Treosulfan vs busulfan conditioning for allogeneic bmt in children with nonmalignant disease: a randomized phase 2 trial

Abstract

Optimal conditioning prior to allogeneic hematopoietic stem cell transplantation for children with non-malignant diseases is subject of ongoing research. This prospective, randomized, phase 2 trial compared safety and efficacy of busulfan with treosulfan based preparative regimens. Children with non-malignant diseases received fludarabine and either intravenous (IV) busulfan (4.8 to 3.2 mg/kg/day) or IV treosulfan (10, 12, or 14 g/m²/day). Thiotepa administration (2 × 5 mg/kg) was at the investigator's discretion. Primary endpoint was freedom from transplantation (treatment)-related mortality (freedom from TRM), defined as death between Days -7 and +100. Overall, 101 patients (busulfan 50, treosulfan 51) with at least 12 months follow-up were analyzed. Freedom from TRM was 90.0% (95% CI: 78.2%, 96.7%) after busulfan and 100.0% (95% CI: 93.0%, 100.0%) after treosulfan. Secondary outcomes (transplantation-related mortality [12.0% versus 3.9%]) and overall survival (88.0% versus 96.1%) favored treosulfan. Graft failure was more common after treosulfan (n = 11), than after busulfan (n = 2) while all patients were rescued by second procedures except one busulfan patient. CTCAE Grade III adverse events were similar in both groups. This study confirmed treosulfan to be an excellent alternative to busulfan and can be safely used for conditioning treatment in children with non-malignant disease.

Fig. 1. Consort diagramm.

Patient disposition, for In- and Exclusion Criteria see Supplementary Information (1.4).

Fig. 2. Kaplan-Meier curves and forest plots for transplantation-related mortality and overall survival.

All Death Events in Overall Survival are Attributed to Events of Transplantation-related Mortality a Kaplan-Meier estimate of transplantation-related mortality of children with non-malignant disease randomized to treosulfan or busulfan based conditioning prior to allogeneic transplantation (FAS). b Forest plot for transplantation-related mortality displaying 12-month rates by subgroups (FAS) c Kaplan-Meier estimate of overall survival of children with non-malignant disease randomized to treosulfan or busulfan based conditioning prior to allogeneic transplantation (FAS). d Forest plot for overall survival displaying 12-month rates by subgroups (FAS).