[Rhinosinusitis in Hurler syndrome patients requiring hematopoietic stem cells transplantation]. / Problema rinosinusita u patsientov s sindromom Gurler pri transplantatsii gemopoéticheskikh stvolovykh kletok.

INTRODUCTION: Allogenic transplantation of hemopoetic stem cells (allo-THSC) is one of the most effective treatment methods for Hurler syndrome, aimed at maximal correction of complications related to the genetic disorder. Presence of infection in the recipient is an adverse risk factor, affecting the possibility of starting the conditioning regimen and THSC peforming in general. AIM: To assess the condition of the nasal cavity and paranasal sinuses in Hurler syndrome patients before the allo-THSC, dynamics of these changes after the transplantation taking into account the correction of alpha-L-iduronidase enzyme level with donor blood cells. MATERIAL AND METHODS: From February 2012 to December 2017, In the Raisa Gorbacheva Research Institute of Child Oncology, Hematology and Transplantology of the Pavlov First Saint Petersburg State Medical University, eighteen Hurler syndrome patients (10 girls and 8 boys) received an allo-THSC. Median age at the time of the procedure was 23,5 months (min - 3,4; max - 24,8). Each patient with the shadowing of paranasal sinuses, rhinitis or nasal breathing difficulty received a standard rhinosinusitis treatment before the transplantation, effect of which was insignificant. Symptoms of rhinitis, condition of pharyngeal tonsil and paranasal sinuses were assessed before and auto the allo-THSC. RESULTS: In the post-allo-THSC, with the correction of alpha-L-iduronidase level each evaluated parameter has improved reliably (p-value < 0,05). Comparative analysis of the condition of the nasal cavity and pharyngeal tonsil before and after THSC was conducted on 14 patients out of 18. Rhinitis symptoms decreased in 9 (64,2%) patients; in 11 patients (78,5%) adenoids size reduced. Comparative analysis of the condition of paranasal sinuses was possible in 12 patients out of 18. Sinuses aeration improved in eight (66,6%) if patients. CONCLUSION: Nasal cavity and paranasal sinuses changes in Hurler syndrome patients before and after allo-THSC is poorly studied. Our experience demonstrates the normalization of nasal cavity, pharyngeal tonsila and paranasal sinuses symptoms in the majority of the patients receiving allo-THSC. These symptoms are, it seems a consequence of the underlying disease.

[Russian experts' clinical guidelines for acute myeloid leukemia treatment in patients less than 60 years of age].

The purpose of the paper is to present Russian experts' consolidated opinion about acute myeloid leukemia (AML) treatment in adult patients aged less than 60 years. The guidelines have been elaborated having regard to foreign publications and Russian experience, on the basis of global and Russian clinical trials to treat AML and to define indications for allogeneic bone marrow transplantation in patients during first complete remission.

[Allogeneic hematopoietic stem cell transplantation for acute myeloblastic leukemia in first remission].

AIM: To evaluate the efficiency of allogeneic hematopoietic stem cell transplantation (allo-HSCT) in patients with acute myeloblastic leukemia in first remission depending on the regimens of conditioning, the source of a graft, and the characteristics of a donor and a recipient. SUBJECTS AND METHODS: In 66 treated patients, including from partially HLA-mismatched relatives (n=4), the efficiency of allo-HSCT from related donors (n=26) and unrelated donors (n=40), were compared. According to cytogenetic findings, 7 (11%), 31 (47%), and 10 (15%) patients belonged to low-, intermediate-, and high-risk groups, respectively. RESULTS: Five-year overall survival (OS) and mortality associated with transplantation were 56 and 22% for allo-HSCT from related donors, 68 and 23% for that from HLA-matched donors, and 71 and 25% for that from partially HLA-mismatched donors, respectively (p=0.8 and p=0.7). The relapse risk after allo-HSCT from unrelated donors was significantly lower than after that from related donors (13 and 35%, respectively; p=0.8). Univariate analysis showed that the OS rates depended on the cytogenetic risk group (OS was 24 and 64% in the high- and intermediate-risk groups, respectively (p=0.027). The relapse risk in chronic graft-versus-host reaction (GVHR) and in grade 3 acute GVHR (p=0.01) was shown to be less than that in grades 1-2 acute GVHR (p=0.06). CONCLUSION: OS rates after allo-HSCT from related and unrelated donors were comparable and unrelated to the source of a graft, the regimen of conditioning, and other characteristics of a donor and a recipient.

[Efficacy of donor lymphocyte infusion in patients after different types of allogeneic hematopoietic stem cell transplantation].

AIM: To evaluate the efficacy of donor lymphocyte infusion (DLI) to prevent and treat recurrences in patients after different types of allogeneic hematopoietic stem cell transplantation (allo-HSCT). SUBJECTS AND METHODS: Data from 118 patients with malignant blood diseases were analyzed. Allo-HSCTs from HLA-matched related donors (n=49), HLA-matched unrelated donors (n=50), partially HLA-matched unrelated donors (n=2), and haploidentical donors (n=24) were performed. The indications for DLI were underlying disease relapse (59 DLIs), resistant disease course (n=40), minimal residual disease (n=1 6), falling donor chimerism (n=1 5), and recurrence prevention (n=1 3). RESULTS: Therapy response was obtained after 57 (44%) DLls. There were 36 (25%) and 30 (21%) cases of acute and chronic graft-versus-host reactions (GVHR), respectively. The use of DLI from HLA-matched donors, its performance in the periods of D+100 to one year after allo-HSCT, a donor chimerism level of over 90% at the moment of DLI, the administration of the initial DLI dose of below 1.10(6) CD3+/kg, and the development of chronic GVHR after DLI were associated with the highest rate of therapy responses. The overall survival rates of patients with DLI were significantly influenced by factors, such as DLI periods, donor chimerism levels at DLI, and the development of chronic CVHR after DLI. CONCLUSION: The choice of the optimal dose of cells, the periods of DLI and its preventive administration improve prognosis in patients after allo-HSCT. The occurrence of acute GVHR is affected by the degree of HLA matching and the type of a donor. The development of chronic GVHR after DLI is associated with the highest rate of responses to DLI and higher survival rates.

[Extracorporeal photopheresis in the treatment of patients with refractory chronic graft-versus-host disease after allogeneic bone marrow transplantation].

AIM: To evaluate the efficiency of extracorporeal photopheresis (ECP) in the treatment of patients with refractory chronic graft-versus-host disease (cGVHD) after allogeneic hematopoietic stem cell transplantation (allo-HSCT). SUBJECTS AND METHODS: The study included 49 patients aged 2 to 55 years. Allo-HSCT was carried out in 38 (79%) patients with acute leukemias, 5 (10%) with chronic leukemias, 4 (8%) with myelodysplastic syndrome/myeloproliferative disease, and 2 (3%) with other hematologic diseases. The patients included in the study had glucocorticosteroid (GCS)-refractory disseminated cGVHD or a history of severe complications from GCS therapy. RESULTS: When evaluating the efficiency of therapy, its response was recorded in 37 (77%) cases; the best results were obtained in patients with hepatic (82%), mucosal (76%), and skin (74%) lesions. The mean severity according to the cGVHD Working Group, National Institutes of Health, and a platelet level of more than 100.10(9)/1 were defined as factors improving a therapy response. In the patients receiving ECP, the overall survival was 70%. The latter was higher in the group of patients who had responded to ECP therapy without involving the gastrointestinal tract in the cGVHD process and in those receiving a combination of ECP and other immunosuppressive drugs. CONCLUSION: ECP is an effective treatment for patients with refractory cGVHD, it may be used in those with a history of severe complications from GCS therapy. ECP allows the dose of GCS to be reduced to the point of complete discontinuation.

[Our experience with tracheotomy in the hematological patients in need of prolonged artificial lung ventilation].

The objective of the present work was to study the possibility and technical peculiarities of planned tracheotomy in the hematological patients with thrombocytopenia and coagulopathy suffering severe concomitant pathology. A total of 45 tracheotomies were performed in hematological patients during the period from 2009 till July 2012. The case histories of 32 patients were available for the retrospective analysis. At the time of surgical intervention, 81% of the patients presented with grade IV thrombocytopenia. Five of the patients (15.6%) suffered bleeding from the tracheostomic canal in the early postoperative period. In four of them, hemorhage was stopped by the placement of the hemostatic sponge. One patient had to be managed by means of cauterization . Two (6.25%) patients developed inflammation around tracheotsoma. It is concluded that thrombocytopenia and probable coagulopathy do not constitute an absolute contraindication for planned tracheostomy. However, such operation may have a favourable outcome only after preliminary transfusion, the application of cauterization, and delicate surgical intervention.

[Invasive mycoses during hematopoietic stem cell transplantation].

AIM: To define the frequency, etiology, and risk factors of invasive mycoses (IM) in patients with allogeneic (allo) and autologous (auto) hematopoietic stem cell transplantation (HSCT) and to evaluate the impact of IM on overall survival (OS). MATERIALS AND METHODS: Data on 356 patients after allo-HSCT (n = 237) and auto-HSCT (n = 119) from 2000 to 2010 were analyzed. The diagnosis of IM was established according to the EORTC/MSG 2008 criteria. RESULTS: The incidence of myocardial infarction (MI) was 19.1%; that was 23.2 and 10.9% in allo-HSCT and auto-HSCT recipients, respectively. The incidence of MI following allo-HSCT was significantly higher than that after auto-HSCT. Aspergillus spp. (82.3%), Candida spp. (11.8%), zygomycetes (Mucor spp., Rhizopus spp.) (4.4%), and Cryptococcus neoformans (1.5%) are involved in the etiology of MI. Its risk factors are acute lymphoblastic leukemia; non-myeloablative conditioning regimen; use of fludarabine and antilymphocyte globulin; peripheral blood stem cells as a source for grafting; long-term lymphopenia, neutropenia; use of granulocyte colony-stimulating factor (G-CSF); acute graft-versus-host reaction; grade 3-4 mucositis; infections, such as cytomegalovirus, sepsis. The development of MI in HSCT recipients did not significantly reduce one-year OS after allo-HSCT and auto-HSCT--53.6 and 55% and 86.7 and 90.3% (with and without MI, respectively). In patients with invasive aspergillosis, OS (12 weeks after IM being diagnosed) was significantly longer in those with other invasive mycoses (91.3 and 50%, respectively). CONCLUSION: The incidence of MI after allo-HSCT was higher than that after auto-HSCT. MI induced by the fungal genus Aspergillus spp. was most common. Along with known risk factors, there was a poor prognostic factor, such as G-CSF. The development of MI failed to affect one-year OS, which was indicative of the adequate quality of its early diagnosis and therapy. The prognosis was poor in patients with invasive candidiasis, zygomycosis, and cryptococcosis. Investigations need to be continued to specify the reasons for high morbidity rates and the factors provoking discussion by investigators worldwide.

[Long-term results of clinical application of autologous mononuclear bone marrow fraction for regeneration therapy of ischemic heart disease patients].

An experience with using autologous bone marrow mononuclears for regeneration of the heart was analyzed in 97 patients in whom the intracoronary transplantation of autologous mononuclear bone marrow cells was performed. The results were estimated in terms up to 5 years and compared with a group of 37 patients who underwent only conservative treatment. A distinct positive dynamic of clinical and echocardiographic indices in the main group was noted in a subgroup of patients with a decreased ejection fraction (EF less than 50%) as compared with an analogous subgroup of patients in the control group. Substantial influence is exerted by regeneration therapy upon remote lethality. Thus, as a whole in the main group lethality over 5 years was 13.4% and in the group of control it was 21.6%. In the subgroup with a decreased ejection fraction and symptoms of heart failure lethality was 22.6% in the main group and 54.5%--in the control group. The intracoronary administration of the autologous bone marrow mononuclear fraction to inoperable patients with ischemic heart disease and a severe lesion of the coronary arteries and a decreased ejection fraction of the left ventricle is a safe and useful procedure resulting to substantially decreased lethality followed-up during 5 years against the background of conservative treatment.

[Long-term results of using mononuclear fraction of autologous bone marrow cells in complex surgical treatment of patients with heart valve failure].

The article is devoted to long-term results of pilot clinical investigation of using mononuclear fraction of autologous bone marrow cells as an additional procedure to standard surgical treatment of heart valve failure in order to improve local perfusion and contractive ability of the myocardium. The article presents results of an analysis of findings of the examination of 7 living patients within 6 years or 7 years after operation as also data of pathologicoanatomical investigation of three dead patients. The data obtained show the safety and effectiveness of this method of cell therapy in patients with heart valve failure.

[Autologous peripheral blood hematopoietic cell transplantation in the treatment of AL-amyloidosis].

AIM: To evaluate the efficiency of chemotherapy with standard doses of melfalan and dexamethazone versus autologous peripheral hemopoietic cell transplantation (auto-PHCT) in patients with AL amyloidosis and to reveal poor prognostic factors. SUBJECTS AND METHODS: Of 36 patients diagnosed as having AL-amylodosis, 17 patients underwent auto-PHCT, 11 patients received chemotherapy only; 8 patients died prior to treatment. RESULTS: In patients with AL-amyloidosis after chemotherapy and autotransplantation, 3-year overall survival was 28 and 64%, respectively. Low somatic ECOG status and cardiac lesion were independent poor prognostic factors of the disease. The number of involved organs failed to affect overall survival. CONCLUSION: Auto-PHCT may be proposed as first-line therapy for patients with AL-amyloidosis who have a somatic ECOG score of 0 to 2 and not more than 3 organs involved. Young patients who have a satisfactory somatic status and no benefit from autotransplantation may undergo auto-PHCT. It is expedient to use average-dose melfalan and dexamethasone when treating patients who are ineligible for high-dose chemotherapy.

[Polyclonal rabbit antithymocyte globulin (thymoglobulin): immunomodulatory effects and new aspects of its clinical application].

Antithymocyte immunoglobulins remain to be one of the most effective immunosuppressants used in transplantology and in the treatment of autoimmune diseases. The unique features of the mechanisms of individual antithymocyte globulin preparations should be borne in mind. Due to its polyclonal nature, thymoglobulin provides a wide spectrum of diverse immunomodulatory effects, which is the basis for its wide use in order to reduce the risk for graft rejection and a graft-versus-host reaction and to treat aplastic anemia.

[Use of various nutritional support regimens in patients with transplanted hematopoietic stem cells].

AIM: To study the impact of modified nutritional support (NS) versus standard NS on therapy tolerability and posttransplantation in patients with oncohematological diseases. SUBJECTS AND METHODS: Fifty-three patients, who had been diagnosed as acute myeloblastic (n = 19) or acute lymphoblastic (n = 16) leukemias, lymphomas (n = 10), and other oncohematological diseases (n = 8) and had received large-dose polychemotherapy followed by hematopoietic stem cell transplantation (HSCT), were prospectively examined. The control group (n = 27) used standard NS (NS was prescribed when gastrointestinal (GI) events occurred; on day 1 after HSCT, the study group (n = 26) had modified NS added by glutamine dipeptide (0.57 g/kg/day). Energy demands were 35 kcal/kg/day; protein requirements were 1.5-1.7 g/kg/day. Artificial nutrition preparations were daily given through infusion pumps for 24 hours. In both groups, the criteria for NS discontinuation were natural assimilation of 60% of the required energy within 3 consecutive days or day 14 after HSCT when Gl function was preserved. RESULTS: The patients receiving modified NS showed reductions in the incidence and severity of mucositis (p = 0.05), a less significant decrease in the laboratory and anthropometric indicators of nutritional status (p = 0.01), and a better hospital outcome on day 100 after HSCT (p = 0.01). There were no differences in the rate and severity of acute graft-versus-host reaction (p = 0.7%) and in one-year overall survival (p = 0.7%). CONCLUSION: As compared with standard NS, modified NS enables a patient to sustain negative consequences of the conditioning regimen, HSCT in the early posttransplantation period.

[Role of antithymocyte globulin in reducing the incidence of complications after allogeneic hemopoietic cell transplantation].

AIM: To evaluate the efficacy of antithymocyte globulin (ATG) used in conditioning modes before allogeneic hemopoietic cell transplantation (allo-HCT) and its effect in reducing the incidence of posttransplantation complications. SUBJECTS AND METHODS: The study assessed the results of 92 allo-HCTs depending on the presence or absence of ATG in conditioning modes, the doses of Atgam (60 mg/kg or more), the presence or absence of acute leukemia (AL) in remission before HCT. RESULTS: In patients with AL in remission receiving ATG in conditioning modes (Atgam 60 mg/kg or thymoglobulin 7.5 mg/kg), overall three-year survival was 60%. Increasing the dose of Atgam up to more than 60 mg/kg resulted in higher transplantation-associated mortality (TAM) rates than did with the Atgam dose of 60 mg/kg (p < 0.01). CONCLUSION: Allo-HCT is the treatment of choice for patients with AL in the presence of an HLA-identical related or unrelated donor. The use of Atgam in a course dose of not more than 60 mg/kg or thymoglobulin 7.5 mg/kg in conditioning modes is associated with low TAM rates and higher overall survival in earlier-stage disease in complete clinical hematological remission as compared with those in patients with expanded-stage AL, rather than in AL in remission at the start of conditioning before HCT.

[The use of allogeneic bone marrow transplantation and immunosuppressive therapy in the treatment of patients with acquired aplastic anemia].

AIM: To evaluate the efficiency of related and unrelated allogeneic bone marrow transplantation (alloBMT) versus immunosuppressive therapy (IST) in patients with aplastic anemia (AA) having no HLA-compatible bone marrow donor. SUBJECTS AND METHODS: The study covered 61 patients (34 men and 27 women) diagnosed as having acquired AA. Of them, 51 patients were diagnosed as having severe AA, 5 had supersevere AA, and 5 had non-severe AA. Combined IST (antithymocyte globulin (ATG) + cyclosporin A (CsA)) was used in 43 patients; allo-BMT was performed in 18. The basic types of ATG (ATGAM (Pfizer), thymoglobulin (Genzim), ATG (Fresenius), and goat antilymphocyte globulin (ALG) (Research Institute of Gerontology, Ministry of Health of the Russian Federation) were administered. CsA was given in a dose of 5 mg/kg/day. The standard conditioning regimen (ATGAM + cyclophosphanum) and fludarabine-containing (fludarabine + cyclophosphanum + ATG; busulfan + fludarabine + ATG) programs were used in the allo-BMT group. A combination of CsA and metothrexate was given to prevent a graft-versus-host reaction. RESULTS: Among the IST-receiving patients, overall survival (OS) was 71%. After the first course of IST by follow-up month 6, the response rate was 74%. The second course of IST was performed in 7 patients unresponsive after the first-line IST and in 8 patients with recurrent AA. After the second course of IST, the response rate was 46.7%. Four patients who failed to achieve remission after 2 courses of IST received its third course. A complete response was obtained in 3 patients. In 18 patients following allo-BMT (related and unrelated), OS was 86%; event-free survival was 65. In 12 patients after related allo-BMT, OS was 91.7%. CONCLUSION: Related allo-BMT is the method of choice if there is a HLA-compatible sibling. If there are contraindications to it or no related donor, IST with ATG + CsA is indicated. Ineffective IST is an indication for unrelated allo-BMT that may be recommended as life-saving therapy for young patients under 40 years of age.

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

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

[Intracardial transplantation of mononuclear cells of the autologous bone marrow in complex treatment of patients with valvular heart diseases].

The authors present the first clinical experience with intramyocardial transplantation of the mononuclear fraction of cells of the autologous bone marrow in complex surgical treatment of 10 patients with valvular heart disease. The cellular transplantation was fulfilled intraoperatively when making a prosthetic mitral (5 patients) and aortal (5 patients) valves on the open heart under conditions of extracorporeal circulation. Simultaneously direct revascularization of the myocardium (aorto-coronary and mammary-coronary shunts) was performed in 4 patients (1--with a mitral and 3--with aortal heart diseases). An investigation of the results of the examination including ECG, EchoCG and investigation of the myocardium perfusion using one-photon emission computed tomography fulfilled in the early postoperative period and within 6-12 months after operation has shown that the cell cardiomyoplasty with mononuclear fraction of cells of the autologous bone marrow improves the myocardium perfusion, however, in the early postoperative period the appearance of transitory impairments of the heart rate is possible.

[Effectiveness of using autologous mono-nuclears of the bone marrow in treatment of patients with ischemic heart disease].

The authors have analyzed their experiences with treatment of 50 patients with ischemic heart disease using transplantation of autologous mono-nuclears of the bone marrow. It was shown that this operation resulted in an improvement of indices of the heart functions and myocardium metabolism. Transplantation of stem cells as mononuclear fraction of the bone marrow is indicated in treatment of different groups of patients: in recurrent diseases after previous operations on the coronary arteries; in patients with distal lesions of the coronary bed; transplantation of autologous stem cells of the bone marrow is expedient simultaneously with coronary artery bypass grafting or coronary angioplasty (stenting).

[Intracellular interactions in the hematopoietic system after massive radiation exposure]. / Mezhkletochnye vzaimodeistviia v sisteme gemopoéza posle massivnogo radiatsionnogo vozdeistviia.

The review article deals with acute radiation damage to the bone marrow spatial structure, disturbances of cell-cell interactions, and stromal cytokine(s) production, hence representing limiting factors for effective postradiation recovery of blood system. The evidence for radiation-induced stromal functional activation is discussed, along with opportunity of local growth factors deficiency, thus requiring a replacement therapy with exogenous cytokines.

[Characteristics of DNA replication of the chromosomes of the bone marrow cells in patients with acute leukemia]. / Osobennosti replikatsii DNK khromosom kletok kostnogo mozga bol'nykh ostrym leikozom

A study of the late DNA replication pattern in chromosomes of human acute leucaemia cells revealed a significant diffrence from control. Chromosomes, 2,3 and 4-5 of the acute leucaemia cells finish their DNA replication earlier, and chromosomes 1, 13-15 and 16 later, compared to the control chromosomes. The difference in the pattern of DNA replication between analogous chromosomes of acute leucaemia and donor cells was associated with the discovery of large late-replicating chromatin blocks in the pericentromeric regions of leucaemia cell chromosomes. Some relationship is suggested between the pattern of pericentromeric heterochromatin DNA replication and cell differentiation.

[Role of Epstein-Barr virus in the pathogenesis of lymphogranulomatosis. Immunohistochemical and molecular-biological (hybridization in situ) research]. / O roli virusa Epshteina-Barr v patogeneze limfogranulematoza. Immunogistokhimicheskoe i molekuliarno-biologicheskoe (gibridizatsiia in situ) issledovanie.

EBV was found in 72.7% of 66 LGM patients aged from 4 to 76 years. EBV occurred in 100% of lymphoid depletion, 81% of mixed-cell variant and in 66.6% of nodular sclerosis. The occurrence of virus-positive cases was significantly higher at the age of under 10 years and over 50 years (100%). In the intermediate group it was 65.4 (p < 0.01). Necrotic changes in the lymph nodes were observed more frequently (p < 0.05) when EBV was present. The virus-positive cases of mixed-cell LGM are characterized by increased number of tumor and plasma cells (p < 0.05). EBV was also in a latent state without signs of lytic replication. The influence of the virus manifested in higher expression of antigens CD30 (p < 0.05) and bcl oncoproteins (p < 0.01) as well as in weak CD79 expression (p < 0.05).