Publications by authors named "Alexey Maschan"

30 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 Apr 11. 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
April 2021

Plerixafor added to G-CSF allows mobilization of a sufficient number of hematopoietic progenitors without impacting the efficacy of TCR-alpha/beta depletion in pediatric haploidentical and genoidentical donors failing to mobilize with G-CSF alone.

J Clin Apher 2021 Mar 8. Epub 2021 Mar 8.

Dmitri Rogachev National Research Centre for Pediatric Hematology, Oncology and Immunology, Ministry of Health of Russian Federation, Moscow, Russia.

Background: Collection of a large number of early hematopoietic progenitors is essential for allogeneic apheresis products intended for TCR-alpha/beta depletion.

Materials And Methods: We added plerixafor 0.24 mg/kg body weight (bw) on day 4 of high-dose filgrastim mobilization 10 hours prior to apheresis in 16 (30.5%) pediatric allogeneic donors who failed to recover a sufficient number of CD34+ cells.

Results: On day 4 of G-CSF, the median CD34+ cell count in peripheral blood was 6 per μL (range 4-9 per μL) in 6 poor mobilizers and 16 per μL (range 12-19 per μL) in insufficient mobilizers. In all donors, the threshold of 50 CD34+ cells/μL was achieved, and the median increase was 14.8-fold in poor mobilizers and 6.5-fold in insufficient mobilizers, whereas it was 3.45-fold increase in those mobilized with G-CSF alone.

Discussion: In all donors, a predefined number of >10 × 10 CD34+ cells/kg of recipient bw before depletion was reached in the apheresis product. The use of plerixafor did not affect the purity of further TCR-alpha/beta depletion. Side effects were mild to moderate and consisted of nausea and vomiting.

Conclusion: Thus, the safety and high efficacy of plerixafor was proven in healthy pediatric allogeneic hematopoietic cell donors.
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http://dx.doi.org/10.1002/jca.21891DOI Listing
March 2021

Immunophenotypic changes of leukemic blasts in children with relapsed/refractory B-cell precursor acute lymphoblastic leukemia, who have been treated with Blinatumomab.

Haematologica 2020 12 30;Online ahead of print. Epub 2020 Dec 30.

Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology; 1 Samory Mashela St., Moscow 117998, Russian Federation.

Not available.
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http://dx.doi.org/10.3324/haematol.2019.241596DOI Listing
December 2020

Chimerism evaluation in measurable residual disease-suspected cells isolated by flow cell sorting as a reliable tool for measurable residual disease verification in acute leukemia patients after allogeneic hematopoietic stem cell transplantation.

Cytometry B Clin Cytom 2020 Dec 28. Epub 2020 Dec 28.

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

Background: The presence of minimal/measurable residual disease (MRD) before or after hematopoietic stem cell transplantation (HSCT) is known as a predictor of poor outcome in patients with acute myeloid (AML) or lymphoblastic (ALL) leukemia. When performed with multiparameter flow cytometry (MFC), assessment of residual leukemic cells after HSCT may be limited by therapy-induced shifts in the immunophenotype (e.g., loss of surface molecules used for therapeutic targeting). However, in such cases, questionable cells can be isolated and tested for hematopoietic chimerism to clarify their origin.

Methods: Questionable cell populations were detected during the MFC-based MRD monitoring of 52 follow-up bone marrow samples from 37 patients diagnosed with T cell neoplasms (n =14), B cell precursor ALL (n = 16), AML (n = 7). These cells (suspected leukemic or normal) were isolated by flow cell sorting and tested for hematopoietic chimerism by RTQ-PCR.

Results: The origin of cells was successfully identified in 96.15% of cases (n = 50), which helped to validate the results of MFC-based MRD monitoring.

Conclusions: We believe that a combination of MFC, cell sorting, and chimerism testing may help confirm or disprove MRD presence in complicated cases after HSCT.
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http://dx.doi.org/10.1002/cyto.b.21982DOI Listing
December 2020

Additional flow cytometric studies for differential diagnosis between Burkitt lymphoma/leukemia and B-cell precursor acute lymphoblastic leukemia.

Leuk Res 2021 01 8;100:106491. Epub 2020 Dec 8.

National Medical Research Center of Pediatric Hematology, Oncology and Immunology, 1 Samory Mashela St., 117998, Moscow, Russia. Electronic address:

The differentiation between Burkitt lymphoma/leukemia (BL) and B-cell precursor acute lymphoblastic leukemia (BCP-ALL) is sometimes complicated. Laboratory findings that favor BL (e.g., surface expression of μ heavy chain and/or one of the light chains of immunoglobulin, FAB L3 morphology of blasts, MYC gene rearrangements) are not always present simultaneously. Our previous work demonstrated that BL differed from Ig(+) BCP-ALL by expression of Ig and other surface markers. In the current study, we have evaluated additional flow cytometric markers for reliable differentiation between BL and BCP-ALL. Among three studied surface antigens (CD44, CD38, CD58), only CD58 demonstrated significantly higher expression in BL as compared to BCP-ALL. Moreover, BL cases were associated with an increased level of Ki-67 and a higher percentage of cells in the S-phase of cell cycle. These two features reflect an aggressive proliferative potential of BL. Thus, when BL is suspected and results of surface Ig evaluation are controversial, the flow cytometric analysis of CD58, Ki-67 and cell cycle could assist in the differential diagnosis.
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http://dx.doi.org/10.1016/j.leukres.2020.106491DOI Listing
January 2021

Quantification of NG2-positivity for the precise prediction of KMT2A gene rearrangements in childhood acute leukemia.

Genes Chromosomes Cancer 2021 Feb 20;60(2):88-99. Epub 2020 Nov 20.

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

It has long been known that there is a link between neuron glial antigen 2 (NG2) surface expression and KMT2A gene rearrangements in acute leukemia (AL). However, the exact levels of NG2 positivity that predict the presence of KMT2A rearrangement are not known. The current study focuses on a cohort of 505 pediatric AL patients who showed any level of positive NG2 expression (greater than 1% of cells) for whom comprehensive genetic data were available. NG2 expression was measured as either the percentage of positive cells or the number of molecules on the cell surface. KMT2A gene rearrangements were identified by FISH. The fusion partner was detected with RT-PCR, LDI-PCR or anchored multiplex PCR followed by high-throughput sequencing. KMT2A-positive samples comprised a substantial proportion of the NG2-positive cohort (180 of 505, 36%), with a total of 19 different types of translocation. Despite its occurrence in other AL genetic subgroups, NG2 expression was significantly increased in AL patients with KMT2A rearrangements in terms of both the cell percentage and number of molecules per cell. The threshold levels (TL) for NG2-positivity were established by ROC analysis of the whole cohort and separately for children less than 1 years old and older with lymphoblastic (ALL) and myeloid (AML) leukemia. The lowest TL was defined in infants with ALL (7%), while in older children, the threshold was higher (12%). In AML patients, the situation was reversed, with 28% NG2-positivity in infants and 14% in patients >1 year old. The defined TLs resulted in improved diagnostic performance compared to the conventional thresholds of 10% and 20% for all patient groups.
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http://dx.doi.org/10.1002/gcc.22915DOI Listing
February 2021

Efficacy of romiplostim in treatment of thrombocytopenia in children with Wiskott-Aldrich syndrome.

Br J Haematol 2021 01 31;192(2):366-374. Epub 2020 Oct 31.

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

Wiskott-Aldrich syndrome (WAS) is a life-threatening primary immunodeficiency associated with bleeding of variable severity due to thrombocytopenia. Correction of the thrombocytopenia is of paramount importance for most WAS patients. We report a retrospective analysis of the safety and efficacy of romiplostim treatment in reducing thrombocytopenia and bleeding tendency in 67 children (median age 1·3 years) with genetically confirmed WAS, followed in eight months (range, 1-12 months). Complete or partial primary responses regarding platelet counts were observed in 22 (33%) and 18 (27%) subjects, respectively. Yet, even in the non-responder group, the risk of haemorrhagic events decreased significantly, to 21%, after the first month of treatment. The responses tended to be durable and stable over time, with no significant fluctuations in platelets counts. The results of this retrospective study of a large cohort of WAS patients demonstrates that romiplostim can be used to increase platelet counts and reduce the risks of life-threatening bleeding in WAS patients awaiting haematopoietic stem cell transplantation or forgoing the procedure for various reasons.
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http://dx.doi.org/10.1111/bjh.17174DOI Listing
January 2021

Romiplostim treatment for children with immune thrombocytopenia: Results of an integrated database of five clinical trials.

Pediatr Blood Cancer 2020 11 9;67(11):e28630. Epub 2020 Sep 9.

Amgen Inc., Thousand Oaks, California.

Background: Treatment for chronic immune thrombocytopenia (cITP) in children is largely limited to immunosuppressive agents. Thrombopoietin receptor agonists (TRAs) have been used to treat cITP in adults for over a decade. The objective of this integrated analysis was to examine the safety and efficacy of the TRA romiplostim in children with ITP.

Methods: We examined efficacy and safety in children with ITP across five romiplostim trials: final data from two double-blind placebo-controlled trials and two open-label extensions, and interim data from an ongoing single-arm trial.

Results: Patients (n = 24 initially placebo; n = 262 initially romiplostim) had a median age of 10.0 years (Q1: 6.0, Q3: 13.0), ITP duration of 1.9 years (Q1: 1.0, Q3: 4.0), and baseline platelet count of 14.3 × 10 /L (Q1: 7.5, Q3: 23.0). Among 282 patients receiving romiplostim, median treatment duration was 65 weeks (range 8-471 weeks) and median weekly dose was 6.6 μg/kg (range 0.1-9.7 μg/kg). Overall, 89% of romiplostim-treated patients had platelet responses. Nineteen patients (7%) maintained treatment-free responses for ≥6 months while withholding all ITP therapy. Grade 3 and 4 adverse events of bleeding occurred in 10% and <1% of romiplostim-treated patients, respectively. Twenty-five percent of patients had a serious adverse event, most commonly epistaxis (6%). Seven patients (2%) had neutralizing antibodies against romiplostim postbaseline and none had neutralizing antibodies against endogenous thrombopoietin. Efficacy and safety results appeared similar between children with ITP for ≤12 months and >12 months at baseline.

Conclusions: Across five pediatric clinical trials, romiplostim was well tolerated. Most patients had a platelet response; some maintained responses for at least 6 months while withholding all ITP therapy.
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http://dx.doi.org/10.1002/pbc.28630DOI Listing
November 2020

FLAER-negative CD15+ neutrophils can be used for the simplified screening of suspected PNH cases.

Int J Lab Hematol 2020 Oct 25;42(5):589-593. Epub 2020 May 25.

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

Background: The flow cytometry analysis of GPI-linked proteins on red blood cells and leukocytes is crucial for paroxysmal nocturnal hemoglobinuria (PNH) diagnostics. However, the commonly used multicolor panels cannot be implemented in low-resourced hematology laboratories. In order to develop a simple prediagnostic test for PNH screening, we analyzed the diagnostic accuracy of the two-color (FLAER/CD15) detection of GPI-deficient neutrophils.

Methods: We reanalyzed multicolor data set of 1594 peripheral blood samples of patients screened for PNH applying only two markers (FLAER/CD15). The quantitative positivity/negativity was reported. Then, these results were compared in a blinded manner with previously obtained multicolor data from the same samples.

Results: Among the 1594 samples included in the study, 507 samples were PNH-positive by the multicolor assay. The two-color method revealed 510 PNH-positive samples. The detailed examination of this discrepancy revealed 12 false-positives and 9 false-negatives. Therefore, FLAER/CD15 screening method displayed 98.90% of the diagnostic specificity and 98.22% of the sensitivity.

Conclusion: This simple two-color evaluation of FLAER-negative neutrophils is a highly effective screening test for PNH. Although this approach is not intended to replace the multicolor diagnostic procedure, it could minimize the number of patients requiring a conventional multicolor flow cytometric assay.
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http://dx.doi.org/10.1111/ijlh.13239DOI Listing
October 2020

Control of graft-versus-host disease with rabbit anti-thymocyte globulin, rituximab, and bortezomib in TCRαβ/CD19-depleted graft transplantation for leukemia in children: a single-center retrospective analysis of two GVHD-prophylaxis regimens.

Pediatr Transplant 2020 02 3;24(1):e13594. Epub 2019 Nov 3.

Department of Hematopoietic Stem Cell Transplantation, Dmitriy Rogachev National Center for Pediatric Hematology, Oncology and Immunology, Moscow, Russia.

Both acute GVHD and chronic GVHD remain the leading cause of morbidity and death after allogeneic HSCT. We conducted a retrospective analysis comparing two GVHD-prophylaxis regimens: 35 patients received "Regimen 1" (horse ATG, tacrolimus, and methotrexate) and 46 "Regimen 2" (rabbit ATG, rituximab, and peritransplant bortezomib). All 81 patients with a median age of 9 (0.6-23) years with ALL (n = 31) or AML (n = 50) in complete remission received TCRαβ/CD19-depleted transplants between May 2012 and October 2016, from 40 HLA-matched unrelated and 41 haploidentical donors. After a median follow-up of 3.9 years, the CI of acute GVHD II-IV was 15% (95% CI: 7-30) in the "Regimen 2" group and 34% (95% CI: -54) in the "Regimen 1" group, P = .05. "Regimen 2" was also more effective in the prevention of chronic GVHD; the CI at 1 year after HSCT was 7% (95% CI: 2-19) vs 31% (95% CI: 19-51), P = .005. The CI of relapse at 3 years adjusted for the GVHD-prophylaxis regimen groups 31% (95% CI: 19-51) for the "Regimen 1" vs 21% (95% CI: 11-37) for the "Regimen 2", P = .3. The retrospective observation suggests that the use of the rATG, rituximab, and bortezomib was associated with significantly lower rate of GVHD without the loss of anti-leukemic activity.
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http://dx.doi.org/10.1111/petr.13594DOI Listing
February 2020

Mismatched related vs matched unrelated donors in TCRαβ/CD19-depleted HSCT for primary immunodeficiencies.

Blood 2019 11;134(20):1755-1763

Department of Hematopoietic Stem Cell Transplantation.

TCRαβ+/CD19+ graft depletion effectively prevents graft-versus-host disease (GVHD). In the current study, we compared the outcomes of hematopoietic stem cell transplantation (HSCT) with TCRαβ+/CD19+ depletion from matched unrelated donors (MUDs) and mismatched related donors (MMRDs) in patients with primary immunodeficiency (PID). A total of 98 pediatric patients with various PIDs underwent HSCT with TCRαβ+/CD19+ graft depletion from MUDs (n = 75) and MMRDs (n = 23). All patients received a fludarabine-/treosulfan-based conditioning regimen, with 73 also receiving a second alkylating agent. For GVHD prophylaxis, all but 2 received serotherapy (antithymocyte globulin) before HSCT and a short course of posttransplant immunosuppression. Neutrophil and platelet engraftment in both the MUD and MMRD groups occurred on days 14 and 13, respectively. The incidence of secondary graft failure was 0.16 and 0.17 (P = .85), respectively. The cumulative incidence of acute GVHD grade 2 to 4 was 0.17 in the MUD group and 0.22 in the MMRD group (P = .7). The incidence of cytomegalovirus (CMV) viremia was 0.5 in the MUD group and 0.6 in the MMRD group (P = .35). The frequency of CMV disease was high (17%), and the most common manifestation was retinitis. The kinetics of immune recovery was similar in both groups. The overall survival was 0.86 in the MUD group and 0.87 in the MMRD group (P = .95). In our experience, there was no difference in the outcomes of HSCT performed from MUD and MMRD. Hence, given the immediate availability of donors, in the absence of HLA-identical siblings, HSCT with TCRαβ+/CD19+ graft depletion from MMRDs can be considered as the first choice in patients with PID.
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http://dx.doi.org/10.1182/blood.2019001757DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6856988PMC
November 2019

Phase 2 study of nilotinib in pediatric patients with Philadelphia chromosome-positive chronic myeloid leukemia.

Blood 2019 12;134(23):2036-2045

Department of Pediatrics, Hematology and Oncology Division, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand.

Chronic myeloid leukemia (CML) is rare in children and accounts for ≤15% of all myeloid leukemia cases. When we initiated this study with nilotinib, imatinib was the only tyrosine kinase inhibitor indicated for pediatric patients with Philadelphia chromosome-positive (Ph+) CML in chronic phase (CP); alternative treatment options were needed, particularly for patients who developed resistance or intolerance (R/I) to imatinib. This phase 2 study enrolled pediatric patients with either Ph+ CML-CP R/I to imatinib or dasatinib or newly diagnosed Ph+ CML-CP. Data presented are from analyses with minimum follow-up of up to 24 cycles (1 cycle is 28 days). Fifty-nine patients with Ph+ CML-CP were enrolled, and 58 were treated (R/I, n = 33; newly diagnosed, n = 25). Major molecular response (MMR) rate at cycle 6 in the R/I cohort was 39.4% (primary end point); 57.6% of patients achieved or maintained MMR and 81.8% achieved or maintained complete cytogenetic response (CCyR) by 24 cycles. In patients with newly diagnosed disease, rates of MMR by cycle 12 and CCyR at cycle 12 were 64.0% each (primary end points); by cycle 24, cumulative MMR and CCyR rates were 68.0% and 84.0%, respectively. The safety profile of nilotinib in pediatric patients was generally comparable with the known safety profile in adults, although cardiovascular events were not observed in this study, and hepatic laboratory abnormalities were more frequent; no new safety signals were identified. In summary, nilotinib demonstrated efficacy and a manageable safety profile in pediatric patients with Ph+ CML-CP. This trial was registered at www.clinicaltrials.gov as #NCT01844765.
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http://dx.doi.org/10.1182/blood.2019000069DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6923664PMC
December 2019

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

Rituximab and reduced-intensity chemotherapy in children and adolescents with mature B-cell lymphoma: interim results for 231 patients enrolled in the second Russian-Belorussian multicentre study B-NHL-2010M.

Br J Haematol 2019 08 9;186(3):477-483. Epub 2019 May 9.

Dmitri Rogachev National Research Centre for Paediatric Haematology, Oncology and Immunology, Moscow, Russian Federation.

The value of adding rituximab to chemotherapy in children with aggressive B-cell non-Hodgkin lymphoma (B-NHL) is still insufficiently studied. We enrolled 231 patients [mean age 9 years old (range 2-17); male:female ratio 3·4:1] with Burkitt (BL, 179 patients, 76·7%), diffuse large B-cell (32 patients, 14%), primary mediastinal B-cell (14 patients, 6%), and other (6 patients, 2·6%) B-cell lymphomas in a prospective study of immuno-chemotherapy. Stages were I-II in 32% and III-IV in 68% of the patients. Four doses of 375 mg/m rituximab were added to the Berlin-Frankfurt-Munster-NHL-90-like chemotherapy, with methotrexate being reduced or omitted in the first 2 induction blocks. The complete remission rate was 100% in limited-stage and 91·4% in advanced-stage patients. Five advanced-stage patients (2·2%) died in induction and 1 patient with stage 2 B-NHL died in remission; 11 patients in the high-risk group progressed on therapy (3 non-BL are alive after salvage) and 5 relapsed. Sixteen patients (9·7%) with advanced stage disease proceeded to transplant. With a median follow-up of 46 months, 98·5 ± 1% of patients with limited disease and 88·1 ± 2% (88·1% in Risk Group 3; 82·6% in Risk Group 4) in advanced stages are alive. This study confirmed that combined immunochemotherapy for B-lymphomas is highly effective in children, despite reducing the intensity of the induction blocks.
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http://dx.doi.org/10.1111/bjh.15944DOI Listing
August 2019

Thrombopoietin receptor agonist switch in children with persistent and chronic severe immune thrombocytopenia: A retrospective analysis in a large tertiary center.

Pediatr Blood Cancer 2019 06 11;66(6):e27704. Epub 2019 Mar 11.

Dmitri Rogachev National Research Center for Pediatric Hematology, Oncology and Immunology, Moskva, Russia.

We retrospectively analyzed sequential therapy with romiplostim and eltrombopag in 23 children with immune thrombocytopenia: switching from romiplostim to eltrombopag (10 patients) or vice versa (13 patients). The median age of patients at enrollment in the study was 5.6 years (2-15 years). Switching from romiplostim to eltrombopag was effective in eight (80%) patients, whereas switching from eltrombopag to romiplostim was effective in eight (62%) patients. The response rate was similar in patients failing the first thrombopoietin receptor agonist and those who had previous response. To date, all responders continue to maintain platelets over 50 × 10 /L at 13-39 months after switching.
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http://dx.doi.org/10.1002/pbc.27704DOI Listing
June 2019

Prospective Study of a Cohort of Russian Nijmegen Breakage Syndrome Patients Demonstrating Predictive Value of Low Kappa-Deleting Recombination Excision Circle (KREC) Numbers and Beneficial Effect of Hematopoietic Stem Cell Transplantation (HSCT).

Front Immunol 2017 24;8:807. Epub 2017 Jul 24.

Dmitry Rogachev National Research and Clinical Center for Pediatric Hematology, Oncology and Immunology, Moscow, Russia.

Background: Nijmegen breakage syndrome (NBS) is a combined primary immunodeficiency with DNA repair defect, microcephaly, and other phenotypical features. It predominantly occurs in Slavic populations that have a high frequency of carriers with the causative NBN gene c.657_661del5 mutation. Due to the rarity of the disease in the rest of the world, studies of NBS patients are few. Here, we report a prospective study of a cohort of Russian NBS patients.

Methods: 35 Russian NBS patients of ages 1-19 years, referred to our Center between years 2012 and 2016, were prospectively studied.

Results: Despite the fact that in 80% of the patients microcephaly was diagnosed at birth or shortly thereafter, the average delay of NBS diagnosis was 6.5 years. Though 80% of the patients had laboratory signs of immunodeficiency, only 51% of the patients experienced significant infections. Autoimmune complications including interstitial lymphocytic lung disease and skin granulomas were noted in 34%, malignancies-in 57% of the patients. T-cell excision circle (TREC)/kappa-deleting recombination excision circle (KREC) levels were low in the majority of patients studied. Lower KREC levels correlated with autoimmune and oncological complications. Fifteen patients underwent hematopoietic stem cell transplantation (HSCT), 10 of them were alive and well, with good graft function. Three patients in the HSCT group and five non-transplanted patients died; tumor progression being the main cause of death. The probability of the overall survival since NBS diagnosis was 0.76 in the HSCT group and 0.3 in the non-transplanted group.

Conclusion: Based on our findings of low TRECs in most NBS patients, independent of their age, TREC detection can be potentially useful for detection of NBS patients during neonatal screening. KREC concentration can be used as a prognostic marker of disease severity. HSCT is a viable treatment option in NBS and should be especially considered in patients with low KREC numbers early on, before development of life-threatening complications.
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http://dx.doi.org/10.3389/fimmu.2017.00807DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5523727PMC
July 2017

Eight-year follow-up in pediatric living donor kidney recipients receiving alemtuzumab induction.

Pediatr Transplant 2017 Aug 10;21(5). Epub 2017 Jun 10.

Laboratory Department, Boris Petrovsky Research Center of Surgery, Moscow, Russia.

Recipient lymphocytes are crucial for direct and indirect pathways of allorecognition. We proposed that the administration of alemtuzumab several weeks pretransplantation could eradicate peripheral lymphatic cells and promote donor-specific acceptance. This was a single-center, retrospective review of 101 consecutive living donor kidney transplantations in pediatric patients (age 7 months-18 years), performed between September 2006 and April 2010. IS protocol included two 30 mg doses of alemtuzumab: The first was given 12-29 days prior to transplantation, and the second at the time of transplantation. Maintenance IS was based on combination of low-dose CNI and mycophenolate, with steroids tapered over the first 5 days post-transplantation. Patients were followed for 7.8±1.3 years, and protocol biopsies were taken 1 month, 1, 3, and 5 years post-transplant. The Kaplan-Meier 8-year patient and graft survival rates in the cyclosporine-treated patients were 82.0±7.3% and 71.6±7.3, and in the tacrolimus-treated patients were 97.2±5.4 and 83.8±6.0%. Biopsy-proven acute rejection developed in 35% of cyclosporine-treated patients and in 8% of tacrolimus-treated patients. Alemtuzumab pretreatment prior to LRD kidney transplantation, followed by maintenance immunosuppression with tacrolimus and MMF, is associated with reasonable long-term results in pediatric patients.
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http://dx.doi.org/10.1111/petr.12941DOI Listing
August 2017

Very long survival in complete cytogenetic remission in an adolescent with lymphoid blast crisis of chronic myeloid leukemia after treatment with intensive ALL-directed chemotherapy combined with continuous imatinib.

Pediatr Blood Cancer 2016 12 19;63(12):2243-2245. Epub 2016 Jul 19.

Dmitri Rogachev Federal Research Center for Pediatric Hematology, Oncology and Immunology, Russian Federation, Moscow, Russia.

An 11-year-old male was diagnosed with chronic-phase chronic myeloid leukemia (CML) in 1998 and received therapy with interferon-α2b and low-dose cytarabine. In 6 years, he progressed to lymphoid blast crisis and received induction chemotherapy with prednisolone, vincristine, daunorubicin, and l-asparaginase concomitantly with imatinib 400 mg/day, and continuation with vincristine + prednisolone, cytarabine + etoposide, vincristine + l-asparaginase, cyclophosphamide + etoposide, and 6-mercaptopurine + methotrexate. Complete molecular response (MR) was achieved and therapy was continued with imatinib 800 mg/day. He relapsed to chronic-phase CML after interruption of imatinib and regained MR after its restart. The patient is alive 17.5 years after CML diagnosis and 11.5 years after lymphoid blast crisis.
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http://dx.doi.org/10.1002/pbc.26148DOI Listing
December 2016

Brentuximab vedotin in the treatment of a patient with refractory Hodgkin disease and Proteus syndrome - a case report and discussion.

Clin Case Rep 2015 Jul 11;3(7):646-9. Epub 2015 Jun 11.

Federal Center for Pediatric Hematology, Oncology and Immunology, Named by D. Rogachev Moscow, Russia.

Treatment of patients with refractory Hodgkin lymphoma is a significant issue. We report a patient with Proteus syndrome and relapsed Hodgkin lymphoma, whose remission was finally achieved after brentuximab vedotin therapy, allowing her to receive a haploidentical stem cell transplant. The possible relationship between both disorders was discussed.
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http://dx.doi.org/10.1002/ccr3.297DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4527816PMC
July 2015

Clinical and genomic heterogeneity of Diamond Blackfan anemia in the Russian Federation.

Pediatr Blood Cancer 2015 Sep 6;62(9):1597-600. Epub 2015 May 6.

Dmitry Rogachev Federal Clinical Research Center for Pediatric Hematology, Oncology and Immunology, Moscow, Russia.

Background: Diamond Blackfan anemia (DBA) is a genetically and clinically heterogeneous ribosomopathy and inherited bone marrow failure syndrome characterized by anemia, reticulocytopenia, and decreased erythroid precursors in the bone marrow with an increased risk of malignancy and, in approximately 50%, physical abnormalities.

Methods: We retrospectively analyzed clinical data from 77 patients with DBA born in the Russian Federation from 1993 to 2014. In 74 families there was one clinically affected individual; in only three instances a multiplex family was identified. Genomic DNA from 57 DBA patients and their first-degree relatives was sequenced for mutations in RPS19, RPS10, RPS24, RPS26, RPS7, RPS17, RPL5, RPL11, RPL35a, and GATA1.

Results: Severe anemia presented before 8 months of age in all 77 patients; before 2 months in 61 (78.2%); before 4 months in 71 (92.2%). Corticosteroid therapy was initiated after 1 year of age in the majority of patients. Most responded initially to steroids, while 5 responses were transient. Mutations in RP genes were detected in 35 of 57 patients studied: 15 in RPS19, 6 in RPL5, 3 in RPS7, 3 each in RPS10, RPS26, and RPL11 and 1 each in RPS24 and RPL35a; 24 of these mutations have not been previously reported. One patient had a balanced chromosomal translocation involving RPS19. No mutations in GATA1 were found.

Conclusion: In our cohort from an ethnically diverse population the distribution of mutations among RP genes was approximately the same as was reported by others, although within genotypes most of the mutations had not been previously reported.
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http://dx.doi.org/10.1002/pbc.25534DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4515145PMC
September 2015

The prognostic significance of early treatment response in pediatric relapsed acute myeloid leukemia: results of the international study Relapsed AML 2001/01.

Haematologica 2014 Sep 24;99(9):1472-8. Epub 2014 Apr 24.

Pediatric Oncology/Hematology, VU University Medical Center, Amsterdam, The Netherlands Dutch Childhood Oncology Group, The Hague, The Netherlands.

The prognostic significance of early response to treatment has not been reported in relapsed pediatric acute myeloid leukemia. In order to identify an early and easily applicable prognostic factor allowing subsequent treatment modifications, we assessed leukemic blast counts in the bone marrow by morphology on days 15 and 28 after first reinduction in 338 patients of the international Relapsed-AML2001/01 trial. Both day 15 and day 28 status was classified as good (≤20% leukemic blasts) in 77% of patients. The correlation between day 15 and 28 blast percentages was significant, but not strong (Spearman correlation coefficient = 0.49, P<0.001). Survival probability decreased in a stepwise fashion along with rising blast counts at day 28. Patients with bone marrow blast counts at this time-point of ≤5%, 6-10%, 11-20% and >20% had 4-year probabilities of survival of 52%±3% versus 36%±10% versus 21%±9% versus 14%±4%, respectively, P<0.0001; this trend was not seen for day 15 results. Multivariate analysis showed that early treatment response at day 28 had the strongest prognostic significance, superseding even time to relapse (< or ≥12 months). In conclusion, an early response to treatment, measured on day 28, is a strong and independent prognostic factor potentially useful for treatment stratification in pediatric relapsed acute myeloid leukemia. This study was registered with ISRCTN code: 94206677.
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http://dx.doi.org/10.3324/haematol.2014.104182DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4562536PMC
September 2014

Therapy of advanced-stage mature B-cell lymphoma and leukemia in children and adolescents with rituximab and reduced intensity induction chemotherapy (B-NHL 2004M protocol): the results of a multicenter study.

J Pediatr Hematol Oncol 2014 Jul;36(5):395-401

*Federal Research Centre of Pediatric Hematology, Oncology and Immunology named after Dmitry Rogachev †Russian Pediatric Clinical Hospital, Moscow ‡Municipal Clinical Hospital No. 31, Saint-Petersburg §Regional Pediatric Clinical Hospital, Yekaterinburg ∥Regional Pediatric Clinical Hospital, Nizhniy Novgorod ¶Territorial Pediatric Clinical Hospital, Perm, Russia.

Pediatric mature B-cell non-Hodgkin lymphomas (B-NHLs) are highly aggressive malignant tumors that are curable with chemotherapy (ChT). High-dose methotrexate (MTX) is considered indispensable for successful treatment, but this therapy frequently induces severe mucositis and infectious complications, especially in induction, which can cause treatment failure. A prospective multicenter trial of combined immunochemotherapy for advanced-stage B-NHL with rituximab and the modified NHL-BFM-90 protocol was conducted. The major differences from the original protocol were a decrease in the dose of MTX from 5000 to 1000 mg/m/24 h in the first 2 ChT blocks and the addition of rituximab at 375 mg/m to each of the first 4 blocks of ChT. Eighty-three newly diagnosed patients with a median age of 8.84 years with Burkitt lymphoma/leukemia and diffuse large B-cell lymphomas stage III to IV were included. Four patients died during induction ChT due to tumor lysis syndrome and infection. Two additional patients died subsequently due to tumor resistance. Complete remission was achieved in 77 (92.8%) patients; 2 patients relapsed at 1 and 3 months, and 2 developed secondary malignancies at 1 and 6.5 years, respectively, after the completion of therapy. The overall survival probability was 82%±8% with a median follow-up of 65.2 months. Combined therapy with rituximab and intensive ChT with a reduced MTX dose of 1 g/m in the 2 induction courses was feasible and produced high cure rates in patients with pediatric advanced-stage mature B-NHL.
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http://dx.doi.org/10.1097/MPH.0b013e31829d4900DOI Listing
July 2014

NPM1, FLT3, and c-KIT mutations in pediatric acute myeloid leukemia in Russian population.

J Pediatr Hematol Oncol 2013 Apr;35(3):e100-8

Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Moscow, Russia.

We evaluated frequencies of NPM1, FLT3, c-KIT mutations in childhood acute myeloid leukemia (AML) in Russia and assessed prognostic relevance of the mutations. RNA and DNA were extracted from bone marrow samples of 186 (106 male and 80 female) pediatric patients younger than 17 year with de novo AML. Mutations and chromosomal rearrangements were detected by sequencing of a corresponding gene. NPM1 mutations were found in 5.2%, FLT3 mutations in 12.1%, c-KIT mutations in 3.7% of the patients. NPM1 mutations were associated with the absence of chromosomal aberrations (P=0.007) and FLT3/ITD (P=0.018). New data on incidence of c-KIT mutations in various AML subtypes as well as new variations of c-KIT mutations in the exon 8 are presented. The results are compared to previously published studies on NPM1, FLT3, c-KIT mutations in various populations. No statistically significant differences in survival rates between groups with or without of FLT3, NPM1, c-KIT mutations were found (P>0.05). Meanwhile, 4-year overall survival rates were higher in patients having NPM1 mutations comparing with NPM1/WT patients (100% vs. 50%) and in patients having FLT3 mutations comparing with FLT3/WT patients (70% vs. 50%). The data presented contribute to knowledge on incidence and prognostic significance of the mutations in pediatric AML.
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http://dx.doi.org/10.1097/MPH.0b013e318286d261DOI Listing
April 2013

Alemtuzumab induction in pediatric kidney transplantation.

Pediatr Transplant 2013 Mar;17(2):168-78

Organ Transplant Division, Russian Scientific Center of Surgery, Moscow, Russia.

Recipient parenchymal lymphatic cells are crucial for direct and indirect pathways of allorecognition. We proposed that alemtuzumab, being infused several weeks pretransplant could eradicate peripheral lymphatic cells and promote donor-specific tolerance. We present here a single center, retrospective review of 101 consecutive living-donor kidney transplantations to pediatric patients aged from seven month to 18 yr, performed between September 2006 and April 2010. Immunosupression protocol included two 30 mg doses of alemtuzumab: first given 12-29 d prior to transplantation and second at the time of transplantation. Maintenance immunosupression was based on combination of low dose and wide range CNI and mycophenolate. Patients were followed for 3.8 ± 1.4 yr and protocol biopsies were taken one month, one, and three yr post transplant. The Kaplan-Meier graft and patient survival was 96% and 97% for one yr, 89% and 93% for three yr. Biopsy proven acute rejection developed in 26% patients at one yr and in 35% at two yr, no rejections occurred beyond two yr. We conclude that alemtuzumab pretreatment prior to living related donor kidney transplantation allows to reach satisfactory middle-term results in pediatric patients with wide range and low CNI concentrations.
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http://dx.doi.org/10.1111/petr.12048DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3644867PMC
March 2013

Response of pure red cell aplasia to cyclophosphamide after failure of mycofenolate mofetil in a patient with polyglandular syndrome type I.

J Pediatr Hematol Oncol 2013 Nov;35(8):e338-40

*Endocrinology Research Centre, Institute of Pediatric Endocrinology †Federal Research Center for Pediatric Hematology, Oncology, and Immunology, Moscow, Russian Federation.

A 26-year-old female with the classic major and minor components of autoimmune polyglandular syndrome type 1 was diagnosed as having pure red cell aplasia. Treatment with 1.5 g/d mycofenolate mofetil for 3 months failed to restore erythroid production. Treatment with cyclosporine A produced a good partial response but led to renal toxicity and was therefore substituted with cyclophosphamide, which had a good partial effect and lasted for 18 months. The relapse of anemia was not observed during the 6-month follow-up period after the cessation of treatment.
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http://dx.doi.org/10.1097/MPH.0b013e3182755c52DOI Listing
November 2013

Bone marrow transplantation for Fanconi anemia using fludarabine-based conditioning.

Biol Blood Marrow Transplant 2011 Sep 8;17(9):1282-8. Epub 2011 Jan 8.

Department of Pediatric Hematology-Oncology, Hadassah Hebrew University Medical Center, Jerusalem, Israel.

In the mid-1990s, we introduced a fludarabine (Flu)-based conditioning regimen for hematopoietic stem cell transplantation (HSCT) in patients with Fanconi anemia (FA).The aim of this study is to compare Flu-based conditioning to alternative regimens in patients with FA. Forty-one patients with FA (aged 0.5-31, median, 10.3 years) who underwent allogeneic HSCT were included in this retrospective study. Hospital records were reviewed for conditioning regimens, engraftment data, and toxicity. The median (range) follow-up was 32 (0.5-149) months. Flu-based conditioning regimens were used in 24 patients: 17 patients were treated with alternative conditioning regimens including a radiation-based regimen/cyclophosphamide and busulfan regimen. The disease-free survival (DFS) after Flu-based regimens is 83% (20/24) versus 35% (6/17) for the alternative regimens (P = .002). Toxicity was significantly lower in patients who received Flu-based conditioning (modified Bearman toxicity score [P = .001]). Seven patients received transplants from matched unrelated donors without irradiation (5 of whom are currently alive and well). All patients who survived are disease free and in good clinical condition. We conclude that a combination of fludarabine with antithymocyte globulin (ATG) and low-dose cyclophosphamide (Cy) and/or busulfan (Bu) is safe, demonstrates low rejection rates, and is well tolerated by FA patients.
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http://dx.doi.org/10.1016/j.bbmt.2011.01.001DOI Listing
September 2011

Retroviral WASP gene transfer into human hematopoietic stem cells reconstitutes the actin cytoskeleton in myeloid progeny cells differentiated in vitro.

Exp Hematol 2006 Sep;34(9):1161-9

Department of Pediatric Hematology and Oncology, Hannover Medical School, Hannover, Germany.

Objective: Wiskott-Aldrich syndrome (WAS) is a primary immunodeficiency disorder characterized by recurrent infections, autoimmunity, microthrombocytopenia, and susceptibility to malignant tumors. Compared with the conventional treatment using allogeneic bone marrow transplantation, hematopoietic stem cell gene therapy might offer more specific and less toxic therapeutic options.

Methods: We investigated retroviral WAS protein (WASP) gene transfer to assess functional correction and potential toxicities in human CD34(+) cells from WAS patients and healthy individuals, respectively.

Results: WASP mRNA and protein levels were restored in CD14(+) cells derived from WASP-transduced hematopoietic stem cells. Functional reconstitution in WASP-transduced myeloid cells was documented by podosome formation and Fc gamma R-mediated phagocytosis. Importantly, overexpression of WASP in CD34(+) cells from healthy donors did not cause any discernible toxic effects.

Conclusions: Our studies document the feasibility of WASP gene transfer into human CD34(+) cells and suggest that the phenotype of WASP-deficient myeloid cells can be restored upon retroviral gene transfer.
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http://dx.doi.org/10.1016/j.exphem.2006.04.021DOI Listing
September 2006

657del5 mutation in the gene for Nijmegen breakage syndrome (NBS1) in a cohort of Russian children with lymphoid tissue malignancies and controls.

Am J Med Genet A 2003 Jul;120A(2):174-9

Department of Immunology, Research Institute for Paediatric Hematology, Moscow, Russia.

Nijmegen breakage syndrome (NBS, OMIM 251260) is a rare hereditary disease, characterized by immune deficiency, microcephaly, and an extremely high incidence of lymphoid tissue malignancies. The gene mutated in NBS, NBS1, was recently cloned from its location on chromosome 8q21. The encoded protein, nibrin (p95), together with hMre11 and hRad50, is involved in the double-strand DNA break repair system. We screened two Russian cohorts for the 657del5 NBS1 mutation and found no carriers in 548 controls and two carriers in 68 patients with lymphoid malignancies: one with acute lymphoblastic leukemia (ALL) and one with non-Hodgkin lymphoma (NHL). Several relatives of the second patient, who were carriers of the same mutation, had cancer (ALL, breast cancer, GI cancers). These preliminary data suggest that NBS1 mutation carriers can be predisposed to malignant disorders.
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http://dx.doi.org/10.1002/ajmg.a.20188DOI Listing
July 2003