompanied by polyclonal hypergammaglobulinaemia in 9 of 11 cases, hypogammaglobulinaemia - in 2., Conclusion: Quantitative and qualitative immunoglobulinopathies are observed in most patients at the onset of AITL. Quantitative abnormalities were determined more often than qualitative. Monoclonal gammapathy can be a manifestation of lymphoproliferation and other concomitant disorders. The prognostic value of immunochemical parameters is still unclear and requires dynamic observation and study. more...

B-cell acute lymphoblastic leukemia (B-ALL) is a diverse group of malignant blood disorders both with regard to the biological properties of the tumor and to therapeutic approaches. Immunophenotyping, molecular genetic techniques, whole-genome sequencing characterize B-ALL as a very diverse group for sensitivity to chemotherapy and prognosis. We present three clinical cases of patients with B-ALL and expected good response to standard therapy, in whom standard protocol treatment failured: refractoriness, persistence of minimal residual disease (MRD), and progression (MRD increase). The remission in these patients was achieved after chemotherapy change to immunological targeted therapy. Nowadays a unified therapeutic approach to all primary patients of the B-ALL is considered generally outdated. Great efforts are carrying out to develop molecular genetic classifications. The molecular dissection of subtypes of B-ALL goes on, and new protocols for selective treatment with targeting are clearly outlined for each subtype of B-ALL. more...

Aim: To analyze treatment results of 172 patients with acute myeloid leukemia (AML) aged 18-60 years in National Medical Research Center for Hematology of MHRF., Materials and Methods: Inductive and consolidation program for 139 (80%) patients was based on a standardized protocol: 4 courses "7+3" with different anthracycline use (2 courses of daunorubicin, idarubicin, mitoxantrone) and continuous use of cytarabine on the second inductive course. In 20% of patients cytarabine courses at the dose of 1 g/m2 2 times a day for 1-3 days combined with idarubicin and mitoxantrone were used as two consolidation courses. Allogenic bone marrow transplantation was performed in the first complete remission (CR) period in 40% of patients., Results: The frequency of CR achievement in all patients was 78.6%, refractory forms were observed in 13.9% of patients, early mortality - in 7.5% of patients. Seven-year overall survival (OS) rate was 40.7%, relapse free survival (RFS) - 43.2%. When estimating effectiveness depending on cytogenetic risk group it was demonstrated that 5-year OS and RFS in patients with translocation (8; 21) cannot be considered as satisfying, it accounted for 50 and 34%, respectively. At the same time in patients with 16th chromosome inversion (inv16) these characteristics accounted for 68.6 and 63.5%. Acquired results forced reconsidering of the consolidation program in AML patients of this subgroup. The median time to allogenic blood stem cells transplantation (allo-BSCT) in patients with first CR was 6.5 months that was taken as a reference point in landmark analysis of patients in whom allo-BSCT was not performed. Landmark analysis showed that in AML patients of favorable prognosis group allo-BSCT does not significantly reduce the probability of relapse (0 and 36%) and does not influence RFS (33 and 64%). In patients of border-line and poor prognosis allo-BSCT significantly reduces relapse probability (26 and 66%; 20 and 100%) and significantly increases a 7-year RFS (68.7 and 30%; 45.6 and 0%). Allo-BSCT also results in significant RFS increase and reduces the probability of relapse (25 и 78%) in patients in whom CR was achieved only after the second induction course. At the same time allo-BSCT does not influence patients who achieved CR after the first treatment course: 55 and 50%., Conclusion: Multivariate analysis showed that cytogenetic risk group (HR=2.3), time of CR achievement (HR=2.9), and allo-BSCT transplantation (HR=0.16) are independent factors for disease relapse prognosis after achieving CR. more...

Nodal anaplastic ALK-negative large cell lymphoma (nALCL, ALK-) is a Т-cell lymphoma that is characterized by aggressive clinical course and low sensitivity to СНОР (cyclophosphamide, doxorubicin, vincristine, prednisolone) and other chemotherapy regimen. In the article we present a literature review and describe our clinical case of nALCL, ALK-. For the first time a combination of Brentuximab vedotin with modified program NHL-BFM-90 was used as a first-line therapy. As a result of immunochemotherapy a complete antineoplastic effect was obtained. For consolidation of this effect high-dose chemotherapy with following autologous blood stem cell transplantation was performed. The chosen treatment tactics allowed to achieve a complete remission in a medium risk group patient. more...

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. more...

Aim: To assess the results of following up patients with chronic myeloid leukemia (CML) and a deep molecular response (MR) without tyrosine kinase inhibitor (TKI) therapy., Subjects and Methods: The reasons for TKI discontinuation in 70 patients with CML and a deep MR of more than 1 year's duration were adverse events, pregnancy, and patients' decision. Information was collected retrospectively and prospectively in 2008-2016., Results: The median follow-up after TKI therapy discontinuation was 23 months (2 to 100 months). At 6, 12 and 24 months after TKI therapy discontinuation, the cumulative incidence of major MR (MMR) loss was 28, 41 and 48%, respectively; the survival rates without TKI therapy were 69, 50, and 39%, respectively. MMR loss was noted in 28 (88%) patients at 12 months; it was not seen without TKI therapy at 2-year follow-up. Deaths due to CML progression were absent. The Sokal risk group was a reliable factor influencing MMR loss (p ≤ 0.05). The cumulative recovery rate for deep MR after resumption of TKI use was 73 and 100% at 12 and 24 months, respectively, with a median follow-up of 24 months (1 to 116 months). Deep MR recovered at a later time when the therapy was resumed more than 30 days after MMR loss., Conclusion: Safe follow-up is possible in about 50% of the patients with CML and stable deep MRs without TKI therapy. The introduction of this approach into clinical practice requires regular molecular genetic monitoring and organizational activities. Biological factors in maintaining remission after TKI discontinuation need to be separately studied. more...

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. more...

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. more...

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. more...

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. more...

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. more...

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. more...

Aim: To evaluate the detection rate of markers for hepatitis B virus (HBV) in the blood samples taken from patients with blood system diseases, by applying the current approaches to examining donated blood and its components for markers of viral infections., Material and Methods: The investigation included blood samples from patients with blood system diseases (n=364) and donors (n=5,011). The results of laboratory screening of donated blood samples (n=13,081) were retrospectively analyzed. Commercial kits of reagents were used for immunochemical assay and polymerase chain reaction., Results: Patients with blood system diseases were recorded to have markers of active HBV infection in 12.6% of cases, anti-HBc in 31.3%, and anti-HBs in 37.6%. A retrospective analysis of the results of screening donated blood samples showed the presence of markers for active HBV infection in 0.28% of cases. A prospective examination of blood donors revealed markers of HBV infection in 4.83% of cases, including those of active forms in 0.54% and anti-HBc in 4.79%. The markers of active HBV infection in donors were only anti-HBc IgM in 0.42% of cases. The blood samples from donors with an anti-HBs titer of >200 mIU/ml contained anti-HBc IgM in 10.5%., Conclusion: In the last 5-7 years, the detection rate of markers of HBV infection in the blood samples of patients with blood system diseases have remained at a high level. Screening for decreed markers fails to identify people with inapparent infections among the donors. Even high anti-HBs concentrations in the donated blood may be a risk for HBV transmission by transfusion to a recipient. more...

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. more...

Aim: to provide the clinical characteristics of patients with diffuse large B-cell lymphoma (DLBCL) with monoclonal immunoglobulin secretion and to evaluate the efficiency of intensified mNHL-BFM-90 or R-DA-EPOCH/R-HMA therapy programs in patients with Ig-secreting DLBCL., Subjects and Methods: A clinical trial was conducted in 93 patients with newly diagnosed DLBCL, among whom 21 (22.6%) were found to have monoclonal immunoglobulin secretion., Results: Ig-secreting DLBCL is shown to be characterized by bone marrow involvement (p<0.001), as well as generalized injury (Ann Arbor Stage 4) and a high risk in accordance with the international prognostic index (p=0.001 and p=0.026, respectively). Analysis of overall and event-free survival rates has indicated that the patients have a poor prognosis versus those with non-Ig-secreting DLBCL and poor prognostic factors even when implementing intensified therapy programs, such as mNHL-BFM-90 or R-DA-EPOCH/R-HMA ones., Conclusion: The investigation has demonstrated that there is a high association of the secretion of monoclonal paraproteins with bone marrow involvement in DLBCL (p<0.001). The intensified therapy using the mNHL-BFM-90 and R-DA-EPOCH/R-HMA programs involving autologous hematopoietic stem cell transplantation also permits the patients with Ig-secreting DLBCL to achieve long-term sustained remissions in not all cases. more...

In the past decade, a notable advance has been made in the understanding of the pathogenesis of NK/T-cell lymphomas; however, their diagnosis remains difficult because of their rarity and clinical and morphological variabilities. The paper generalizes the ten-year experience of the Hematology Research Center, Ministry of Health of Russia, in diagnosing and treating hepatosplenic T-cell lymphoma (HSTL), considers the problems of differential diagnosis with other hematological diseases occurring with similar clinical and laboratory symptoms, and lays down current approaches to the diagnosis and treatment of this condition. A clinician's view of the problem of diagnosis and treatment of this disease is given. HSTL is shown to be a heterogeneous group of diseases differing in a T-cell receptor chain gene rearrangement, the clinical course of the disease, and overall survival (OS). According to our data, 3-year OS was 12%; the median survival was 26 months. Two-year OS for γδ and αβ HSTL was equal to 25 and 70%, respectively. The difference in OS for the variants of HSTL failed to reach statistical significance (because the sample might be insufficient). more...

Aim: To generalize hematologists' experience of the diagnosis and differential diagnosis of splenic red pulp lymphoma (SRPL)., Material and Methods: Eighty-seven splenic biopsy specimens taken from patients with different B-cell lymphoproliferative diseases were examined in the Hematology Research Center in 2013-2014. The diagnosis of SRPL was based on the morphological, immunohistochemical, immunophenotypic, and molecular examinations of the splenic biopsy specimens, blood and bone marrow (BM) tests in 4 (4.6%) cases., Results: There was significant splenomegaly in all SRPL cases, lymphocytosis in 56 to 94% (leukocytes, 55 and 75·109/l in 2 cases), circulation of hairy lymphocytes with the phenotypes CD20+ (markedly), CD11c+/±, CD103+/± (weakly), LAIR-1+, CD25-, CD5-, CD10-, and CD23-, which did not contain tartate-resistant acid phosphatase, without BRAFV600E mutation, BM with insignificant lymphoid infiltration of CD20+, CD25-, Annexin 1-, and Cyclin D1-. The weight of the spleen averaged 3900 g (1450-9500 g); its tissue exhibited lymphoid infiltration of the red pulp with the phenotypes CD20+, DBA.44+, CD25-, Annexin1-, Cyclin D1-, CD103-, CD123-, CD27-, focal СD11c±, and TRAP±. Four patients (2 after splenectomy (SE) and 2 after SE and chemotherapy with cladribine and rituximab) are being followed up in remission., Conclusion: SRPL is a rare disease that should be presumed to be in significant splenomegaly and lymphocytosis with hairy lymphocytes, which have only some markers for classical hairy cell leukemia (HCL), in minor BM lesion. SE is the standard for diagnosis and treatment. The differential diagnosis of SRPL with HCL has clear criteria and that with HCL-v is undetected. more...

Myeloproliferative disease associated with FGFR1 rearrangement (8p11), which is included in the 2008 WHO Classification of Myeloid Neoplasms, is a rare and extremely aggressive abnormality. The paper describes a clinical case of a 39-year-old female patient who was detected to have leukocytosis (as high as 47.2·109/l), absolute eosinophilia (as high as 3.1·109/l), and enlarged peripheral lymph nodes during her visit to a doctor. The bone marrow (BM) showed the changes typically encountered in myeloproliferative disease with eosinophilia. The patient was found to have t(8;13)(p11;q12) translocation associated with the rearrangement of the FGFR1 gene located at the 8p11 locus. Molecular and cytogenetic examinations failed to reveal BCR-ABL chimeric transcript, Jak2 V617F mutation, and deletions and translocations involving PDGFRA (4q12) and PDGFRB (5q32-33). The similar changes in the karyotype were also found in the lymph node cells. The undertaken treatment with hydroxyurea and the tyrosine kinase inhibitor dasatinib turned out to be ineffective. The patient underwent allogeneic BM transplantation from a HLA-identical sibling. Graft rejection occurred 6 months later. Allogeneic BM transplantation from the same donor (100% donor chimerism; FGFR1/8р11 translocation was not detected), which was complicated by the development of chronic graft-versus-host reaction, was performed again in March 2015. The patient is being followed up and continues to receive immunosuppressive therapy. more...

Aim: to estimate the spread of weak D antigen types of the Rhesus system in the citizens of the Russian Federation and a possibility of serologically identifying these types., Subjects and Methods: The red blood cells and DNA of people with weakened expression of D antigen were investigated using erythrocyte agglutination reaction in salt medium (2 methods); agglutination reaction in the gel columns containing IgM + IgG anti-D antibodies, indirect antiglobulin test with IgG anti-D antibodies (2 methods); polymerase chain reaction to establish the type of weak D., Results: A rhesus phenotype was determined in 5100 people in 2014-2015. The weakened agglutinable properties of red blood cells were detected in 102 (2%) examinees. 63 examinees underwent genotyping to identify the variants of the weak D antigen, which identified 6 weak D types. There were the most common weak D types 3 (n=31 (49.2%)) and weak D type 1 (n=18 (28.6%)), including weak D type 1.1 in one (1.6%) case. The other 4 weak D antigen types were as follows: weak D type 2 (14.3% (n=9)), weak D type 15 (4.8% (n=3)), weak D type 4.2 (DAR) (1.6% (n=1)) and weak D type 6 (1.6% (n=1)). The antiglobulin test in the gel column containing antiglobulin serum was the most sensitive serological assay to identify the weak D antigen. Only a molecular test could establish weak D type 15 in 2 samples of red blood cells with Ccdee and ccdEe phenotypes., Conclusion: The weak D antigen could be serologically identified in 96.8% of cases. When testing for weak D, particular attention should be given to people with the D-negative phenotype who had the C or E antigens. Our investigations conducted for the first time in Russia will be able to improve the immunological safety of red blood cell-containing medium transfusions for patients. more...

Aim: to analyze well-known risk factors (RFs), such as age, immunophenotype, baseline leukocytosis, enhanced lactate dehydrogenase (LDH) activity, time to achieve complete remission, a risk group, and cytogenetic abnormalities) in patients with acute lymphoblastic leukemia (ALL) in the use of the ALL-2009 protocol., Subjects and Methods: The protocol covered 298 patients (137 women (including 13 pregnant women) and 161 men) aged 15 to 55 years (median age 28 years) with Ph-negative ALL. The phenotype was unknown in 6 patients. Three (1%) were ascertained to have a biphenotypic variant. 182 (62.4%) patients were found to have B-cell ALL (early pre-B ALL (n=51); common ALL (n=92), and pre-B ALL (n=39); 107 (36.6%) patients had T-cell ALL (early T-ALL (n=56); thymic T-ALL (n=41), and mature T-ALL (n=10). According to the baseline clinical and laboratory parameters (leukocytosis of 30·109/l and more for B-ALL; and that of 100·109/l and more for T-ALL; phenotype В-I for B-ALL, phenotype Т-I-II-IV for T-ALL; LDH activity was more than twice the normal values; the presence of translocation t(4;11)), the high-risk group included most patients with B-ALL (n=110 (72.8%)) and T-ALL (n=76 (76%)). Thirty-five patients with T-ALL underwent autologous bone marrow transplantation (BMT). Allogeneic BMT was performed in 18 (7%) of the 258 patients who had undergone an induction phase., Results: Five-year overall survival for all the patients included in the investigation was 59%; relapse-free survival was 65%, which was significantly different in the patients with B-ALL and in those with T-ALL: the overall survival rates were 53.3 and 67.5% (p=0.1); the relapse-free survival was 56 and 79% (p=0.005), respectively. Multivariate analysis including the well-known RFs demonstrated that the latter for T-ALL were of no independent prognostic value and only the patient's age was identified for B-ALL (p=0.013)., Conclusion: A lower chemotherapeutic load and a small number of allogeneic BMTs did not affect total positive treatment results in adult patients with ALL, by complying with the principle achieving the continuity of cytostatic effects and by preserving the total cytostatic loading dose. The results of the Russian investigation casts some doubt on the necessity of using very intensive consolidation cycles and performing a large number of allogeneic BMTs in adult patients with ALL. more...

Aim: To estimate the informative value of ultrasonography (USG) in the diagnosis of lung injuries in pregnant women with blood system tumors., Subjects and Methods: Lung ultrasound was performed in 5 pregnant patients with blood cancers. The women's age was 29-38 years; gestational age was 14-33 weeks. Four women had different types of acute leukemia; one had primary mediastinal large B-cell lymphoma. All the women received chemotherapy for blood cancer. When there were signs of lung injury, USG was conducted, the results of which necessitated therapy or bronchoalveolar lavage (BAL)., Results: Three patients developed acute respiratory failure; 2 of them required noninvasive ventilation. Based on the detection of consolidation with a dynamic air bronchogram and pleural effusion, the authors diagnosed bilateral pneumonia and alveolar-interstitial syndrome in 1 patient, right-sided pneumonia in 1, left-sided one in 1, and transfusion-related pulmonary edema in 1. Lung ultrasound did not verify the diagnosis of pneumonia in 1 patient. According to USG data, BAL procedures were performed in 2 patients; one of them was diagnosed as having Pneumocystis pneumonia; the other was found to have no pathogens in lavage fluid. Treatment resulted in clinical improvements and normalization of the lung ultrasound pattern in all the pregnant women. Later on, 4 women delivered via cesarean section done at 32-34 weeks' gestation and gave birth to healthy babies. One patient died from infectious complications after chemotherapy., Conclusion: Lung sound may be used to diagnose lung injury in pregnant women with blood cancers. more...

Aim: To determine the immunoglobulin variable heavy chain (gVH) genes and their somatic mutations and to compare these data with the clinical and laboratory parameters of patients and the outcomes of the disease., Subjects and Methods: The investigation enrolled 24 patients (9 men and 15 women whose age was 32 to 77 years (median age, 60 years) with splenic marginal zone B-cell lymphoma (SMZBCL). The latter was diagnosed on the basis of histological and immunohistochemical examinations of a bone marrow trephine biopsy specimen, immunophenotyping of peripheral lymphoid cells or bone marrow aspirates., Results: The mutational status of the IgVH genes was analyzed in all the 24 patients. It was found that the tumor cells contained mutated IgVH genes (the VH1-family genes participated in most cases) in 15 (62.5%) patients with SMZBCL and unmutated ones in 9 (37.5%). There was a tendency towards more common tumor progression in patients with unmutated IgVH genes than in those with mutated ones., Conclusion: The presence of SMZBCL cases with both mutated and unmutated IgVH genes and the higher frequency of the VH1-2 gene are likely to indicate the molecular heterogeneity of the origin of this lymphoma. more...

Aim: To study the impact of the genes of donor killer cell immunoglobulin-like receptors (KIR) and HLA-KIR ligands on overall (OS) and event-free survival (EFS) rates in patients with myeloid leukemia after transplantation with allogeneic hematopoietic stem cells (allo-HSCT) from HLA-identical related and HLA-compatible unrelated donors., Subjects and Methods: The investigation enrolled 29 patients who had undergone allo-HSCT from KIR-genotyped donors at the Department of Bone Marrow Transplantation, Hematology Research Center (see symbol) in 2010-2013. OS and EFS rates after allo-HSCT were calculated using the Kaplan-Meier method., Results: The main predictor of recurrence and survival in patients after allo-HSCT was a recurrence-risk group the patient belonged to before transplantation. The standard-risk group patients whose donors had telomeric gene-content motifs of KIR-B haplotypes had higher EFS rates than those whose donors lacked these genes. The standard-risk patients homozygous for HLA-1 alleles (i.e. without HLA-C2 ligand) tended to have higher EFS rates, so did the patients without HLA-Bw4 ligand., Conclusion: The donors having telomeric gene-content motifs of KIR-B haplotypes are more preferred for allo-HSCT for patients with myeloid leukemia as the presence of donor telomeric KIR-B genes increases EFS rates in standard-risk patients. more...

Aim: To evaluate the efficiency of the treatment policy for patients with acute myeloid leukemia (AML) and hyperleukocytosis (HL), which is aimed at preventing rapid hypercytolysis and massive tumor lysis (cytolysis) syndrome and/or at reducing the degree of the latter at the start of induction polychemotherapy., Subjects and Methods: In 2010 to 2014, the Hematology Research Center, Ministry of Health of Russia, treated 92 patients with AML, out of them 18 patients were found to have white blood cell counts of 100 to 408-10(9)/1 (median, 130-10(9)/l) at the onset of the disease. All the examinees received cytoreductive therapy with hydroxyurea and, in presence of leukostasis and/or leukocytosis (≥150-10(9)/1), with leukocytapheresis. In case of reduced leukocytosis, plasmapheresis was carried out to prevent (treat) cytolysis. Daunorubicin was injected on days 3-5 of the 7+3 induction cycle., Results: The signs of leukostases were detected in more than half of the 18 patients with higher white blood cell counts: 13 (72%) with lung injury, including 5 of them with signs of respiratory distress syndrome, 6 (27.8%) with neurological symptomatology, 7 (38.9%) with disseminated intravascular coagulation syndrome, including 1 with intracranial hemorrhage. Cytoreduction therapy with hydroxyurea (10 mg/kg/day) was performed 1-5 (median 2) days before initiating induction chemotherapy in 17 patients; 9 patients underwent 1-2 (median 2) leukocytapheresis sessions. Sixteen patients received 1-4 (median 2) plasmapheresis sessions prior to and within the first days of the 7+3 treatment regimen. Daunorubicin (60 mg/m2) was administered to 16 patients on days 5-7 of the 7+3 cycle and to 2 patients on days 3-5 of the cycle. There were no signs of severe cytolysis with the development of multiple organ dysfunction in any patient. 50% (9/18) achieved remission after the first 7+3 cycle and 7 more examinees did after the second cycle. Thus, the remission rate was 89%; early mortality was 5.5% (1/18), three-year overall and relapse-free survival rates were 50%., Conclusion: Adequate cytoreductive and accompanying therapies for AML with HL can virtually completely prevent massive tumor cytolysis syndrome and early mortality during the first days of induction chemotherapy. more...

Aim: To analyze the efficiency of the ALL-2009 protocol (ClinicalTrials.gov NCT01 193933) in patients with T-cell leukemias, particularly the role of autologous hematopoietic stem cell transplantation (auto-HSCT) after non-myeloablative BEAM conditioning, followed by maintenance therapy., Subjects and Methods: Since 2009, the ALL-2009 study has enrolled 90 patients with T-cell acute lymphoblastic leukemia (T-ALL), the treatment results were assessed in 86 patients: 6 and 28 patients underwent allogeneic HSCT and auto-HSCT, respectively. A landmark analysis was used to compare survival rates in patients who had undergone auto-HSCT and in those who had not. For this, the median time from complete remission to the date of auto-HSCT was determined (the median was 6 months). Then to compare with the auto-HSCT group, only 27 patients who had been in complete remission for 6 months or more were included in a chemotherapy group., Results: The achievement of complete remission in patients with thymic T-ALL (100%) was significantly higher than in those with early (85.7%) or mature (70%) variants. The patients with early and mature T-ALL as compared to those with thymic T-ALL showed high death rates in the remission induction (7.4 and 10% versus 0) and the patients with mature T-ALL had a.higher proportion of refractory forms (20% versus 0). The 5-year overall and relapse-free survival rates in all the T-ALL patients were 66 and 76%, respectively. After auto-HSCT, the risk of recurrence was 0% versus 21% after chemotherapy (p=0.03). The relapse-free survival rates significantly differed in the auto-HSCT and non-auto-HSCT groups: 100 and 66%, respectively (p=0.047)., Conclusion: The long-term survival rates obtained during this multicenter study in the T-ALL patients treated according to the ALL-2009 protocol, the basis for which is the principle of continuity of cytostatic effects, are exclusively optimistic. Late consolidation with auto-HSCT following non-myeloablative BEAM conditioning, followed by maintenance therapy, considerably reduces the risk of recurrence. more...

Aim: To study the clinical features of Castleman's disease (CD) and to elaborate therapeutic approaches in its different morphological types., Subjects and Methods: The clinical and laboratory data were studied in 59 prospectively examined patients and 17 retrospectively examined ones with CD who had been treated at the Outpatient Department, Hematology Research Centre, in 1996 to 2014. There were a total of 37 men (median age, 36 years) and 39 women (median age, 34 years). The diagnosis was established from the results of histological and immunohistochemical examinations of removed lymph nodes (LN) or tumors in all the cases., Results: A hyaline vascular variant (HVV) with local LN involvement was diagnosed in 38 (50%) patients; a plasma cell variant (PCV) was in 38 (50%); among the latter, 17 (22%) patients were found to have local involvement and 21 (28%) had generalized (multicentriC) involvement (multicentric Castleman's diseases (MCD)). Five (24%) patients with MCD were established to be infected with human herpesvirus type 8 (HHV-8). HVV was more frequently diagnosed in women (4%) than in men (29%); PCV was equally common in both men (47%) and women (53%); MCD was statistically significantly more frequently encountered in men (86%) than in women (14%) (p=0.05). The basic involvement areas in local HVV and PCV were peripheral (38%), mediastinal (29), retroperitoneal (18%), abdominal (9%), and small pelvic (6%) LNs. HVV and local PCV were benign and these were cured by surgical removal of LNs involved in the pathological process. MCD took its aggressive course with obvious constitutional symptoms, generalized lymphadenopathy, hepatosplenomegaly, hypergammaglobulinemia, autoimmune hemolysis, thrombocytopenia, and involvement of extranodal foci in the pathological process. MCD transformation to plasmablastic lymphoma was observed in 4 of the 5 HHV8-positive patients and followed by a poor outcome. The prognosis of untreated MCD was unfavorable. In a number of cases prednisolone monotherapy worsened prognosis and the MCD patients receiving timely multiple-drug R-CHOP or R-VD chemotherapy could achieve sustained remission (the 5-year overall survival was 55%)., Conclusion: CD must be included into the differential diagnosis of lymphadenopathies. When specific treatment is performed, the prognosis of HVV and local PCV is favorable: the disease is surgically cured in 95% of cases. Multidrug chemotherapy according to the B-cell lymphoproliferative disease program is indicated for the treatment of MCD: sustained remission can be achieved by the use of R-CHOP or R-VD programs. The HHV-8-positive variants of MCD increase the probability of transforming the disease to incurable plasmablastic lymphoma. Overall, prognosis and therapy choice in HIV-negative patients with CD depend on the histological variant of the disease, the extent of a tumor, and HHV-8 infection. more...

The described case of FIP1L1-PDGFRА-positive myeloproliferative disease is characterized by an atypical aggressive course to develop severe specific complications as injuries to the brain, heart, lung, and intestine. Pathogenetic therapy with imatinib could stabilize a patient's state, but failed to produce a complete hematological response. Switching from imatinib to dasatinib could produce sustained clinical, hematological, and molecular remissions. more...

Myeloid sarcoma (MS) is a rare malignant solid tumor presented with myeloid blast cells showing varying degrees of maturation. MS may have an extramedullary site, precede, or develop simultaneously with the clinical manifestations of acute myeloid leukemia (AML); it may also occur as an AML relapse. Besides AML, MS may be a manifestation of chronic myeloid leukemia or other chronic myeloproliferative diseases. Due to the fact that this disease is rare, the bulk of the literature on MS is presented with single descriptions of retrospective studies and clinical cases. The paper describes 3 cases of MS with inversion of chromosome 16 and small bowel lesion. more...

Aim: To make a randomized comparison of 2 consolidation treatment options (two patient groups): 2 cycles of cytarabine in average (Ig/m2 in Group 2) and standard (100 mg/mi2 in Group 1) doses in combination with idarubicin (8-12 mg/m2) and mitoxantrone (10 mg/m2), after two 7+3 induction cycles of daunorubicin (60 mg/mi2) and subsequent 6 cycles of maintenance therapy., Subjects and Methods: In January 2010 to October 2013, a Russian multicenter trial was conducted to treat patients with acute myeloid leukemias (AML) in accordance with the AML-01.10 protocol (ClinicalTrials.gov Identifier: NCT01587430). The trial enrolled 243 AML patients from 21 centers, including 71 patients (median age 38 years) from the State Hematology Center, Ministry of Health of the Russian Federation; 35 and 36 patients were randomized to Groups 1 and 2, respectively. The randomized groups were balanced by basic clinical and laboratory parameters. Favorable, intermediate, and high cytogenetic prognoses were in 14 (21.9%), 40 (62.5%), and 10 (15.6%) patients, respectively., Results: Prior to treatment, 2 patients died; one patient refused treatment. Fifty-eight (85.3%) of the 68 patients achieved complete remission (CR); early deaths was in 2 (2.9%) and resistance in 8 (11.8%). Four (6.9%) patients died during CR. Protocol deviations (doses, intervals, and the number of cycles) were recorded in 12 (20.7%) of the 58 patients. Other 8 (11.8%) patients were switched to low-dose cytarabine because of complications, withdrawn from the protocol and not included into the analysis of randomized comparison. Twenty allogeneic bone marrow transplantations (allo-BMT) (7 related, 12 unrelated, and 1 haploidentical) were performed; of them 15 allo-BMTs were done during first CR. In the 68 patients, 3-year overall survival (OS) was 45.6%; relapse-free survival (RFS) was 41.5%. OS was 64.6% in Group 1 and 58.3% in Group 2; RFS was 62 and 38.8% in Groups 1 and 2, respectively (p>0.5). In the favorable, intermediate, and high prognosis groups, OS was 79.5, 60, and 31.1% and RFS was 81.8, 41.3, and 33.3%, respectively (p=0.1). The consolidation treatment option unchanged survival rates in the above risk groups. Unachieved CR after the first cycle considerably decreased RFS (33.9% versus 60%) and served as an indication for allo-BMT during first CP (RFS without BMT was 0; that with BMT was 78%)., Conclusion: No differences were found between both consolidation options according to long-term results. Protocol deviations were recorded in one-third of the patients. While implementing the protocol, the efficiency of treatment was high. Allo-BMT during first CR substantially increased RFS if CP was not achieved after the first cycle. more...

Aim: To give the results of an investigation conducted at the Hematology Research Center (HRC), Ministry of Health of the Russian Federation (MHRF), to treat adult patients with acute promyelocytic leukemia (APL) according to the AIDA protocol elaborated by Spanish investigators., Subjects and Methods: The investigation enrolled 33 patients diagnosed with APL verified by cytogenetic and molecular studies, who had been treated at the HRC, MHRF, in July 2009 to January 2012. The patients classified in the low-, intermediate-, and high-risk groups were 30, 46.7; and 23.3%, respectively. The analysis was made in January 2013., Results: The number of patients who achieved complete remission, as well as the mortality rates during remission induction were wholly comparable to those previously obtained when using the 7+3+ATRA protocol: 90.3 and 9.7%, respectively. One patient in remission died (3.6% mortality rate). The likelihood of recurrence in this investigation was high (21%), which was due to gross noncompliance with maintenance therapy. On examining the clearance of the malignant clone by FISH and polymerase chain reaction, a naturally chimeric transcript identified by a molecular study was statistically significantly more frequently revealed during postinduction therapy, which was associated with different sensitivity of the techniques. Comparison of changes in the disappearance of a chimeric marker for APL with the AIDA and 7+3+ARTA programs showed that the clearance of the malignant clone was much slower., Conclusion: The AIDA program is a highly effective treatment protocol for patients with APL. more...

Aim: To study the experience in managing patients with acute promyelocytic leukemia (APL) diagnosed in different periods of pregnancy., Subjects and Methods: Nine women with APL were treated in 1998-2013. When APL was diagnosed in the first trimester of pregnancy, the latter was terminated (n = 1); when its diagnosis was made in the second trimester, chemotherapy (CT) followed by delivery (D) was performed (n = 3); when it was done in the third trimester, D followed by CT was done in relation to gestational age (n = 2) or these were performed at a later gestational age (n = 1). APL was treated in 5 and 1 patients according to the AIDA protocol and the 7+3 plus ATRA one, respectively., Results: All the patients with APL achieved remission after the first cycle of induction CT; 5 of the 6 patients did at the moment of delivery; one patient underwent emergency delivery during cytopenia after the cycle. The gestational age at delivery after CT was 34 (34-40) weeks. Spontaneous term labor occurred in 2 patients at an obstetric hospital. Cesarean section was made in 4 of the 6 patients. All babies were born alive, healthy, and without developmental abnormalities. Their age at the time of analyzing the results was 2.5 months to 15 years. Four of the 9 patients are presently alive. Late recurrences occurred in 3 (33%) patients. The median overall survival is 26 (0.25-128) months; the median relapse-free survival is 17.5 (0-127) months., Conclusion: APL treatment in pregnant women, which is aimed at saving two lives, is effective and reasonable. more...

The paper describes a case of a patient with refractory hairy cell leukemia. In spite of the absence of CD25 expression, the disease was classified as a classical form according to the WHO classification (2008), as also confirmed by the detection of BRAFV600E mutation. The disease was characterized by resistance to all lines of therapy (interferon-a, splenectomy, cladribin). Clinical and hematological remission was achieved within 2 months of administration of the BRAF kinase inhibitor vemurafenib. more...