Цель. Оценить прогностическое значение сложного кариотипа, включающего аномалии del(5q),-7, del(7q) при острых миелоидных лейкозах (ОМЛ) у больных после аллогенной трансплантации гемопоэтических стволовых клеток (аллоТГСК). Материалы и методы. Обследовано 44 больных ОМЛ с аномалиями хромосомы 5 и/или 7 (22 женского и 22 мужского пола в возрасте от 1,2 до 67 лет, медиана 31,2 года). Проведен анализ предикторов общей (ОВ) и бессобытийной выживаемости (БСВ) после аллоТГСК у больных с различными клиническими, трансплантационными и цитогенетическими характеристиками. Результаты. До аллоТГСК сложный кариотип (≥ 3 хромосомных нарушений) был выявлен у 19 (43 %) больных, моносомный кариотип-у 8 (18 %). По данным однофакторного анализа, показатели ОВ и БСВ после аллоТГСК отличались у больных различных возрастных групп (≥ 18 vs < 18 лет; p = 0,01 и p = 0,05 соответственно), с различным клиническим статусом болезни на момент трансплантации (1 ремиссия vs другой статус; p = 0,1 и p = 0,008 соответственно), со сложным кариотипом и без такового (СК-vs СК+; p = 0,05 и p = 0,002 соответственно), с моносомным кариотипом и без такового (МК+ vs МК-; p = 0,009 только для БСВ) и в зависимости от источника стволовых клеток (костный мозг vs другие источники; p = 0,03 только для ОВ). Многофакторный анализ подтвердил, что независимыми предикторами ухудшения ОВ и БСВ были возраст 18 лет и старше (p = 0,02 и p = 0,01 соответственно), активная стадия заболевания на момент аллоТГСК (p = 0,04 и p = 0,005 соответственно), СК (p = 0,04 и p = 0,0008 соответственно) и когда источником
Aim. To evaluate the prognostic impact of the different cytogenetic characteristics, including the modal number, the number of chromosomal aberrations in a complex karyotype, and adverse chromosomal abnormalities (ACA) (-7/7q-, -5/5q-, -17/17p-, t(6; 9)(p22; q34)) on the results of allogeneic hematopoietic stem cell transplantation (allo-HSCT) in patients with hyperdiploid acute myeloid leukemia (H-AML). Methods. Forty seven H-AML patients (21 women and 26 men, aged from 1 to 58 years, median - 23.9 years) were examined. The analysis of overall (OS) and event-free survival (EFS) predictors after allo-HSCT in patients with different clinical, transplant and cytogenetic characteristics was performed. Results. The modal number of chromosomes (MN) of 4748 was the most common one in the karyotype which was observed in 31 (66 %) patients. High hyperdiploidy with the modal number of 49-65 was identified in 13 (28 %) patients, near-triploid and near-tetraploid karyotypes were found in 3 (6 %) patients. Quantitative chromosomal abnormalities were nonrandom. Chromosome 8 (50 %), 21 (32 %), 13 (16 %) and 22 (16 %) trisomy was the most common one. Structural chromosomal abnormalities were detected in 22 (47 %) patients, at that, ACA were found in 7 (19 %) patients. In univariate analysis, the OS and EFS after allo-HSCT differed in patients with different clinical status (remission vs. active disease; p = 0.003 and p = 0.002, respectively), different chromosomal abnormalities in hyperdiploid karyotype (ACA- vs. ACA+; p = 0.001 and p = 0.03, respectively). An additional analysis of selected patients group with a structurally complex karyotype (n = 19) showed, that patients without ACA had a higher OS than patients with ACA (p = 0.03). In multivariate analysis, the disease status (relapse) at allo-HSCT was an independent predictor of decreased OS and EFS (p = 0.004 и p = 0.006, respectively), as well as the presence of the ACA (p = 0.002 only for OS). Conclusion. ACA were high-risk factors in H-AML patients received allo-HSCT. Therefore, the patients with formal criteria of a complex karyotype should not be automatically included in the cytogenetic unfavorable risk group.
Aim. To estimate the efficacy of chemotherapy in acute leukemia patients resistant to previous standard treatment according to the series measurement of WT1 expression. Materials & Methods. The series measurement of WT1 expression formed the basis of the efficacy estimation of induction chemotherapy in 31 patients (15 men and 16 women aged from 3 months to 68 years; the median age was 28 years) with prognostically unfavourable variants of acute myeloid (AML) and lymphoblastic leukemia (ALL) (23 AML and 8 ALL patients). The WT1 gene expression was measured at baseline and 2-3 weeks after the treatment by the quantitative real-time PCR. The threshold level for detection was 250 copies of WT1/10<sup>4</sup> copies of ABL. The cytogenetic profile of leukemia cells was assessed by standard cytogenetics and FISH. Results. The baseline expression level of WT1 varied from 305 to 58,569 copies/10<sup>4</sup> copies of ABL. The expected reduction of WT1 expression after the first induction chemotherapy treatment was reported in 22/23 (96 %) AML patients and in 6/8 (75 %) ALL patients. According to our results WT1 expression reached the threshold in 13/31 (42 %) patients, including 9 AML patients and 4 ALL patients. After 11/31 (35 %) patients received the second course of treatment, WT1 expression level became normal in 8 cases (5 ALL and 3 AML patients). Despite high dose chemotherapy, HSCT and such agents as blinatumomab and gemtuzumab, an unfavourable outcome was observed in 18/31 (58 %) patients including 6 patients with complex karyotype (CK+) and 2 patients with monosomal karyotype (MK+). Once the MK+ and CK+ combination was observed, in another case the MK+ was combined with the prognostically unfavourable inv(3)(q21q26) inversion. Conclusion. Our results show that the molecular monitoring should be included as part of treatment of the prognostically unfavourable acute leukemia. The WT1 gene was shown to be the most appropriate marker. WT1 expression was shown to correlate with the common fusion genes allowing to estimate the blast cell count at the molecular level.
Цель. Оценить в соответствии со строгими критериями частоту возникновения, предтрансплантационные факторы риска и исходы тяжелой гипофункции трансплантата (тГФТ) после аллогенной трансплантации гемопоэтических стволовых клеток (аллоТГСК) у взрослых. Материалы и методы. В исследование включено 710 взрослых пациентов (медиана возраста 31 год, диапазон 18-70 лет; 55 % мужчин, 45 % женщин) с различными гематологическими заболеваниями и документированным приживлением трансплантата после аллоТГСК от совместимого сиблинга (20 %), неродственного (67 %) и гаплоидентичного (13 %) доноров в период с 2008 по 2016 г. Миелоаблативное кондиционирование и режимы со сниженной интенсивностью использовались у 30 и 70 % больных соответственно. Критерии тГФТ: цитопения в 2 линиях и более (тромбоциты < 20 × 10 9 /л, абсолютное число нейтрофилов < 0,5 × 10 9 /л, гемоглобин < 70 г/л в любой момент времени после документированного приживления), полный или стабильный смешанный донорский химеризм > 90 % и отсутствие признаков рецидива, отторжения и тяжелой острой реакции «трансплантат против хозяина». Анализировались следующие факторы: возраст, пол, диагноз, наличие/отсутствие ремиссии при острых лейкозах, уровень ферритина крови, тип донора, HLA-совместимость, совместимость по группе крови и полу, источник трансплантата, число трансплантированных клеток CD34+, режим кондиционирования. Многофакторный анализ включал параметры со значением p < 0,05 в однофакторном анализе. Результаты. тГФТ после аллоТГСК диагностирована у 103 пациентов с 2-летней кумулятивной частотой 15 % (95%-й доверительный интервал [95% ДИ] 12-18 %).
Aim. The aim was to evaluate the results of the allogeneic hematopoietic stem cells transplantation (allo-HSCT) in children and adults with the most prognostically unfavorable acute lymphoblastic leukemia (ALL) with t(4; 11)(q21; q23)/KMT2A-AFF1 translocation. Methods. We examined 21 patients (12 females, 9 males) aged from 3 months to 48 years (median 18.9 years). The analysis of prognostic factors of overall (OS) and eventfree survival (EFS) after allo-HSCT in patients of different age groups with various clinical, transplantation and cytogenetic characteristics was performed. Allo-HSCT from HLA-compatible related and unrelated donors, as well as haploidentical allo-HSCT were performed in 4, 9 and 8 patients of age groups < 1 year, 1-18 years, and >18 years, respectively. In 10 (48 %) patients, allo-HSCT was performed in the first remission, in 2 (10 %) patients in the second remission, and in 9 (43 %) patients during the disease relapse. Results. In 8 (38 %) patients, the only chromosomal disorder was the translocation t(4; 11)(q21; q23). Additional changes in chromosomes were found in 11 (52 %) patients. In 8 (38 %) of them, 3 or more chromosomal abnormalities in the karyotype were found. According to the results of a univariant analysis, the OS and EFS were significantly different in patients with allo-HSCT performed in the first remission and at other stages of ALL (in the second remission and in relapse: p < 0.001 in both cases), as well as in patients with or without 3 or more cytogenetic disorders in the karyotype (p = 0.04 in both cases). The multivariant analysis showed that the only independent prognostic factor affecting the OS and EFS in ALL patients with t(4; 11) was the allo-HSCT, including the haploidentical procedure, during the first complete hematological and molecular remission (p = 0.002 and p = 0.0004, respectively). Conclusion. ALL with t(4; 11)/KMT2A-AFF1 was as an absolute indication for allo-HSCT in first remission, including children of < 1 year age group. Satisfactory results can be obtained with the use of haploidentical transplantation from the parents. This approach eliminates the search in the registers completely HLA-compatible donor and facilitates the treatment procedure.
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