Dose-escalated treosulphan in combination with cyclophosphamide as a new preparative regimen for allogeneic haematopoietic stem cell transplantation in patients with an increased risk for regimen-related complications

Abstract

Summary:Treosulphan has recently demonstrated antileukaemic activity and potent haematopoietic stem cell toxicity. Dose-escalated treosulphan (3 Â 12 or 3 Â 14 g/m 2 ) combined with cyclophosphamide (Cy) was chosen for a new preparative regimen before allogeneic haematopoietic stem cell transplantation in 18 patients (median age 44, range 19-64 years) with haematological malignancies, considered ineligible for other myeloablative preparative regimens. Pharmacokinetic studies demonstrated rapid treosulphan plasma clearance and a dose-dependent increase of its maximum plasma concentrations and area under the concentration-time curves. Rapid and sustained white blood cell and platelet recovery and full donor chimerism was attained in all evaluable patients. Nonhaematological regimen-related CTC grades 3-4 adverse events were transient and predominantly consisted of cardiac (28%), gastrointestinal (39%), and hepatic (39%) toxicities. The 1-year nonrelapse mortality was 22%. Principal causes of transplant-related lethal events were infections in three of four affected patients. Only one patient died from regimen-related cardiac toxicity. The 1-year relapse estimate is 22%, overall and progressionfree survival estimates are 67 and 56%, respectively. In conclusion, this new treosulphan and Cy combination is an effective, comparatively well-tolerated myeloablative preparative regimen even in patients with an increased risk for regimen-related toxic complications. Treosulphan (L-treitol-1,4-bis-methanesulphonate) is a water-soluble bifunctional alkylating agent registered in several European countries for the treatment of ovarian cancer. In conventionally dosed chemotherapy, haematotoxicity is limiting at an intravenous (i.v.) dose of 10 g/m 2 . 1 If combined with autologous haematological stem cell rescue, a substantial dose escalation in the range of five times of the conventional maximum tolerated dose is feasible. At this escalated dose, mucositis, diarrhoea, skin toxicity, and metabolic acidosis have been found to be dose-limiting at doses of 47 and 49 g/m 2 , respectively. 2,3 Pharmacokinetic studies demonstrated linear pharmacokinetic characteristics of treosulphan up to single doses of 47 g/m 2 with a comparably low intra-and interindividual variability. 2 Recently, preclinical evaluation of the agent revealed further evidence for its feasibility as a component of preparative regimens for allogeneic haematopoietic stem cell transplantation (HSCT) in that treosulphan demonstrated pronounced haematopoietic stem cell toxicity in vitro. 4 In a murine transplantation model, repeated doseregimens of treosulphan proved to be at least as effective as busulphan or total body irradiation (TBI), and further allowed the development of stable donor chimerism in recipient animals. [5][6][7][8][9] Beside its potent haematopoietic stem cell toxicity, treosulphan also demonstrated in vitro activity against a variety of haematological malignancies including acute leukaemias, chronic myelogenous leukaemia, and multiple myeloma. [10...

Pharmacokinetics of high-dose i.v. treosulfan in children undergoing treosulfan-based preparative regimen for allogeneic haematopoietic SCT

“…AUC of the remaining children were in the range of 579-1080 mg/l h (mean 906) and were comparable with the literature data for adult patients. 7 In addition, high value was obtained for child treated with 14 g/m 2 dose. The metabolic acidosis as a result of the methanesulphonic acid formation from treosulfan can cause increasing AUC, because the activation of treosulfan is pH dependent and at pH o6 almost no treosulfan is metabolized.…”

“…[3][4][5][6] In addition, it was demonstrated both in vivo and in vitro that treosulfan reveals an excellent toxicity against all stem cell lines of the BM and this caused that it was recently administered in high doses within the conditioning regimen prior to allogeneic haematopoietic SCT in patients with haematological malignancies. 7 Despite the clinical use of the oral and i.v. formulation, pharmacokinetic data for adult patients are rather scarce.…”

“…formulation, pharmacokinetic data for adult patients are rather scarce. [3][4][5]7,8 Treosulfan represents linear increase of area under the concentration (AUC) up to 56 g/m 2 in adult patients, whereas other pharmacokinetic parameters, such as halflife, volume of distribution and renal elimination, were independent of dose. 8 According to growing clinical experience, the high-dose treosulfan demonstrates low organ toxicity in paediatric patients when used as a part of the preparative regimen for haematopoietic SCT, 9,10 but until now there were no studies of the pharmacokinetics of the drug in children.…”

Autologous SCT with a dose-reduced BU and CY regimen in older patients with non-Hodgkin's lymphoma

“…28 Four patients experienced transient atrial fibrillation, which may be related to CYconditioning. 29 Patients over age 55 receiving CY-based conditioning regimens have been reported to experience a decrease in cardiac output, suggesting that high-dose CY in older patients may be associated with cardiac toxicity. 30 There are little published data on the outcomes of autologous SCT for patients more than the age of 70 years.…”

Idarubicin-intensified BUCY2 regimens may lower relapse rate and improve survival in patients undergoing allo-SCT for high-risk hematological malignancies: a retrospective analysis

“…Some nonrandomized studies on the use of an intensified conditioning have reported better disease control for high-risk patients, but higher rates of toxicity and TRM have also been reported. [6][7][8] The search for alternative regimens to the standard BUCY2 aimed at reducing the relapse rate and also TRM has proven to be difficult. [9][10][11][12] Idarubicin (IDA, 4-demethoxydaunorubicin) was first introduced as a new anthracycline and now it has been widely used to treat AML or relapsed/refractory ALL because it is more effective in multidrug-resistant cell lines and has relatively low cardiotoxicity, but a high penetration rate to central nervous system, compared with DNR or doxorubicin.…”