Targeting to an optimal AUC of intravenous busulfan prevents graft failure in transplantation in children with non-malignant diseases

• Published in: Bone marrow transplantation (Basingstoke) Vol. 43; no. S1; p. S183
• Main Authors: Bartelink, I.H, Bredius, R.G.M, Belitser, S.V, Bierings, M, Knibbe, C.A.J, Egeler, M, Lankester, A.C, Egberts, A.C.G, Zwaveling, J, Boelens, J.J
• Format: Journal Article
• Language: English
• Published: Nature Publishing Group 01-03-2009
• Subjects: Busulfan; Dosage and administration; Drug therapy; Graft versus host reaction; Hematopoietic stem cells; Risk factors; Transplantation; Netherlands
• ISSN: 0268-3369

Background: Busulfan combined with therapeutic drug monitoring guided dosing is associated with higher event free survival (EFS) rates due to less graft-failure/relapses and lower toxicity in haematological stem cell transplantation (HSCT). In an earlier study, our group showed an optimal AUC between 74-82 mg*h/L in a group of children with malignant and nonmalignant indications. Nonmalignant diseases, especially inborn error of metabolism (IEM) are known to be associated with high graft-failure rates. It is not known whether there is an optimal target AUC in nonmalignant diseases. Historically intravenous busulfan has been used in the two Dutch pediatric stem cell transplantation centers in various myelo-ablative regimens with different targets for the area under the curve (AUC) and different dosing regimens of busulfan. We retrospectively analyzed the association between busulfan AUC and clinical outcome. Methods: All children, transplanted between 2001-2008, receiving intravenous busulfan as part of a myeloablative regimen for non-malignant indications, were included. The association between an AUC below or above the optimum of 74mg*h/L and the endpoints overall survival (OS), treatment related mortality (TRM), event free survival (EFS) and toxicity (acute-Graft-versus-Host Disease grade 2-4 (aGvHD) and Veno-occlusive Disease (VOD), were tested using uni- and multivariable Cox regression analysis. Results: 28 patients with IEM, 36 with immune defiencies and 5 patients with bone marrow failures were included, with a median follow up time of 2.5 years. EFS was negatively influenced by Graft-failure below the lower limit of the AUC (18% in patients receiving <74mg*h/L, vs 0% in patients receiving > 74mg*h/L, HR=0.2, P=0.016). OS was similar in both groups (OS 20% vs 19%). All but one patients died due to TRM. EFS was 72% vs 82% (not significantly different). Acute graft-versus-host disease (aGvHD) grade 2-4 did occur more frequently in patients receiving a high exposure of busulfan (5% vs 20%), but this was not significantly different. VOD was seen in 13% vs 17% of the two AUC-groups. Conclusion: Dose targeting of busulfan to a high therapeutic range decreases the amount of graft failures in patients with non-malignant diseases, without compromising the treatment due to treatment related mortality.