Validation of the United Kingdom copy-number alteration classifier in 3239 children with B-cell precursor ALL

Genetic abnormalities provide vital diagnostic and prognostic information in pediatric acute lymphoblastic leukemia (ALL) and are increasingly used to assign patients to risk groups. We recently proposed a novel classifier based on the copy-number alteration (CNA) profile of the 8 most commonly deleted genes in B-cell precursor ALL. This classifier defined 3 CNA subgroups in consecutive UK trials and was able to discriminate patients with intermediate-risk cytogenetics. In this study, we sought to validate the United Kingdom ALL (UKALL)-CNA classifier and reevaluate the interaction with cytogenetic risk groups using individual patient data from 3239 cases collected from 12 groups within the International BFM Study Group. The classifier was validated and defined 3 risk groups with distinct event-free survival (EFS) rates: good (88%), intermediate (76%), and poor (68%) (P < .001). There was no evidence of heterogeneity, even within trials that used minimal residual disease to guide therapy. By integrating CNA and cytogenetic data, we replicated our original key observation that patients with intermediate-risk cytogenetics can be stratified into 2 prognostic subgroups. Group A had an EFS rate of 86% (similar to patients with good-risk cytogenetics), while group B patients had a significantly inferior rate (73%, P < .001). Finally, we revised the overall genetic classification by defining 4 risk groups with distinct EFS rates: very good (91%), good (81%), intermediate (73%), and poor (54%), P < .001. In conclusion, the UKALL-CNA classifier is a robust prognostic tool that can be deployed in different trial settings and used to refine established cytogenetic risk groups

Features of the chemokine profile of blood plasma by neurotoxic complications of acute lymphoblastic leukemia in children: preliminary report

The article presents an assessment of the neurotoxicity of chemotherapy in children with acute lymphoblastic leukemia receiving specific treatment according to the protocols used in pediatric oncological practice. An analysis of the neurological state with the determination of the chemokine profile of blood plasma was performed in 21 children aged 3 to 17 at the Regional Children’s Clinical Hospital in Yekaterinburg and the Central Research Laboratory of the Ural State Medical University in 2019. In the study group of children, neurotoxic complications were recorded in 42.9% of cases. At the same time, the appearance of neurological symptoms in most patients (77.7%) was observed during co chemotherapy at the stages of reinduction during consolidating treatment with a predominant clinical picture of chemo-induced polyneuropathy. In a comparative analysis of the indicators of the chemokine profile in groups of children, depending on the formation of neurotoxic complications during chemotherapy, we selected the chemokines CXCL10 (IP-10) and CXCL12 (SDF-1α) as possible prognostic biomarkers of damage to the nervous system

Vincristine polyneuropathy in children with acute lymphoblastic leukemia: the association with the hereditary rs924607 polymorphism in the <i>CEP72</i> gene

Background: Vincristine polyneuropathy is a major neurotoxic complication of treatment for acute lymphoblastic leukemia in children. A close relationship between genetic variants in candidate genes associated with the vincristine neurotoxicity in various ethnic groups has been proposed. Therefore, identification of the genetic risk factors underlying the predisposition to vincristine polyneuropathy could allow the development of effective tools for preventive diagnostics aimed at identifying a high-risk group among patients treated with vincristine for a personalized approach to their chemotherapy. Aim: To study an association between the rs924607 polymorphism of the CEP72 gene and vincristine polyneuropathy in children with acute lymphoblastic leukemia. Materials and methods: This single center cohort study enrolled 199 children aged 3 to 17 years with newly diagnosed acute lymphoblastic leukemia, who received ALL-MB 2015 chemotherapy regimen. All patients were genotyped for the single nucleotide variant rs924607 in the CEP72 gene by real-time polymerase chain reaction and subsequent allelic discrimination. A comparative analysis of the incidence and clinical signs of vincristine polyneuropathy depending on the carrier of the genetic polymorphism was performed. Results: The incidence of vincristine polyneuropathy in the study pediatric group was 81.0% (n = 161); mostly these were patients with NCI-STCAE grade 2 severity. The rs924607 single nucleotide variant in the CEP72 gene was significantly associated with the neurotoxic complication, with 19.1% (n = 38) of the patients were homozygous for the minor allele (rs924607 genotype TT) and 46.2% (n = 92) had the ST genotype. Among the carriers of at least one rs924607 risk allele (T), the odds ratio for vincristine polyneuropathy was 2.91 (95% confidence interval 1.415.99, p = 0.004). No significant association between the genetic variant assessed and clinical signs of vincristine-induced polyneuropathy was found. Conclusion: The single nucleotide rs924607 polymorphism of the CEP72 gen can be a putative pharmacogenetic marker for vincristine polyneuropathy

Prognostic value of initial bone marrow disease detection by multiparameter flow cytometry in children with neuroblastoma

Purpose: Multicolor flow cytometry (MFC) is widely available, fast and has an easy-to perform approach for finding neuroblastoma (NB) cells among normal bone marrow (BM) hematopoietic cells. Aim of the study was to investigate prognostic significance of initial MFC tumor cells’ detection in BM of children with NB. Methods: 51 patients (24 boys and 27 girls) aged from 6 days to 15 years (median age 1 year 3 months) with NB were included in the study. BM samples at the time of diagnosis were obtained from 2 to 5 aspiration sites per patient. CD45(−)CD56(+)CD81(+)GD2(+)-cells were evaluated by MFC. Results: NB cells were detected in BM by FC more frequently compared to conventional cytomorphology (49.0% and 29.4% patients, respectively, р = 0.043). Patients with NB cells detected in BM by MFC had significantly worse event-free survival and cumulative incidence of relapse/progression [0.24(0.08) and 0.60(0.10), respectively] compared to children with negative result of immunophenotyping [0.85(0.07) and 0.12(0.06), respectively, p < 0.001 in both cases]. BM involvement detection by MFC maintained its prognostic significance in various patients groups. In multivariate analysis, immunophenotyping proved to be an independent prognostic factor when analyzed jointly with other NB risk factors. In 42 patients BM involvement was also studied by RQ-PCR for PHOX2B and TH genes expression. Within groups of patients divided by RQ-PCR positivity, MFC-positivity retained prognostic significance. Conclusions: Thus flow cytometric BM involvement detection has very strong prognostic impact even stronger than RQ-PCR. It could be used in combination with other parameters for the treatment strategy choice in patients with NB

Concurrent type 1 diabetes mellitus and beta-cell lymphoma in a 12 year-old child: treatment with rituximab does not changethe clinical course of diabetes

В последнее десятилетие произошел значительный прогресс в понимании механизмов развития различных аутоиммунных заболеваний, в том числе и сахарного диабета 1 типа (СД1), что инициировало поиск новых методов и препаратов для их лечения. При СД1 в настоящее время проводится ряд клинических исследований по применению препаратов моноклональных антител против иммунокомпетентных клеток, участвующих в патоге- незе СД (анти-CD20, анти-CD3). Из опубликованных работ наибольший интерес представляют результаты, полученные Hu Ch. с соавт., которые в экспериментальном исследовании после применения ритуксимаба (анти-CD20) у 1/3 мышей линии NOD получили обратное развитие диабета. Эти данные вселяют определенный оптимизм в отношении возможности успешного лечения этим препаратом манифестного СД и у людей, а также являются основанием для изучения его эффективности в клинических исследованиях. В свете этого может представлять интерес наше наблюдение о применении ритуксимаба при лечении В-клеточной лимфомы у девочки с СД дли- тельностью 2 года