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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Hypomethylating Agents in Oncohematology

AD Shirin, OYu Baranova

NN Blokhin Russian Cancer Research Center, 24 Kashirskoye sh., Moscow, Russian Federation, 115478

For correspondence: Anton Dmitrievich Shirin, PhD, 24 Kashirskoye sh., Moscow, Russian Federation, 115478; Tel.: +7(499)324-28-24; e-mail: shirin-anton@mail.ru

For citation: Shirin AD, Baranova OYu. Hypomethylating Agents in Oncohematology. Clinical oncohematology. 2016;9(4):369–82 (In Russ).

DOI: 10.21320/2500-2139-2016-9-4-369-382


ABSTRACT

The review describes epigenetic processes, including methylation of nuclear and mitochondrial DNA, as well as RNA. It dwells on mechanisms of demethylation and corresponding medicinal products. It presents detailed information on results of numerous large randomized studies intended to evaluate hypomethylating agents (azanucleosides). Special attention is paid to outcomes of azanucleoside therapy in patients with acute myeloid leukemias. The article describes several prognostic systems and treatment algorithms for myelodysplastic syndromes. Two azanucleosides have been approved in Russia to date: azacitidine (for SQ administration) and decitabine (for IV administration). International authors analyze the experience in oral and subcutaneous administration of decitabine. However, the problem of off-label use of hypomethylating agents is still open. The review gives a brief description of ongoing clinical trials with azanucleosides.


Keywords: epigenetics, acute myeloid leukemias, myelodysplastic syndromes, azacitidine, decitabine, hypomethylating agents, azanucleosides.

Received: May 10, 2016

Accepted: May 20, 2016

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Allogeneic Hematopoietic Stem Cell Transplantation in Acute Myeloid Leukemias: Prognostic Significance of Complex Karyotype Including del(5q), –7, del(7q) Abnormalities

TL Gindina, NN Mamaev, SN Bondarenko, ES Nikolaeva, IA Petrova, OA Slesarchuk, AS Borovkova, SV Razumova, AL Alyanskii, LS Zubarovskaya, BV Afanas’ev

R.M. Gorbacheva Scientific Research Institute of Pediatric Hematology and Transplantation; Academician I.P. Pavlov First St. Petersburg State Medical University, 6/8 L’va Tolstogo str., Saint Petersburg, Russian Federation, 197022

For correspondence: Tat’yana Leonidovna Gindina, PhD, 6/8 L’va Tolstogo str., Saint Petersburg, Russian Federation, 197022; Tel.: +7(812)233-12-43; e-mail: cytogenetics.bmt.lab@gmail.com

For citation: Gindina TL, Mamaev NN, Bondarenko SN, et al. Allogeneic Hematopoietic Stem Cell Transplantation in Acute Myeloid Leukemias: Prognostic Significance of Complex Karyotype Including del(5q), –7, del(7q) Abnormalities. Clinical oncohematology. 2016;9(3):271-78(In Russ).

DOI: 10.21320/2500-2139-2016-9-3-271-278


ABSTRACT

Aim. To evaluate the prognostic significance of the complex karyotype including del(5q), –7, del(7q) abnormalities in acute myeloid leukemia (AML) after allogeneic hematopoietic stem cell transplantation (allo-HSCT).

Materials & Methods. Forty-four AML patients with chromosome 5 and/or 7 abnormalities (22 women and 22 men, aged from 1.2 to 67 years, median 31.2 years) were examined. Analysis of overall (OS) and event-free survival (EFS) predictors after allo-HSCT in patients with different clinical, transplant and cytogenetic characteristics was performed.

Results. Prior to allo-HSCT, the complex karyotype (with three or more chromosomal abnormalities) was observed in 19 (43 %) patients, the monosomal karyotype was in 8 (18 %) patients. Univariate analysis demonstrated that OS and EFS differed in patients from different age groups (³ 18 vs. < 18 years; = 0.01 and = 0.05, respectively), with different disease status at transplantation (1 remission vs. other clinical status; = 0.1 and = 0.008, respectively), with and without complex karyotype (СK– vs. CK+; = 0.05 and = 0.002, respectively), with and without monosomal karyotype (МK– vs. MK+; = 0.009, only for EFS), and with different stem cells source (bone marrow vs. other source; = 0.03 only for OS). Multivariate analysis confirmed that age of 18 years and more (= 0.02 and = 0.01, respectively), active disease at allo-HSCT (= 0.04 and = 0.005, respectively), complex karyotype (= 0.04 и = 0.0008, respectively) and stem cell source other than bone marrow (= 0.02 only for OS) were independent predictors of OS and EFS deterioration.

Conclusion. The study demonstrates that chromosome 5 and/or 7 abnormalities as a part of the complex karyotype is high-risk factor in AML patients undergoing allo-HSCT (unlike the monosomal karyotype), that requires the special therapeutic approach.


Keywords: acute myeloid leukemias, complex karyotype, chromosome 5 and 7 abnormalities, allogeneic hematopoietic stem cell transplantation, prognosis.

Received: March 5, 2016

Accepted: April 5, 2016

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REFERENCES

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Diagnostic Value of C-Reactive Protein as Marker of Infections in Patients with De Novo Acute Myeloid Leukemias

L.N. Tarasova1, S.G. Vladimirova1, V.V. Cherepanova2

1 Kirov Scientific Research Institute for Hematology and Blood Transfusion under the Federal Medico-Biological Agency of Russia, 72 Krasnoarmeiskaya str., Kirov, Russian Federation, 610027

2 Municipal Hospital No. 33, 54 pr-t Lenina, Nizhny Novgorod, Russian Federation, 603122

For correspondence: Lyudmila Nikolaevna Tarasova, DSci, Professor, 72 Krasnoarmeiskaya str., Kirov, Russian Federation, 610027; Tel.: +7(8332)67-57-00; e-mail: vlsg@mail.ru

For citation: Tarasova LN, Vladimirova SG, Cherepanova VV. Diagnostic Value of C-Reactive Protein as Marker of Infections in Patients with De Novo Acute Myeloid Leukemias. Clinical oncohematology. 2015;8(4):442–446 (In Russ).

DOI: 10.21320/2500-2139-2015-8-4-442-446


ABSTRACT

Aim. To determine diagnostically relevant C-protein levels (CRP) as an early infection marker in patients with de novo acute myeloid leukemias (AML), to evaluate the dependence of CRP concentrations on the WBC count and leukemic blast cells in the peripheral blood.

Methods. CRP was tested in 39 patients with de novo AML (17 males and 22 females) at the age of 20 to 76 years (median age is 49). AML types according to the FAB grading were as follows: М0 — 2, М1 — 4, М2 — 23, М4 — 8, and М5 — 2 patients.

Results. CRP concentrations in patients without symptoms of an infection (n = 16) were within the range from 0 to 43 mg/l (median 5.5 mg/l). The Spearman’s rank correlation coefficients between the CRP level and WBC and blast cell counts were 0.664 (= 0.006) and 0.473 (= 0.062), respectively. The obtained data confirm activation of CRP synthesis in case of leukemia. In patients with an infection and/or fever (n = 23), CRP levels were significantly higher than those in patients without an infection: 8–383 mg/l (median 81 mg/l). No correlation between the CRP level and WBC and blast cell counts was found. Therefore, the CRP synthesis during the onset of AML is significantly increased as a response to the infection. In groups of patients with and without infections, 95% CI were equal to 0–40 mg/l and 12–315 mg/l, respectively. Since they overlap within the range from 12 to 40 mg/l, they may be considered a «grey zone». The CRP concentrations within this range suggest infection. CRP levels lower than 12 mg/l or higher than 40 mg/l with a high degree of probability confirm either absence or presence of infectious complications, respectively.

Conclusion. Therefore, CRP is an accessible and informative marker of infection in patients with AML during the onset of the disease. Monitoring of its levels permits to start a timely antimicrobial therapy; at that, the efficacy of the therapy can be assessed based on the dynamics of this parameter.


Keywords: acute myeloid leukemias, infectious complications, acute-phase proteins, C-reactive protein, blast cells, white blood cells.

Received: April 20, 2015

Accepted: October 22, 2015

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Molecular Monitoring of WT1 Gene Expression Degree in Acute Myeloid Leukemias after Allogeneic Hematopoietic Stem Cell Transplantation

N.N. Mamaev, A.V. Gorbunova, I.M. Barkhatov, Ya.V. Gudozhnikova, T.L. Gindina, V.A. Katerina, E.V. Volchkov, A.L. Alyanskii, E.V. Babenko, O.A. Slesarchuk, N.V. Stancheva, S.N. Bondarenko, B.V. Afanas’ev

R.M. Gorbacheva Scientific Research Institute of Pediatric Hematology and Transplantation; Academician I.P. Pavlov First St. Petersburg State Medical University, 6/8 L’va Tolstogo str., Saint Petersburg, Russian Federation, 197022

For correspondence: Nikolai Nikolaevich Mamaev, DSci, Professor, 6/8 L’va Tolstogo str., Saint Petersburg, Russian Federation, 197022; Tel.: +7(812)233-12-43; e-mail: nikmamaev524@gmail.com

For citation: Mamaev NN, Gorbunova AV, Barkhatov IM, et al. Molecular Monitoring of WT1 Gene Expression Level in Acute Myeloid Leukemias after Allogeneic Hematopoietic Stem Cell Transplantation. Clinical oncohematology. 2015;8(3):309–20 (In Russ).

ABSTRACT

Objective. To evaluate the possibility of serial analysis of WT1 gene expression level for prediction and diagnosis of post-transplant acute myeloid leukemia (AML) relapses.

Methods. Serial analyses of WT1 gene expression were performed using quantitative real-time PCR during the post-transplant period of 34 patients with AML. All patients underwent allogeneic hematopoietic stem cell transplantation: unrelated (= 22), related (= 12), including haploidentical (= 4). 5 of 34 patients had AML transformed from the myelodysplastic syndromes (MDS). In addition, the level of donor chimerism and the bone marrow/peripheral blood blast cells counts were evaluated. AML1/ETO (= 4) or EVI1 (= 4) gene expression degrees were measured in 8 patients in order to compare those with the WT1 gene expression.

Results. Based on obtained data on the WT1 gene expression, two equal subgroups of patients were formed. The first one consisted of patients with stable normal expression of the investigated molecular indicator during the post-transplant period, whereas the second group consisted of patients with impaired expression. The initial level of WT1 gene expression almost did not depend on both cytological and cytogenetic AML subtypes. During the post-transplant period, the WT1 gene expression degree correlated with that of AML1/ETO or EVI1. Increased WT1 gene expression take the lead over the decreased donor chimerism and blast cell count increase in bone marrow and blood typical for post-transplant relapses of AML.

Conclusion. The higher level of WT1 gene expression may serve not only as a marker for timely diagnosis of post-transplant relapses in AML patients, but also as a monitoring parameter for testing their treatment quality.


Keywords: acute myeloid leukemias, hematopoietic stem cell transplantation, WT1 gene expression monitoring, AML1/ETO and EVI1, diagnosis of post-transplant relapses, molecular monitoring of treatment.

Received: March 19, 2015

Accepted: June 1, 2015

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