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Busulfan is used in preparative regimens before stem cell transplantation. There is significant interpatient variability in busulfan pharmacokinetics (PK) and exposure is related to outcome. Polymorphisms in genes encoding glutathione-S-transferases have been associated with busulfan PK but only explain a limited portion of the observed variability.The aim of this study is to identify additional genetic variants associated with busulfan PK by interrogating 1936 variants in 225 genes involved in drug absorption, distribution, metabolism, and excretion (ADME).In an exploratory cohort (n=65), patients who received busulfan were genotyped with the DMET array. Top SNPs and haplotypes associated with busulfan clearance were validated in an independent validation cohort (n=78).In the exploratory cohort, seven variants were identified to be associated with busulfan clearance (P<0.001). In the validation cohort, only GSTA5 (rs4715354 and rs7746993) remained significantly associated with busulfan clearance (P=0.025).This is the first study using an exploratory pharmacogenetic approach to explain the interindividual variability in busulfan PK. The role of glutathione-S-transferases was confirmed, but no additional genetic markers involved in drug ADME appear to be associated with busulfan PK. [ABSTRACT FROM AUTHOR]

To treat patients with refractory cytomegalovirus (CMV) reactivation after allogeneic stem cell transplantation, a phase I/II clinical study on adoptive transfer of in vitro-generated donor-derived or patient-derived CMV pp65-specific CD8* T-cell lines was performed. Peripheral blood mononuclear cells from CMV seropositive donors or patients were stimulated with HLA-A*0201-restricted and/or HLA-B*0702-restricted CMV pp65 peptides (NLV/TPR) and 1 day after stimulation interferon-γ)-producing cells were enriched using the CliniMACS Cytokine Capture System (interferon-γ), and cultured with autologous feeders and low-dose interluekin-2. After 7-14 days of culture, quality controls were performed and the CMV-specific T-cell lines were administered or cryopreserved. The T-cell lines generated contained 0.6-17 × 10(6) cells, comprising 54%-96% CMV pp65-specific CD8 T cells, and showed CMV-specific lysis of target cells. Fifteen CMV-specific T-cell lines were generated of which 8 were administered to patients with refractory CMV reactivation. After administration, no acute adverse events and no graft versus host disease were observed and CMV load disappeared. In several patients, a direct relation between administration of the T-cell line and the in vivo appearance of CMV pp65-specific T cells could be documented. In conclusion, administration of CMV pp65-specific CD8* T-cell lines was found to be feasible and safe, and enduring efficacy of administered CMV pp65-specific CD8* T-cell lines could be demonstrated.

Reduced-intensity conditioning (RIC) has allowed the use of allogeneic stem cell transplantation (alloSCT) for haematological malignancies in elderly patients. A major problem of this type of transplantation is the high incidence of persisting chronic graft-versus-host disease (GvHD), leading to increased morbidity and mortality. The inclusion of alemtuzumab added to the graft ('Campath in the bag') for donor T-cell depletion offers an easy procedure to diminish the incidence of GvHD. Good engraftment is observed in most patients, whereas almost no GvHD is observed after transplantation. Most patients become mixed chimeric after transplantation, requiring donor lymphocyte infusion for conversion to full donor chimerism. Although subsequent acute and chronic GvHD is observed in 50-60% of patients, it is responsive to therapy in many patients, resulting in a low incidence of persisting chronic GvHD. AlloSCT with RIC and alemtuzumab-induced T-cell depletion offers a suitable platform for the investigation of novel cellular immunotherapy.