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
Pharmacotherapy plays an essential role in an allogeneic hematopoietic stem cell transplantation (allo-HSCT) procedure. Busulfan and treosulfan are two alkylating agents often applied in the... Show morePharmacotherapy plays an essential role in an allogeneic hematopoietic stem cell transplantation (allo-HSCT) procedure. Busulfan and treosulfan are two alkylating agents often applied in the conditioning regimen administered prior to the allo-HSCT. Finding the right balance between efficacious conditioning and toxicity remains the challenge for both agents. A majore One of the major complications after allo-HSCT is Acute graft-versus-host disease (aGvHD). When patients are diagnosed with grade 2 or higher aGvHD, systemic treatment with high-dose glucocorticoids is started as first line treatment. However, only half of the patients respond adequately to this therapy and also in other diseases non-responsiveness to glucocorticoids has been observed. Optimization of current drug therapies in allo-HSCT holds the potential to improve the outcome and safety. The goal of this thesis is to optimize busulfan- and treosulfan-based conditioning regimens and acute GvHD treatment with glucocorticoids by applying pharmacokinetic and pharmacogenetic profiling. Studies are performed in adults and pediatric patients. Show less
