Use of Busulfan in Conditioning for Allogeneic Hematopoietic Stem Cell Transplantation in Adults: A Survey By the Complications and Quality of Life Working Party of the EBMT

Background : With the introduction of an intravenous formulation, options for the administration of busulfan in conditioning for allogeneic hematopoietic stem cell transplantation have increased. Practical issues in which the policies of transplant centers are likely to vary include the route of administration, number of daily doses, and the use of pharmacokinetic (PK) measurements for dose adjustment. Following the general policy of the European Society for Blood and Marrow Transplantation (EBMT) to aim at standardizing transplantation procedures, the Complications and Quality of Life Working Party has carried out a survey among EBMT centers about their practice in the use of busulfan for conditioning in allogeneic transplantation.

Results : All allogeneic transplant centers reporting to the EBMT and treating adult patients were invited to participate. One hundred and nine centers (28 %) sent their report. One hundred and five of these centers used busulfan for conditioning, 4 did not. One hundred and one centers used it in full conventional doses, 92 centers in lower doses for reduced intensity conditioning (RIC). The oral dose in conventional conditioning was 16 mg/kg, the intravenous dose usually 12.8 mg/kg. Six centers determined the dose according to body surface area. The most common indications for conventional dose myeloablative conditioning were AML (99 centers), MDS (87), CML (75), ALL (56), lymphoma (26), thalassemia and other hemoglobinopathies (22), CLL (17), and myeloproliferative disorders (MPD, 6 centers). Lower doses of busulfan (RIC) were most commonly used for MDS (69 centers), AML (66), CML (49), ALL (37), lymphoma (36), CLL (31), and MPD (11 centers). The busulfan dose in RIC conditioning was usually 8 mg/kg in oral administration, in i.v. administration most often (66% of the centers) 6.4 mg/kg. Four centers determined the dose according to body surface area. Eleven centers gave full conventional dose busulfan orally and 94 i.v., while in RIC transplantations the drug was given orally in 10 and i.v. in 77 centers. Overall, 17 of the 105 centers used PK measurements to adjust busulfan doses. Busulfan concentration was measured using liquid chromatography (+ mass spectrometry in 8 centers). With one exception, the parameter used for dose adjustment was AUC. The details of the sampling for PK measurements as well as the method of AUC calculation varied. There was no difference between centers giving oral and those giving i.v. busulfan in the use of PK for dose adjustment, in full dose conditioning 2/11 vs. 14/94 centers, respectively. In RIC transplantations, PK-based dose adjustment was used in 1/10 centers giving oral busulfan and 8/77 using i.v. busulfan. The centers using oral busulfan or those adjusting the doses according to PK did not differ significantly from the rest of the centers in center experience, transplant numbers, JACIE accreditation, or gross national income of their country.Full conventional doses were always given in 4 days. Oral busulfan was given in 4 daily doses with one exception (2 doses). In i.v. administration, the number of daily doses was one in 46 centers, four in 42 centers, and two in 4 centers. In RIC conditioning, busulfan was in most cases given in 2 days, i.v. busulfan usually in one (35 centers) or four (28 centers) daily doses. Twenty-seven centers reported having alternative busulfan administration schedules depending on the disease, 20 centers depending on other components of the conditioning regimen. In myeloablative conditioning, 73 centers adjusted the dose of busulfan in obese patients, whereas 25 centers did not. Thirty-two centers reported defining obesity based on body mass index, whereas 28 centers used actual body weight in relation to ideal body weight. In obese patients, the busulfan dose was determined according to actual body weight (12 centers), ideal body weight (15), AIBW-25 (ideal body weight + 0.25 x (actual body weight - ideal body weight)) (46), AIBW-40 (10), or other (11 centers). In RIC, busulfan doses were adjusted because of obesity in 52 centers but not in 32 centers.

Conclusions : There is marked variation between centers in the details of busulfan administration for conditioning in allogeneic transplantation. The clinical impact of this variation remains uncertain. The present results are useful in the production of recommendations toward a more standardized use of busulfan in the conditioning.