Treosulfan-Based Conditioning Regimen in Haematopoietic Stem Cell Transplantation with TCRαβ/CD19 Depletion in Nijmegen Breakage Syndrome.

Abstract

Nijmegen breakage syndrome (NBS) is a DNA repair disorder characterized by combined immunodeficiency and a high predisposition to malignancies. HSCT appears to cure immunodeficiency, but remains challenging due to limited experience in long-term risks of transplant-associated toxicity and malignancies. Twenty NBS patients received 22 allogeneic HSCTs with TCRαβ/CD19+ graft depletion with fludarabine 150 mg/m2, cyclophosphamide 20–40 mg/kg and thymoglobulin 5 mg/kg based conditioning regimens (CRs). Twelve patients additionally received low-dose busulfan 4 mg/kg (Bu group) and 10 patients (including 2 recipients of a second HSCT) treosulfan (Treo group) 30 g/m2. Overall and event-free survival were 0.75 vs 1 (p = 0.16) and 0.47 vs 0.89 (p = 0.1) in the Bu and Treo groups, respectively. In the Bu group, four patients developed graft rejection, and three died: two died of de novo and relapsed lymphomas and one died of adenoviral hepatitis. The four living patients exhibited split chimerism with predominantly recipient myeloid cells and predominantly donor T and B lymphocytes. In Treo group, one patient developed rhabdomyosarcoma. There was no difference in the incidence of GVHD, viral reactivation, or early toxicity between either group. Low-dose Bu-containing CR in NBS leads to increased graft failure and low donor myeloid chimerism. Treo-CR followed by TCRαβ/CD19-depleted HSCT demonstrates a low level of early transplant-associated toxicity and enhanced graft function with stable donor chimerism.

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Acknowledgements

The authors thank the Immunology and HSCT Departments staff and other hospital staff for continued support of patient care.

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AL collected the data, performed the analysis and wrote the manuscript. ES and AK contributed to the data collection and analysis. EG, SR and ED contributed to patient care. VB performed chimerism assays. JS elaborated the HSCT research database. AS led pre-HSCT patient care. AM and MM led the HSCT programme. DB conducted the study. All co-authors contributed to manuscript preparation.

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Correspondence to Alexandra Laberko.

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MM: lecturer’s fee from Miltenyi Biotec. The remaining authors declare no conflicts of interest.

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Laberko, A., Sultanova, E., Gutovskaya, E. et al. Treosulfan-Based Conditioning Regimen in Haematopoietic Stem Cell Transplantation with TCRαβ/CD19 Depletion in Nijmegen Breakage Syndrome.. J Clin Immunol 40, 861–871 (2020). https://doi.org/10.1007/s10875-020-00811-9

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Keywords

  • Nijmegen breakage syndrome
  • Haematopoietic stem cell transplantation
  • TCRαβ/CD19 depletion
  • Treosulfan
  • DNA repair disorder