Search

Introduction. Down syndrome (DS) is one of the most common chromosomal abnormalities. Children with DS have an increased risk of developing acute lymphoblastic leukemia (ALL). Standard therapy is usually used to treat ALL in children with Down syndrome, but the outcome is worse than in the general population. The high toxicity of therapy is a particular problem.The purpose of the study – in this study we presents a comparative analysis of the results of therapy for children with DS and ALL (DS-ALL) who received therapy according to the ALL-MB 2008 and ALL-MB 2015 protocols.Materials and methods. The analysis included primary ALL patients, aged 1 to 18 years, who received therapy in Russian and Belarusian clinics participating in the Moscow–Berlin study from January 2008 to December 2020. To analyze the treatment results of DS-ALL patients, a “comparison group” was formed from all patients with ALL registered in the database, using the matched-pair method. Survival was calculated using the Kaplan–Meier method, toxicity analysis and clinical-genetic parameters were investigated using nonparametric statistical methods.Results. The results of therapy both among patients with DS-ALL who received therapy according to ALL-MB 2008 and ALL-MB 2015 in comparison with “sporadic” ALL (non-DS-ALL) are unsatisfactory. The event-free survival rate of patients with DS-ALL in the ALL-MB 2008 group was 61 ± 7 % versus 85 ± 4 % among non-DS-ALL (p = 0.001), in the ALL-MB 2015 group – 67 ± 7 % versus 84 ± 4 % respectively. Overall survival in the ALL-MB 2008 group was 70 ± 7 % in children with DS versus 88 ± 4 % in non-DS (p < 0.001), in the ALL-MB 2015 group – 78 ± 6 % versus 92 ± 3 % respectively (p < 0.001). The risk of therapy-related death was higher in patients with DS: 20.6 ± 6.1 % versus 4.6 ± 2.2 %; p < 0.001 in the ALL-MB 2008 group and 18 ± 4.1 % versus 3.3 ± 1.3 %; p < 0.001 in the ALL-MB 2015 group, without a significant increase in the risk of relapse. The effectiveness of induction therapy among patients with DS treated according to ALL-MB 2008 versus children with DS-ALL treated according to ALL-MB 2015 was 80 % versus 92 % respectively (p = 0.018). The probability of achieving continuous complete remission was also lower in the ALL-MB 2008 group compared to ALL-MB 2015 – 57 % versus 75 %; p < 0.001 respectively. Thus, the results of treatment of DS-ALL according to the ALL-MB 2015 protocol were better than those according to the ALL-MB 2008.Conclusion. The results of therapy for patients with DS-ALL are still unsatisfactory today, this circumstance dictates the need for new approaches to optimize therapy. The main problem for these patients remains the high toxicity of therapy and the associated lethality. Further progress in the treatment of DS-ALL may be associated with the development of new approaches to concomitant therapy, the use of molecular-targeted drugs and immunotherapy, as well as with the study of the molecular genetic characteristics of this subgroup of patients.

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.

Clinical efficacy of 3rd generation cephalosporins i.e. oral cefpodoxime and parenteral ceftriaxone was studied in the treatment of children with oncohematologic pathology. Cefpodoxime proved to be efficient in cases of moderate infectious complications in regard to the respiratory tracts. The oral administration of the drug provided its usage in outpatients. Ceftriaxone had a favourable effect in the treatment of children with more severe processes as a rule at the background of agranulocytosis and a lower immune response often with a tendency to generalization. No side effects of the cephalosporins were observed.

The authors investigated cellular and humoral immunity in 53 children over 3 years of age suffering from acute lymphoblastic leukemia. The children had remission lasting from 6 to 120 months and were followed up for 7-14 years after the diagnosis was made. The treatment was performed according to programs of polychemotherapy practiced in 1981-1988. In November of 1995 42 children were alive, 15 had the disease for 10 years. Lymphocytopenia (absolute number of T-cells and B-cells fell 3-5 and 2-3-fold, respectively) was reported in all the examinees both in early remission and later (6-12, 24-60, 60 and more months since the disease onset). In early remission there was a significant reduction in the serum IgG, IgA and IgM. In children with ALL lethal outcome serum IgM and absolute number of E-RFCa dropped in early remission more significantly indicating deep drug-induced depression of lymphocytopoiesis. After 5 years of treatment the pool of peripheral T-lymphocytes and T/B lymphocyte proportion changed for the best, though their absolute number was subnormal. Serum IgG, IgA and circulating immune complexes were 1.3-1.5 times higher than normal which may be explained by gastrointestinal pathology and food allergy in the majority of children treated.

Monoclonal immunophenotyping of leukemia cells of the bone marrow was carried out by the method of rapid immune alkaline phosphatase (RIAP) in 30 patients with acute lymphoblastic leukemia (ALL) aged 6 months-14 years. The authors used a panel of monoclonal antibodies (MCA) produced by Leu (Belgium) and DAKO (Denmark) directed to antigens of differentiation clusters: Tdt, HLA-DR, CD: 10, 19, 20, 22, 7, 8, 2, 5, 13, 33, 14. The results indicate diversity of compositions of differentiating antigens on leukemia cells of the dominant population and a different degree of leukemic cell pool heterogenicity. RIAP advantages over flow cytometry in immunotyping of ALL cells are shown. Arguments are provided in favor of introduction of broader MCA panel.

Two types of receptor systems for glucocorticoids: membranous and intracellular have been found on lymphoblasts of children with acute lymphoblastic leukemia by means of radioassay. They differed by localization and affinity for different glucocorticoids either. Modern radioassay needs modification because of no attention paying for interaction of hormones with different types of receptor system.

The activity of nucleoli-organizing (NOR's) regions was studied in leukemic cells of 53 children with immunologically typical ALL. The Ag-negative type of ALL was found in 9 cases of IA-ALL and Comm(+)-ALL. Dominating cells were not argentaffin. Some cytological peculiarities of Ag-negative cases have been demonstrated: lower presence of E(+)-receptor on circulating lymphoid cells, the greater number of cells with smooth surface which was revealed by the scanning electron microscopic method. The cases when the product of Ag-philic reaction was impossible to be revealed are discussed.

The study of the activity of nucleolus-forming areas in bone marrow and blood cells in 67 children with acute leukemia has shown the parameter variability depending on histogenetic affiliation, differentiation degree and on the proliferative activity of the cells.