Vol 24, No 1 (2025)

In the past decades, significant advancements have been made in the treatment of children with acute myeloid leukemia (AML) with the introduction of more effective treatment regimens, extended indications for hematopoietic stem cell transplantation as well as better supportive therapy and prophylaxis of infectious complications. Nevertheless, an improvement in treatment outcomes is still an important goal. One of the key ways to enhance treatment effectiveness is risk stratification of AML patients based on molecular and genetic characteristics of the disease. A multicenter treatment protocol (the AML-MRD-2018 protocol) was developed at the Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology of Ministry of Healthcare of the Russian Federation. Our study includes 525 patients from 54 Russian hospitals who underwent treatment from November 2018 to December 2023. A total of 205 patients with a median age of 8.9 years (1 month – 17.6 years) were re-stratified to the intermediate-risk group. The 3-year overall and event-free survival for this group was 77% and 47%, respectively. The patients with biallelic CEBPA (dCEBPA) mutations had the most favorable prognosis. In the intermediate-risk group, early death before remission occurred in 6% of the patients; 8% of the patients died in first remission. Death of progressive disease occurred in 32% of all the deceased patients. The study was approved by the Independent Ethics Committee and the Scientific Council of the Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology of Ministry of Healthcare of the Russian Federation.

The treatment results of children with acute myeloid leukemia (AML) still remain unsatisfactory. The standard chemotherapy allows achieving complete remission in 91–96% of patients, but the event-free (EFS) and overall (OS) survival rates are still not high enough, the main cause of treatment failure in children with AML is relapse of the disease. DNA methylation and histone modification are major epigenetic changes in AML, leading to silencing of tumor suppressor genes. Research of the epigenetic control of gene expression in AML through histone modification and DNA demethylation promotes better understanding of the biology of blasts.

The aim of our study: to prove the effectiveness of the NII DOG AML 2012 protocol based on the combination of standard chemotherapy and epigenetic therapy. The study was approved by the Independent Ethics Committee and the Scientific Council of the N.N. Blokhin NMRC of Oncology of Ministry of Healthcare of the Russian Federation. From 01.01.2013 to 31.05.2019, the following patients were enrolled in the study: 35 patients who were receiving treatment according to the NII DOG AML 2012 protocol and 52 patients who were receiving treatment according to the AML-BFM 2004 protocol. Between two groups, there was no significant difference in sex, age, and distribution by risk groups. The high-risk and intermediate-risk patients received 5 courses of chemotherapy (AIE, HAM, AI, hAM, HAE) and the standard-risk patients received 4 courses of chemotherapy (AIE, AI, hAM, HAE). Epigenetic therapy according to the NII DOG AML 2012 protocol consisted of valproic acid (weeks 1–78), all-trans-retinoic acid (days 1–43 and then days 1–14 of each subsequent chemotherapy course) and decitabine 20 mg/m² which was given within a therapeutic window in 5 patients and 26 patients received it on days 16–20 from the beginning of treatment. Six patients received 5-azacitidine instead of decitabine. There was no toxicity in 5 patients who received decitabine within a therapeutic window: one patient developed relapse (13 months) and one patient died of severe infection after induction therapy on day 17, three patients are still alive in complete remission (67, 70, and 72 months), with two of them having received haploidentical hematopoietic stem cell transplantation. All the patients who received decitabine on days 16–20 achieved complete remission after induction therapy (2 patients of them did not respond to AIE treatment and achieved remission only after decitabine treatment). Among the patients who were treated with chemotherapy only, complete remission was achieved in 82.6% (p = 0.04). In the patients treated according to the NII DOG AML 2012 protocol, the 5-year EFS and OS was 69.1 ± 9.8%, and 73.5 ± 9.4%, respectively, vs 54.0 ± 7.3% (p = 0.2) and 69.2 ± 6.4% (p = 0.58) in the patients treated with chemotherapy only. The five-year EFS and cumulative incidence of relapse (CIR) of the high-risk patients treated according to the NII DOG AML 2012 and AML-BFM 2004 protocol were 77.8 ± 13.4% vs 50.0 ± 8.6% (p = 0.044) and 15.2 ± 10% vs 42.5 ± 9.2% (p = 0.056), respectively. None of the patients treated according to the NII DOG AML 2012 protocol underwent allogeneic hematopoietic stem cell transplantation (HSCT) during the first remission. After excluding from the analysis 6 patients who received allogeneic HSCT during the first remission and were treated according to the AML-BFM 2004 protocol, the EFS and CIR rates of the high-risk patients were 46.4 ± 9.4% (p = 0.02) and 47.4 ± 9.5% (p = 0.029), respectively. All the six patients who received 5-azacitidine instead of decitabine died (one patient died during induction therapy and 5 patients died of AML progression) and further study of this arm of the protocol was closed. Thus, the addition of epigenetic therapy to standard chemotherapy in pediatric patients with AML reduced the CIR, increased the number of complete remissions and the overall survival compared with the patients treated with chemotherapy only. The high-risk patients treated according to the NII DOG AML 2012 protocol achieved higher EFS and lower CIR rates compared with the patients who received no demethylating agents and underwent no allogeneic HSCT. Probably, epigenetic therapy may allow patients to avoid allogeneic HSCT during the first complete remission. According to our study results, decitabine has shown to be more effective than 5-azacitidine. Decitabine should be given after the first course of induction therapy during the period of aplasia.

Acute myeloid leukemia (AML) with KMT2A rearrangements is one of the most common AML subtypes in children. KMT2A rearrangements are extremely heterogeneous because of different breakpoint locations in the DNA of this gene in combination with a large number of various partner genes. Patients with KMT2A-rearranged AML are typically stratified into a high-risk group. However, there are reports of different prognostic significance of different rearrangements of this gene found both in Russian and international literature. For example, several studies including both adults and children suggested that AML with t(1;11)(q21;q23.3)/KMT2A::MLLT1 and t(9;11)(q21;q23.3)/KMT2A::MLLT3 translocations had a more favorable prognosis. However, these findings failed to be reproduced in other studies. What is more, a number of studies stated that the prognosis of survival in patients aged 0–24 months affected by KMT2A-rearranged acute leukemia may depend not only on the partner gene but also on the location of a breakpoint in the KMT2A gene, while also saying that patients with a breakpoint in intron 11 have the worst prognosis. Here, we aimed to evaluate the prognostic significance of KMT2A rearrangements in children with AML. The study was approved by the Independent Ethics Committee and the Scientific Council of the Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology of Ministry of Healthcare of Russia. We concluded that specific partner gene and breakpoint location did not have any significant influence on treatment outcomes in children with KMT2A-rearranged AML who had been treated according to the AML-MRD-2018 protocol. These findings may indicate that such patients should be stratified into a high-risk group irrespective of the involved partner gene and breakpoint location.

This study presents the results of treatment of 339 patients with acute promyelocytic leukemia (APL) from 57 regions of the Russian Federation (RF) and the Republic of Belarus (RB) according to the 2003/2008 APL treatment protocols, from 2008 to 1 January 2024. Based on the data from the AML-MRD-2018 protocol, the proportion of APL among childhood acute myeloid leukemia (AML) cases in the RF was investigated. The study was approved by the Independent Ethics Committee and the Scientific Council of the Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology. It was established that the APL cases comprised 26% of AML cases, and APL incidence rate varied across the regions of the RF. Our findings suggest that the incidence of APL in Russian children is higher than in children from Europe and the USA, but further epidemiological research is needed to confirm this. The 5-year overall (OS) and event-free (EFS) survival rates in the patients treated according to the 2003/2008 APL protocols were 82% (95% confidence interval (CI) 78–86) and 73% (95% CI 67–78), respectively. In the low-risk group (LRG) the five-year OS and EFS rates were statistically significantly higher than in the high-risk group (HRG), with 5-year OS reaching 93% (95% CI 89–97) in the LRG and 63% (95% CI 55–72) (p < 0.001) in the HRG, and EFS – 85% (95% CI 79–91) and 52% (95% CI 44–63) (p < 0.001), respectively. The risk of relapse was higher in the HRG: 15% (95% CI 9.1–25) in the HRG vs 8.7% (95% CI 4.9–15%) in the LRG (p < 0.045). The difference in the survival rates in the LRG and HRG was attributable to a higher mortality rate during remission induction in the HRG as compared to the LRG: 30.1% and 2.9%, respectively. Notably, 83.7% of deaths were caused by brain haemorrhage. Decreasing early death rate is key to improving APL treatment results in children in the RF and RB.

Burkitt lymphoma/leukemia (BL) is a highly aggressive B-cell non-Hodgkin lymphoma with a strong predilection for extranodal involvement and frequent multi-organ dissemination. When the bone marrow is affected, BL is typically characterized by three key signs: L3 morphology as defined by the French-American-British classification, a MYC gene rearrangement, and a mature immunophenotype with surface immunoglobulin expression as confirmed by flow cytometry. However, in some BL cases, some of these features may be absent. Here, we studied a correlation between L3 morphology and the presence of MYC gene rearrangements in the bone marrow. The study was approved by the Independent Ethics Committee and the Scientific Council of the Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology of Ministry of Healthcare of the Russian Federation. Out of the 127 patients with L3 morphology, 89.8% (n = 114) harbored MYC rearrangements, while in the patients with L1/L2 morphology such rearrangements were extremely rare (0.1%; 2 out of 2049). We identified the following MYC rearrangements: t(8;14)(q24;q32)/IGH::MYC (91.2%; n = 104), t(8;22)(q24;q11)/IGK::MYC (7.0%; n = 8), t(2;8)(p12;q24)/IGL::MYC (1%; n = 1), and t(8;14)(q24;q32)/IGH::MYC combined with t(14;18)(q32;q21)/IGH::BCL2 (n = 1). At the same time, 13 patients with L3 morphology did not have MYC rearrangements. Among these cases, 69.2% (n = 9) of patients harbored other chromosomal aberrations commonly associated with B-lineage acute lymphoblastic leukemia, including rearrangements involving the KMT2A and ETV6 genes and IGH locus, as well as hyperdiploidy and hypodiploidy. According to the findings of the initial analysis of cytogenetic samples using the fluorescence in situ hybridization (FISH) method, 23.6% (n = 25) of the MYC-positive cases either did not have abnormal cells or had a minimal amount. In such cases, MYC positivity was reliably confirmed by FISH performed on morphological samples with established blastosis. Notably, the percentage of blast cells varied significantly among the MYC-positive samples depending on the puncture site, which can potentially lead to false negative cytogenetic results. However, this variation was much lower in other genetic alterations such as hyperdiploidy, KMT2A rearrangements, and t(12;21)(p13;q22)/ETV6::RUNX1. Therefore, if there are any discrepancies between the results of morphological and cytogenetic analyses, it is recommended to perform additional testing using morphological smears with previously confirmed blastosis with L3 morphology.

Essential thrombocythemia (ET) is a clonal myeloproliferative disease characterized by the uncontrolled proliferation of megakaryocytes. Hemorrhagic manifestations in ET depend largely on the extent of decrease in von Willebrand factor (vWF) activity that is disproportionate to vWF antigen concentration, which may be associated with an increased loss of the most hemostatically active high molecular weight vWF multimers. The aim of our study was to analyze clinical and laboratory manifestations as well as multimer profile and functional characteristics of vWF in children with ET. The study was approved by the Independent Ethics Committee and the Scientific Council of the Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology of Ministry of Healthcare of the Russian Federation. Five patients with ET were tested for platelet count, vWF ristocetin cofactor activity (vWF:RCo) and vWF antigen (vWF:Ag), factor VIII binding capacity of vWF (vWF:FVIIIВ) and vWF collagen binding capacity (vWF:СВ). VWF multimer analysis with quantitative assessment of multimers was also performed. All the patients had decreased vWF activity of less than 50%, however vWF antigen levels were within the reference ranges. There was a significant association between thrombocytosis and reduced vWF:RCo (the Pearson coefficient –0.975, р = 0.005) and vWF:CB (the Pearson coefficient –0.916, р = 0.029). None of the patients had any changes in standard coagulation test results or decreased vWF:FVIIIВ. Assessment of vWF multimer distribution revealed a reduction in high-molecular weight vWF multimers. A correlation analysis showed no significant relationship between platelet count, vWF:RCo, vWF:Ag, vWF:CB and the concentration of different vWF multimers. Hemorrhagic syndrome presenting as generalized ecchymosis and petechiae was observed in one patient with vWF:RCo equal to 0. Patients with ET have unique laboratory characteristics that do not appear to correlate with clinical symptoms. The specifics of vWF multimer structure and vWF function characterized by a decrease in high-molecular weight vWF multimers and a significant decrease in vWF:RCo which are disproportionate to a decrease in vWF:CB deserve special attention. VWF:CB can probably serve as one the criteria for assessing the risk of hemorrhagic events.

Although surgical removal of head and neck tumors remains a relevant method of local control in pediatric patients, it can lead to the formation of extensive, complex maxillofacial defects. There is no doubt that restoration of anatomical integrity and function of the mandible in children is necessary in the majority of cases, however the choice of reconstruction method is still controversial. In this article, we present a method of combined mandibular reconstruction in children involving the use of a customized endoprosthesis with a temporomandibular joint implant and microsurgical reconstruction with a fibula free flap, which provides optimal functional and aesthetical results and enables patients to receive complete dental rehabilitation in the future (including the placement of permanent dental implants), and report a case series demonstrating this method. The study was approved by the Independent Ethics Committee and the Scientific Council of the Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology of Ministry of Healthcare of the Russian Federation. The patients' parents gave their consent to the use of their child's data, including photographs, for research purposes and in publications.

Primary immunodeficiencies constitute a large group of genetically determined disorders characterized by the impairment of mechanisms involved in the immune response. Syndromes of immune dysregulation are a group of primary immunodeficiencies that are characterized by frequent autoimmune manifestations, including immune cytopenia. CTLA4 haploinsufficiency with autoimmune infiltration is a remarkable example of immune dysregulation disorders. Here, we describe a case of CTLA4 haploinsufficiency that manifested with immune thrombocytopenia. We also review the current knowledge of etiopathogenesis, clinical manifestations and treatment of CTLA4 haploinsufficiency with autoimmune infiltration. The patient's parents gave consent to the use of their child's data, including photographs, for research purposes and in publications.

Familial cases of acute leukemia in children are very rare and are mainly reported in cases of genetically determined predisposition syndromes (mutations in the RUNX1, ETV6, ANKRD26, GATA2, SAMD9/SAMD9L, CEBPA genes) which have been well characterized in the last 15 years. In twins, leukemia is even more rare and is of particular interest for the study of leukemogenesis patterns and evolution of leukemic subclones. Here, we report about three pairs of twins: in one pair, KMT2A-r-leukemia was diagnosed simultaneously, while in the other two cases the second child remained healthy despite the development of KMT2A-r-leukemia in their twin. The patients’ parents gave consent to the use of their children's data, including photographs, for research purposes and in publications.

Thyroid gland ectopia is a rare condition occurring as a developmental anomaly during the embryonic period, when the thyroid primordium migrates. The prevalence of thyroid gland ectopia is 1 per 100 000–300 000 healthy individuals. Struma ovarii is a variant of thyroid gland ectopia, defined by the presence of thyroid tissue in the ovary. Cases of struma ovarii are very rare, and in the pediatric population they are even more rare than in adults. Only a few cases of struma ovarii in patients under 18 years have been described in the literature. Here, we present a clinical case of papillary thyroid cancer in ectopic thyroid tissue in a 13-year-old girl. The patient's parents gave their consent to the use of their child's data, including photographs, for research purposes and in publications. Surgery remains the main treatment option for all histological subtypes of thyroid cancer, however patients with distant metastasis are treated with radioactive iodine therapy. In this case, as adjuvant therapy, the patient received a combination of thyroidectomy and radioactive iodine therapy due to the presence of implantation metastases. Malignant transformation of ectopic thyroid tissue is extremely rare, and it may be difficult for a clinician to determine the best treatment option due to the lack of uniform treatment guidelines for this disease. This case report describes the clinical course of struma ovarii as well as an option for surgical treatment and adjuvant therapy for this disease.

This review presents the FLT3 gene structure and the working principle of the FLT3 protein coded by the gene, details the molecular mechanisms of FLT3 internal tandem duplication formation, the detailed structure and localization of tandem duplications in the FLT3 gene. Modern methods of FLT3-ITD diagnosis are described: fragment analysis, which provides an opportunity to estimate the allelic ratio, and next-generation sequencing, which allows for the study of the character of duplicated fragments and the localization of tandem duplications. This work presents the results of recent studies on the clinical significance of FLT3-ITD in acute myeloid leukemia with a normal karyotype and in the combination of FLT3-ITD with recurrent cytogenetic aberrations, as well as the results of studies showing the influence of the character of duplicated fragments and the location of FLT3-ITD insertion on survival rates. The main types of FLT3-inhibitors, their mechanism of action and clinical efficacy are described. Modern possibilities of FLT3-ITD monitoring and its practical significance for predicting the outcome of acute myeloid leukemia are presented.

Iron deficiency anemia has medical and social consequences worldwide, so the treatment of iron deficiency is an important goal. Oral iron therapy may not be optimal in some clinical situations requiring rapid replenishment of iron stores or due to possible ineffectiveness or intolerance. Intravenous iron therapy is an effective method for the treatment of iron deficiency anemia. So far, the use of intravenous iron preparations in pediatric patients has been limited, despite extensive experience of their use in adults and the results of studies conducted with children that have also demonstrated the efficacy and safety of this therapeutic option in pediatric patients. First of all, it is due to concerns about a risk of severe allergic reactions which was quite high in the era of first-generation intravenous iron medicines. The emergence of a new generation of more effective and safer intravenous iron preparations, including high-dose parenteral iron products, makes this type of therapy a promising means of treatment for iron deficiency in children and adolescents.