Prognostic Value and Correlation Between WT1 Overexpression and NPM1 Mutation in Patients with Acute Myeloblastic Leukemia

LL Girshova, IG Budaeva, EG Ovsyannikova, SO Kuzin, DV Motorin, RSh Badaev, DB Zammoeva, VV Ivanov, KV Bogdanov, OS Pisotskaya, YuV Mirolyubova, TS Nikulina, YuA Alekseeva, AYu Zaritskii

VA Almazov National Medical Research Center, 2 Akkuratova str., Saint Petersburg, Russian Federation, 197341

For correspondence: Irina Garmaevna Budaeva, 2 Akkuratova str., Saint Petersburg, Russian Federation, 197341; Tel.: +7(931)351-07-06; e-mail: irina2005179@mail.ru

For citation: Girshova LL, Budaeva IG, Ovsyannikova EG, et al. Prognostic Value and Correlation Between WT1 Overexpression and NPM1 Mutation in Patients with Acute Myeloblastic Leukemia. Clinical oncohematology. 2017;10(4):485–93 (In Russ).

DOI: 10.21320/2500-2139-2017-10-4-485-493


ABSTRACT

Background. Acute myeloblastic leukemia (AML) with NPM1 mutation amounts to 30 % of all AML and is characterized by good prognosis with the exception of cases with FLT3-ITD mutation. Despite the good prognosis, the likelihood of relapses in patients with NPM1 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 (NPM1 mutation) and non-specific marker (WT1 overexpression) of MRD, as well as to identify the correlation between the levels of NPM1 and WT1 at different stages of therapy and in the follow-up period.

Materials & Methods. The research included 14 patients with AML. All patients had the NPM1 mutation and WT1 overexpression: 50 % of patients had additional molecular markers (BAALC overexpression, FLT3-ITD, DNMT3A, and MLL mutations). Real-time PCR was used for long-term monitoring of WT1 expression levels and NPM1 mutation.

Results. The median decrease of NPM1 levels after the induction therapy was 3 log. All patients had relapses, NPM1 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 WT1 expression level < 2 log and > 2 log on day 28 of treatment. At the same time, the decrease of WT1 expression by > 2 log was associated with significant differences in early relapses, which correlated with the decrease of NPM1 levels (> and < than 3 log) is revealed. RFS rates were higher in patients with WT1 expression level of < 100 per 104 copies ABL on day 28 and WT1 of < 250 per 104 copies ABL on day 14 of treatment. WT1 expression was significantly lower on days 14 and 28 in patients with NPM1 decrease of > 3 log on day 28. The decrease in WT1 expression of < 100 per 104 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 104 copies ABL), and for the first time, the importance of the early assessment WT1 expression reduction on day 14 of induction therapy.

Keywords: acute myeloblastic leukemia, AML, NPM1, WT1, molecular monitoring.

Received: February 22, 2017

Accepted: May 26, 2017

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