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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 Transplantation volume 56, pages 1614–1624 (2021)Cite this article

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Abstract

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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Fig. 1: Consort diagram and overall trial design.
Fig. 2: The incidence of GVHD.
Fig. 3: The incidence of CMV viremia.
Fig. 4: Immune recovery.
Fig. 5: Recovery of pathogen-specific immune response.
Fig. 6: Key clinical outcomes.

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Acknowledgements

The authors would wish to thank “Podari zhizn” charitable foundation and “Science for children” endowment foundation for constant support of research in the field of hematopoietic stem cell transplantation and clinical care of children in the Department of Hematopoietic Stem Cell Transplantation of the Dmitriy Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology.

Funding

This work was partially supported by Ministry of Health of Russia via approbation protocols 2015-25-4 and 2018-45-7. MM, AM, and EO were partly supported by the grant of the Ministry of Science and Higher Education of the Russian Federation No. 075-15-2020-807.

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Authors and Affiliations

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

    Maria Dunaikina, Zhanna Zhekhovtsova, Larisa Shelikhova, Sergey Blagov, Rimma Khismatullina, Dmitriy Balashov, Alexei Maschan & Michael Maschan

  2. Transplantation Immunology and Immunotherapy Laboratory, Dmitriy Rogachev National Medical Center of Pediatric Hematology, Oncology and Immunology, Moscow, Russia

    Svetlana Glushkova & Dmitriy Pershin

  3. Stem Cell Physiology Laboratory, Dmitriy Rogachev National Medical Center of Pediatric Hematology, Oncology and Immunology, Moscow, Russia

    Ruslan Nikolaev & Elena Osipova

  4. Transfusion Medicine Service, Dmitriy Rogachev National Medical Center of Pediatric Hematology, Oncology and Immunology, Moscow, Russia

    Elena Kurnikova, Yakov Muzalevskii & Alexei Kazachenok

  5. Clinical Center, Dmitriy Rogachev National Medical Center of Pediatric Hematology, Oncology and Immunology, Moscow, Russia

    Natalia Miakova, Dmitriy Litvinov & Galina Novichkova

  6. Department of Hematology, Oncology and Radiation Therapy, Pirogov Russian National Research Medical University, Moscow, Russia

    Michael Maschan

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Contributions

MM, LS, MD, ZZ, SG, and RN contributed equally to this work. MM designed the study, analyzed data, and wrote the paper. LS and ZZ designed the study, collected and analyzed data, and wrote the paper. MD, DP, SG, RN, SB, and RK collected and analyzed data and wrote the paper. DB, EK, YM, AK, and EO collected data and reviewed the paper. NM, DL, GN, and AM contributed to study design and reviewed the paper.

Corresponding author

Correspondence to Michael Maschan.

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Conflict of interest

MM received lecturer’s fee from Miltenyi Biotec, all other authors declare no competing interests in relation to the current paper.

Ethical approval

The trial was approved by the local ethics committee and IRB of the Dmitriy Rogachev National Medical Center of Pediatric Hematology, Oncology and Immunology and registered as NCT02942173 at clinicaltrials.gov.

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Dunaikina, M., Zhekhovtsova, Z., Shelikhova, L. et al. 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 56, 1614–1624 (2021). https://doi.org/10.1038/s41409-021-01232-x

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