AML

Acute Myeloid Leukemia Patient-Derived Xenograft Models Generated with the Use of Immunodeficient NSG-SGM3 Mice

AUTOIMMUNE THROMBOCYTOPENIA

EV Baidyuk1, EV Belotserkovskaya1, LL Girshova1,2, VA Golotin1, KA Levchuk2, ML Vasyutina2, YaA Portnaya1, EV Shchelina2, OG Bredneva2, AV Petukhov1,2,3, AYu Zaritskey2, ON Demidov1,3

1 Institute of Cytology, 4 Tikhoretskii pr-t, Saint Petersburg, Russian Federation, 194064

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

3 Sirius University of Science and Technology, 1 Olimpiiskii pr-t, Sochi, Russian Federation, 354340

For correspondence: Ekaterina Viktorovna Baidyuk, PhD in Biology, 4 Tikhoretskii pr-t, Saint Petersburg, Russian Federation, 194064; e-mail: katya_bay@mail.ru; Ekaterina Vasilevna Belotserkovskaya, PhD in Biology, 4 Tikhoretskii pr-t, Saint Petersburg, Russian Federation, 194064; e-mail: belotserkovskaya.ev@gmail.com

For citation: Baidyuk EV, Belotserkovskaya EV, Girshova LL, et al. Acute Myeloid Leukemia Patient-Derived Xenograft Models Generated with the Use of Immunodeficient NSG-SGM3 Mice. Clinical oncohematology. 2021;14(4):414–25. (In Russ).

DOI: 10.21320/2500-2139-2021-14-4-414-425

ABSTRACT

Background. Up to the present the survival rates of acute myeloid leukemia (AML) patients have remained low. A successful OML management presupposes generating personalized models of the disease. The most promising research activity in this field is creation of AML patient-derived xenograft models using the advanced strain of immunodeficient humanized NSG-SGM3 mice.

Aim. To generate AML patient-derived xenograft models using immunodeficient NSG-SGM3 mice.

Materials & Methods. The creation of PDX models was based on bone marrow aspirates taken from 4 patients with newly diagnosed AML who were treated at the VA Almazov National Medical Research Center. Patient-derived tumor cells were transplanted to NSG-SGM3 mice. Test experiment consisted in injecting AML cells OCI-АМL2 and HL60 in NSG-SGM3 mice. The efficacy of tumor engraftment was evaluated in terms of physical condition of animals and laboratory tests (blood count, blood smear, PCR, and flow cytofluorometry).

Results. The engraftment of applied tumor cells derived from 4 AML patients was achieved in half (2 out of 4) of the mice. In 2 mice with successful transplantation leukocytosis was reported. Blast cells were identified in peripheral blood on Day 30 after transplantation. The mice with injected AML cells OCI-АМL2 and HL60 showed a more aggressive course of disease. Among tested approaches to evaluate tumor engraftment in mouse recipients, the PCR method was marked by highest sensitivity.

Conclusion. The use of immunodeficient humanized NSG-SGM3 mice enables successful generation of AML patient-derived xenograft models.

Keywords: xenograft model, immunodeficient humanized mice, AML, NSG-SGM3 mice.

Received: April 27, 2021

Accepted: August 1, 2021

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Статистика Plumx английский

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Antibiotic Treatment of Febrile Neutropenia in Patients with Acute Leukemia

ANTINEOPLASTIC THERAPY COMPLICATIONS , , , , , ,

VA Okhmat, GA Klyasova, EN Parovichnikova, VV Troitskaya, EO Gribanova, VG Savchenko

National Medical Hematology Research Center, 4 Novyi Zykovskii pr-d, Moscow, Russian Federation, 125167

For correspondence: Vladimir Aleksandrovich Okhmat, PhD, 4 Novyi Zykovskii pr-d, Moscow, Russian Federation, 125167; Tel.: +7(495)614-92-72; e-mail: okhmatvladimir@mail.ru

For citation: Okhmat VA, Klyasova GA, Parovichnikova EN, et al. Antibiotic Treatment of Febrile Neutropenia in Patients with Acute Leukemia. Clinical oncohematology. 2018;11(1):100-9.

DOI: 10.21320/2500-2139-2018-11-1-100-109

ABSTRACT

Aim. To estimate the efficacy of antibiotic treatment of febrile neutropenia in patients with acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL).

Materials & Methods. The prospective study (2013 to 2015) included 66 AML and 44 ALL patients receiving 480 chemotherapy cycles within the period of 6 months.

Results. Febrile neutropenia was registered during 242 (50 %) chemotherapy cycles occurring more frequently in AML than in ALL patients (93 % vs. 18 %, p < 0.0001). In AML patients infections were more common during induction and consolidation (98 and 89 %) phases compared to ALL patients who most commonly had infection during induction phase (55 %). Compared to ALL patients, AML patients had lower recovery rates after first-line antibiotic monotherapy (24 % vs. 57 %, p < 0.0001), compared to combination therapy (37 % vs. 18 %, p = 0.01). The use of beta-lactam antibiotics in ALL patients was associated with lower recovery rates during the induction phase compared to consolidation phase (47 % vs. 72 %, p = 0.0004). In cases of granulocytopaenia longer that 14 days the clinical recovery rate with administration of the first-line antibiotics and carbapenems accounted for 23–24 % compared to 47 % with other antimicrobials, more commonly with antifungal (21 %) administration. In patients with fever of unknown origin the monotherapy with first-line antibiotics proved to be successful (45 %). In patients with clinically and microbiologically defined infections the best results were achieved by the combined treatment with the beta-lactam antibiotics and other drugs (43 %).

Conclusion. Antibiotic escalation has proved to be the optimal strategy in treatment of ALL patients and in cases of fever of unknown origin. The efficacy of the beta-lactam antibiotic monotherapy was lower in AML patients during the induction phase as well as in cases of continuous neutropenia (> 14 days) and clinically and microbiologically diagnosed infections. The adding of other antimicrobial administration resulted in the recovery in 37–48 % of cases.

Keywords: acute leukemia, AML, ALL, febrile neutropenia, fever of unknown origin, clinically and microbiologically defined infections, antibiotics.

Received: July 2, 2017

Accepted: October 20, 2017

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

MYELOID TUMORS , ,

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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Cytogenetic and Molecular Genetic Prognostic Factors of Acute Myeloid Leukemia

REVIEWS , , , ,

AV Misyurin

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

For correspondence: Andrei Vital’evich Misyurin, PhD, 24 Kashirskoye sh., Moscow, Russian Federation, 115478; e-mail: and@genetechnology.ru

For citation: Misyurin AV. Cytogenetic and Molecular Genetic Prognostic Factors of Acute Myeloid Leukemia. Clinical oncohematology. 2017;10(2):227–34 (In Russ).

DOI: 10.21320/2500-2139-2017-10-2-227-234

ABSTRACT

The review presents data on the diagnostic and prognostic value of cytogenetic and molecular genetic markers of acute myeloid leukemia (AML). It demonstrates that some cases, different types of AML subdivided on the basis of clinical and morphological characteristics earlier may be distinguished based on identification of specific genetic and chromosomal defects. However, some repeated chromosomal abnormalities may be detected in AML patients that may be assigned to different variants based in clinical and morphocytochemical signs. At present, it is widely accepted that changes in the karyotype are the key prognostic factors which are more important than criteria based on morphological and cytochemical signs. Therefore, the risk-adaptive therapy of AML should be chosen based on the cytogenetic test findings. The review contains a section discussing gene mutations known to date that may affect the AML treatment outcome.

Keywords: AML, chromosomal aberration, chimeric oncogene, gene expression, gene mutation.

Received: September 16, 2016

Accepted: January 3, 2017

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Molecular Monitoring of RUNX1-RUNX1T1 Transcript Level in Acute Myeloblastic Leukemias on Treatment

MYELOID TUMORS , ,

LL Girshova, EG Ovsyannikova, SO Kuzin, EN Goryunova, RI Vabishchevich, AV Petrov, DV Motorin, DV Babenetskaya, VV Ivanov, KV Bogdanov, IV Kholopova, TS Nikulina, YuV Mirolyubova, YuA Alekseeva, AYu Zaritskii

VA Almazov Federal North-West Medical Research Center, 2 Akkuratova str., Saint Petersburg, Russian Federation, 197341

For correspondence: Ekaterina Gennad’evna Ovsyannikova, 2 Akkuratova str., Saint Petersburg, Russian Federation, 197341; Tel: +7(921)313-68-35; e-mail: katrin51297@mail.ru

For citation: Girshova LL, Ovsyannikova EG, Kuzin SO, et al. Molecular Monitoring of RUNX1-RUNX1T1 Transcript Level in Acute Myeloblastic Leukemias on Treatment. Clinical oncohematology. 2016;9(4):456–64 (In Russ).

DOI: 10.21320/2500-2139-2016-9-4-456-464

ABSTRACT

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.

Keywords: acute myeloblastic leukemia, AML, RUNX1-RUNX1T1, molecular monitoring.

Received: April 5, 2016

Accepted: April 18, 2016

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Genetic Mutations in Acute Myeloid Leukemia

REVIEWS , , , , ,

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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