Background. Acute myeloblastic leukemia (AML) with NPM7 mutation amounts to 30 % of all AML and is characterized by good prognosis with the exception of cases with FLT3-/TD mutation. Despite the good prognosis, the likelihood of relapses in patients with NPM7 mutation may significantly differ. Thus, the estimation of the minimal residual disease (MRD) after chemotherapy and during follow-up is becoming increasingly important. This approach will make it possible to predict the sensitivity of a tumoral clone to chemotherapy. Aim. To evaluate the prognostic value of highly specific marker (NPM7 mutation) and non-specific marker (WT1 overexpression) of MRD, as well as to identify the correlation between the levels of NPM7 and WT7 at different stages of therapy and in the follow-up period. Materials & Methods. The research included 14 patients with AML. All patients had the NPM7 mutation and WT7 overexpression: 50 % of patients had additional molecular markers (BAALC overexpression, FLT3-/TD, DNMT3A, and MLL mutations). Real-time PCR was used for long-term monitoring of WT7 expression levels and NPM7 mutation. Results. The median decrease of NPM7 levels after the induction therapy was 3 log. All patients had relapses, NPM7 mutation, and lower rates of OS/RFS, which significantly correlated with prognostically negative molecular markers. There were no statistically significant differences in RFS in groups with the decrease of WT7 expression level < 2 log and ≥ 2 log on day 28 of treatment. At the same time, the decrease of WT7 expression by > 2 log was associated with significant differences in early relapses, which correlated with the decrease of NPM7 levels (> and < than 3 log) is revealed. RFS rates were higher in patients with WT7 expression level of < 100 per 10<sup>4</sup> copies ABL on day 28 and WT7 of < 250 per 10<sup>4</sup> copies ABL on day 14 of treatment. WT7 expression was significantly lower on days 14 and 28 in patients with NPM7 decrease of > 3 log on day 28. The decrease in WT7 expression of < 100 per 10<sup>4</sup> copies ABL on day 28 was more common in patients with isolated NPM1 mutation, compared to patients with additional negative molecular markers. Conclusion. The decrease in NPM1 levels after the induction therapy may serve as reliable prognostic marker of RFS and OS rates. New correlation between the degree of NPM1 reduction and the presence of additional molecular markers was established. Highly specific (NPM1 mutation) was shown to be more specific compared to non-specific markers ( WT1 overexpression). The research showed the predictive value of a lower limit level of WT1 on day 28 of treatment (100 per 10<sup>4</sup> copies ABL), and for the first time, the importance of the early assessment WT1 expression reduction on day 14 of induction therapy.
Актуальность и цели. Аутологичная трансплантация гемопоэтических стволовых клеток является эффективным методом лечения злокачественных лимфопролиферативных заболеваний, множественной миеломы и чувствительных к химиотерапии солидных опухолей. Предшествующая трансплантации заготовка аутологичных гемопоэтических стволовых клеток (ГСК) может быть неэффективной в 40 % случаев при наличии отягощающих факторов. Одним из способов преодоления сниженной мобилизационной способности является включение обратимого антагониста СXCR4-рецептора ГСК (плериксафора) в схемы мобилизации. Цель-оценить эффективность и безопасность различных режимов мобилизации аутологичных ГСК на основе плериксафора. Методы. У 63 пациентов с солидными и гематологическими опухолями использовались 2 схемы мобилизации: филграстим + плериксафор (n = 47) и пэгфилграстим + плериксафор (n = 16). Филграстим назначался в 1-4-й день по 5 мкг/кг п/к 2 раза в сутки, 4-й день в 24.00-плериксафор 0,24 мг/кг п/к, 5-й день-филграстим 5 мкг/кг п/к, затем в 10.00-сеанс цитафереза. Пэгфилграстим
Aim. To assess the efficacy, safety, and tolerance of gemtuzumab ozogamicin (GO) combined with FLAG/FLAG-Ida chemotherapy or azacitidine in patients with relapsed/refractory acute myeloblastic leukemia (AML) in clinical practice. Materials & Methods. The study included 32 patients (16 men and 16 women). The median age was 44 years (range 23-83 years). Among them there were 15 (46.8 %) patients with refractory and 17 (53.2 %) patients with relapsed AML. GO combined with FLAG/FLAG-Ida was administered to 15 (46.8 %) patients, whereas 17 (53.2 %) patients were treated with GO and azacitidine combination. Therapy safety was assessed according to CTCAE v. 5.0. Results. Overall response rate including complete remission (CR), CR MRD-, CR with incomplete hematologic recovery, and morphologic leukemia-free status was 59.4 % (19/32). Refractoriness was observed in 31.25 % (10/32) of patients. Early mortality was 9.4 % (3/32). Overall response was 64.7 % (11/17) in the azacitidine and 53.3 % (8/15) in the FLAG/FLAG-Ida groups. In 4 (80 %) out of 5 patients with prior to FLAG treatment refractoriness, the response was achieved after GO + azacitidine therapy. In 58.9 % (10/17) of patients who received GO + azacitidine therapy, allogeneic hematopoietic stem cell transplantation (allo-HSCT) could be performed. The incidence of GO infusion complications in the tested groups did not significantly differ (p = 0.72) and was 46.7 % (7/15) (40 % with grade 1/2 and 6.7 % with grade 3) in the GO + FLAG/FLAG-Ida group and 35.3 % (6/17) (29.4 % with grade 1/2 and 5.9 % with grade 4) in the GO + azacitidine group. In the GO + FLAG/FLAG-Ida group 5 (33.3 %) patients experienced serious adverse events (SAE) of sepsis. In the GO + azacitidine group SAEs were reported in 6 (35.3 %) patients: 4 (66.6 %) with sepsis, 1 (16.7 %) with acute cardiovascular failure, and 1 (16.7 %) with acute respiratory failure. The median (range) duration was 23 (10-39) days for neutropenia grade 4, 24 (11-38) days for neutropenia grade 3, 21 (11-41) days for thrombocytopenia grade 4, 26 (16-45) days for thrombocytopenia grade 3, and 25 (22-45) days for thrombocytopenia grade 1/2. Thrombocytopenia duration was longer in patients with GO + FLAG/FLAG-Ida therapy, however, no significant differences were identified. No cases of veno-occlusive liver disease were reported. Median overall survival (OS) for both groups (n = 32) was 31.4 months, median disease-free survival (n = 21) was 13.3 months. In the group of patients with effective treatment, the median OS was not reached. In non-responders, it was 18 months (р = 0.0442). Conclusion. GO combined with FLAG/FLAG-Ida chemotherapy or azacitidine proved effective in relapsed/refractory AML patients. Remission did not appear to be associated with ELN risk, gender, age, CD33 expression, number of prior therapy lines, or number of relapses. GO + azacitidine combination showed efficacy, safety, and good tolerance in patients with prior high-dose chemotherapy refractoriness as well as low ECOG performance status. That allowed for the subsequent allo-HSCT administration to these patients. There was no significant difference between the groups of patients in the incidence of hematologic, non-hematologic toxicity, and time to hematologic recovery. Thrombocytopenia duration was longer in patients with GO + FLAG/FLAG-Ida therapy which is consistent with literature data. GO-based effective treatment in relapsed/refractory AML considerably improves OS: during 36 months of follow-up the median was not reached.
Background. The current approach to treatment of acute myeloblastic leukemia (AML) includes the achievement of maximum tumor reduction and, therefore, eradication of a leukemic clone. The goal of the therapy is to achieve undetectable levels of the target gene, except an isolated molecular rearrangement of RUNX1-RUNX1T1. Aim. To estimate the dynamics of the RUNX1-RUNX1T1 level and relevant clinical manifestations during the monitoring of various stages of the program therapy and after its completion. Methods. The article presents a description of 10 cases of AML with isolated RUNX1-RUNX1T1 expression (n = 4) and the expression in combination with different molecular and cytogenetic abnormalities (n = 6). In addition, a long-term monitoring of the gene expression by quantitative determination of RUNX1-RUNX1T1 using a real-time PCR was presented. Results. The incidence of relapses in a group with a decreased RUNX1-RUNX1T1 expression level of >2 log is 75 % as compared to patients with a less significant reduction of the transcript level (with the relapse incidence equal to 0 %) (p = 0.05). The increase of the RUNX1-RUNX1T1 level against the background of bone marrow remission by more than 1 log coincided with a bone marrow relapse within 5-18 weeks. In addition, long-term persistence of a certain transcript level after the completion of a program therapy without relapse is possible. Conclusion. The study analyzed possible molecular background of different clinical outcomes of long-term persistence of the RUNX1-RUNX1T1 transcript that might lead to an individualized approach to AML patients.
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