Publications by authors named "Grigory Tsaur"

15 Publications

  • Page 1 of 1

Blinatumomab following haematopoietic stem cell transplantation - a novel approach for the treatment of acute lymphoblastic leukaemia in infants.

Br J Haematol 2021 Jul 11;194(1):174-178. Epub 2021 Apr 11.

Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology, Moscow, Russian Federation.

Blinatumomab with subsequent haematopoietic stem cell transplantation was applied in 13 infants with acute lymphoblastic leukaemia (ALL). Eight patients were treated in first remission due to slow clearance of minimal residual disease (MRD); one for MRD-reappearance after long MRD negativity, one for primary refractory disease and three during relapse treatment. In slow MRD responders, complete MRD response was achieved prior to transplantation, with an 18-month event-free survival of 75%. In contrast, only one of five patients with relapsed/refractory ALL is still in complete remission. These data provide a basis for future studies of immunotherapy in very high-risk infant ALL.
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http://dx.doi.org/10.1111/bjh.17466DOI Listing
July 2021

Prognostic value of minimal residual disease measured by fusion-gene transcript in infants with KMT2A-rearranged acute lymphoblastic leukaemia treated according to the MLL-Baby protocol.

Br J Haematol 2021 Jun 14;193(6):1151-1156. Epub 2021 Feb 14.

Regional Children's Hospital, Ekaterinburg, Russian Federation.

The prognostic value of minimal residual disease (MRD) measured by fusion-gene transcript (FGT) detection was investigated in 76 infants (aged ≤1 year) with acute lymphoblastic leukaemia (ALL) with lysine methyltransferase 2A (KMT2A) rearrangements. Either at the end of induction or at later time-points, FGT-MRD-positivity was associated with poor outcome. FGT-MRD-positivity after first consolidation or first high-risk block detected 46·5% of infants with extremely poor outcome [disease-free survival (SE) 0·06 (0·06), cumulative incidence of relapse (SE) 0·91 (0·05)], which was also confirmed in multivariable analysis. Thus, FGT-MRD measurement at a single time-point clearly identifies infants with ALL who are curable with conventional chemotherapy and those who would benefit only from other treatment approaches.
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http://dx.doi.org/10.1111/bjh.17304DOI Listing
June 2021

Heterogeneity of childhood acute leukemia with mature B-cell immunophenotype.

J Cancer Res Clin Oncol 2019 Nov 28;145(11):2803-2811. Epub 2019 Aug 28.

Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology, 1 Samory Mashela St., GSP-7, Moscow, 117997, Russia.

Background: Flow cytometry (FCM) plays a crucial role in the differential diagnosis of Burkitt lymphoma/leukemia (BL) and B-cell precursor acute lymphoblastic leukemia (BCP-ALL). The presence of surface IgM (sIgM) alone or with light chain restriction indicates a mature blast phenotype (BIV by EGIL) and is usually observed in BL. However, sIgM expression could also be detected in transitional BCP-ALL cases. These similarities in immunophenotype and ambiguous correspondence with other laboratory findings may challenge the correct BL diagnostics.

Methods: We retrospectively reviewed the available data from immunophenotypic, morphological, cytogenetic, and molecular genetic studies of 146 children (85 boys and 61 girls) with a median age of 10 years (range 0-18 years) who were diagnosed with BL and BCP-ALL. The blasts' immunophenotype was studied by multicolor FCM. The conventional cytogenetic analysis included G-banded karyotyping and fluorescence in situ hybridization (FISH).

Results: In 54 children classified as BIV-ALL according to the EGIL, it was demonstrated that sIgM in a minority of cases can be associated with various types of BCP-ALL. Analysis of the antigen expression profile of 105 patients with verified BL (n = 21) and BCP-ALL (n = 84) showed significant differences in BL and the sIgM(+) vs BCP-ALL immunophenotype. Thus, even in cases of ambiguous sIgM expression, these two diseases could be reliably discriminated by complex immunophenotyping. Moreover, 10 patients (7 boys and 3 girls) with BL leukemic cells did not express sIgM, and they were diagnosed with BL on the basis of other laboratory and clinical signs.

Conclusions: In conclusion, our study shows that BIV subtype is heterogeneous group of leukemia including not only the BL, but also BCP-ALL. In ambiguous cases, only a combination of multiple immunophenotypic, cytomorphologic, and genetic diagnostic technologies can allow the precise discrimination of BL and BCP-ALL and selection of the appropriate treatment scheme.
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http://dx.doi.org/10.1007/s00432-019-03010-1DOI Listing
November 2019

IKZF1 Deletions with COBL Breakpoints Are Not Driven by RAG-Mediated Recombination Events in Acute Lymphoblastic Leukemia.

Transl Oncol 2019 May 13;12(5):726-732. Epub 2019 Mar 13.

Molecular Cancer Study Group, Division of Clinical Research, Research Center, Instituto Nacional de Câncer, Rio de Janeiro, Brazil. Electronic address:

IKZF1 deletion (ΔIKZF1) is an important predictor of relapse in both childhood and adult B-cell precursor acute lymphoblastic leukemia (B-ALL). Previously, we revealed that COBL is a hotspot for breakpoints in leukemia and could promote IKZF1 deletions. Through an international collaboration, we provide a detailed genetic and clinical picture of B-ALL with COBL rearrangements (COBL-r). Patients with B-ALL and IKZF1 deletion (n = 133) were included. IKZF1 ∆1-8 were associated with large alterations within chromosome 7: monosomy 7 (18%), isochromosome 7q (10%), 7p loss (19%), and interstitial deletions (53%). The latter included COBL-r, which were found in 12% of the IKZF1 ∆1-8 cohort. Patients with COBL-r are mostly classified as intermediate cytogenetic risk and frequently harbor ETV6, PAX5, CDKN2A/B deletions. Overall, 56% of breakpoints were located within COBL intron 5. Cryptic recombination signal sequence motifs were broadly distributed within the sequence of COBL, and no enrichment for the breakpoint cluster region was found. In summary, a diverse spectrum of alterations characterizes ΔIKZF1 and they also include deletion breakpoints within COBL. We confirmed that COBL is a hotspot associated with ΔIKZF1, but these rearrangements are not driven by RAG-mediated recombination.
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http://dx.doi.org/10.1016/j.tranon.2019.02.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6423364PMC
May 2019

Exome, transcriptome and miRNA analysis don't reveal any molecular markers of TKI efficacy in primary CML patients.

BMC Med Genomics 2019 03 13;12(Suppl 2):37. Epub 2019 Mar 13.

Laboratory of Mutagenesis, Federal State Budgetary Institution, Research Centre for Medical Genetics, Moskvorechie str., 1, Moscow, Russian Federation, 115522.

Background: Approximately 5-20% of chronic myeloid leukemia (CML) patients demonstrate primary resistance or intolerance to imatinib. None of the existing predictive scores gives a good prognosis of TKI efficacy. Gene polymorphisms, expression and microRNAs are known to be involved in the pathogenesis of TKI resistance in CML. The aim of our study is to find new molecular markers of TKI therapy efficacy in CML patients.

Methods: Newly diagnosed patients with Ph+ CML in chronic phase were included in this study. Optimal and non-optimal responses to TKI were estimated according to ELN 2013 recommendation. We performed genotyping of selected polymorphisms in 62 blood samples of CML patients, expression profiling of 33 RNA samples extracted from blood and miRNA profiling of 800 miRNA in 12 blood samples of CML patients.

Results: The frequencies of genotypes at the studied loci did not differ between groups of patients with an optimal and non-optimal response to TKI therapy. Analysis of the expression of 34,681 genes revealed 26 differently expressed genes (p < 0.05) in groups of patients with different TKI responses, but differences were very small and were not confirmed by qPCR. Finally, we did not find difference in miRNA expression between the groups.

Conclusions: Using modern high-throughput methods such as whole-exome sequencing, transcriptome and miRNA analysis, we could not find reliable molecular markers for early prediction of TKI efficiency in Ph+ CML patients.
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http://dx.doi.org/10.1186/s12920-019-0481-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6416830PMC
March 2019

Absolute count of leukemic blasts in cerebrospinal fluid as detected by flow cytometry is a relevant prognostic factor in children with acute lymphoblastic leukemia.

J Cancer Res Clin Oncol 2019 May 6;145(5):1331-1339. Epub 2019 Mar 6.

Regional Children Hospital, 32, S. Deryabina Str., 620149, Ekaterinburg, Russian Federation.

Background: Usually, central nervous system (CNS) involvement in acute lymphoblastic leukemia (ALL) is diagnosed by cytomorphology (CM) of cerebrospinal fluid (CSF) on cytospin slides. Multicolor flow cytometry (MFC) provides the opportunity to detect low numbers of leukemia cells undetectable by CM. The present study aimed at evaluating the clinical significance of MFC for the diagnosis of CNS involvement at initial manifestation of childhood ALL.

Methods: In 155 children with ALL, CSF samples were studied in parallel by CM and MFC. Patients were treated according to protocol ALL-MB-2008 for childhood ALL. The prognostic impact of the leukemia burden in CSF was determined categorizing the findings as positive/negative. In addition, the absolute blast cell count per 1 ml of CSF was studied as a continuous variable.

Results: CSF positivity was significantly more frequent using MFC compared with CM (35.3% vs. 15.3% of patients). The outcome of MFC-positive and MFC-negative patients was not different in clinically relevant patient risk groups-CNS1, standard and intermediate-risk groups. Using the quantitative approach, at the threshold level of 20 blasts per ml of CSF, patients could be divided into two groups with a significantly different outcome, irrespective of the clinical risk group, the type of CNS-directed therapy, and the CNS status determined by CM.

Conclusions: Our data do not support the concept of re-stratification and modification of therapy based on qualitative CSF investigation by MFC. However, MFC is a highly sensitive technique of CSF investigation improving the definition of CNS involvement in childhood ALL, and quantitative measurement of blast cells in CSF, if well-organized, can be a useful additional tool for stratification of patients in clinical trials.
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http://dx.doi.org/10.1007/s00432-019-02886-3DOI Listing
May 2019

Validation of the United Kingdom copy-number alteration classifier in 3239 children with B-cell precursor ALL.

Blood Adv 2019 01;3(2):148-157

Hematology-Oncology Department, Hospital de Pediatría "Prof. Dr. J. P. Garrahan," Buenos Aires, Argentina.

Genetic abnormalities provide vital diagnostic and prognostic information in pediatric acute lymphoblastic leukemia (ALL) and are increasingly used to assign patients to risk groups. We recently proposed a novel classifier based on the copy-number alteration (CNA) profile of the 8 most commonly deleted genes in B-cell precursor ALL. This classifier defined 3 CNA subgroups in consecutive UK trials and was able to discriminate patients with intermediate-risk cytogenetics. In this study, we sought to validate the United Kingdom ALL (UKALL)-CNA classifier and reevaluate the interaction with cytogenetic risk groups using individual patient data from 3239 cases collected from 12 groups within the International BFM Study Group. The classifier was validated and defined 3 risk groups with distinct event-free survival (EFS) rates: good (88%), intermediate (76%), and poor (68%) ( < .001). There was no evidence of heterogeneity, even within trials that used minimal residual disease to guide therapy. By integrating CNA and cytogenetic data, we replicated our original key observation that patients with intermediate-risk cytogenetics can be stratified into 2 prognostic subgroups. Group A had an EFS rate of 86% (similar to patients with good-risk cytogenetics), while group B patients had a significantly inferior rate (73%, < .001). Finally, we revised the overall genetic classification by defining 4 risk groups with distinct EFS rates: very good (91%), good (81%), intermediate (73%), and poor (54%), < .001. In conclusion, the UKALL-CNA classifier is a robust prognostic tool that can be deployed in different trial settings and used to refine established cytogenetic risk groups.
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http://dx.doi.org/10.1182/bloodadvances.2018025718DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6341196PMC
January 2019

Acute myeloid leukemia with t(10;11)(p11-12;q23.3): Results of Russian Pediatric AML registration study.

Int J Lab Hematol 2019 Apr 9;41(2):287-292. Epub 2019 Jan 9.

Dmitry Rogachev National Medical and Research Center of Pediatric Hematology, Oncology and Immunology, Moscow, Russia.

Introduction: Translocations involving the KMT2A gene (also known as MLL) are frequently diagnosed in pediatric acute leukemia cases with either lymphoblastic or myeloid origin. KMT2A is translocated to multiple partner genes, including MLLT10/AF10 localizing at chromosomal band 10p12. KMT2A-MLLT10 is one of the common chimeric genes diagnosed in acute leukemia with KMT2A rearrangement (8%), especially in acute myeloid leukemia (AML; 18%). MLLT10 is localized in very close proximity to two other KMT2A partner genes at 10p11-12-NEBL and ABI1, so they could not be distinguished by conventional cytogenetics.

Methods: In this work, we present a cohort of 28 patients enrolled into Russian Pediatric AML registration study carrying rearrangements between chromosomal regions 11q23.3 and 10p11-12. G-banding, FISH, reverse transcription PCR, and long-distance inverse PCR were used to characterize the KMT2A gene rearrangements in these patients.

Results: We demonstrate that 25 patients harbor the KMT2A-MLLT10 rearrangement, while three patients show the rare KMT2A rearrangements (2× KMT2A-NEBL; 1× KMT2A-ABI1).

Conclusions: Therefore, the combination of cytogenetic and molecular genetic methods is of high importance in diagnosing cases with t(10;11)(p11-12;q23.3).
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http://dx.doi.org/10.1111/ijlh.12969DOI Listing
April 2019

Prognostic value of initial bone marrow disease detection by multiparameter flow cytometry in children with neuroblastoma.

J Cancer Res Clin Oncol 2019 Feb 2;145(2):535-542. Epub 2019 Jan 2.

Research Institute of Medical Cell Technologies, 22A, K. Marx st, Yekaterinburg, 620026, Russian Federation.

Purpose: Multicolor flow cytometry (MFC) is widely available, fast and has an easy-to perform approach for finding neuroblastoma (NB) cells among normal bone marrow (BM) hematopoietic cells. Aim of the study was to investigate prognostic significance of initial MFC tumor cells' detection in BM of children with NB.

Methods: 51 patients (24 boys and 27 girls) aged from 6 days to 15 years (median age 1 year 3 months) with NB were included in the study. BM samples at the time of diagnosis were obtained from 2 to 5 aspiration sites per patient. CD45(-)CD56(+)CD81(+)GD2(+)-cells were evaluated by MFC.

Results: NB cells were detected in BM by FC more frequently compared to conventional cytomorphology (49.0% and 29.4% patients, respectively, р = 0.043). Patients with NB cells detected in BM by MFC had significantly worse event-free survival and cumulative incidence of relapse/progression [0.24(0.08) and 0.60(0.10), respectively] compared to children with negative result of immunophenotyping [0.85(0.07) and 0.12(0.06), respectively, p < 0.001 in both cases]. BM involvement detection by MFC maintained its prognostic significance in various patients groups. In multivariate analysis, immunophenotyping proved to be an independent prognostic factor when analyzed jointly with other NB risk factors. In 42 patients BM involvement was also studied by RQ-PCR for PHOX2B and TH genes expression. Within groups of patients divided by RQ-PCR positivity, MFC-positivity retained prognostic significance.

Conclusions: Thus flow cytometric BM involvement detection has very strong prognostic impact even stronger than RQ-PCR. It could be used in combination with other parameters for the treatment strategy choice in patients with NB.
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http://dx.doi.org/10.1007/s00432-018-02831-wDOI Listing
February 2019

Clinical significance of cytogenetic changes in childhood T-cell acute lymphoblastic leukemia: results of the multicenter group Moscow-Berlin (MB).

Leuk Lymphoma 2019 02 1;60(2):426-432. Epub 2018 Aug 1.

i Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology, Charité CVK, Universitätsmedizin Berlin , Berlin , Germany.

The prognostic significance of genetic lesions in T-cell ALL still needs to be elucidated. Karyotyping and FISH were performed in samples from 120 patients with T-cell ALL registered in the trial Moscow-Berlin 2008. Most frequent rearrangements were TLX3 (N = 29; 24%) and TAL1 (N = 18; 15%), followed by KMT2A (N = 6; 5%), TLX1 (N = 5; 4.2%), and 11p13-15 (N = 5; 4.2%). In 16.7% of patients, the karyotype was normal, and in 30.8% 'other' aberrations were seen. Patients with a normal karyotype, TAL1, or KMT2A rearrangements had the most favorable outcome (probability of event free survival (pEFS): 82% ± 6%), while prognosis for patients with TLX3 and TLX1 rearrangements and 'other' aberrations was less favorable (pEFS: 62% ± 6%). Worst outcome was observed for five patients with 11p rearrangements (pEFS: 20% ± 18%). In summary, three subgroups of patients with T-cell ALL with significantly different outcomes could be defined by cytogenetic profiling.
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http://dx.doi.org/10.1080/10428194.2018.1485904DOI Listing
February 2019

Prospective investigation of applicability and the prognostic significance of bone marrow involvement in patients with neuroblastoma detected by quantitative reverse transcription PCR.

Pediatr Blood Cancer 2018 11 14;65(11):e27354. Epub 2018 Jul 14.

Regional Children's Hospital N1, Yekaterinburg, Russian Federation.

Background: Detection of bone marrow (BM) involvement in patients with neuroblastoma is crucial for staging and defining prognosis. Furthermore, the persistence of residual tumor cells in the BM is associated with an unfavorable outcome.

Methods: Expression of PHOX2B, TH, ELAVL4, and B4GALNT1 (GD2-synthase) was analyzed by quantitative polymerase chain reaction in neuroblastoma cell lines, control BM samples, and in BM samples from patients. The threshold level of expression for each gene was established through receiver operator characteristic analysis and used to determine the diagnostic test performance. The prognostic significance of BM involvement was assessed by survival rates calculations. The median of follow-up time was 36.1 months.

Results: Neither PHOX2B nor TH expression was detected in control BM, while expression of ELAVL4 was found in 20 (76.9%) and GD2-synthase in 15 (57.7%) of 26 samples. The overall correct predictive value for TH, ELAVL4, and GD2-synthase, based on thresholds levels, was 0.952, 0.828, and 0.767, respectively, whereas the overall correct predictive value for PHOX2B was 0.994. The PHOX2B/TH expression in diagnostic BM of patients with neuroblastoma corresponded with a decreased survival rate (P < 0.001) in the total cohort and in different risk groups. Predominance of normalized expression of PHOX2B over TH > 1.68 in the diagnostic BM samples demonstrated an adverse prognostic effect (P = 0.006). Persistence of PHOX2B/TH expression in the BM during and after induction chemotherapy resulted in dismal outcome (P = 0.022 and P = 0.012).

Conclusion: PHOX2B and TH are the most optimal markers for detection of BM involvement, allowing identification of high-risk patients. Predominance of PHOX2B expression over TH has a strong adverse prognostic impact.
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http://dx.doi.org/10.1002/pbc.27354DOI Listing
November 2018

A new variant of KMT2A(MLL)-FLNA fusion transcript in acute myeloid leukemia with ins(X;11)(q28;q23q23).

Cancer Genet 2015 Apr 7;208(4):148-51. Epub 2015 Mar 7.

Federal Scientifc Clinical Centre of Pediatric Hematology, Oncology and Immunology, Moscow, Russia.

The KMT2A gene (previously known as MLL) located at 11q23 is often involved in recurrent chromosomal translocations that lead to the development of acute leukemia, particularly in infants. Acute leukemias with KMT2A rearrangements have different prognoses, which depend on the partner gene involved in the translocation. The detection of all possible types of KMT2A gene rearrangements is of key importance for the identification of biological subgroups, which may differ in clinical outcome. In this report, we describe a case study of a 7-month-old boy who presented with AML-M4; however, no obvious 11q23 rearrangement was detected in the analyzed karyotype. Fluorescence in situ hybridization evaluation showed a nonstandard signal distribution in blast cells, corresponding to the presence of two KMT2A copies and one additional copy of 5'-KMT2A inserted into the long arm of the X chromosome (ins(X;11)(q28;q23q23)). Subsequent molecular analysis showed a novel variant form of the previously described KMT2A-FLNA fusion gene, in which the KMT2A intron 9 is fused to the FLNA exon 16.
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http://dx.doi.org/10.1016/j.cancergen.2015.03.001DOI Listing
April 2015

A Novel Three-Colour Fluorescence in Situ Hybridization Approach for the Detection of t(7;12)(q36;p13) in Acute Myeloid Leukaemia Reveals New Cryptic Three Way Translocation t(7;12;16).

Cancers (Basel) 2013 Mar 11;5(1):281-95. Epub 2013 Mar 11.

Leukaemia and Chromosome Research Laboratory, Division of Biosciences, Brunel University, London, Middlesex UB8 3PH, UK.

The t(7;12)(q36;p13) translocation is a recurrent chromosome abnormality that involves the ETV6 gene on chromosome 12 and has been identified in 20-30% of infant patients with acute myeloid leukaemia (AML). The detection of t(7;12) rearrangements relies on the use of fluorescence in situ hybridization (FISH) because this translocation is hardly visible by chromosome banding methods. Furthermore, a fusion transcript HLXB9-ETV6 is found in approximately 50% of t(7;12) cases, making the reverse transcription PCR approach not an ideal screening method. Considering the report of few cases of variant translocations harbouring a cryptic t(7;12) rearrangement, we believe that the actual incidence of this abnormality is higher than reported to date. The clinical outcome of t(7;12) patients is believed to be poor, therefore an early and accurate diagnosis is important in the clinical management and treatment. In this study, we have designed and tested a novel three-colour FISH approach that enabled us not only to confirm the presence of the t(7;12) in a number of patients studied previously, but also to identify a cryptic t(7;12) as part of a complex rearrangement. This new approach has proven to be an efficient and reliable method to be used in the diagnostic setting.
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http://dx.doi.org/10.3390/cancers5010281DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3730311PMC
March 2013
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