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)... Show moreAfter 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. Show less
Zwan, M. van der; Clahsen-Van Groningen, M.C.; Hoogen, M.W.F. van den; Kho, M.M.L.; Roodnat, J.I.; Mauff, K.A.L.; ... ; Hesselink, D.A. 2020
Rabbit anti-thymocyte globulin (rATG) is currently the treatment of choice for glucocorticoid-resistant, recurrent, or severe acute allograft rejection (AR). However, rATG is associated with severe... Show moreRabbit anti-thymocyte globulin (rATG) is currently the treatment of choice for glucocorticoid-resistant, recurrent, or severe acute allograft rejection (AR). However, rATG is associated with severe infusion-related side effects. Alemtuzumab is incidentally given to kidney transplant recipients as treatment for AR. In the current study, the outcomes of patients treated with alemtuzumab for AR were compared with that of patients treated with rATG for AR. The patient-, allograft-, and infection-free survival and adverse events of 116 alemtuzumab-treated patients were compared with those of 108 patients treated with rATG for AR. Propensity scores were used to control for differences between the two groups. Patient- and allograft survival of patients treated with either alemtuzumab or rATG were not different [hazard ratio (HR) 1.14, 95%-confidence interval (CI) 0.48-2.69,p= 0.77, and HR 0.82, 95%-CI 0.45-1.5,p= 0.52, respectively). Infection-free survival after alemtuzumab treatment was superior compared with that of rATG-treated patients (HR 0.41, 95%-CI 0.25-0.68,p< 0.002). Infusion-related adverse events occurred less frequently after alemtuzumab treatment. Alemtuzumab therapy may therefore be an alternative therapy for glucocorticoid-resistant, recurrent, or severe acute kidney transplant rejection. Show less
Following allogeneic stem cell transplantation (alloSCT), most patients experience a period of profound and prolonged T cell deficiency due to the immune suppression and/or T cell depletion (TCD... Show moreFollowing allogeneic stem cell transplantation (alloSCT), most patients experience a period of profound and prolonged T cell deficiency due to the immune suppression and/or T cell depletion (TCD). In this period the patients are at risk for developing infectious complications by reactivation of endogenous herpes like viruses cytomegalovirus (CMV), Epstein-Barr virus (EBV) and varicella zoster virus (VZV). Reactivation of endogenous CMV is the most frequently occurring herpes virus reactivation following alloSCT. Approximately 60% of alloSCT recipients are seropositive for CMV and are therefore at risk for endogenous reactivation of latent CMV. CMV reactivation can lead to potentially fatal CMV disease, comprising CMV pneumonitis, CMV colitis or CMV encephalitis. The aim of this thesis was to evaluate factors that influence the incidence of CMV disease after TCD alloSCT. These factors include the conditioning regimen, serostatus of the donor, pharmacological intervention following alloSCT and adoptive T cell transfer for treatment of refractory CMV reactivation or CMV disease. Show less
