Effect of Busulphan Dose Adjustment on Regimen-Related Toxicity.
Authors: Hassan Zuzana , Remberger Mats , Ringden Olle , Oberg Gunnar , Bekassy Albert N. , Hassan Moustapha 
Published: October 2019

Abstract
Stem cell transplantation (SCT) is a successful treatment for many patients with malignant and non-malignant diseases. Conditioning regimen is an important part of SCT, however, regimen-related toxicity (RRT) is a major drawback of myeloablative regimens. In order to decrease RRT, many strategies have been introduced such as therapeutic drug monitoring (TDM) and dose adjustment of busulphan and optimization of time interval between different drugs. The present study, include 470 patients collected from three transplantation centres in Sweden between 1987 and 2002. All patients underwent allogeneic or autologous SCT using busulphan-based conditioning regimen prior to SCT. We investigated the effect of TDM and dose adjustment of busulphan (Bu) on the occurrence of RRT in these patients. Bu was administered orally in total dose of 16 mg/kg with or without dose adjustment and cyclophosphamide administered iv at a total dose of 120 mg/kg. Anti-thymocyte globulin was given to all patients transplanted from unrelated or mismatched donor. Prevention of GVHD consisted of the combination cyclosporin A and four doses of methotrexate or monotherapy with either of the agents. Several strategies for TDM of Bu were based on the actual knowledge, determination of trough levels, the estimation of the area under the concentration-time curve (AUC) using full pharmacokinetics or limited sapling model with follow up of trough concentrations of Bu (Hassan, 1996). The target trough concentrations of Bu were 450–600 ng/ml, the target AUC after the first dose of Bu was 4500–5500 ng. hr/ml. For the purpose of this study, mean Bu plasma concentrations were used. Bu plasma concentrations were measured in all 470 patient, however, TDM was applied in 277 patients, while only determination of plasma concentrations of Bu without dose adjustment was used in 193 patients. Mean trough Bu plasma concentrations followed a Gaussian distribution pattern. One half of the patients had Bu trough concentrations within the range 450–650 ng/ml. The difference between adjusted and non-adjusted groups was observed (57% vs 39%, resp.). Dose adjustments decreased the variation in exposure to Bu between and within the different age groups. Veno-oclussive disease (VOD) was diagnosed in 11/277 patients (4.0%) in patients where Bu doses were adjusted according to plasma concentrations compared to 38/193 patients (19.7%) who were treated without dose adjustment (p<0.001). Busulphan plasma concentrations above 600 ng/ml predispose to VOD. Hemorrhagic cystitis (HC) was found in 8/277 patients (2.9 %) with dose adjustment compared to 26/193 patients (13.5%) without dose adjustment of Bu (p<0.001). Interstitial pneumonitis syndrome (IPS) decreased from 15 % in patients without dose adjustment to 4.3 % in patients whose doses were adjusted (p<0.001), however, almost all patients with IPS had Bu mean trough concentrations above 800 ng/ml. Multiorgan failure was diagnosed in 3/277 patients (1.1 %) with dose adjustment compared to 8/193 patients (4.1 %) without dose adjustment of Bu (p=0.03). These results show, that TDM and dose adjustment of Bu during myeloablative conditioning regimen decrease the occurrence of RRT.