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.
Цель. Оценить эффективность режима FLAG/FLAG-Ida, выявить факторы, влияющие на достижение ремиссии, продолжительность безрецидивной (БРВ) и общей выживаемости (ОВ) у пациентов с рецидивами и рефрактерным течением острого миелобластного лейкоза (ОМЛ). Материалы и методы. В исследование включено 54 пациента (28 мужчин, 26 женщин), медиана возраста составила 37 лет (диапазон 18-70 лет). У 27 (50 %) из 54 пациентов имело место рефрактерное течение ОМЛ, у 27 (50 %)-рецидивы. В качестве индукционной терапии использовались режимы FLAG и FLAG-Ida. Трансплантация костного мозга выполнена 37 (68,5 %) пациентам. Молекулярно-генетическое и цитогенетическое исследования проводились до терапии и на 28-й день после ее начала. Уровень экспрессии гена WT1 оценивался на 14-16-й день лечения. Результаты. Полные ремиссии (ПР) достигнуты у 42 (77,8 %) из 54 пациентов. Рефрактерность к терапии наблюдалась у 9 (16,7 %) из 54 пациентов, летальность составила 5,5 % (3/54). Частота достижения ремиссии была выше при рецидивах ОМЛ в сравнении с рефрактерным течением ОМЛ-85,2 (23/27) и 70,4 % (19/27) соответственно. Пациенты с числом бластных клеток в костном мозге (КМ) ≥ 10 % на 14-16-й день терапии имели статистически значимо более низкий уровень достижения ПР (60 %) в сравнении с группой < 10 % бластных клеток в КМ (89,6 %; p = 0,024) и меньшую БРВ (медиана 7,6 vs 17,6 мес. соответственно; p = 0,03). Медиана БРВ у пациентов со снижением экспрессии гена WT1 < 1 log на 14-16-й день составила 5 vs 18 мес. у больных без этого снижения (p = 0,01). Показатели БРВ различались в группах пациентов с числом бластных клеток в КМ < 10 % на 14-16-й день терапии в зависимости от уровня редукции экспрессии гена WT1 (p = 0,04). Пациенты с МОБ
Aim. To identify mutations in IDH1/IDH2, DNMT3A, and ASXL1 genes responsible for genome epigenetic regulation and their co-occurrence with FLT3, NPM1, and RUNX1 mutations in newly diagnosed adult acute myeloid leukemias (AML). Materials & Methods. The study included 56 patients with newly diagnosed AML treated at the VA Almazov National Medical Research Center. Among them there were 34 men and и 22 women aged 18-76 years (median 46 years). Mutation status of IDH1, IDH2, DNMT3A, and ASXL1 genes of epigenetic regulation was assessed by Sanger sequencing method. Molecular genetic analysis of FLT3, NPM1, and RUNX1-RUNX1T1 genes was performed using commercial kits. Results. Mutations in epigenetic regulation genes were detected in 14 (25 %) out of 56 patients. Mutation prevalence was not associated with risk groups (p = 0.072). IDH1/2 mutations were identified in 15.6 % of patients and were significantly oftener observed concurrent with NPM1 mutations (62.5 %; p = 0.01) compared to patients with wild-type IDH1/2. In most patients IDH1/2 mutations were associated with normal karyotype (p = 0.002). The DNMT3A (R882) mutation was identified in 4 (7.1 %) out of 56 patients within the analyzed group. In 6 patients (11.1 %) ASXL1 mutations were detected co-occurring with RUNX1-RUNX1T1 and FLT3-ITD mutations. Conclusion. Mutations in epigenetic regulation genes are often identified in AML patients and can be concurrent with abnormalities in NPM1, FLT3 и RUNX1 genes.
The treatment of refractory acute myeloid leukemia (AML) patients presents considerable challenges. They are often critically ill. The critical conditions of these patients are mainly associated with severe infectious complications resulting in sepsis as well as with the extramedullary lesions with organ dysfunctions. So far, the obtained data demonstrated the successful use of gemtuzumab ozogamicin, the mechanism of which is likely to be based not only on depletion of CD33-positive tumor cells but also on its immunomodulatory eff ect. The present article focuses on the fast-eff ect mechanisms of gemtuzumab ozogamicin and deals with clinical experience of successful use of this drug combined with hypomethylating agents in patients with refractory AML whose condition is critical by the time therapy begins. The use of this drug combination results in fast stabilization of health status, recovery of internal organs, and apyrexia with the decreasing systemic infl ammatory response within the fi rst days of therapy. All this together with signifi cantly lower blast count in blood and in bone marrow can bring critically ill patients to recovery.
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