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

Bone Marrow Transplantation volume 55, pages 256–259 (2020)Cite this article

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Technology of ex-vivo depletion of αβ T cells was developed and applied in the clinic to overcome major barriers, associated with hematopoietic stem cell transplantation (HSCT) from mismatched donors, including graft failure, severe graft-versus-host disease (GVHD) and delayed immune reconstitution [1,2,3,4,5,6,7]. Recent report suggests that αβ T cell-depleted haploidentical HSCT may result in non-inferior outcomes compared to T-replete MUD HSCT among children with acute leukemia [8]. We have used αβ T cell depletion to process both haploidentical and matched unrelated donor (MUD) grafts since 2012 in order to improve safety and provide universal access to the HSCT procedure, independent of HLA haplotype frequency and registry access. We report here the results of a retrospective analysis in a cohort of children with acute myeloid leukemia (AML), grafted in complete remission (CR). Seventy-three consecutive children with AML underwent HSCT at the Dmitriy Rogachev National Medical Center of Pediatric Hematology between 01.01.2012 and 31.09.2016. Thirty-seven patients received haploidentical grafts, and 36 received a graft from a MUD. Disease status at transplant was a CR 1 in 59 pts, CR ≥ 2 in 14 pts. HSCT in CR1 was performed in cases of genetic high risk or induction failure, according to the institutional protocol, supplementary fig. 1 and table 1. The preparative regimen included treosulfan at 14 g/m2/day, day −5, −4, −3 and fludarabine at 30 mg/m2/day, day −6, −5, −4, −3, −2. Either melphalan (n = 59) at 140 mg/m2 or thiotepa (n = 14) at 10 mg/kg was added. Serotherapy included either horse anti-thymocyte globulin (ATGAM, Pfizer) at 25 mg/kg/day, day −8, −9 or day −5, −4 (n = 25) or rabbit anti-thymocyte globulin (Thymoglobuline, Genzyme) at 2.5 kg/day, day d −5, −4 (n = 48). Hematopoietic stem cell grafts were derived from a G-CSF-mobilized PBSC. TCRαβ and CD19 depletion was performed with a CliniMACS Plus instrument (Miltenyi Biotec, Bergish Gladbach, Germany). The comparative characteristics of the patients, donors and grafts are presented in the supplementary table 2. GVHD prophylaxis included tacrolimus at 0.02 mcg/kg/day until day +30 and methotrexate (Mtx) at 10 mg/m2 on day +1, +3, +6 (n = 26). Since 2015 the GVHD prophylaxis included only bortezomib at 1.3 mg/m2/day administered on days −5, −2, +2, +5, and rituximab at 200 mg/m2 on day −1 (n = 47). The schema of the preparative regimen and GVHD prophylaxis is summarized in the supplementary table 3. Fifteen patients received a median of three prophylactic modified donor lymphocyte infusions (DLI) consisting of cryopreserved parts of the original αβ T-depleted graft. Since 2014 patients were eligible to take part in a pilot trial of memory T cell DLI, as detailed in Maschan et al. [9], or its extension. Thirty-six patients received a median of three memory (CD45RA-depleted) DLIs. This study was approved by the local ethics committee and patients and/or their legal guardians provided informed consent to participate in the study. The pilot study of memory DLI was registered at clinicaltrials.gov under #NCT02337595. Donor type, KIR mismatch, KIR genotype, CMV reactivation, DLI, CR#, donor and patient age and gender and cytogenetic risk group were tested in univariate analysis for association with major outcome measures. The endpoints included cumulative incidence of relapse (CIR), transplant-related mortality (TRM), incidence of the acute and chronic GVHD, event-free survival (EFS), overall survival (OS) and a composite end-point of GVHD-free and relapse-free survival (GRFS). XLSTAT, Addinsoft, 2015 software was used for the statistical analysis. Surviving patients were censored on 05.05.2018 with a median follow-up of 3.4 (1.7–5.9) years.

αβ T cell depletion was developed as a platform to improve the outcome of HSCT from haploidentical donors [1, 2]. Different from the largest published cohort of αβ-T cell depletion in acute leukemia, the backbone of the preparative regimen used here was a radiation-free combination of treosulfan with either melphalan or thiotepa [7]. In univariate analysis we demonstrate that the use of haploidentical grafts was associated with a significant reduction in the incidence of leukemia relapse. This was not accompanied by an increased incidence of GVHD and TRM and translated into significant benefit in overall, event-free and GVHD-free and relapse-free survival. Due to a strong association between the donor type (haplo) and use of memory DLI, multivariable model could not be built to separate the effects of these two parameters. Serotherapy is an important component of most protocols of αβ T cell-depleted transplantation. Use of ATG-Fresenius proximal to the graft infusion seems to ensure optimal control of GVHD [7]. Our experience confirms that dose and type of ATG should be carefully selected, since use of horse ATG was associated with increased GVHD rate. In the future it might be possible to replace ATG with non-lymphodepleting immunomodulation in order to improve early immune recovery [10]. One drawback for this analysis is that αβ T cell depletion is not a standard procedure for MUD transplantation and that this manipulation could diminish anti-leukemia activity of the MUD HSCT. It should be noted however, that the outcomes of MUD in the current series are similar to the registry and prospective data for MUD HSCT in pediatric AML [8, 11, 12]. It is postulated that NK-alloreactivity is a major mechanism of leukemia cure by haplo HSCT [2, 13,14,15,16]. We however were not able to detect an influence of either donor KIR genotype or KIR mismatch on the outcomes, corroborating recent report [7]. It should be noted that significant variability of the pharmacological GVHD prophylaxis and of the DLI application after HSCT make it difficult to draw firm conclusions regarding the influence of individual factors. However, it should be appreciated that the use of αβ T cell depletion as a platform allowed for high flexibility in choosing donor, preparative regimen and DLI approach. As a conclusion, we believe that the data suggest that αβ-T cell depletion creates a solid basis for improvement of the results of HSCT from haploidentical donors among children with AML. Applied to a population with high-risk AML in CR, this technology in combination with an irradiation-free conditioning regimen, is associated with high success rate. Our results suggest that haploidentical donors could be prioritized over unrelated donors in the future.

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Acknowledgements

The authors thank the physicians and nursing staff of the Hematopoietic stem cell transplantation Units 1 and 2 for outstanding patient care, the staff of molecular biology, cytogenetics, microbiology and transplant biology laboratories for excellent service, Marina Persiantseva and Susanne Morsch for unrelated donor search. We are grateful to the “Podari Zhizn” foundation for continued support of the care of the patients and research in the field of hematopoietic stem cell transplantation.

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Authors and Affiliations

  1. 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

    Michael Maschan, Larisa Shelikhova, Maria Ilushina, Zhanna Shekhovtsova, Rimma Khismatullina, Dmitriy Balashov & Alexei Maschan

  2. Blood Bank and Hematopoietic Stem Cell Processing Laboratory, Dmitriy Rogachev National Medical Research Сenter of Pediatric Hematology, Oncology and Immunology, Samory Mashela street, 1, Moscow, 117997, Russia

    Elena Kurnikova, Yakov Muzalevskii & Alexei Kazachenok

  3. Laboratory of Transplantation Biology and Immunotherapy, Dmitriy Rogachev National Medical Research Сenter of Pediatric Hematology, Oncology and Immunology, Samory Mashela street, 1, Moscow, 117997, Russia

    Dmitriy Pershin

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

    Irina Kalinina, Dina Baidildina, Galina Novichkova & Alexei Maschan

  5. Laboratory of Molecular Biology, Dmitriy Rogachev National Medical Research Сenter of Pediatric Hematology, Oncology and Immunology, Samory Mashela street, 1, Moscow, 117997, Russia

    Viktoria Zakharova

  6. Laboratory of Cytogenetics and Molecular Genetics, Dmitriy Rogachev National Medical Research Сenter of Pediatric Hematology, Oncology and Immunology, Samory Mashela street, 1, Moscow, 117997, Russia

    Yulia Olshanskaya

  7. Department of Adolescent Hematology and Oncology, Dmitriy Rogachev National Medical Research Сenter of Pediatric Hematology, Oncology and Immunology, Samory Mashela street, 1, Moscow, 117997, Russia

    Dmitriy Litvinov

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  1. Michael Maschan
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Correspondence to Michael Maschan.

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MM received lecturer’s fee from Miltenyi Biotec GmbH. The remaining authors declare that they have no conflict of interest.

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Maschan, M., Shelikhova, L., Ilushina, M. et al. Outcome of αβ T cell-depleted transplantation in children with high-risk acute myeloid leukemia, grafted in remission. Bone Marrow Transplant 55, 256–259 (2020). https://doi.org/10.1038/s41409-019-0531-3

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