Prognostic Value of Genetic Mutations in Patients with Acute Myeloid Leukemias: Results of a Cooperative Study of Hematology Clinics of Saint Petersburg (Russia) and Charite Clinic (Germany)

EV Motyko1, OV Blau2, LB Polushkina1, LS Martynenko1, MP Bakai1, NYu Tsybakova1, YuS Ruzhenkova1, EV Kleina1, NB Pavlenko1, AM Radzhabova1, EV Karyagina3, OS Uspenskaya4, SV Voloshin1, AV Chechetkin1, IS Martynkevich1

1 Russian Research Institute of Hematology and Transfusiology, 16 2-ya Sovetskaya str., Saint Petersburg, Russian Federation, 191024

2 Charite Clinic, Berlin Medical University, 30 Hindenburgdamm, Berlin, Germany, 12200

3 Municipal Hospital No. 15, 4 Avangardnaya str., Saint Petersburg, Russian Federation, 198205

4 Leningrad Regional Clinical Hospital, 45–49 Lunacharskogo pr-t, Saint Petersburg, Russian Federation, 194291

For correspondence: Ekaterina Vadimovna Motyko, PhD in Biology, 16 2-ya Sovetskaya str., Saint Petersburg, Russian Federation, 191024; Tel.: +7(812)925-05-62; e-mail: genetics.spb@mail.ru

For citation: Motyko EV, Blau OV, Polushkina LB, et al. Prognostic Value of Genetic Mutations in Patients with Acute Myeloid Leukemias: Results of a Cooperative Study of Hematology Clinics of Saint Petersburg (Russia) and Charite Clinic (Germany). Clinical oncohematology. 2019;12(2):211–9.

DOI: 10.21320/2500-2139-2019-12-2-211-219


ABSTRACT

Aim. To analyze the effect on prognosis of mutations that are typical of acute myeloid leukemia (AML) patients.

Materials & Methods. The study included 620 AML patients surveyed at Hematology Clinics of Saint Petersburg (Russia) and Charite Clinic (Berlin, Germany). G-banding of chromosomes was employed for cytogenetic testing. Aberration screening in DNMT3A, IDH1/2 genes was based on real-time polymerase chain reaction (PCR) with subsequent analysis of melting and sequencing profiles. Mutations in FLT3, NPM1 genes were revealed by PCR.

Results. Mutations were identified in 343 (55.3 %) out of 620 patients. Significantly more often mutations were discovered in patients with normal karyotype (NK) (= 0.001). FLT3-ITD mutation was associated with reduced medians of overall survival (OS) and disease-free (DFS) survival: 11.3 vs. 15.8 months with FLT3-ITD– (= 0.005) and 10.0 vs. 13.3 months with FLT3-ITD+ (= 0.009), respectively. The relation of FLT3-ITD allele burden to OS duration was also assessed. In the ITDlow/ITD– group the OS median was considerably longer than in the ITDhigh group (= 0.028). In the group of patients with 1 mutation in NPM1 gene OS and DFS were much better in comparison with other patients (medians of 27.4 and 13.9 months, respectively, = 0.040; 19.3 and 12.0 months, = 0.049). Negative impact of mutations in DNMT3A gene was noticed while assessing OS median: 12 (DNMT3A+) and 15 months (DNMT3A–), respectively (= 0.112). Mutations in IDH1 gene correlated with a better OS than in the group without mutations (= 0.092). The rs11554137 polymorphism in IDH1 gene was associated with worse OS in the group of patients with NK (= 0.186). In 144 patients various mutation combinations (from 2 to 5) were identified. It was demonstrated that mutations in FLT3 (FLT3-ITD), NPM1, DNMT3A, and IDH2 were identified significantly more often in combinations with other mutations (= 0.001): NPM1+/FLT3-ITD+ (20.8 %), NPM1+/FLT3-ITD+/DNMT3A+ (8.3 %), and FLT3-ITD+/DNMT3A+ (8.3 %). Patients with 1 mutation had a noticeably longer OS median compared with patients with 2 mutations (18.1 and 12.2 months; = 0.003). In patients with NPM1+ according to their OS the most unfavorable additional mutation was FLT3-ITD (median 27.4 vs. 9.2 months; = 0.019) and the combination of NPM1+/FLT3-ITD+/DNMT3A+ (median 27.4 vs. 14.6 months; = 0.141). OS of patients with DNMT3A+ showed a downward trend if FLT3-ITD additional mutation was identified (17.3 vs. 7.1 months; = 0.074).

Conclusion. Mutations in FLT3, DNMT3A, IDH1/2, NPM1 genes frequently occur in AML intermediate-risk patients, i.e. they determine the intermediate prognosis group in AML. The studied mutations considerably impact prognosis. It is important to take into consideration mutation type, its allele burden, and the presence of additional mutations. A patient with 2 mutations has a considerably worse OS compared with a patient with 1 mutation. The studied group of patients with the combination of NPM1+/FLT3-ITD+, NPM1+/FLT3-ITD+/DNMT3A+, DNMT3A+/FLT3-ITD+ mutations has the poorest prognosis. Comprehensive analysis of genetic damages in AML patients allows to most accurately predict the course and prognosis of the disease and to plan targeted therapy.

Keywords: acute myeloid leukemias, mutations in FLT3, NPM1, DNMT3A, IDH1/2 genes, karyotype, prognosis.

Received: July 13, 2018

Accepted: January 16, 2019

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Genetic Mutations in Acute Myeloid Leukemia

OV Blau

Charite Clinic, Berlin Medical University, 30 Hindenburgdamm, Berlin, Germany, 12200

For correspondence: Ol’ga Vladimirovna Blau, DSci, Department of Hematology, Oncology and Tumorimmunology, Charite University School of Medicine, Hindenburgdamm 30, 12200, Berlin, Germany; e-mail: olga.blau@charite.de.

For citation: Blau OV. Genetic Mutations in Acute Myeloid Leukemia. Clinical oncohematology. 2016;9(3):245-56 (In Russ).

DOI: 10.21320/2500-2139-2016-9-3-245-256


ABSTRACT

Acute myeloid leukemia (AML) is a clonal malignancy characterized by ineffective hematopoiesis. Most AML patients present different cytogenetic and molecular defects associated with certain biologic and clinical features of the disease. Approximately 50–60 % of de novo AML and 80–95 % of secondary AML patients demonstrate chromosomal aberrations. Structural chromosomal aberrations are the most common cytogenetic abnormalities in about of 40 % of de novo AML patients. A relatively large group of intermediate risk patients with cytogenetically normal (CN) AML demonstrates a variety of outcomes. Current AML prognostic classifications include only some mutations with known prognostic value, namely NPM1, FLT3 and C/EBPa. Patients with NPM1 mutation, but without FLT3-ITD or C/EBPa mutations have a favorable prognosis, whereas patients with FLT3-ITD mutation have a poor prognosis. A new class of mutations affecting genes responsible for epigenetic mechanisms of genome regulations, namely for DNA methylation and histone modification, was found recently. Among them, mutations in genes DNMT3A, IDH1/2, TET2 and some others are the most well-studied mutations to date. A number of studies demonstrated an unfavorable prognostic effect of the DNMT3A mutation in AML. The prognostic significance of the IDH1/2 gene is still unclear. The prognosis is affected by a number of biological factors, including those associated with cytogenetic aberrations and other mutations, especially FLT3 and NPM1. The number of studies of genetic mutations in AML keeps growing. The data on genetic aberrations in AML obtained to date confirm their role in the onset and development of the disease.


Keywords: acute myeloid leukemia, AML, karyotype, cytogenetic aberrations, gene mutation, prognosis.

Received: January 23, 2016

Accepted: April 4, 2016

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Clinico-hematological and molecular genetic variability of acute myeloid leukemia with CD7 expression on blasts cells

S.V. Gritsayev1, Z.V. Chubukina1, I.S. Martynkevich1, I.I. Kostroma1, T.V. Glazanova1, Ye.V. Petrova1, L.S. Martynenko1, S.A. Tiranova1, N.A. Potikhonova1, I.S. Zyuzgin2, L.N. Bubnova1, and K.M. Abdulkadyrov1

1 Russian Research Institute of Hematology and Transfusiology, FMBA, Saint Petersburg, Russian Federation

2 Leningrad Regional Hospital, Saint Petersburg, Russian Federation


ABSTRACT

The objective of the study was to evaluate the heterogeneity of patients with acute myeloid leukemia with CD7 aberrant expression. The retrospective analysis of 31 AML patients’ laboratory and clinical data was performed. Marked morphological, cytogenetic, and molecular heterogeneity of AML with CD7 coexpression was established. Also, it was found that these patients could be stratified into groups by overall survival. Four patients with t(8;21) or t(15;17) translocations or inv(16) inversion were followed-up for 53, 33, 11, and 10 months, respectively. The median of OS was not reached among the patients with t(8;21), t(15;15), and inv(16). The median OS among 10 patients with normal karyotype with no FLT3-ITD mutation was 17 months. The median OS among 17 patients with other genetic abnormalities including 7 patients with normal karyotype and FLT3-ITD mutation was 8 months; p = 0.033. We conclude that CD7 expression on AML blast cells is not an independent prognostic factor.


Keywords: acute myeloid leukemia, myeloblasts, CD7 coexpression, karyotype, FLT3-ITD mutation.

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