There is a limited number of publications on the incidence of different mutations in the BCR-ABL kinase domain, the efficacy and safety of therapy in children and adolescents with resistant forms of chronic myeloid leukemia (СML).Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is still the only method able to cure the disease completely in pediatric and adolescent patients with CML, however, being associated with life-threatening complications.This article analyzes the course, treatment and outcomes of chronic myeloid leukemia in 3 pediatric patients pre-treated with tyrosine kinase inhibitors (TKI) who exhibited the T315I mutation in BCR-ABL kinase domain.

Актуальность. Появление ингибиторов сигнальных путей (ИСП) значительно улучшило прогноз пациентов с рецидивами хронического лимфолейкоза (Р-ХЛЛ). Тем не менее у части пациентов не удается достичь оптимального и устойчивого ответа. Наличие дефектов гена TP53 определяет рефрактерность к иммунохимиотерапии (ИХТ) и более низкие показатели выживаемости без прогрессирования при терапии ИСП. Однако прогностическое значение комплексного кариотипа (КК) при ХЛЛ долгое время оставалось дискутабельным. В последние годы все больше внимания уделяется прогностическому влиянию КК в контексте терапии ИСП. Материалы и методы. В исследование включено 180 пациентов, получавших по поводу Р-ХЛЛ лекарственное лечение (113 — ИХТ, 67 — ИСП). В качестве маркеров прогноза оценивались возраст на начало второй линии терапии, ответ на терапию первой линии, раннее (< 24 мес.) прогрессирование после терапии первой линии, число линий терапии, наличие КК и дефекта гена TP53. С учетом клональной эволюции при ХЛЛ для анализа степени значимости перечисленных предикторов использовался регрессионный анализ пропорциональных рисков Кокса с временно-зависимыми переменными. Результаты. Независимыми факторами, статистически значимо снижающими риск летального исхода, оказались достижение ответа непосредственно после первой линии терапии (отношение рисков [ОР] 0,38; 95%-й доверительный интервал [95% ДИ] 0,20–0,72; p = 0,003) и число линий проводимой терапии (ОР 0,56; 95% ДИ 0,37–0,86; p = 0,008). Применение только ИХТ во второй и последующих линиях было связано с повышением риска летального исхода (ОР 2,25; 95% ДИ 1,09–4,63; p = 0,028). Наличие генетического риска с высокой статистической значимостью ухудшало прогноз как в случае наличия дефекта гена TP53 с исключенным или неизвестным статусом КК (ОР 10,54; 95% ДИ 4,25–26,17; p < 0,001), так и при наличии КК (ОР 14,08; 95% ДИ 5,77–34,35; p < 0,001). Значимым предиктором неблагоприятного исхода оказался фактор неизвестного статуса по КК при отсутствии поломки гена TP53 (ОР 4,15; 95% ДИ 1,72–10,00; p = 0,002). Срок рецидивов после первой линии терапии и возраст ≥ 65 лет не имели независимого прогностического значения. Заключение. Проведение стандартного кариотипирования лимфоцитов периферической крови со специфической стимуляцией позволяет более четко определить прогноз заболевания и выбрать оптимальную стратегию лечения пациентов с Р-ХЛЛ.

Introduction.The biological heterogeneity of chronic lymphocytic leukemia (CLL) is reflected in the rate of progression, the need for therapy, and the response to treatment. Analysis of prognostic factors contributes to improving the quality of treatment and rational distribution of healthcare resources.Materials and methods.Among 890 patients with documented stage of CLL, 405 (45.5 %) received treatment. As the first-line of treatment, 173 patients received intensive regimens (FCR or BR), 6 – new agents, and 226 – all other regimens. The initial stage of the disease, mutation status of IGHV, del17p with or without complex karyotype were analyzed as prognostic markers.Results.Immunochemotherapeutic regimens were shown to be highly effective in case planned amount of treatment was completed. The combination of such prognostic parameters as the initial stage of the disease, the mutation status of IGHV, and the presence of del17p and/or complex karyotype allows us to clearly identify a group of patients with an unfavorable prognosis, for which it is advisable to use either intensive programs or new agents in the first-line therapy.

Background. The emergence of signaling pathway inhibitors (SPI) considerably improved the prognosis in relapsed chronic lymphocytic leukemia (R-CLL). Nevertheless, some patients cannot achieve optimal and sustained response. TP53 gene defects determine the refractoriness to immunochemotherapy (ICT) and lower rates of progression-free survival on SPI therapy. However, the prognostic value of complex karyotype (CK) in CLL has long been disputed. In recent years, greater attention has been placed on the prognostic impact of CK in the context of SPI therapy. Materials & Methods. The study included 180 patients who received the drug treatment for R-CLL (113 of them with ICT, 67 of them with SPI). Their age at the onset of second-line therapy, the response to first-line therapy, early (< 24 months) progression after first-line therapy, the number of therapy lines, and the presence of CK and TP53 gene defect were regarded as prognostic markers. Taking into account the clonal evolution in CLL, to assess the significance degree of the above predictors, Cox proportional hazards regression model with time-dependent variables was used. Results. The following independent factors proved to significantly reduce the risk of death: response achieved immediately after first-line therapy (hazard ratio [HR] 0.38; 95% confidence interval [95% CI] 0.20-0.72; p = 0.003) and the number of therapy lines (HR 0.56; 95% CI 0.37-0.86; p = 0.008). Treatment with only ICT in first and subsequent lines was associated with increasing risk of death (HR 2.25; 95% CI 1.09-4.63; p = 0.028). Genetic risks worsened the prognosis to a high degree of significance in the case of TP53 gene defect with excluded or unknown CK status (HR 10.54; 95% CI 4.25-26.17; p < 0.001) as well as in the case of CK (HR 14.08; 95% CI 5.77-34.35; p < 0.001). A significant predictor of poor outcome was reported to be the factor of unknown CK status without TP53 gene defect (HR 4.15; 95% CI 1.72-10.00; p = 0.002). Neither relapse time after first-line therapy nor the age > 65 years showed independent prognostic value. Conclusion. Standard karyotyping of peripheral lymphocytes with specific stimulation establishes a clearer disease prognosis and suggests the optimal choice of R-CLL treatment strategy.

Aim. To assess the prognostic value of the mutation of DNA methylation genes, SF3B1, and TP53 in patients with myelodysplastic syndrome (MDS). Materials & Methods. Out of 35 MDS patients included into the trial 2 had multilineage dysplasia, 13 with excess blasts-I, 19 with excess blasts-II, and 1 had 5q-syndrome (criteria WHO 2016). In 30 patients primary MDS was identified, in 5 patients it was detected after prior chemo- or radiotherapy. 25 patients received allogeneic hematopoietic stem cell transplantation (allo-HSCT). According to IPSS-R there were 1 low-risk, 5 intermediate risk, 17 high-risk, and 12 very highrisk patients. Hypomethylating agents were administered to 28 patients. Median age of patients was 49 years (range 18-80 years). Next-generation sequencing was applied for identifying somatic mutations in DNA methylation genes (TET2, IDH1/2, ASXL1, and DNMT3A) as well as in SF3B1, TP53, and RUNX1. Time to progression (TTP) was defined as the time from the initial diagnosis to the date of acute leukemia diagnosis. Allo-HSCT- or antitumor therapy-associated death was considered as competing risk. Results. Methylation gene analysis showed no mutation in 37 % of patients, in 40 % mutation was detected only in one of the genes, in 23 % mutation was identified in > 2 genes. SF3B1 mutations were reported in 23 % and TP53 in 11 % of patients. Median follow-up was 25 months (range 5-116 months). Univariate analysis showed no considerable differences in overall survival depending on mutation status. Median TTP in the group with allo-HSCT was not achieved, in the group without allo-HSCT it was 6 months (p = 0.0001). In patients with no SF3B1 mutation median TTP was 35 months, in patients with this mutation it was not achieved (p = 0.043). With ≥ 2 mutations in methylation genes median TTP was 12 months, in other cases it was not achieved (p = 0.024). In cases of TP53 mutation median TTP was 6 months, in cases without this mutation it was 43 months (p = 0.023). Multivariate analysis confirmed unfavorable prognostic value of TP53 mutation or ≥ 2 mutations in methylation genes in terms of TTP regardless of the drug treatment or allo-HSCT performed (hazard ratio 7.1; 95% confidence interval 2.6-19.6; p = 0.0001). Conclusion. The analysis of molecular markers yields additional data concerning the MDS prognosis. Further research is required to determine the prognostic value of molecular markers in clinical practice which will enable to individualize approaches to MDS treatment.