Publications by authors named "Dmitriy Balashov"

8 Publications

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Serotherapy-Free Regimen Improves Non-Relapse Mortality and Immune Recovery Among the Recipients of αβ TCell-Depleted Haploidentical Grafts: Retrospective Study in Childhood Leukemia.

Transplant Cell Ther 2021 Apr 14;27(4):330.e1-330.e9. Epub 2021 Jan 14.

Department of Hematopoietic Stem Cell Transplantation, Dmitriy Rogachev National Medical Center Of Pediatric Hematology, Oncology And Immunology, Moscow, Russia. Electronic address:

Depletion of αβ T cells from the graft prevents graft-versus-host disease (GVHD) and improves the outcome of hematopoietic stem cell transplantation (HSCT) from haploidentical donors. Delayed recovery of adaptive immunity remains a problem, which can be approached by adoptive T-cell transfer. In a randomized trial, we have assessed the safety and efficacy of low-dose memory (CD45RA-depleted) donor lymphocytes (mDLI) after HSCT with αβ T-cell depletion. Antithymocyte globulin (ATG) is viewed as an essential component of preparative regimen, critical for both prevention of graft failure and GVHD. Variable pharmacokinetics of ATG may significantly affect lymphocyte subpopulations after HSCT. To uncover the potential of mDLI, we replaced rabbit ATG with tocilizumab and abatacept. Here we compare post hoc the immune recovery and the key clinical outcomes, including nonrelapse mortality (NRM), overall- and event-free survival (OS and EFS), between the cohort enrolled in the prospective randomized trial and a historical cohort, comprised of patients grafted with a conventional ATG-based HSCT with αβ T cell depletion. A cohort of 149 children was enrolled in the prospective trial and 108 patients were selected as historical controls from a prospectively populated database. Patient population was comprised of children with high-risk hematologic malignancies, with more than 90% represented by acute leukemia. Median age at enrollment was 8.8 years. In the prospective cohort 91% of the donors were haploidentical parents, whereas in the historical cohort 72% of the donors were haploidentical. Conditioning was based on either 12Gy total body irradiation or treosulfan. Thiotepa, fludarabine, bortezomib, and rituximab were used as additional agents. Patients in the historical cohort received rabbit ATG at 5 mg/kg total dose, while prospective cohort patients received tocilizumab at 8 mg /kg on day -1 and abatacept at 10 mg/kg on days 0, 7, 14, and 28. Patients in the prospective trial cohort were randomized 1:1 to receive mDLI starting on day 0, whereas 69% of historical cohort patients received mDLI after engraftment, as part of previous trials. Primary engraftment rate was 99% in the prospective cohort and 98% in the historical cohort. The incidence of grade II-IV aGVHD was 13% in the prospective cohort and 16 % in the control group. Chronic GVHD developed among 13% (historical) and 7% (prospective) cohorts (P = .07). The incidence of cytomegalovirus viremia was 51% in the prospective cohort arm and 54% in the historical control arm (p = ns). Overall, in the prospective cohort 2-year NRM was 2%, incidence of relapse was 25%, EFS was 71%, and OS was 80%, whereas in the historical cohort 2-year NRM was 13%, incidence of relapse was 19%, EFS was 67%, and OS was 76%, difference non-significant for relapse and survival. NRM was significantly improved in the ATG-free cohort (P = .002). Recovery of both αβ- and γδ- T cells was significantly improved at days +30 and +60 after HSCT in recipients of ATG-free preparative regimens, as well as recovery of naïve T cells. Among the recipients of αβ T-cell-depleted grafts, replacement of ATG with nonlymphodepleting abatacept and tocilizumab immunomodulation did not compromise engraftment and GVHD control and was associated with significantly lower NRM and better immune recovery early after HSCT.
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http://dx.doi.org/10.1016/j.jtct.2021.01.010DOI Listing
April 2021

Safety and efficacy of the low-dose memory (CD45RA-depleted) donor lymphocyte infusion in recipients of αβ T cell-depleted haploidentical grafts: results of a prospective randomized trial in high-risk childhood leukemia.

Bone Marrow Transplant 2021 Feb 16. Epub 2021 Feb 16.

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

Depletion of αβ T cells from the graft prevents graft-vs.-host disease (GVHD) and improves outcome of HSCT from haploidentical donors. In a randomized trial, we aimed to evaluate the safety and efficacy of low-dose memory (CD45RA-depleted) donor lymphocytes (mDLI) after HSCT with αβ T-cell depletion. A cohort of 149 children was enrolled, 76 were randomized to receive scheduled mDLI and 73 received standard care. Conditioning was based on either 12 Gy total body irradiation or treosulfan. Rabbit antithymocyte globulin was replaced by tocilizumab and abatacept. Primary end points were the incidence of acute GVHD grades II-IV and the incidence of cytomegalovirus (CMV) viremia. The incidence of grades II-IV aGVHD was 14% in the experimental arm and 12% in the control arm, p-0.8. The incidence of CMV viremia was 45% in the experimental arm and 55% in the control arm, p-0.4. Overall, in the total cohort 2-year NRM was 2%, cumulative incidence of relapse was 25%, event-free survival 71%, and overall survival 80%, without difference between the study arms. Memory DLI was associated with improved recovery of CMV-specific T-cell responses in a subcohort of CMV IgG seropositive recipients.
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http://dx.doi.org/10.1038/s41409-021-01232-xDOI Listing
February 2021

T-cell tracking, safety, and effect of low-dose donor memory T-cell infusions after αβ T cell-depleted hematopoietic stem cell transplantation.

Bone Marrow Transplant 2021 Apr 17;56(4):900-908. Epub 2020 Nov 17.

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

The delayed recovery of adaptive immunity underlies transplant-related mortality (TRM) after αβ T cell-depleted hematopoietic stem cell transplantation (HSCT). We tested the use of low-dose memory donor lymphocyte infusions (mDLIs) after engraftment of αβ T cell-depleted grafts.A cohort of 131 pediatric patients (median age 9 years) were grafted with αβ T cell-depleted products from either haplo (n = 79) or unrelated donors (n = 52). After engraftment, patients received mDLIs prepared by CD45RA depletion. Cell dose was escalated monthly from 25 × 10 to 100 × 10/kg (haplo) and from 100 × 10 to 300 × 10 /kg (MUD). In a subcohort of 16 patients, T-cell receptor (TCR) repertoire profiling with deep sequencing was used to track T-cell clones and to evaluate the contribution of mDLI to the immune repertoire.In total, 343 mDLIs were administered. The cumulative incidence (CI) of grades II and III de novo acute graft-versus-host disease (aGVHD) was 5% and 2%, respectively, and the CI of chronic graft-versus-host disease was 7%. Half of the patients with undetectable CMV-specific T cells before mDLI recovered CMV-specific T cells. TCR repertoire profiling confirmed that mDLI-derived T cells significantly contribute to the TCR repertoire up to 1 year after HSCT and include persistent, CMV-specific T-cell clones.
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http://dx.doi.org/10.1038/s41409-020-01128-2DOI Listing
April 2021

Outcome of αβ T cell-depleted transplantation in children with high-risk acute myeloid leukemia, grafted in remission.

Bone Marrow Transplant 2020 01 15;55(1):256-259. Epub 2019 Apr 15.

Department of Hematopoietic Stem Cell Transplantation, Dmitriy Rogachev National Medical Research Сenter of Pediatric Hematology, Oncology and Immunology, Samory Mashela street, 1, Moscow, 117997, Russia.

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http://dx.doi.org/10.1038/s41409-019-0531-3DOI Listing
January 2020

αβ T Cell-Depleted Haploidentical Hematopoietic Stem Cell Transplantation without Antithymocyte Globulin in Children with Chemorefractory Acute Myelogenous Leukemia.

Biol Blood Marrow Transplant 2019 05 21;25(5):e179-e182. Epub 2019 Jan 21.

Department of Hematopoietic Stem Cell Transplantation, Dmitriy Rogachev National Medical Research Center of Pediatric Hematology, Oncology, and Immunology, Moscow, Russia. Electronic address:

We evaluated the outcome of αβ T cell-depleted haploidentical hematopoietic stem cell transplantation (HSCT) in a cohort of children with chemorefractory acute myelogenous leukemia (AML). Twenty-two patients with either primary refractory (n = 10) or relapsed refractory (n = 12) AML in active disease status received a transplant from haploidentical donors. The preparative regimen included cytoreduction with fludarabine and cytarabine and subsequent myeloablative conditioning with treosulfan and thiotepa. Antithymocyte globulin was substituted with tocilizumab in all patients and also with abatacept in 10 patients. Grafts were peripheral blood stem cells engineered by αβ T cell and CD19 depletion. Post-transplantation prophylactic therapy included infusion of donor lymphocytes, composed of a CD45RA-depleted fraction with or without a hypomethylating agent. Complete remission was achieved in 21 patients (95%). The cumulative incidence of grade II-IV acute graft-versus-host disease (GVHD) was 18%, and the cumulative incidence of chronic GVHD was 23%. At 2 years, transplantation-related mortality was 9%, relapse rate was 42%, event-free survival was 49%, and overall survival was 53%. Our data suggest that αβ T cell-depleted haploidentical HSCT provides a reasonable chance of long-term survival in a cohort of children with chemorefractory AML and creates a solid basis for further improvement.
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http://dx.doi.org/10.1016/j.bbmt.2019.01.023DOI Listing
May 2019

Low-dose donor memory T-cell infusion after TCR alpha/beta depleted unrelated and haploidentical transplantation: results of a pilot trial.

Bone Marrow Transplant 2018 03 21;53(3):264-273. Epub 2017 Dec 21.

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

Recovery of immunity is delayed in recipients of T-depleted grafts. Adoptive transfer of memory T-cells may improve immune response to common pathogens. A cohort of 53 patients with malignant (n = 36) and non-malignant conditions (n = 17) received TCR alpha/beta depleted grafts from haploidentical (n = 25) or MUD (n = 28) donors. Donor lymphocytes were depleted of CD45RA-positive cells. At a median of 48 days after transplantation, patients received DLI at 25 × 10/kg CD3 cells from haploidentical or 100 × 10/kg CD3 from MUD donors. Up to 3 doses of donor lymphocytes were administered at monthly intervals, escalating to 100 × 10/kg in haploidentical transplants and 300 × 10/kg in MUD transplants. At a median follow-up of 23 months, the cumulative incidence of de novo acute GVHD after DLI is 2% (1 of 43), while the rate of reactivation of preexisting aGVHD was 50% (5 of 10). The transplant-related mortality is 6%. The overall survival rates are 80% and 88% in malignant and non-malignant conditions, respectively. Among patients with absent CMV-specific immune reactivity at baseline (n = 31) expansion of CMV-specific T-cells was demonstrated in 20 (64.5%) within 100 days. Infusions of low dose donor memory T-lymphocytes are safe and constitute a simple measure to prevent infections in the setting of alpha/beta T cell-depleted transplantation.
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http://dx.doi.org/10.1038/s41409-017-0035-yDOI Listing
March 2018

Risk Factors for and the Clinical Impact of Cytomegalovirus and Epstein-Barr Virus Infections in Pediatric Recipients of TCR-α/β- and CD19-Depleted Grafts.

Biol Blood Marrow Transplant 2017 Mar 27;23(3):483-490. Epub 2016 Dec 27.

Department of Hematopoietic Stem Cell Transplantation, Dmitriy Rogachev Federal Center for Pediatric Hematology, Oncology and Immunology, Moscow, Russia. Electronic address:

Alpha/beta T cell and CD19 depletion are used to improve the outcomes of hematopoietic stem cell transplantation (HSCT). We evaluated the burden of cytomegalovirus (CMV) and Epstein-Barr virus (EBV) in pediatric patients after this HSCT type. A cohort of 182 patients with malignant (n = 114) or nonmalignant (n = 68) disorders was transplanted from either matched unrelated (n = 124) or haploidentical (n = 58) donors. The cumulative incidence of CMV and EBV viremia were 51% and 33%, respectively. Acute graft-versus-host disease (GVHD) grades II to IV, D-/R+ serology, and malignant HSCT indications were associated with increased risk of CMV viremia. CMV disease developed in 10 patients (6%). The occurrence of CMV viremia was not associated with inferior outcomes. Acute GVHD grade ≥ II was the only factor significantly associated with an increased risk of EBV viremia. Rituximab significantly decreased the rate of EBV reactivation in a subgroup that received a higher B cell dose in the graft. The rate of EBV-associated disease was .5%, and EBV viremia did not affect survival. TCR-α/β and CD19 depletion are associated with a significant rate of CMV viremia that does not affect survival. The hazard of EBV post-transplant lymphoproliferative disease (PTLD) is eliminated by the combination of CD19 depletion and rituximab.
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http://dx.doi.org/10.1016/j.bbmt.2016.12.635DOI Listing
March 2017

Control of bleeding caused by thrombocytopenia associated with hematologic malignancy: an audit of the clinical use of recombinant activated factor VII.

Clin Appl Thromb Hemost 2005 Oct;11(4):401-10

Thrombosis and Hemostasis Unit, Department of Hematology and Bone Marrow Transplantation, Rambam Medical Center, Haifa, Israel.

This paper presents an analysis of 24 cases in which recombinant factor VIIa (rFVIIa) was used in the management of hemorrhage in patients with thrombocytopenia associated with hematologic malignancies. This is the largest case aggregation to date and focuses on preliminary experience in the off-label use of this hemostatic agent. Data were extracted from the international, Internet-based registry, www.haemostasis.com, accessed in September 2003. The search results were manually cross-checked against monthly summary reports. The physicians providing the cases were contacted individually to approve the use of their cases, supply any information missing from the database, and validate the data already held. Patients with acute myeloid leukemia, acute lymphoblastic leukemia, Hodgkin's disease, non-Hodgkin's lymphoma, Burkitt's lymphoma, B-cell or T-cell lymphoma, or aplastic anemia received rFVIIa at total doses of between 18 and 1040 mug/kg body weight. Bleeding stopped in 11 of 24 (46%) patients, markedly decreased in 8 of 24 (33%) patients, and decreased in 4 of 24 (17%) patients. In most patients, the response was achieved within 2.5 hours of administration of rFVIIa. The use of rFVIIa was generally well tolerated -- 1 case of ischemic stroke was considered to be possibly related to rFVIIa administration, but this has yet to be confirmed. A review of these 24 cases submitted to the www.haemostasis.com database suggests that rFVIIa is beneficial in the management of hemorrhage in patients with thrombocytopenia and hematologic malignancies. This warrants further investigation in rigorously controlled clinical trials.
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http://dx.doi.org/10.1177/107602960501100406DOI Listing
October 2005