Targeting to optimal busulfan exposure is associated with a low relapse rate and high acute-GvHD 2-4 rates in MDS and JMML patients

• Published in: Bone marrow transplantation (Basingstoke) Vol. 43; no. S1; p. S221
• Main Authors: Bartelink, I.H, Bredius, R.G.M, 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: Bone marrow; Busulfan; Care and treatment; Complications and side effects; Dosage and administration; Graft versus host reaction; Myelodysplastic syndromes; Patient outcomes; Prevention; Risk factors; Transplantation; Netherlands
• ISSN: 0268-3369

Background: Busulfan combined with therapeutic drug monitoring and 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. We previously demonstrated an optimal AUC between 74-82 [mg.sup.*] h/L in a group of children with (non)-malignant indications. Therapeutic drug monitoring of busulfan is still controversial. The optimal target AUC in these children is not known. We retrospectively analyzed the association between busulfan exposure (AUC) and clinical outcomes in MDS and JMML patients. Methods: All children, transplanted for MDS and JMML between 2001-2008, receiving intravenous busulfan as part of a myeloablative regimen, were included. 34 patients received busulfan, cyclophosphamide 120mg/kg, and melphalan 140mg/[m.sup.2]. Based on the findings of these patients the most recent transplantations (n = 3) were performed using busulfan and cyclophosphamide 120mg/kg only (AUC of >74[mg.sup.*] h/L).The association between an AUC below or above the previously found lower limit of the optimum of 74[mg.sup.*] h/L and the main endpoints; relapse rate, overall survival (OS) and event free survival (EFS) and the toxicity endpoints: acute-Graft-versus-Host Disease (aGvHD) grade 2-4; and Veno-occlusive Disease (VOD), were tested using Cox regression analysis and log-rank statistics. Results: 38 patients (27 MDS, 11 JMML) were transplanted (1 patient was excluded because of unpredictable pharmacokinetics). Median follow up time was 2.2 (range 1-18) years. EFS in the <74[mg.sup.*] h/L and >74[mg.sup.*] h/L was 58% and 82% (p = 0.13), resp. OS rates were respectively 51% and 82% for these AUCs. EFS and OS were negatively influenced by higher rates of graft-failures/relapses in the <74[mg.sup.*] h/L group (38% vs. 0%, P = 0.047). Regarding the toxicity endpoints, high busulfan exposure was associated with more aGvHD grade 2-4: 20% vs 58% (p = 0.037), and showed a trend to a higher VOD-rate: 12% vs 34%, (p = 0.105). Conclusion: Higher busulfan exposure (>74[mg.sup.*] h/L) was associated with higher EFS / OS rates due to lower rates of graftfailure/ relapses. A concern however is the incidence of toxicity (aGvHD grade 2-4 and VOD) in the higher exposure group in patients receiving a combination of busulfan, cyclophosphamide and melphalan. More precise targeting (defining the upper limit for AUC) might further optimize the outcomes in SCT for MDS/JMML.