Alpha-mannosidosis is a rare autosomal recessive hereditary disease from the group of lysosomal storage diseases with diverse clinical manifestations, the most typical of which are neurodegenerative process, hearing loss, skeletal deformities and immunodeficiency. The only radical treatment for this disease currently is allogeneic hematopoietic stem cell transplantation (allo-HSCT). Successfully performed allo-HSCT not only allows stoppage of the disease progression, but also leads to partial improvement in previously developed complications. The Article provides general information on the disease and demonstrates the Authors’ own experience of performing allo-HSCT in a patient with alpha-mannosidosis as well.

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a common treatment for a large number of pediatric diseases. Treatment planning is based on a careful selection of patients and donors, taking into account factors contributing to a successful outcome. The aim of our study was to analyze the results of 10 years’ experience in allo-HSCT gained at the Department of Bone Marrow Transplantation of the Russian Children's Clinical Hospital of the N.I. Pirogov Russian National Research Medical University. We retrospectively analyzed 506 patients who had undergone their first allo-HSCTs between January 2010 and December 2020. The study was approved by the Independent Ethics Committee and the Scientific Council of the N.I. Pirogov Russian National Research Medical University of Ministry of Healthcare of the Russian Federation. We included 243 patients who had received allo-HSCT before December 2015 and 263 patients who had received allo-HSCT after January 2016. The gender distribution was 60.1% male (n = 304) and 39.9% female (n = 202). The median age was 7.13 years. Allo-HSCT recipients were divided into two groups: 236 children with non-malignant disease, 270 children with malignant disease. In the malignant group, 89 patients were in first complete remission (CR1), 92 were in second complete remission (CR2), and 20 were in third complete remission (CR3) and beyond; 63 patients had active disease (AD); 6 patients received no prior treatment. Two hundred and twenty patients underwent allo-HSCT from a fully matched family donor (MFD), 172 from a matched unrelated donor (MUD), 33 from a mismatched unrelated donor (MMUD) and 81 from a haploidentical (mismatched) family donor (MMFD). Two hundred and eighty-eight patients received bone marrow as a stem cell source, 208 received peripheral blood stem cells; 10 transplants were performed using umbilical cord blood stem cells. The 5-year overall survival (OS) in the entire cohort was 71.34 %. The 5-year OS in the patients who had undergone allo-HSCT between 2016 and 2020 was higher (p = 0.0014). After 2015, the rates of primary graft failure, the incidence of grade III–IV acute “graft-versus-host” disease (GVHD), and recurrence rates were significantly lower. No difference in the incidence of grade III–IV acute GVHD (p = 0.494) and OS rates (p = 0.138) was seen between different sources of hematopoietic stem cells in the patients who received an HLA-compatible transplant (MFD, MUD). Chronic GVHD was significantly dependent on the severity of acute GVHD and donor type. The 3-year OS rate for the patients in CR1, CR2, ≥ CR3, and AD was 84.4 %, 60.5 %, 56.8 %, and 46 % (p = 0.0034), respectively. The relapse rate of the patients in any remission was lower than of those in active disease (p = 0.015). The transplantation-related mortality in the first 100 days after allo-HSCT was 6.92% (n = 35). The patients who had undergone allo-HSCT after 2015 had lower rates of primary graft failure, a decreased incidence of severe GVHD, improved OS and relapse-free survival rates. The frequency of grade III–IV acute GVHD strongly correlated with HLA compatibility. Chronic GVHD was less frequent in MFD recipients. The risk of chronic GVHD increased with the severity of acute GVHD. The HLA mismatch between a donor and a recipient was associated with a decrease in OS. With each subsequent remission, the OS rate decreased. The risk of recurrence was higher in the patients transplanted in active disease. The results of this study can be used in clinical practice to plan therapy, choose an optimal donor, and develop strategies for the prevention and treatment of complications.

BCG (Bacillus Calmette–Guerin) vaccine is widely used for the vaccination of newborns within the first few days of life to prevent mycobacterial infections. However, complications occurring after BCG vaccination in patients with primary immunodeficiencies (PIDs) can lead to serious consequences for their health and life. BCG vaccine-related complications occurring in patients with severe combined immunodeficiency (SCID) and chronic granulomatous disease (CGD) after hematopoietic stem cell transplantation (HSCT) constitute an important problem. The article presents a retrospective observational analysis of 45 patients with SCID and CGD who received BCG vaccination and underwent HSCT. In the post-transplant period, 33 (73.3%) patients had BCG-related complications, either localized or generalized. The presence of BCG vaccine-related complications in the pre-transplant period was a significant predictor of the development of post-transplant complications. The most severe and long-term BCG vaccine-related complications were observed in the patients with SCID: the median time to the resolution of symptoms of BCG infection was 30 days and 100 days in the CGD patients and the SCID patients, respectively (p< 0.001). The severity of BCG vaccine-related complications, the nature of the primary disease and the presence of pre-transplant BCG vaccine-related complications did not affect the overall survival (OS) of the patients: OS for the entire study group was 79.5 ± 6.6%. Non-compliance with antimycobacterial prophylaxis prior to HSCT resulted in severe infections in a number of patients. The treatment of BCG vaccine-related complications included a combination of several antimycobacterial agents, and anti-inflammatory drugs (such as glucocorticoids, interleukin-1 and 6 receptor antagonists) in cases of immune reconstitution inflammatory syndrome (n= 18). The only effective method of prophylaxis of BCG-related infections in patients with SCID and CGD in the pre- and post-transplant period is the exemption of newborns from BCG vaccination based on their family history. Uninterrupted antimycobacterial prophylaxis in vaccinated patients in the pre- and post-transplant period is also important. Furthermore, an effective uniform strategy for the prevention and treatment of BCG vaccine-related complications in PID patients both before and after HSCT is needed.

Umbilical cord blood (CB) has been used successfully as hematopoietic stem cells (HSCs) in adults and adults with malignant and non-malignant diseases in which there are indications for HSC transplantation (HSCT), and when an HLA-compatible related or unrelated donor is not available. CB, like any source of HSC, has certain advantages and disadvantages, which also determine the features of its use in transplantation. The article presents the experience of using CB as a source of HSC in pediatric patients at the Russian Children's Clinical Hospital (RCCH). Materials and methods of research: in a retrospective single-center continuous non-randomized uncontrolled open study includes 16 patients with various malignant diseases and 16 patients with non-malignant diseases, who underwent CB transplantation in the bone marrow transplantation department of the Russian Children's Clinical Hospital from 1997 to 2012. The peak of CB transplant activity occurred in the period from 2006 to 2010. The age of the patients at the time of the transplantation ranged from 6 months to 14 years. In 10 patients, a CB transplant from HLA-identical related donors was used, in 22 – from unrelated HLA-identical and HLA-incompatible for 2 or more antigens obtained from domestic CB banks. In addition to CB, six children were given bone marrow or peripheral blood stem cells from HLA-identical siblings as a transplant. The majority of patients (n=20) received one CB sample, 10 patients – 2 samples and two – 3. Results: implantation of the transplant was recorded in 27 children (84%), which 17 (53%) were alive, 10 (31%) died at different timesof post-transplant period. In 5 (16%) patients, implantation did not occur, of which one (3%) died, the cause of mortality in pediatric patients was a relapse of the underlying diseases. Acute graftversus-host reaction (GVHD) after CB transplantation was assessed in 27 (84%) patients of this study, among them 17 (63%) were diagnosed with acute GVHD stages I-II, 3 (11%) – stage III–IV (life-threatening form). Chronic GVHD was assessed in 18 (56%) patients included in the study, with 5 (28%) diagnosed with a limited form and 3 (17%) with an extensive form. Overall survival (OS) for the entire group of patients (n=32) was 58,3±8,8%, 5-year dormant survival rate (DSR) – 53±8.8%. OS in non-malignant diseases was higher (68%) than for malignant diseases (56%), but no statistically significant differences in OS were obtained in the two groups (p>0,05), as well as when comparing OS and DSR when using one or several samples of CB. Conclusion: CB remains available and acceptable source of stem cells for HSCT. At our center, the survival rates of patients after CB transplantation are comparable to those of international registries. The improvement of the method and the results of haploidentical SCT in recent years has led to a decrease in interest and transplantation activity (including in our center) using CB as a source of HSC. However, the unexplored antileukemic potential of CB stem cells, as well as a number of potential resources for improving and optimizing the use of this HSC source, may increase the chances of future CB transplantation.

Relevance. Infectious septic complications caused by polyresistant gram-negative micro-organisms are a pressing issue in the treatment of patients after polychemotherapy (PCT) and hematopoietic stem cell transplantation at the high risk of the fulminant current and high lethality against the background of hematopoesis aplasia. One of the therapeutic strategies of antimicrobial treatment is the systematic use of 0.5 % hydroxymethylquinoxaline dioxide (dioxidine) solution in the complex antibacterial therapy of patients with severe infectious-septic complications. The preparation has a bactericidal type of action, a wide spectrum of antibacterial activity. Experience in adult clinical practice has demonstrated the effectiveness of dioxidine in the treatment of the most severe forms of aerobic and anaerobic infection. Strict dose enforcement and injection technique to avoid the appearance of side effects. Data on the intravenous use of dioxin in children are presented in a limited number of scientific literature.The aim of the study was to demonstrate the efficacy of systemic use of hydroxymethylquinoxaline dioxide (0.5 % dioxidine solution) in children with infectious complications progressing against the background of aplasia of hematopoiesis caused by multidrug-resistant pathogens Pseudomonas aeruginosa, Klebsiella pneumoniae, Enterobacter cloacae, Stenotrophomonas maltophilia.Materials and methods. 16 patients with a verified gram-negative infection were prescribed 0.5 % hydroxymethylquinoxaline dioxide solution as part of a combination antimicrobial therapy were included in the retrospective study. The median age of patients was 5 years (6 months – 16 years), 11 (69 %) were boys and 5 (31 %) girls.All children included in the study has infectious-septic complications at the PCT-induced hematopoietic aplasia, obtained according to the protocols of the main disease: severe combined immune deficiency (n = 2), idiopathic aplastic anaemia (n = 3), solid tumor (n = 2), acute myeloblastic leukemia (n = 7), acute lymphoblastic leukemia (n = 2). The main criterion for adding to the study was the existence at the least one site with a verified gram-negative infection (Pseudomonas aeruginosa, Klebsiella pneumoniae, Enterobacter cloacae, Stenotrophomonas maltophilia): bacteriemia (n = 11), oral mucosa (n = 6), ulcerative necrotic damage of perineum (n = 6), enterocolite (n = 6), infectionseptic compartments in the subcutaneous fat (n = 4), pleuropneumonia (n = 4), abscesses and inflammatory infiltration of the liver, spleen, pancreas, kidneys, lymph nodes (n = 1), infection of soft tissues in the area of the ventricular bypass with inflammatory changes of the brain membranes (n = 1).All patients received 0.5 % of the solution of dioxin by injection according of vital importance, as they had pathogens with confirmed laboratory resistance or clinical progression of the infectious process against the background of combined antibacterial therapy.Discussion. There is a complete control of fulminant developing infectious-septic processes caused by polyresistant micro-organisms against the background of hydroxymethylquinoxaline dioxide therapy in all 16 patients. The eradication of the pathogen, according to the microbiological study, has been confirmed in almost all observed patients, the efficacy of the drug has been preserved throughout the period of treatment, and the resistance of micro-organisms has not been observed. Strict adherence to the dosing and infusion technique of hydroxymethylquinoxaline dioxide has helped to achieve the full resolution of the infection process in all children without side-effects.Conclusion. On the basis of the experience presented, in immunocomputed patients of young age, 0.5 % dioxidine solution can be used as a necessary reserve preparation for the treatment of the most severe forms of infections of different localization, caused by polyresistant strains of gram-negative micro-organisms.

BCG (Bacillus Calmette–Guérin) vaccine is widely used for the vaccination of newborns within the first few days of life to prevent mycobacterial infections. However, complications occurring after BCG vaccination in patients with primary immunodeficiencies (PIDs) can lead to serious consequences for their health and life. BCG vaccine-related complications occurring in patients with severe combined immunodeficiency (SCID) and chronic granulomatous disease (CGD) after hematopoietic stem cell transplantation (HSCT) constitute an important problem. The article presents a retrospective observational analysis of 45 patients with SCID and CGD who received BCG vaccination and underwent HSCT. In the post-transplant period, 33 (73.3%) patients had BCG-related complications, either localized or generalized. The presence of BCG vaccine-related complications in the pre-transplant period was a significant predictor of the development of post-transplant complications. The most severe and long-term BCG vaccine-related complications were observed in the patients with SCID: the median time to the resolution of symptoms of BCG infection was 30 days and 100 days in the CGD patients and the SCID patients, respectively (p< 0.001). The severity of BCG vaccine-related complications, the nature of the primary disease and the presence of pre-transplant BCG vaccine-related complications did not affect the overall survival (OS) of the patients: OS for the entire study group was 79.5 ± 6.6%. Non-compliance with antimycobacterial prophylaxis prior to HSCT resulted in severe infections in a number of patients. The treatment of BCG vaccine-related complications included a combination of several antimycobacterial agents, and anti-inflammatory drugs (such as glucocorticoids, interleukin-1 and 6 receptor antagonists) in cases of immune reconstitution inflammatory syndrome (n= 18). The only effective method of prophylaxis of BCG-related infections in patients with SCID and CGD in the pre- and post-transplant period is the exemption of newborns from BCG vaccination based on their family history. Uninterrupted antimycobacterial prophylaxis in vaccinated patients in the pre- and post-transplant period is also important. Furthermore, an effective uniform strategy for the prevention and treatment of BCG vaccine-related complications in PID patients both before and after HSCT is needed.

Relevance. Chronic granulomatous disease (CGD) belongs to the group of primary immunodeficiencies. Patients with CGD have an impaired quality of life, severe infections and inflammatory organ damage. Allogeneic hematopoietic stem cell transplantation (HSCT) is an effective treatment method for CGD. The authors of the article presented the experience of HSCT in patients with CGD in the Russian Children’s Clinical Hospital.Materials and methods. 20 (19 primary and 1 repeated) HSCT during the period from 2009 to 2020 were performed in nineteen patients with CGD. All patients had a long history of infections, three or more foci of chronic infection, 9 patients had a generalized BCG infection. Bone marrow (ВМ) from a related HLA-identical donor was the source of hematopoietic stem cells (HSC) for 4 (21 %) patients, peripheral blood stem cells (PBSC) for 2 (10.5 %). ВМ from a unrelated fully HLA-identical donor was performed in 9 (47.4 %) patients, PBSC – 2 (10.5 %). ВМ from a unrelated 9/10 HLA-compatible donor was performed in one (5.3 %) patient. In one case (5.3 %) the HSC source became PBSC from a unrelated 9/10 HLA-compatible donor after TcRαβ/CD19+ depletion. In 68.5 % (n = 13) cases the conditioning regimen included threosulfan, fludarabine, melphalan, and antithymocyte globulin. In 2 (10.5 %) patients, melphalan was excluded from the conditioning regimen; in 4 (21 %), it was replaced by thiotepa.Results. The overall survival (OS) was 88.9 ± 10.5 %, the event-free survival (EFS) was 88.1 ± 7.9 %, and there was no transplant mortality. Transplant rejections were observed in two patients who received HSC from a unrelated 9/10 HLA-compatible donor with a previous conditioning regimen that included only one alkylating agent. In 4 patients (21 %) there was a prolonged persistence of mixed chimerism after HSCT without clinical and laboratory signs of CGD. After successful transplantation all patients were cured of the infectious and inflammatory diseases characteristic of CGD.Conclusion. Results of HSCT in patients with CGD can be considered satisfactory, the OS and EFS are high. Failure of HSCT is associated with transplant rejection, which is most likely due to the donor and patient mismatch, as well as the use of conditioning modes with reduced intensity.

Relevance. Allogeneic hematopoietic stem cell transplantation (HSCT) is the only effective treatment method for the majority of patients with juvenile myelomonocytic leukemia (JMML). The authors of the article presented the experience of conducting HSCT in patients with JMML in the Russian Children’s Clinical Hospital.Materials and methods. 55 HSCT for the period from 2003 to 2019 were performed in forty-two patients with JMML. 14 (33.3 %) patients from a related HLA-identical donor were given primary HSCT, 1 (2.4 %) from a related 9/10 HLA-compatible, 16 (38.1 %) – from unrelated HLA-identical, 6 (14.3 %) – from unrelated 9/10 HLA-compatible, 5 (11.9 %) – from haploidentical. The source of hematopoietic stem cells (HSC) in primary HSCT for 22 (52.4 %) patients was bone marrow (BM), for 13 (31.0 %) – peripheral blood stem cells (PBSC), for 4 (9.5 %) – cord blood (CB), for 3 (7.1 %) – BM in combination with CB. Twenty-two (52.4 %) patients received a myeloablative busulfan-containing conditioning regimen, 20 (47.6 %) – treosulfan-containing.Results. The overall survival (OS) of patients for the entire observation period was 53 ± 8.3 %; transplantation lethality (TL) – 21.2 ± 6.8 %, relapse-free survival (RFS) – 72.0 ± 7.7 %, event-free survival (EFS) – 49.4 ± 7.8 %. The factors negatively influencing the results of HSCT in patients with JMML were the progression of the underlying disease at the time of HSCT, incomplete compatibility of the HSC donor, the use of CB as a source of HSC.Conclusion. Indicators of OS, RFS, EFS patients with JMLL after HSCT are low. The reasons for treatment failure are TL, graft failure and relapse after transplantation. To improve the results of treatment of patients with JMML, careful selection of the donor and the source of HSC, the maximum possible reduction in the toxicity of conditioning regimens is necessary.

Adenovirus infection is one of the causes of transplant-associated mortality after allogeneic hematopoietic stem cell transplantation. Fulminant liver failure with adenovirus infection is a diagnostic and therapeutic problem due to its aggressive clinical course and extremely poor prognosis, while modern methods of treating adenovirus infection are based on the use of virostatic drugs and virus-specific lymphocytes and are associated with severe side effects. The article presents a rare clinical case of elimination of disseminated adenoviral infection with fulminantly developing liver failure in a patient after allogeneic bone marrow transplantation from a haploidentical donor.

Adenovirus infection is one of the causes of transplant-associated mortality after allogeneic hematopoietic stem cell transplantation. Fulminant liver failure with adenovirus infection is a diagnostic and therapeutic problem due to its aggressive clinical course and extremely poor prognosis, while modern methods of treating adenovirus infection are based on the use of virostatic drugs and virus-specific lymphocytes and are associated with severe side effects. The article presents a rare clinical case of elimination of disseminated adenoviral infection with fulminantly developing liver failure in a patient after allogeneic bone marrow transplantation from a haploidentical donor.

Primary immunodeficiencies (PID) include a group of congenital diseases, many of which are associated with a high risk of developing life-threatening infectious and non-infectious complications. Many of PIDs require hematopoietic stem cell transplantation (HSCT), which can lead to a complete cure of the disease. The article presents more than 20 years of experience in conducting HSCT with PID in the Russian Children's Clinical Hospital for the period from 1997 to 2018. 88 HSCTs were performed in 80 patients (64 boys and 16 girls) with various PIDs: severe combined immune deficiency (SCID, n = 34), hemophagocytic lymphohistiocytosis (HLH, n = 12), chronic granulomatous disease (CGD, n = 11), Wiskott–Aldrich syndrome (WAS, n = 10), congenital agranulocytosis (n = 4), hyper IgM syndrome type 1 (n = 3), Nijmegen breakage syndrome (n = 2), lymphoproliferative syndrome (n = 2), Chediak–Higashi syndrome (n = 1), leukocyte adhesion deficiency (n = 1). Оverall survival (OS) and event-free survival (EFS) after HSCT with PID was 63.1% and 49.3%. OS after HSCT with SCID was 65.5%, EFS – 48.4%. The article presents the results of HSCT taking into account the type of HSCT, the source of hematopoietic stem cells (HSC) and the type of graft manipulation, conditioning regimen. Growth of positive results of HSCT in patients with PID in recent years is associated with the improvement of accompanying therapy (improving the quality of infection control, the introduction of new drugs for the prevention and treatment of hepatic veno-occlusive disease); technology application TcRα+β+/CD19+ depletion at haploidentical transplantation; optimization of conditioning regimens; successes in the prevention and treatment of the graftversus- host disease (antithymocyte globulin and rituximab administration during the period of conditioning, post-transplant administration of cyclophosphamide at haploidentical HSCT). The study was approved by the Independent Ethics Committee of Russian Children's Clinical Hospital.

Цитомегаловирусная (ЦМВ) инфекция является одним из распространенных осложнений среди пациентов, получающих полихимиотерапию. Однако вопрос влияния ЦМВ-инфекции вне контекста аллогенной трансплантации гемопоэтических стволовых клеток остается малоизученным. В статье представлен редкий клинический случай – достижение полной клинико-гематологической ремиссии рефрактерной нейролейкемии на фоне ЦМВ-инфекции у пациентки с острым миелобластным лейкозом, с последующими отторжениями гемопоэтических трансплантатов на фоне активизации TcRα/β-клона лимфоцитов и ЦМВ-виремии.