Randomized trial of two different conditioning regimens for bone marrow transplantation in thalassemia – the role of busulfan pharmacokinetics in determining outcome

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.…”

Conditioning regimens in allo-SCT for thalassemia major

“…25 BM has been the preferred choice of stem cells to reduce the risk of GVHD in this nonmalignant condition, although the incidence of both acute and chronic GVHD in this predominantly pediatric population is low. 27,30 PBSC grafts, when used, have been reported to be associated with faster engraftment and lower requirement of blood product support in the peri-transplant period 25,31,32 and have also been associated with a low incidence of graft rejection. 25,33 However, the risk of chronic GVHD is increased.…”

“…25 Treosulfan was hence especially attractive in the context of an allo-SCT for high-risk b-thalassemia major because of its reported low hepatic toxicity profile and consistent pharmacokinetic profile, which are both significant problems with conventional BU in this population. 6,26,27 However, it is also important to recognize that the pharmacokinetic profile of treosulfan-based regimens, both in patients with thalassemia major and when it is combined with other high-dose chemotherapeutic agents as part of the conditioning regimen, have not been studied extensively.…”

Reduced-Intensity Regimens in Allogeneic Hematopoietic Stem Cell Transplantation for Hemoglobinopathies

“…39 The addition of thiotepa to the preparative regimen and the substitution of cyclophosphamide with fludarabine, a drug displaying comparable immune suppression with lower extra-medullary toxicity, were also shown to improve the outcome of patients with thalassemia transplanted from an unrelated volunteer or with cord blood progenitors. 6,8,9,11 Use of intravenous busulfan 40,41 should also reduce the risk of either inappropriately low (in some reports demonstrated to predict the occurrence of graft failure) 42 or excessive systemic exposure to the drug, especially in younger children in whom a marked interpatient variability in plasmatic level of busulfan has been reported after oral administration, due to accelerated clearance, wider distribution volume and unpredictable intestinal absorption. 43 Likewise, new opportunities could be offered by the new alkylating agent treosulfan, which in the future could represent a valid alternative to busulfan in terms of efficacy and safety.…”