This article presents data demonstrating frequent BAALC hyperexpression, also in combination with WT1 hyperexpression, in children and adults with acute myeloid leukemia (AML). Treatment included allogeneic hematopoietic stem cell transplantation. The analysis of serial measurements of BAALC and WT1 expression level in 50 AML patients (37 adults and 13 children) showed that the increased BAALC expression is more common in patients with M1, M2, M4, and M5 FAB variants of AML with equal frequency in adults and children. Furthermore, the increased BAALC expression was rather common in combination with the increased WT1 expression, which predicted poorer prognosis. Since BAALC expression level in AML patients is closely related to AMLproducing progenitor cells of leukemia hemato poiesis, a serial study of this phenomenon off ers insights into the role of these cells in emergence and development of post-transplantation relapses, which is of both theoretical and practical importance.
В статье обсуждаются полученные в последние годы данные о феномене гиперэкспрессии гена WT1 у пациентов с острыми лейкозами, миелодиспластическими синдромами, хроническим миелолейкозом, неходжкинскими лимфомами и множественной миеломой. Показана перспективность мониторинга уровня экспрессии гена WT1 в посттрансплантационный период и после индукционной химиотерапии. Такой подход может использоваться в диагностике минимальной остаточной болезни и раннем выявлении рецидивов лейкозов, а также для их своевременного и контролируемого лечения. Из других исследовательских направлений представляется перспективным тестирование аутотрансплантата на наличие или отсутствие в нем опухолевых элементов, а также оценка эффективности индукционной терапии у больных из группы повышенного прогностического риска. Ключевые слова: феномен гиперэкспрессии гена WT1, трансплантация гемопоэтических стволовых клеток, химиотерапия, молекулярный мониторинг лечения.
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.
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.
Aim. To demonstrate diagnostic and prognostic significance of series measurement of WT1 expression in patients with acute myeloid leukemia (AML) after allogenic hematopoietic stem cell transplantation (allo-HSCT). Materials & Methods. The clinical trial included 88 AML patients (38 females (43 %) and 50 males (57 %) aged 2-68, median 30 years). All the patients received allo-HSCT. Bone marrow was aspirated before (D0) and after HSCT (D+30, D+60, and D+100). Results. The univariate analysis showed statistically significant differences in 2-year overall survival with respect to the following factors: with and without remission at the moment of HSCT (p < 0.001), with and without chronic graft vs. host disease (cGVHD) (p = 0.002), primary or secondary (MDS) AML (p = 0.028), WT1 gene expression < and > 250 copies before HSCT (p < 0.001) and at time points D+60 (p = 0.012), and D+100 (p < 0.001). Multivariate analysis revealed similar statistical significance of differences among patients transplanted in remission (p = 0.041) and with cGVHD (p = 0.03). In univariate analysis statistically significant differences in 2-year event-free survival (EFS) were found: a) in patients with allo-HSCT, either in remission or not (p < 0.001); b) using HSC, but not bone marrow, as transplant source (p < 0.026); c) with normal or high WT1 expression at the stage of HSCT (p < 0.001) and at time point D+100 (p < 0.001); d) using HSC from related or unrelated donor (p = 0.006); e) in patients with cGVHD (p = 0.05). In multivariate analysis independent positive effect on EFS was observed only in patients with normal WT1 expression at D+100 (p = 0.011) and with cGVHD (p = 0.038). Cumulative incidence of posttransplant relapse (PTR) in AML patients with normal or high WT1 expression at the stage of HSCT within the 2-year follow-up was significantly different (28.2 vs. 58.9 %; p = 0.002), also in measurements of this parameter at D+60 and D+100 (p = 0.015 and p < 0.001, respectively). In 1/4 of patients cytological relapses (cPTR) appeared considerably later than molecular relapses (mPTR), i.e. 13-489 days later (median 35 days), which is accounted for by early preventive therapy aimed at cPTR prophylaxis against the background of already recorded mPTR. According to our data, GVHD plays a crucial role in cPTR management. Conclusion. Phenomenon of WT1 expression normalization after allo-HSCT in AML patients proves to have a high diagnostic and prognostic significance. Introduction of this approach into clinical practice seems highly advisable for national oncohematological centers.
Aim. To evaluate the effectiveness of preventive and prophylactic post-transplantation therapy using azacitidine (5-AZA) in patients at high risk of post-transplantation relapse. Methods. 136 patients were included in the study performed by the pairwise comparison: 68 of them received 5-AZA after allo-HSCT and 68 patients were included in the historical control group. 5-AZA was prescribed for prophylactic or preventive purposes. The results were assessed according to the OS, RR, EFS, DUM, and relapse-free and GVHR-free survival. Results. 1-year OS was 76 % in the 5-AZA group (95% CI 60-84 %) and 44 % in the reference group (95% CI 33-55 %) (р = 0.001); 2-year OS was 63 % (95% CI 39-67 %) and 37 % (95% CI 26-48 %) (р = 0.007), respectively. The relapse rate (RR) in the 5-AZA group was 34 % (95% CI 22-46 %) during 1 year and 51 % (95% CI 38-64 %) in the reference group (р = 0.02). 1- and 2-year disease unrelated mortality (DUM) was similar: 5 % in the 5-AZA group (95% CI 0.1-14.0 %) and 25 % (95% CI 13-37 %) in the reference group (р = 0.005). 1-year EFS was 76 % in the 5-AZA group (95% CI 61-85 %) and 44 % in the reference group (95% CI 33-55 %) (р = 0.001); 2-year EFS was 63 % (95% CI 39-67 %) and 37 % (95% CI 2648 %) (р = 0.01), respectively. 1-year relapse-free and GVHR-free survival was 55 % in the 5-AZA group (95% CI 41-69 %) and 28 % in the reference group (95% CI 17-39 %) (р = 0.001); 2-year relapse-free and GVHR-free survival was 47 % (95% CI 32-62 %) and 27 % (95% CI 17-37 %) (р = 0.002), respectively. Conclusion. The use of 5-AZA for prophylactic and preventive purposes after allo-HSCT does not increase the risk of GVHR and DUM, does not suppress the GVL effect and can be used in combination with the donor lymphocyte infusion (DLI). The therapy with 5-AZA is safe during the early period after allo-HSCT. The drug does not suppress the GVL effect and can be used in high risk patients to prevent early post-transplantation relapse. The use of 5-AZA in combination with DLI does not increase the incidence of severe GVHR.
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