Vol 21, No 3 (2022)

From 2010 to 2020, we investigated 197 children with hemolytic anemia of unknown etiology at the Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology of Ministry of Healthcare of the Russian Federation. Fifty-four of them were found to have hemoglobinopathy caused by unstable abnormal hemoglobins: Hb Monroe/Kairouan, Hb Tacoma, Hb Köln/SanFrancisco, Hb Cheverly, Hb City of Hope, Hb Southampton/Casper, Hb M-Hyde Park/Akita/Milwaukee-2, Hb Buenos Aires/Bryn Mawr, Hb Louisville/Bucureşti, Hb Genova/Hyogo, Hb Roseau-Pointe a Pitre, Hb Bristol/Alesha, Hb Henri Mondor, Hb Knossos, Hb Leiden, Hb Little Venice, Hb Olmsted, Hb Sabine, Hb Showa-Yakushiji, Hb Terre Haute, Hb Tübingen, Hb Quin-Hai. 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 signed the informed consent for molecular genetic testing and gave their consent to the use of their children's data, including photographs, for research purposes and in publications.

This paper presents the results for the patients with acute lymphoblastic leukemia (ALL) from the high-risk group (HRG) treated according to the ALL-MB 2002 Protocol. The registration phase of the study was performed from 15.04.2002 to 01.01.2008. 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 study involved 36 departments (centers) of pediatric hematology/oncology in Russia and Belarus. One hundred and ten primary patients with ALL aged 1 to 18 years who met the criteria for high risk group, were analyzed: 29 patients with t(9;22), 11 patients with t(4;11), and 70 patients without stratifying genetic abnormalities who did not achieve remission by day 36 of induction therapy (16 patients from the standard risk group and 54 patients from the intermediate risk group, at initial). Median follow-up was 10.75 (8.6–13.8) years. First remission (CR1) was achieved in 80.9% of patients. 37.27% of patients relapsed, 51.22% of relapses were very early. The proportion of isolated bone marrow relapse was 73%, while isolated central nervous system relapses were observed in 4.55% of the cases. None of the patients developed a secondary tumor, 5.45% of patients were lost from follow-up. Only 15.7% of patients with CR1 received allogeneic hematopoietic stem cell transplantation. Only half of the patients with Ph-positive ALL received treatment with tyrosine kinase inhibitors. In total, 26.36% of patients remain in CR1. Overall and event-free survival were 32.9 ± 4.6% and 31.5 ± 4.5%, respectively. The cumulative risks of relapses and treatment-related mortality were 37.6 ± 4.3% and 20.9 ± 3.8%, respectively. There were no significant difference in the initial parameters and responses to therapy between the subgroups of patients. Overall and event-free survival were the highest in patients with ALL with t(4;11): 54.5 ± 15% and 45.5 ± 15%, respectively. The lowest overall and event-free survival were observed in the subgroup of patients without stratifying anomalies who did not achieve remission on day 36: 29.1 ± 5.6% and 27.1 ± 5.3%, respectively. The cumulative risk of relapse was the highest in patients who did not respond to induction therapy (42.9 ± 5.2%). The cumulative risk of treatment-related mortality was the highest in patients with Ph-positive ALL (31.0 ± 8.6%). The 5-year overall survival of patients with ALL relapse after high-risk therapy was extremely low – 7.7% (95% confidence interval 0–16.1), median overall survival after relapse in this group was only 187 days. This indicates that the options for second-line therapy of high-risk patients were severely limited at the time of ALL-MB 2002 study, because they included only chemotherapeutic strategies.

This study presents the clinical and laboratory data of 50 patients with ataxia-telangioectasia syndrome (AT) (Louis-Bar syndrome) treated at the Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology (Moscow, Russia) between 2012 and 2021. 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. We found that the patients experienced a significant diagnostic delay (the median delay in diagnosis was 4.5 years), although the first typical symptoms of AT were present at an earlier age (the median age was 1.5 years). The majority of patients showed laboratory signs of immunodeficiency, yet only 24% of the children developed severe infections. However, lung infections resulted in bronchiectasis in 16% of the patients and were the cause of death in 4/10 cases. Fifty-two percent of the patients had autoimmune complications, including interstitial lung disease and skin granulomas, and 24% of the patients developed malignant neoplasms. Of patients who underwent testing, 85% had KREC and/or TREC levels below the cutoff values used for neonatal screening of primary immunodeficiency disorders in Russia, which suggests that the majority of AT cases could be diagnosed by neonatal screening. Early diagnosis, multidisciplinary approach and high clinical suspicion for neoplastic manifestations are crucial for the successful management of AT.

Mutations in the MECOM gene (MDS1 and EVI1 complex locus) may be one of the causes of a rare combination of congenital radioulnar synostosis resulting in extremely limited forearm pronation and supination, and amegakaryocytic thrombocytopenia. The clinical spectrum of the disease can range from isolated radioulnar synostosis with or without hematologic manifestations to severe bone marrow failure without skeletal abnormalities. Other phenotypic manifestations include clinodactyly, brachydactyly, cardiac and renal malformations, presenile hearing loss, and B-cell deficiency. In view of the heterogeneity of phenotypic manifestations of the disease, the term “MECOM-associated syndrome” was proposed for all patients with mutations in the MECOM gene. Here we report 3 pediatric cases of MECOM-associated syndrome with different clinical manifestations, diagnostic approaches, therapeutic options, and outcomes. The patient’s parents agreed to use the information, including the child’s photo, in scientific research and publications.

In the 2020 World Health Organization classification, for the first time, three new groups of tumors were formalized, initially isolated from the group of undifferentiated round cell sarcomas, the so-called Ewing-like sarcomas, namely sarcoma with BCOR genetic alterations, CIC-rearranged sarcoma and sarcomas with EWSR1 gene rearrangement with atypical (non-ETS family) partner genes. This review will focus on sarcoma with BCOR genetic alterations, which will be illustrated by one of our clinical case, characterized by relatively typical features, both in terms of morphological presentation and immunophenotype, and in terms of biological behavior and response to tumor therapy. The patient's parents gave their consent to the use of their child's data, including photographs, for research purposes and in publications.

Acute lymphoblastic leukemia (ALL) with translocation t(17;19)(q21-q22;p13) TCF3::HLF (E2A::HLF) accounts for less than 1% of childhood B-lineage ALL. Since the first description, patients with this type of ALL are stratified into high-risk group. The disease often has a unique clinical presentation with disseminated intravascular coagulation and hypercalcemia, that are uncommon in other types of B-lineage ALL. This type of ALL is characterized by an extremely poor prognosis despite intensive treatment and hematopoietic stem cell transplantation (HSCT) in the first remission. In the last decade, some new data on the mechanisms of leukemogenesis in this type of ALL made it possible to come closer to understanding the reasons for the high refractoriness to chemotherapeutic agents. Along with the reports on the possible effectiveness of the BCL-2 (venetoclax) and Aurora kinase A (alisertib) inhibitors in this type of ALL, cellular immunotherapy (various chimeric antigen receptor (CAR)-T cell constructs), anti-CD19 (blinatumomab) and anti-CD22 (inotuzumab ozogamicin) monoclonal antibodies appear promising in the treatment of this disease. To date, there are neither published data on direct comparisons of the effectiveness of these methods nor specific recommended therapy protocols for these patients. It is also unclear if the new therapeutic approaches can completely replace HSCT or they only increase relapse-free survival after it. Here, we review the data on this translocation published in the medical literature and present a case report of a 3-year-old boy with this type of leukemia, who did not respond to four-component induction therapy according to the ALL-MB 2015 Protocol and received anti-CD19 CAR-T therapy with the achievement of the first MRD (minimal residual disease)-negative remission, which lasted 11 months. After MRD-relapse and unsuccessful attempt at therapy with autologous CD19/CD22 CAR-T cells, the patient developed an extended isolated bone marrow relapse. He achieved the second MRD-negative remission after reinduction therapy with inotuzumab ozogomycin and received allogeneic HSCT from a related donor. At the time of writing, the patient is in complete molecular remission for 16 months after transplantation. The patient's parents have consented to the use of de-identified clinical information and photos of the patient in scientific research and publications.

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Conditions associated with defects in the SAMD9/SAMD9L genes represent a relatively new group of diseases characterized by a diverse range of clinical manifestations: from multisystem disorders such as MIRAGE syndrome to isolated hematological manifestations. A previous history of infectious diseases in patients with SAMD9/SAMD9L gene defects before the onset of hematological manifestations is in most cases associated with the defects of the immune system. Gain- or change-of-function germline mutations in the SAMD9/SAMD9L genes are the most common predisposition factors for pediatric myelodysplastic syndrome (MDS) with monosomy 7. However, SAMD9/SAMD9L patients with cytogenetic rearrangements but without any signs or symptoms of MDS can have spontaneous remission due to various compensatory cellular mechanisms. The presence of primary immunodeficiency and a predisposition to MDS at an early age requires a more detailed approach to this group of patients and early determination of indications for allogeneic hematopoietic stem cell transplantation. The patients’ parents gave their consent to the use of their child’s data, including photographs, for research purposes and in publications.

For a long time, red blood cells have been known to have a procoagulant effect on hemostatic system. This effect was usually ascribed to either general increase of blood viscosity due to increased hematocrit value, RBCs' transport-enhancing effect on platelets adhesion under flow conditions. It is known that red blood cells can have a procoagulant effect on the hemostasis system. This effect is usually explained either by a general increase in blood viscosity due to an increase in hematocrit, or by the effect of red blood cells on the transport of platelets to the vessel wall and their further adhesion. However, recent studies indicate that the role of red blood cells in blood coagulation is much wider. In this review, we will consider the main mechanisms currently known, through which red blood cells can influence the processes of hemostasis and thrombosis in normal and pathological conditions.