Peripheral blood stem cell transplantation (PBSCT) with in vivo lymphodepletion can provide faster neutrophil recovery with limited risk of severe graft-versus-host disease (GVHD) in children with... Show morePeripheral blood stem cell transplantation (PBSCT) with in vivo lymphodepletion can provide faster neutrophil recovery with limited risk of severe graft-versus-host disease (GVHD) in children with nonmalignant disorders (NMDs). We aimed to provide an historical comparison of these 2 strategies regarding the prevalence of GVHD, viral reactivation, timing of immune reconstitution, and final outcomes. Data on 98 children undergoing PBSCT were collected from 5 European pediatric transplantation centers. Only patients with NMDs receiving treosulfan or myeloablative busulfan conditioning and 9-10/10 HLA-matched transplant were included. The patients were divided into 2 groups according to in vivo lymphodepletion with antithymocyte globulin (ATG) or with alemtuzumab. We compared rates of acute and chronic GVHD; Epstein-Barr virus, cytomegalovirus, and adenovirus reactivation; chimerism; lymphocyte recovery; overall survival (OS) and event-free survival (EFS) between the 2 groups. The rate of severe acute GVHD (grade III-IV) was significantly higher in patients receiving ATG (26% vs 10% in alemtuzumab recipients; P <.05), whereas viral reactivations occurred with a similar rate in the 2 groups (alemtuzumab, 56%; ATG, 57%). Alemtuzumab was the major risk factor for delayed T cell immune reconstitution in the first 3 months after transplantation (odds ratio [OR], 6.0; 95% confidence interval [CI], 1.8 to 19; P <.005). Extended chronic GVHD, ADV reactivation, slower CD3(+) cell recovery, and HLA-mismatch reduced the probability of survival. Infections were the main cause of mortality in our cohort, and delayed T cell recovery was significantly associated with mortality in multivariate analysis (OR, 12; 95% CI, 1.2 to 114; P <.05). Ultimately, no differences in OS and EFS survival were seen between the ATG and alemtuzumab groups. ATG and alemtuzumab showed similar impacts on outcomes of children undergoing PBSCT for NMDs. The 2 strategies of in vivo lymphodepletion showed specific drawbacks that were counterbalanced by benefits that ultimately led to a comparable survival rate. A patient-centered lymphodepletion strategy can be advised in children undergoing PBSCT for NMDs, by favoring T cell recovery in the presence of invasive infection or GVHD prevention in high-risk mismatched donor transplantation. (C) 2021 The American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc. All rights reserved. Show less
HLA-matched allogeneic stem cell transplantation (alloSCT) is a potential curative therapy for patients with high-risk hematologic malignancies. The therapeutic effect of alloSCT is mediated by T... Show moreHLA-matched allogeneic stem cell transplantation (alloSCT) is a potential curative therapy for patients with high-risk hematologic malignancies. The therapeutic effect of alloSCT is mediated by T cells derived from the stem cell donor that have the potential to recognize and eliminate malignant cells of patient origin, better known as the graft-versus-leukemia effect. Besides, donor-derived T cells are of importance for the protection against viruses early after alloSCT. On the other hand, T cells of donor origin can also initiate harmful graft-versus-host disease if healthy cells of the patient are recognized. Therefore, the major challenge in the field of alloSCT is to find a balance between graft-versus-leukemia effect and viral protection versus graft-versus-host disease with the aim to reduce complications early after alloSCT. In this thesis, the manipulation of donor-derived T cells at different stages during the process of HLA-matched alloSCT was investigated: from in vitro T-cell depletion of the graft before infusion into the patient until adoptive T-cell therapy early after alloSCT to support anti-viral immunity and graft-versus-leukemia effect. Show less
Alemtuzumab (ALM) is a cytotoxic monoclonal antibody that is used as a therapeutic agent in a variety of clinical settings. The target antigen for ALM is CD52, which is highly expressed on the... Show moreAlemtuzumab (ALM) is a cytotoxic monoclonal antibody that is used as a therapeutic agent in a variety of clinical settings. The target antigen for ALM is CD52, which is highly expressed on the membrane of mature lymphocytes, but not or only marginally on hematopoietic stem cells, red blood cells, and non-hematopoietic tissues. As such, ALM can be administered for the purpose of lymphocyte depletion with no or only minimal toxicity to other tissues. In this thesis, the mechanism of action of ALM was investigated in the context of two clinical settings, i.e. T-cell depletion before allogeneic stem cell transplantation (alloSCT) and depletion of malignant cells in B lymphoblastic leukemia (B-ALL). Show less
Administration of alemtuzumab (targeting the CD52 antigen) to the patient (in-vivo) or to the graft (in-vitro) before allogeneic stem cell transplantation (alloSCT) decreases the incidence of graft... Show moreAdministration of alemtuzumab (targeting the CD52 antigen) to the patient (in-vivo) or to the graft (in-vitro) before allogeneic stem cell transplantation (alloSCT) decreases the incidence of graft-versus-host disease (GvHD). Effectiveness of this treatment relies on depletion of donor T cells. Currently, no data are available on alemtuzumab pharmacokinetics and pharmacodynamics in patients who received combined in-vivo and in-vitro alemtuzumab-based T-cell depletion. In this prospective study, we analyzed alemtuzumab pharmacokinetics and its effect on the circulating T cells in 36 patients who received an allogeneic T-cell-depleted graft by addition of 20 mg alemtuzumab "to the bag" with or without prior alemtuzumab (30 mg cumulative dose intravenously) as part of the conditioning regimen. Effective T-cell depletion was shown for all patients, even though alemtuzumab plasma levels varied considerably. Peak alemtuzumab levels were observed directly after graft infusion and were not associated with the number of circulating T cells pre-infusion, but with plasma volumes of the patients. All patients engrafted, confirming feasibility of this transplantation protocol. Only three patients with low alemtuzumab levels developed acute GvHD (grade II in 2 patients and grade III in 1 patient). Persistence of circulating alemtuzumab at 3 weeks after transplantation had prevented reconstitution of CD52-positive T cells when alemtuzumab plasma levels were above 0.7 mu g/mL. However, overall T-cell reconstitution did not correlate with the levels of alemtuzumab exposure, due to early reconstitution of CD52-negative alemtuzumab-resistant T cells. The protective effect of these cells likely explains the low incidence of Epstein-Barr-virus- and cytomegalovirus-related disease despite circulating alemtuzumab. Show less
Heiden, P.L.J. van der; Egmond, H.M. van; Veld, S.A.J.; Meent, M. van de; Eefting, M.; Wreede, L.C. de; ... ; Jedema, I. 2018
