Busulphan level and early mortality in thalassaemia patients after BMT

Abstract

Summary:The aim of the study was to correlate busulphan (BU) levels of thalassaemia patients with outcome of allogeneic transplant. BU levels were measured by gas chromatography mass fragmentography. All patients received a standardised dose of BU 16 mg/kg, and cyclophosphamide 150 or 200 mg/kg. For area-under-thecurve analysis (AUC), blood samples were obtained at 0, 1, 2, 3, 4 and 6 h after the first and fifth dose for all patients, and additional levels were measured after ninth and/or 13th dose in most patients. Outcome parameters examined included veno-occlusive disease of liver (VOD), idiopathic interstitial pneumonitis, chimerism, and day 90 survival. Twenty consecutive thalassaemia patients who underwent haematopoietic stem cell transplantation were studied. The median age at transplant was 11.2 years (range 3-21 years). Mean BU AUC levels were correlated with age at transplant (r ‫؍‬ 0.58, P ‫؍‬ 0.007). Nine patients developed VOD and six had mixed chimerism, but these did not correlate with mean BU AUC level. Four patients died before day 50 from VOD and interstitial pneumonitis. Patients with BU AUC levels greater than the median (908 mol ؋ min/l) had significantly lower probability of survival at day 90 (60%), whereas patients with BU AUC level less than the median all survived beyond day 90. No patient had graft rejection. In conclusion, a high BU AUC level was associated with a higher treatment-related mortality in thalassaemia patients after transplant. Keywords: busulphan; early mortality; thalassaemia Thalassaemia major is the most common non-malignant disease being treated by haematopoietic stem cell transplant. Conditioning with busulphan (BU) and cyclophosphamide has been adopted by most centres. The long-term disease-free survival has been reported to be in the range of 60 to 90% depending on risk factors which include age, hepatomegaly, iron chelation and hepatic fibrosis. 1 Early results have shown a high incidence of treatment-related mortality (TRM) in the high risk patients. Reduction of intensity of conditioning reduces the TRM but at the expense of higher rejection rate. 2 It has been suggested that use of BU in conditioning is associated with a higher incidence of veno-occlusive disease (VOD) and interstitial pneumonitis. BU kinetics based on area-under-the-curve or concentration at steady state has been studied to correlate with treatment complications, graft rejection, relapse of leukaemia and transplant-related mortality. [3][4][5][6] We analysed the plasma BU levels in 20 thalassaemia patients and the relationship with outcome parameters.

Novel pharmacokinetic behavior of intravenous busulfan in children with thalassemia undergoing hematopoietic stem cell transplantation: a prospective evaluation of pharmacokinetic and pharmacodynamic profile with therapeutic drug monitoring

“…The incidence of hepatic VOD in our study was lower (1.4%) compared with the reported incidence of VOD in children with thalassemia and treated with oral Bu, which varied between 4.5% and 45%. [4][5][6] It has been suggested that dosing Bu close to the dose of Cy may increase hepatotoxicity that occurred more frequently with shorter intervals (7-15 hours) compared with longer intervals (24-48 hours) between the last dose of Bu and the first dose of Cy. 41 In the present study, the interval between the last dose of Bu and the first dose of Cy was 14 hours in 42%, and it was 38 hours in the remaining 58% of patients.…”

“…[1][2][3] High-dose busulfan (Bu) combined with cyclophosphamide (Cy) is the preferred preparatory regimen for patients with thalassemia and is a valid alternative to regimens that include total body irradiation. Although the BuCy regimen has been extensively used in patients with thalassemia few data are available on relationship of Bu pharmacokinetics (PK) to transplantation outcome with controversial results: one study found no effect of oral Bu exposure to transplantation outcome, 4 whereas in 2 other studies a relationship between oral Bu PK and rejection, hepatic veno-occlusive disease (VOD), 5 or mortality 6 was observed. These discrepancies might be the result of the unreliability of oral Bu pharmacokinetic assessment because of erratic intestinal absorption and possible dose loss with emesis.…”

Haematopoietic stem cell transplantation for thalassaemia major in Hong Kong: prognostic factors and outcome

“…14 In our previous study, busulphan levels (area under curve) greater than 908 mol × min/l were associated with higher mortality. 15 The occurrence of VOD is related to number of transfusions and age. Thus, older patients are at risk of severe VOD and other treatmentrelated complications.…”

Glutathione S-transferase M1 polymorphism: a risk factor for hepatic venoocclusive disease in bone marrow transplantation

“…Patients with thalassemia major undergoing BMT are particularly prone to developing HVOD and the incidence can be as high as 30% to 40% 18,19 in those with significant pre-existing hepatic damage. The aim of the present study was to assess whether the polymorphisms of the GST genes are associated with the risk of developing HVOD in this group of patients.…”