Competitive Repopulation and Allo-Immunologic Pressure Determine Chimerism Kinetics after T Cell-Depleted Allogeneic Stem Cell Transplantation and Donor Lymphocyte Infusion

Koster, Eva A.S.; Borne, Peter A. von dem; Balen, Peter van; Egmond, Esther H.M. van; Marijt, Erik W.A.; Veld, Sabrina A.J.; Jedema, Inge; Snijders, Tjeerd J.F.; Lammeren, Daniëlle van; Veelken, Hendrik; Falkenburg, J.H. Frederik; Wreede, Liesbeth C. de; Halkes, Constantijn J.M.

doi:10.1016/j.jtct.2022.12.022

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“…Relapse was defined as the recurrence of at least 5% blasts on cytomorphologic bone marrow examination or at least 1% blasts in peripheral blood (if possible, confirmed by BM biopsy). We defined clinically significant GvHD as the start of therapeutic systemic immunosuppression for GvHD ( 26 ). We defined ‘other failure’ as the occurrence of an adverse event with a potential impact on the immune cell kinetics: death, graft failure, start of systemic immunosuppression for a non-GvHD indication, and virus-specific T-cell infusion for a severe viral infection (whichever occurred first).…”

Section: Methodsmentioning

confidence: 99%

Joint models quantify associations between immune cell kinetics and allo-immunological events after allogeneic stem cell transplantation and subsequent donor lymphocyte infusion

Koster,

Bonneville,

Borne

et al. 2023

Front. Immunol.

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Alloreactive donor-derived T-cells play a pivotal role in alloimmune responses after allogeneic hematopoietic stem cell transplantation (alloSCT); both in the relapse-preventing Graft-versus-Leukemia (GvL) effect and the potentially lethal complication Graft-versus-Host-Disease (GvHD). The balance between GvL and GvHD can be shifted by removing T-cells via T-cell depletion (TCD) to reduce the risk of GvHD, and by introducing additional donor T-cells (donor lymphocyte infusions [DLI]) to boost the GvL effect. However, the association between T-cell kinetics and the occurrence of allo-immunological events has not been clearly demonstrated yet. Therefore, we investigated the complex associations between the T-cell kinetics and alloimmune responses in a cohort of 166 acute leukemia patients receiving alemtuzumab-based TCD alloSCT. Of these patients, 62 with an anticipated high risk of relapse were scheduled to receive a prophylactic DLI at 3 months after transplant. In this setting, we applied joint modelling which allowed us to better capture the complex interplay between DLI, T-cell kinetics, GvHD and relapse than traditional statistical methods. We demonstrate that DLI can induce detectable T-cell expansion, leading to an increase in total, CD4+ and CD8+ T-cell counts starting at 3 months after alloSCT. CD4+ T-cells showed the strongest association with the development of alloimmune responses: higher CD4 counts increased the risk of GvHD (hazard ratio 2.44, 95% confidence interval 1.45-4.12) and decreased the risk of relapse (hazard ratio 0.65, 95% confidence interval 0.45-0.92). Similar models showed that natural killer cells recovered rapidly after alloSCT and were associated with a lower risk of relapse (HR 0.62, 95%-CI 0.41-0.93). The results of this study advocate the use of joint models to further study immune cell kinetics in different settings.

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Section: Methodsmentioning

confidence: 99%