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.

In children without Down syndrome who have acute megakaryoblastic leukemia (AMKL), inv(16)(p13q24)/CBFA2T3::GLIS2 is the most frequent genetic aberration. Pediatric CBFA2T3::GLIS2-positive AMKL is strongly associated with a poor prognosis and a high cumulative incidence of relapse. One of the key laboratory signs of CBFA2T3::GLIS2-positive AMKL is the RAM immunophenotype, which looks very similar to that of solid-tumor bone marrow (BM) infiltration. For this reason, in cases of isolated extramedullary involvement of CBFA2T3::GLIS2-positive AMKL, excluding solid tumors may be challenging. We report a case of a girl with isolated extramedullary CBFA2T3::GLIS2-positive AMKL relapse, which was misdiagnosed as secondary Ewing sarcoma. The morphological differential diagnosis between Ewing sarcoma and AMKL presented significant challenges owing to their overlapping histological features (small, round blue-cell morphology and similar growth patterns). The tumor cells’ immunophenotype completely mirrored that at the initial diagnosis of AMKL. Additional cytogenetic and molecular studies confirmed the presence of the CBFA2T3::GLIS2 fusion, but no Ewing sarcoma-specific EWSR1, FUS and CIC fusion transcripts were found. Thus, extramedullary CBFA2T3::GLIS2-positive AMKL relapse was confirmed. The presented case demonstrates the difficulties in differential diagnosis between AMKL relapse and the development of a secondary tumor.

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.

KMT2A gene rearrangements are common genetic events in acute leukemia and lymphoma, particularly in younger patients, and are associated with poor outcome. Due to the wide range of partner genes and breakpoint locations, accurate identification of KMT2A rearrangements can be challenging in clinical molecular diagnostics. To achieve a rapid and cost-effective data on KMT2A translocation partner and fusion gene sequence, we follow a structured approach that includes standard GTG-banded karyotyping, fluorescence in situ hybridization (FISH) with 11q23.3 break-apart or translocation probes, DNA-based next-generation sequencing (NGS) for the entire KMT2A gene, and subsequent confirmation of fusion gene expression using real-time PCR with reverse transcription. Here, we illustrate our diagnostic workflow with a case of pediatric T-cell lymphoma harboring a KMT2A gene rearrangement.

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.

Pediatric Hematology/Oncology and Immunopathology | Peer-rewiev medical journal Вопросы гематологии/онкологии и иммунопатологии в педиатрии | Научный рецензируемый журнал