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Busulfan (BU) is included in many conditioning protocols for haematopoietic stem cell transplantation (HSCT). Pharmacokinetic parameters in individual patients have been related to short-term toxicity and risk of relapse after HSCT. In a series of 11 patients receiving the usual 16 × 1 mg/kg schedule over 4 days, we investigated the pharmacokinetics of replacing one dose with an intravenous formulation (BU in DMSO) which we had previously investigated in dogs. A dose of 0.5–0.6 mg/kg was used. No acute side-effects of BU/DMSO infusions administered over 1 h were observed. Bioavailability of BU powder capsules was on average 70% (range, 44–94%). Interindividual variability of the resulting AUC after intravenous doses was still substantial. Further studies are under way to define the possible role of BU/DMSO infusions in conditioning before HSCT. [ABSTRACT FROM AUTHOR]

Allogeneic peripheral blood stem cell transplantation leads to an earlier engraftment compared to BMT. The feasibility, acceptance and long-term side-effects of G-CSF mobilisation of PBSC in unrelated healthy donors needs to be evaluated. Forty unrelated healthy donors received G-CSF in a dose of 10 microg/kg bodyweight for 5 days and two aphereses were performed. The donors were monitored prospectively. The data were compared to bone marrow harvests from unrelated donors. Almost all stem cell donors reported some side-effects due to Filgrastim application. Bone pain (32), headache (20), chest pain (two) and night sweats (one) were complained of. By taking analgesics, the pain was relieved in most cases. No donor discontinued the filgrastim application. Bone pain and headache resolved within 2-4 days after termination of Filgrastim application. There was, as expected, a seven-fold increase in the number of total WBCs. There were no significant changes of platelet counts during G-CSF application. After 4 weeks haemoglobin concentration and platelet counts showed no significant differences compared to baseline values. The aphereses were mostly tolerated very well. Eighteen donors reported paraesthesia, one donor developed dizziness, two complained of nausea and vomiting. There was a significant decrease in platelet count (242 before, 98 x 10(9)/l after aphereses). Autologous platelets were transfused after the second aphereses in four donors. These data were compared to data from 245 unrelated bone marrow donors, who had on average, 14 days bone pain and tiredness after donation. The G-CSF mobilisation and apheresis of peripheral blood stem cells is an alternative to traditional bone marrow harvesting in unrelated healthy donors. It is well tolerated and the duration of side-effects on average is shorter than after the surgical procedure. So far no long-term effects have been observed in the follow-up.

Pharmacokinetics were studied in relation to hepatic side-effects in 20 patients (19 adults aged 18-53 years and one child of 11 years) undergoing BMT after conditioning with 1 mg/kg busulfan (every 6 hours for 16 doses). Busulfan was quantitated in plasma samples at 10 time points within the 6 h dosing interval using HPLC before and after dose numbers 1, 2, 5, 13 and 14. For 13 patients data on all five doses are available; for the remaining seven patients three to four doses were studied. Mean maximum concentrations were 1512 ng/ml; mean trough levels for second and subsequent doses were 615 ng/ml. Maxima (Cmax) tended to be lower and times of maxima (Tmax) were later when busulfan was taken with a meal. Correlation of the area under the concentration versus time curve (AUC0-6h) between different doses was low within patients. In several patients problems with compartmental fitting of concentration data were observed mainly caused by the short dosing interval, which made estimates of T1/2 and model derived AUCs unstable. Three patients experienced hepatic veno-occlusive disease; kinetic parameters were not helpful in describing a particulate risk constellation for this subgroup. In our experience, the role of drug monitoring in this setting needs to be defined more clearly.

Bacterial and fungal infections continue to be a major threat to bone marrow transplant recipients. While standardized approaches to empiric therapy with early inclusion of antibiotics active against Gram-positive organisms and against fungi may have improved the outcome of these patients during the past decade, other developments (e.g. increasing number of patients in older age groups, unrelated donors, mismatch transplants) may even have increased the problem. Current approaches to the prophylaxis and treatment of these infections are discussed. Concerning fungal infections especially the new azoles and new approaches of amphotericin B administration are of interest.

Thalidomide shows activity in refractory chronic graft-versus-host disease. Best responses were seen in mucocutaneous disease. The studies vary in inclusion criteria (e.g. pretreatment), time of onset of GVHD and dose given. The optimal schedule of thalidomide treatment is not defined. The role of thalidomide must be assessed in large controlled trials for treatment and prophylaxis of GvHD. Due to the variable absorption rate there is a need for an intravenous formulation of thalidomide, and in addition the search for more active and possibly less teratogenic derivatives must be intensified.