Competitive repopulation and allo-immunologic pressure determine chimerism kinetics after T Cell-depleted allogeneic stem cell transplantation and donor lymphocyte infusion

Koster, E.A.S.; Borne, P.A. von dem; Balen, P. van; Egmond, E.H.M. van; Marijt, E.W.A.; Veld, S.A.J.; ... ; Halkes, C.J.M. (2023)

Article / Letter to editor

After allogeneic stem cell transplantation (alloSCT), patient-derived stem cells that survived the pretransplantation conditioning compete with engrafting donor stem cells for bone marrow (BM) repopulation. In addition, donor-derived alloreactive T cells present in the stem cell product may favor establishment of complete donor-derived hematopoiesis by eliminating patient-derived lymphohematopoietic cells. T cell-depleted alloSCT with sequential transfer of potentially alloreactive T cells by donor lymphocyte infusion (DLI) provides a unique opportunity to selectively study how competitive repopulation and allo-immunologic pressure influence lymphohematopoietic recovery. This study aimed to determine the relative contribution of competitive repopulation and donor-derived anti-recipient alloimmunologic pressure on the establishment of lymphohematopoietic chimerism after alloSCT. In this retrospective cohort study of 281 acute leukemia patients treated according to a protocol combining alemtuzumab-based T cell-depleted alloSCT with prophy-lactic DLI, we investigated engraftment and quantitative donor chimerism in the BM and immune cell subsets. DLI-induced increase of chimerism and development of graft-versus-host disease (GVHD) were analyzed as complementary indicators for donor-derived anti-recipient alloimmunologic pressure. Profound suppression of patient immune cells by conditioning sufficed for sustained engraftment without necessity for myeloablative conditioning or development of clinically significant GVHD. Although 61% of the patients without any DLI or GVHD showed full donor chimerism (FDC) in the BM at 6 months after alloSCT, only 24% showed FDC in the CD4+ T cell compartment. In contrast, 75% of the patients who had received DLI and 83% of the patients with clinically significant GVHD had FDC in this compartment. In addition, 72% of the patients with mixed hematopoiesis receiving DLI converted to complete donor-derived hematopoiesis, of whom only 34% developed clinically significant GVHD. Our data show that competitive repopulation can be sufficient to reach complete donor-derived hematopoiesis, but that some alloimmunologic pressure is needed for the establishment of a completely donor-derived T cell compartment, either by the development of GVHD or by administration of DLI. We illustrate that it is possible to separate the graft-versus-leukemia effect from GVHD, as conversion to durable complete donor-derived hematopoiesis following DLI did not require induction of clinically significant GVHD. (c) 2023 The American Society for Transplantation and Cellular Therapy. 

• Allogeneic stem cell transplantation
• Donor lymphocyte infusion
• T cell depletion
• Chimerism
• Graft-versus-host disease
• Acute myeloid leukemia
• Acute lymphoblastic leukemia

• All authors: Koster, E.A.S.; Borne, P.A. von dem; Balen, P. van; Egmond, E.H.M. van; Marijt, E.W.A.; Veld, S.A.J.; Jedema, I.; Snijders, T.J.F.; Lammeren, D. van; Veelken, H.; Falkenburg, J.H.F.; Wreede, L.C. de; Halkes, C.J.M.
• Date: 2023-03-23
• Journal: Transplantation and Cellular Therapy
• Volume: 29
• Issue: 4
• Pages: 268.e1 - 268.e10
• DOI: doi:10.1016/j.jtct.2022.12.022