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1.
NPJ Syst Biol Appl ; 9(1): 41, 2023 09 09.
Article in English | MEDLINE | ID: mdl-37684264

ABSTRACT

Juvenile myelomonocytic leukemia (JMML) is a rare myeloproliferative disease of early childhood that develops due to mutations in the genes of the RAS-signaling pathway. Next-generation high throughput sequencing (NGS) enables identification of various secondary molecular genetic events that can facilitate JMML progression and transformation into secondary acute myeloid leukemia (sAML). The methods of single-cell DNA sequencing (scDNA-seq) enable overcoming limitations of bulk NGS and exploring genetic heterogeneity at the level of individual cells, which can help in a better understanding of the mechanisms leading to JMML progression and provide an opportunity to evaluate the response of leukemia to therapy. In the present work, we applied a two-step droplet microfluidics approach to detect DNA alterations among thousands of single cells and to analyze clonal dynamics in two JMML patients with sAML transformation before and after hematopoietic stem cell transplantation (HSCT). At the time of diagnosis both of our patients harbored only "canonical" mutations in the RAS signaling pathway genes detected by targeted DNA sequencing. Analysis of samples from the time of transformation JMML to sAML revealed additional genetic events that are potential drivers for disease progression in both patients. ScDNA-seq was able to measure of chimerism level and detect a residual tumor clone in the second patient after HSCT (sensitivity of less than 0.1% tumor cells). The data obtained demonstrate the value of scDNA-seq to assess the clonal evolution of JMML to sAML, response to therapy and engraftment monitoring.


Subject(s)
Leukemia, Myelomonocytic, Juvenile , Humans , Child, Preschool , Leukemia, Myelomonocytic, Juvenile/genetics , Leukemia, Myelomonocytic, Juvenile/therapy , Clonal Evolution , High-Throughput Nucleotide Sequencing , Mutation/genetics
2.
Expert Rev Clin Immunol ; 19(11): 1315-1324, 2023.
Article in English | MEDLINE | ID: mdl-37554030

ABSTRACT

INTRODUCTION: Hematopoietic stem cell transplantation is a curative treatment for many inborn errors of immunity (IEI). Incremental improvements and advances in care have led to high rates of >85% survival and cure in many of these diseases. Improvements in HLA-classification and matching have led to increased survival using HLA-matched donors, but survival using T-lymphocyte-depleted mismatched grafts remained significantly worse until fairly recently. Advances in T-lymphocyte depletion methods and graft engineering, although not specific to IEI, have been widely adopted and instrumental in changing the landscape of donor selection, such that a donor should now be possible for every patient. AREAS COVERED: A literature review focusing on T-lymphocyte depletion methodologies and treatment results was performed. The importance of early T-lymphocyte immunoreconstitution to protect against viral infection is reviewed. Two main platforms now dominate the field - immune-magnetic selection of specific cell types and post-transplant chemotherapeutic targeting of rapidly proliferating allo-reactive T-lymphocytes - the emerging literature on these reports, focusing on IEI, is explored, as well as the impact of serotherapy on early immunoreconstitution. EXPERT OPINION: Pharmacokinetic monitoring of serotherapy agents, and use of co-stimulatory molecule blockade are likely to become more widespread. Post-transplant cyclophosphamide or TCR depletion strategies are likely to become the dominant methods of transplantation for nonmalignant diseases.


Subject(s)
Graft vs Host Disease , Hematopoietic Stem Cell Transplantation , Virus Diseases , Humans , T-Lymphocytes , Hematopoietic Stem Cell Transplantation/methods , Treatment Outcome , Lymphocyte Depletion/methods
3.
Sci Rep ; 13(1): 463, 2023 01 10.
Article in English | MEDLINE | ID: mdl-36627334

ABSTRACT

Tumor-derived extracellular vesicles (EVs) are active contributors in metastasis and immunosuppression in tumor microenvironment. At least some of the EVs carry tumor surface molecules such as tumor-associated antigens (TAAs) and/or checkpoint inhibitors, and potentially could interact with T cells or CAR T cells. Upon contact with T cells, EVs could alter their phenotype and functions by triggering signaling through TCR or CAR reprogramming them to escape immune response. We hypothesize that EVs that possess TAA on the surface will probably interact with CAR T cells which can recognize and bind corresponding TAA. This interaction between EVs and CAR T cells may change the outcome of CAR T-based cancer immunotherapy since it should affect CAR T cells. Also, EVs could serve as adjuvants and antigenic components of antitumor vaccines. Herein, we isolated EVs from B cell precursor leukemia cell line (pre-B ALL) Nalm-6 and demonstrated that recognition and binding of CD19+EVs with CD19-CAR T cells strongly depends on the presence of CD19 antigen. CD19+EVs induce secretion of pro-inflammatory cytokines (IL-2 and IFN-y) and upregulated transcription of activation-related genes (IFNG, IFNGR1, FASLG, IL2) in CD19-CAR T cells. Tumor necrosis factor receptor superfamily (TNFRSF4 and TNFRSF9) and T-cell exhaustion markers (CTLA4, LAG3, TIM3 and PDCD1LG2) were also upregulated in CD19-CAR T cells after incubation with CD19+EVs. Long-term cultivation of CD19+ or PD-L1+EVs with CD19-CAR T cells led to increased terminal differentiation and functional exhaustion according to elevated expression of PD-1, TIGIT, CD57. In summary, our results suggest that chronic exposure of CD19-CAR T cells to CD19+EVs mediates activation and systemic exhaustion in antigen-specific manner, and this negative effect is accompanied by the impaired cytotoxic activity in vitro.


Subject(s)
Antineoplastic Agents , Leukemia, Lymphocytic, Chronic, B-Cell , Humans , Immunotherapy, Adoptive/methods , T-Lymphocytes , Cytokines/metabolism , Antineoplastic Agents/metabolism , Antigens, CD19/metabolism , Leukemia, Lymphocytic, Chronic, B-Cell/metabolism , CD3 Complex/metabolism , Receptors, Antigen, T-Cell/metabolism , Tumor Microenvironment
4.
Dokl Biochem Biophys ; 508(1): 17-20, 2023 Feb.
Article in English | MEDLINE | ID: mdl-36653580

ABSTRACT

The development of CAR-T specific therapy made a revolution in modern oncology. Despite the pronounced therapeutic effects, this novel approach displayed several crucial limitations caused by the complications in pharmacokinetics and pharmacodynamics controls. The presence of the several severe medical complications of CAR-T therapy initiated a set of attempts aimed to regulate their activity in vivo. We propose to apply the barnase-barstar system to control the cytotoxic antitumor activity of CAR-T cells. To menage the regulation targeting effect of the system we propose to use barstar-modified CAR-T cells together with barnase-based molecules. Barnase was fused with designed ankyrin repeat proteins (DARPins) specific to tumor antigens HER2 (human epidermal growth factor receptor 2) The application of the system demonstrates the pronounced regulatory effects of CAR-T targeting.


Subject(s)
Antineoplastic Agents , Neoplasms , Receptors, Chimeric Antigen , Humans , Receptors, Chimeric Antigen/genetics , Bacterial Proteins/metabolism , Ribonucleases/metabolism , Antineoplastic Agents/pharmacology , T-Lymphocytes/metabolism
5.
Front Mol Biosci ; 8: 745286, 2021.
Article in English | MEDLINE | ID: mdl-34722633

ABSTRACT

CAR-T cell therapy is the most advanced way to treat therapy resistant hematologic cancers, in particular B cell lymphomas and leukemias, with high efficiency. Donor T cells equipped ex vivo with chimeric receptor recognize target tumor cells and kill them using lytic granules. CAR-T cells that recognize CD19 marker of B cells (CD19 CAR-T) are considered the gold standard of CAR-T therapy and are approved by FDA. But in some cases, CD19 CAR-T cell therapy fails due to immune suppressive microenvironment. It is shown that tumor cells upregulate expression of PD-L1 surface molecule that binds and increases level and signal provided by PD-1 receptor on the surface of therapeutic CAR-T cells. Induction of this negative signaling results in functional impairment of cytotoxic program in CAR-T cells. Multiple attempts were made to block PD-1 signaling by reducing binding or surface level of PD-1 in CAR-T cells by various means. In this study we co-expressed CD19-CAR with PD-1-specific VHH domain of anti-PD-1 nanobody to block PD-1/PD-L1 signaling in CD19 CAR-T cells. Unexpectedly, despite increased activation of CAR-T cells with low level of PD-1, these T cells had reduced survival and diminished cytotoxicity. Functional impairment caused by disrupted PD-1 signaling was accompanied by faster maturation and upregulation of exhaustion marker TIGIT in CAR-T cells. We conclude that PD-1 in addition to its direct negative effect on CAR-induced signaling is required for attenuation of strong stimulation leading to cell death and functional exhaustion. These observations suggest that PD-1 downregulation should not be considered as the way to improve the quality of therapeutic CAR-T cells.

6.
Ter Arkh ; 93(7): 805-810, 2021 Jul 23.
Article in Russian | MEDLINE | ID: mdl-36286732

ABSTRACT

Indications of allogeneic hematopoietic stem cell transplantation (allo-HSCT) in patients with primary myelofibrosis are intermediate-2 and high-risk group of DIPSS (Dynamic International Prognostic Scoring System), beginning of the disease in childhood. The other adverse factors affect engraftment and survival after allo-HSCT, example partialy matched donor. But the result of allo-HSCT from matched related donors and result of allo-HSCT from haploidentical donors are comparable. The method for haploidentical hematopoietic stem cell transplantation is T-cell-depletion. This is clinical case of T-cell-depleted haploidentical hematopoietic stem cell transplantation in patient with primary myelofibrosis, the diagnosis was established in childhood.


Subject(s)
Graft vs Host Disease , Hematopoietic Stem Cell Transplantation , Primary Myelofibrosis , Humans , Receptors, Antigen, T-Cell, alpha-beta , Primary Myelofibrosis/diagnosis , Primary Myelofibrosis/therapy , Hematopoietic Stem Cell Transplantation/methods , Antigens, CD19 , Lymphocyte Depletion/methods , Transplantation Conditioning/methods
7.
Ter Arkh ; 93(7): 811-817, 2021 Jul 23.
Article in Russian | MEDLINE | ID: mdl-36286733

ABSTRACT

Сytokine release syndrome is the common complication of CAR-T therapy. We report a case of patient with B-cell acute lymphoblastic leukemia developing сytokine release syndrome with shock and multiple organ failure and requiring cytokine removal and hemodiafiltration. Remission of the disease was achieved after CAR-T therapy.


Subject(s)
Precursor Cell Lymphoblastic Leukemia-Lymphoma , Receptors, Chimeric Antigen , Humans , Cytokine Release Syndrome/diagnosis , Cytokine Release Syndrome/etiology , Cytokine Release Syndrome/therapy , Antigens, CD19 , Cytokines , Precursor Cell Lymphoblastic Leukemia-Lymphoma/complications , Precursor Cell Lymphoblastic Leukemia-Lymphoma/therapy , Acute Disease , Cell- and Tissue-Based Therapy
8.
Acta Naturae ; 11(4): 33-41, 2019.
Article in English | MEDLINE | ID: mdl-31993233

ABSTRACT

In this article, we present a comprehensive, updated, and elucidative review of the current knowledge on the function played by tumor-derived vesicles (TDVs) in the crosstalk between tumor and immune cells. Characterization of the structure, biogenesis, and the major functions of TDVs is reported. The review focuses on particular ways of suppression or activation of CD4+/CD8+ T cells by tumor-derived vesicles. Tumor-derived vesicles play an important role in the suppression of antitumor immunity. During the last 15 years, vesicle research has elucidated and improved our knowledge about the role of the vesicles in intercellular communication. Nevertheless, there are still blinds spots concerning vesicle heterogeneity and isolation methods, their uptake by target cells, and the role of mRNA in T-cell transformation or suppression. Along with the substantial progress in understanding of the role of tumor-derived vesicles in intercellular communication, novel antitumor therapy strategies based on vesicle inhibition in a tumor microenvironment are likely to appear very soon.

9.
Acta Naturae ; 10(2): 16-23, 2018.
Article in English | MEDLINE | ID: mdl-30116611

ABSTRACT

Chimeric antigen receptor-modified T-cell therapy (CAR-T therapy) is one of the fastest developing areas of immuno-oncology. Over the past decade, it has revolutionized the cell therapy modality and expedited its pace of development, from optimization of the structure of chimeric antigen receptors and animal model experiments to successful clinical application. The initial designs of the CAR configuration focused on increasing T-cell activation, cytotoxicity, and persistence. However, the first attempts to treat patients with CAR T cells have demonstrated the need for increased safety and controlled activation of genetically modified T cells. Herein, we summarize the different molecular approaches to engineering chimeric antigen receptors for reducing the potential clinical risks of T-cell therapy.

10.
Ter Arkh ; 90(7): 38-50, 2018 Aug 17.
Article in English | MEDLINE | ID: mdl-30701921

ABSTRACT

AIM: The analysis of experience of nelarabine use in refractory/relapsed T-cell acute lymphoblastic leukemia (T-ALL) depending on the immunophenotype and the line of therapy. MATERIALS AND METHODS: All the patients with relapsed or refractory T-ALL aged from 0 to 18 years who received treatment with nelarabine as a part of the therapeutic element R6 were included in the study. For all patients a detailed immunological analysis of leukemia cells with discrimination of immunological variants TI, TII, TIII or TIV was performed. Patients administered with nelarabine as a first therapeutic element were referred to the first-line therapy group, other patients were referred to the second-line therapy group. Nelarabine was ad- ministered as intravenous infusion at a dose of 650 mg/m2, on days 1-5. Allogeneic hematopoietic stem cells transplantation (allo-HSCT) was considered for all patients. RESULTS: From 2009 to 2017, 54 patients with refractory/relapsed T-ALL were treated with nelarabine. Five-year event-free survival (EFS) and overall survival (OS) was 28% for all patients, cumulative risk of relapse (CIR) was 27%. EFS was significantly higher in nelarabine first-line therapy group in comparison with second-line therapy group (34±8% vs 8±8%, p=0,05). In patients after allo-HSCT EFS, OS and CIR were 51±10%, 50±10% and 39,1±9,5% accordingly. The best results were achieved in patients with TI immunophenotype. No toxicity-related mortality as well as severe neurologic complications or discontinuation of therapy associated with use of nelarabine were reported. CONCLUSION: The use of nelarabine is an effective strategy for the treatment of relapsed and refractory T-ALL. The best treatment outcomes were obtained in patients with TI immunophenotype and in the first-line therapy group. Optimal dosage regimens can be established dur- ing controlled clinical trials.


Subject(s)
Antineoplastic Agents/therapeutic use , Arabinonucleosides/therapeutic use , Precursor T-Cell Lymphoblastic Leukemia-Lymphoma/drug therapy , Prodrugs/therapeutic use , Antineoplastic Agents/adverse effects , Antineoplastic Agents/pharmacokinetics , Arabinonucleosides/adverse effects , Arabinonucleosides/pharmacokinetics , Clinical Trials as Topic , Humans , Injections, Intravenous , Precursor T-Cell Lymphoblastic Leukemia-Lymphoma/mortality , Prodrugs/adverse effects , Prodrugs/pharmacokinetics , Progression-Free Survival , Recurrence
11.
Ter Arkh ; 90(7): 57-64, 2018 Aug 17.
Article in English | MEDLINE | ID: mdl-30701923

ABSTRACT

AIM: The main goal is to optimize hematopoietic stem cell transplantation (HSCT) approach among adolescents and young adults with paroxysmal nocturnal hemoglobinuria (PNH) by means of Graft-versus-host disease (GVHD) and post-transplant complications risk lowering. MATERIALS AND METHODS: We report our experience of HSCT from HLA-matched unrelated donors using TCR alfa/beta and CD19 depletion in 5 pts (1M/4F) with PNH, developed after successful immunosuppressive therapy (IST) of acquired aplastic anemia (AA). Median age of pts at the moment of transplantation was 17,8 years (range 14,5-22,7), median interval from IST to PNH was 4 years (5mo - 6,5 y). In all patients non-severe pancytopenia was present: granulocytes 0,8х109/l (0,8-1,8 х109/l) platelets 106 х109/l (27-143 х109/l) and Hb -78 g/l, median PNH clone size in granulocytes was 94 (range 75-99)%. One pts previously developed sinus thrombosis. Conditioning consisted of thoraco-abdominal irradiation 4-6 Gy, cyclophosphamide 100 mg/kg, fludarabine 150 mg/m2 and anti-thymocyte globulin (ATG) or alemtuzumab. Eculizumab was given from day (-7) till day (+14) (every 7 days, only 4 times). GVHD prophylaxis was tacrolimus ± methotrexate. RESULTS: Infusedgraft characteristics were: CD34+ - 8,1х106/kg, CD3TCRab·150х103/kg, CD3gd+ - 7,3х106/kg, СD19+ - 221х103/kg, NK -6,4х108/kg. Engraftment was achieved in all 5 pts with a median of 15(12-18) и 13(10-18) days for granulocytes and platelets, respectively. Skin acute GVHD grade I developed in only 1 pt, and subsided with short course of glucocorticoids. CMV reactivation occurred in 1 pt; there were no episodes of Epstein-Barr Virus (EBV) o rAdenovirus (AdV) reactivation. Full donor myeloid chimerism was established in all pts by day +30. Immune reconstitution was delayed until 6 months after transplant but no severe infections occurred. All pts are alive 1,7-5,5 years (med 4 years) after HSCT with normal hematopoiesis and immune function, full donor chimerism and no late sequelae. CONCLUSION: Transplantation of TCRalfa/beta and CD19 depleted hematopoietic cells from matched unrelated donor after immunoablative conditioning and supported with short course of eculizumab is perfectly safe and efficient technology leading to cure in young patients with PNH.


Subject(s)
Antibodies, Monoclonal, Humanized/therapeutic use , Hematopoietic Stem Cell Transplantation/methods , Hemoglobinuria, Paroxysmal/therapy , Lymphocyte Depletion , T-Lymphocytes/drug effects , Transplantation Conditioning/methods , Adolescent , Antibodies, Monoclonal, Humanized/administration & dosage , Antibodies, Monoclonal, Humanized/adverse effects , Dose-Response Relationship, Drug , Female , Graft vs Host Disease/prevention & control , Hemoglobinuria, Paroxysmal/drug therapy , Hemoglobinuria, Paroxysmal/immunology , Humans , Male , T-Lymphocytes/immunology , Treatment Outcome , Young Adult
12.
Ter Arkh ; 89(7): 51-56, 2017.
Article in Russian | MEDLINE | ID: mdl-28766541

ABSTRACT

AIM: To evaluate the safety and efficacy of crizotinib used in pediatric patients with relapsed or refractory ALK-positive anaplastic large-cell lymphoma (ALCL). SUBJECTS AND METHODS: The paper describes the experience with crizotinib used in 8 patients with refractory ALK-ALCL before and after allogeneic hematopoietic stem cell transplantation (HSCT). RESULTS: All the 8 (100%) patients treated with crizotinib were recorded to have complete responses, including complete metabolic ones (tumor disappearance as evidenced by positron emission tomography (PET)/computed tomography. CONCLUSION: Low and manageable toxicity of crizotinib and complete PET-negative responses in patients with resistant ALK lymphomas favor the need to test the drug as first-line therapy, by possibly decreasing the intensification of chemotherapy.


Subject(s)
Hematopoietic Stem Cell Transplantation/methods , Lymphoma, Large-Cell, Anaplastic , Pyrazoles , Pyridines , Receptor Protein-Tyrosine Kinases/analysis , Adolescent , Anaplastic Lymphoma Kinase , Child , Crizotinib , Drug Monitoring/methods , Female , Humans , Immunohistochemistry , Lymphoma, Large-Cell, Anaplastic/pathology , Lymphoma, Large-Cell, Anaplastic/physiopathology , Lymphoma, Large-Cell, Anaplastic/therapy , Male , Positron Emission Tomography Computed Tomography/methods , Protein Kinase Inhibitors/administration & dosage , Protein Kinase Inhibitors/adverse effects , Pyrazoles/administration & dosage , Pyrazoles/adverse effects , Pyridines/administration & dosage , Pyridines/adverse effects , Treatment Outcome
13.
Leukemia ; 31(5): 1145-1153, 2017 05.
Article in English | MEDLINE | ID: mdl-27811849

ABSTRACT

αßT-cell-depleted allogeneic hematopoietic cell transplantation holds promise for the safe and accessible therapy of both malignant and non-malignant blood disorders. Here we employed molecular barcoding normalized T-cell receptor (TCR) profiling to quantitatively track T-cell immune reconstitution after TCRαß-/CD19-depleted transplantation in children. We demonstrate that seemingly early reconstitution of αßT-cell counts 2 months after transplantation is based on only several hundred rapidly expanded clones originating from non-depleted graft cells. In further months, frequency of these hyperexpanded clones declines, and after 1 year the observed T-cell counts and TCRß diversity are mostly provided by the newly produced T cells. We also demonstrate that high TCRß diversity at day 60 observed for some of the patients is determined by recipient T cells and intrathymic progenitors that survived conditioning regimen. Our results indicate that further efforts on optimization of TCRαß-/CD19-depleted transplantation protocols should be directed toward providing more efficient T-cell defense in the first months after transplantation.


Subject(s)
Antigens, CD19 , Graft Survival , Hematologic Diseases/therapy , Hematopoietic Stem Cell Transplantation/methods , Lymphocyte Depletion/methods , Receptors, Antigen, T-Cell, alpha-beta , T-Lymphocytes/immunology , Adolescent , Child , Child, Preschool , Humans , Infant , Time Factors , Young Adult
15.
Bone Marrow Transplant ; 51(5): 668-74, 2016 May.
Article in English | MEDLINE | ID: mdl-26808573

ABSTRACT

We evaluated the depletion of TCR-alpha/beta cells from the graft of children with high-risk AML, who received transplantation from unrelated (n=20) and haploidentical donors (n=13). The preparative regimen included treosulfan, melphalan, fludarabine and anti-thymocyte globulin. Grafts were PBSC engineered by TCR-alpha/beta and CD19 depletion. The graft contained a median of 9 × 10(6)/kg of CD34+ and 20 × 10(3)/kg of αß-T cells. Post-transplant immune suppression included tacrolimus till day +30 and Mtx in 21 patients, tacrolimus in 5, Mtx in 2 and no prophylaxis in 5 patients. Sixteen patients received native or TCR-alpha/beta-depleted donor lymphocytes at a median of 47 (40-204) days. Median follow-up is 1.76 years. Primary engraftment was achieved in 33 patients (100%). Cumulative incidence of acute GvHD (aGvHD) grade 2-3 was 39 (26-60)%, half of them had skin-only aGvHD. Cumulative incidence of chronic GvHD was 30(18-50)%. Transplant-related mortality is 10(4-26)%. Event-free survival (EFS) is 60(43-76)% and overall survival (OS) is 67(50-84)% at 2 years. In a subgroup of patients, who received transplantation in CR, EFS is 66(48-84)% and OS-72(53-90)% at 2 years. Our data suggest that TCR-alpha/beta and CD19 depletion is a robust method of graft manipulation, which can be used to engineer grafts for children with AML.


Subject(s)
Antigens, CD19/analysis , Busulfan/analogs & derivatives , Leukemia, Myeloid, Acute/therapy , Receptors, Antigen, T-Cell, alpha-beta/analysis , Transplantation Conditioning/methods , Transplantation, Haploidentical/methods , Adolescent , Antigens, CD19/isolation & purification , Busulfan/therapeutic use , Child , Child, Preschool , Disease-Free Survival , Female , Graft Survival , Graft vs Host Disease , Humans , Infant , Leukemia, Myeloid, Acute/complications , Leukemia, Myeloid, Acute/mortality , Male , Receptors, Antigen, T-Cell, alpha-beta/isolation & purification , Transplantation, Haploidentical/mortality , Unrelated Donors , Young Adult
16.
Bone Marrow Transplant ; 50(8): 1089-91, 2015 Aug.
Article in English | MEDLINE | ID: mdl-25915808

ABSTRACT

Mobilization of suitable amounts of PBSCs with granulocyte-CSF (G-CSF) can be difficult in children. We report the results of using plerixafor in pediatric patients who failed to mobilize progenitors with G-CSF-based regimens. Thirty-three patients, median age 9 years (range 1-18 years) and median weight 29 kg (range 10-85 kg) were enrolled into the study. After 4 days of G-CSF stimulation, the median CD34+ cell count in peripheral blood was 10.4 per µL (range 0.27-23.0 per µL). Plerixafor was administered subcutaneously (0.24 µg/kg in 30 patients and 0.3 µg/kg in 3 patients) 11-12 h before apheresis. At the time of apheresis, CD34+ cell counts increased to a median of 44.1 per µL (range 8.4-357.0 per µL), a median 4.4-fold increase. Two patients (6%) failed to mobilize. Thirty-one patients underwent apheresis and in 27 >2 × 10(6) CD34+ cells per kg of body weight were collected after one procedure. In total, 31 of 33 patients mobilized successfully and the median number of cryopreserved CD34+ cells was 5.6 × 10(6) /kg body weight (2.7 × 10(6)-27.4 × 10(6)). Twenty-four patients underwent transplantation. Engraftment was achieved in all but one patient, who died on day +9 after hematopoietic stem cell transplantation. The median time of neutrophil and platelet recovery was day +12 and +16, respectively. Our study confirms that plerixafor has impressive efficacy and very modest toxicity in children.


Subject(s)
Granulocyte Colony-Stimulating Factor/administration & dosage , Hematopoietic Stem Cell Mobilization/methods , Hematopoietic Stem Cell Transplantation , Hematopoietic Stem Cells , Heterocyclic Compounds/administration & dosage , Neoplasms/therapy , Adolescent , Autografts , Benzylamines , Child , Child, Preschool , Cyclams , Female , Humans , Infant , Male
17.
Bioorg Khim ; 38(3): 351-64, 2012.
Article in Russian | MEDLINE | ID: mdl-22997707

ABSTRACT

Human genome variability observed within patient cohorts is considered as a goal of functional genomics essential for personalized medicine progress. In the current research we implement functional analysis of 31 polymorphic Alu insertions located within gene introns for individual genomes of patients with acute lymphoblastic leukemia (ALL). As a result we demonstrated a decrease of the primary transcripts content for 21 Alu-containing alleles. The most strong inhibitory effect of 10 Alu insertions was observed in both mononuclear blood cells of healthy donors and B-lymphoblasts of ALL patients. Allele frequencies of three Alu insertions that are located in MEF2C (two of them) and TAX1BP1 genes significantly differ (p-value 0.027. 0.052. 0.014 accordingly) between cohorts of healthy donors and ALL patients. Prolong influence of the Alu insertions on intracellular content of mature mRNA was studied for corresponding allele of TARBP1 gene.


Subject(s)
Alu Elements/genetics , Gene Frequency/genetics , Intracellular Signaling Peptides and Proteins/genetics , Introns/genetics , MADS Domain Proteins/genetics , Myogenic Regulatory Factors/genetics , Neoplasm Proteins/genetics , Precursor Cell Lymphoblastic Leukemia-Lymphoma/genetics , Adult , Alleles , Bone Marrow Cells/chemistry , Case-Control Studies , Child , Child, Preschool , DNA Primers/chemistry , DNA Primers/genetics , Female , Genetic Markers/genetics , Genome, Human , Humans , Infant , Leukocytes, Mononuclear/chemistry , MEF2 Transcription Factors , Male , Mutagenesis, Insertional , Nuclear Proteins/genetics , Polymorphism, Genetic , RNA-Binding Proteins/genetics , Russia/ethnology , Transcription, Genetic
18.
Ter Arkh ; 82(7): 20-5, 2010.
Article in Russian | MEDLINE | ID: mdl-20853604

ABSTRACT

AIM: To analyze the specific features of recurrences of acute promyelocytic leukemia (APL) in children after standard therapy with daunorubicin, cytosine arabinoside (Ara-C), all-trans retinoic acid (ATRA) and to develop further programmed treatment policy. SUBJECTS AND METHODS: The study included 9 patients with recurrent APL. The recurrences developed significantly more frequently in a very high-risk group (patients with minimal residual disease being preserved after the intensive therapy phase). Induction used arsenic trioxide (ATO) and/or standard chemotherapy + ATRA; ATO monotherapy was in consolidation. CD34+ cells were mobilized until molecular remission was achieved with high-dose Ara-C and granulocyte colony-stimulating factor. Pretransplantation conditioning involved melfalan as a basic drug in combination with high-dose AraC (5 pts), treosulfan (1 pt) or bisulfan (1 pt). Six patients received gemtusumab ozogamicin, 3-9 mg/m2, at different stages of therapy. RESULTS: Before therapy one patient died; 8 patients achieved the second molecular remission; CD34+ cell mobilization and sampling were effective in 7 cases. Five patients were in long-term molecular remission after autologous hemopoietic stem cell transplantation (autoHSCT). Follow-up was 23-40 months. One patient is being prepared for transplantation. Following autoHSCT, another patient with a developed repeat recurrence died from complications due to related partially compatible transplantation. Visceral, including cardiological, toxicity of therapy was insignificant. In the APL-2003 protocol, overall and event-free survival rates were 93 +/- 3 and 76 +/- 6%, respectively. CONCLUSION; The application of ATO and autoHSCT in recurrent APL makes it possible to achieve and preserve the second molecular remission in case of insignificant extrahematological toxicity. Russian clinics should have access to ATO.


Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Hematopoietic Stem Cell Transplantation , Leukemia, Promyelocytic, Acute/prevention & control , Transplantation Conditioning/methods , Adolescent , Antineoplastic Combined Chemotherapy Protocols/administration & dosage , Arsenic Trioxide , Arsenicals/administration & dosage , Arsenicals/therapeutic use , Child , Child, Preschool , Combined Modality Therapy , Disease-Free Survival , Humans , Infant , Leukemia, Promyelocytic, Acute/drug therapy , Leukemia, Promyelocytic, Acute/mortality , Leukemia, Promyelocytic, Acute/surgery , Oxides/administration & dosage , Oxides/therapeutic use , Remission Induction , Secondary Prevention , Transplantation, Autologous
19.
Ter Arkh ; 82(7): 34-40, 2010.
Article in Russian | MEDLINE | ID: mdl-20853607

ABSTRACT

AIM: To analyze the results of allogeneic and autologous hemopoietic cell transplantations (allo- and auto-HCT) in children with acute myeloid leukemia (AML) from an intermediate risk group, most of which were performed using lower-intensity conditioning modes. SUBJECTS AND METHODS. The study enrolled 36 children from an intermediate risk group, who had undergone auto-HCT (n = 22) or allo-HCT (n = 14) in December 1994 to December 2008. The patients' age was 0.7 to 16.6 years (median 12.8 years). Chemotherapeutic conditioning regimens were applied to all the patients. Melphalan was a basic myeloablative agent in 83.3% of cases. RESULTS: With a median follow-up of 4.6 years (1.1-13.8 years), three-year relapse-free survival (RFS) was 80.4%; overall survival (OS) was 65.6%. Recurrences were documented only in 6 (16.6%) patients from the auto-HCT. Transplantation-associated mortality (TAM) was 13.8% (five patients died). After allo-HCT versus auto-HCT, RFS, OS, and TAM were 100 and 68.7% (p = 0.03), 93.2 and 55.5% (p = 0.02), and 7.1 and 18.2%, respectively. Acute and chronic graft-versus-host reactions developed in 57.1 and 23.1%, respectively. CONCLUSION: Transplantation of allogeneic hemopoietic cells from a compatible related donor in the intermediate risk group children with AML, by using melphalan-based conditioning regimen, demonstrates a high survival rate with the minimum toxicity.


Subject(s)
Hematopoietic Stem Cell Transplantation/methods , Leukemia, Myeloid, Acute/surgery , Transplantation Conditioning/methods , Adolescent , Child , Child, Preschool , Disease-Free Survival , Female , Graft Survival , Graft vs Host Reaction , Hematopoietic Stem Cell Transplantation/mortality , Humans , Infant , Leukemia, Myeloid, Acute/drug therapy , Leukemia, Myeloid, Acute/mortality , Male , Recurrence , Remission Induction , Risk , Transplantation, Autologous , Transplantation, Homologous
20.
Ter Arkh ; 82(7): 41-7, 2010.
Article in Russian | MEDLINE | ID: mdl-20853608

ABSTRACT

AIM: To analyze the efficiency of transplantation of the bone marrow from a HLA-compatible unrelated donor and continued immunosuppressive therapy (IST) in children with aplastic anemia (AA) unresponsive to 2 courses of IST. SUBJECTS AND METHODS: The study enrolled 14 children aged 2-16 years (median 9 years). A control group comprised 26 patients in whom IST was continued. The median interval between the diagnosis of AA and transplantation was 26 months (9-156 months). The conditioning regimen consisted of thoracoabdominal irradiation in a dose of 2 Gy, fludarabin (Flu) 100-150 mg/m2, cyclophosphamide (Cy) 100-200 mg/kg, antithymocyte globulin (ATG) in 11 patients and Flu, Cy, and ATG in 3. A graft-versus-host reaction was prevented with mycophenolate mefetil in all the patients, tacrolimus in 11, and cyclosporin A in 3. Donors were compatible for high-resolution typing of 10/10 and 9/10 alleles in 8 and 6 patients, respectively; the source of a transplant was bone marrow in 13 patients and granulocyte colony-stimulating factor-mobilized peripheral blood precursors in one case. RESULTS: Thirteen patients achieved primary engraftment after single transplantation; one patient did after repeat transplantation. Grades I to II graft-versus-host reaction (GVHR) developed in 9 patients; postengraftment life-threatening infections in 3, extensive chronic GVHR in 2, circumscribed GVHR in 7. All fourteen hemopoietic cell transplant recipients followed for a median 17.5 months (range 1-71 months) were survivors. CONCLUSION: The likelihood of good survival after unrelated transplantations in AA is much higher than that after continued IST: 100% versus 15 +/- 11%.


Subject(s)
Anemia, Aplastic/surgery , Antilymphocyte Serum/therapeutic use , Bone Marrow Transplantation/methods , Cyclosporine/therapeutic use , HLA Antigens , Immunosuppressive Agents/therapeutic use , Tissue Donors , Transplantation Conditioning/methods , Adolescent , Anemia, Aplastic/drug therapy , Anemia, Aplastic/etiology , Anemia, Aplastic/immunology , Anemia, Aplastic/radiotherapy , Antilymphocyte Serum/administration & dosage , Child , Child, Preschool , Combined Modality Therapy , Cyclosporine/administration & dosage , Disease-Free Survival , Graft Survival , Graft vs Host Reaction/immunology , HLA Antigens/genetics , Humans , Immunosuppressive Agents/administration & dosage , Treatment Failure
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