Discussion
obesity, toxicity, treosulfan-based, infections, organ dysfunction, CGD, cGVHD, non-malignant disease, PIDs, anorexia
OBESITY, CGD, DISEASE, CHRONIC GRANULOMATOUS DISEASE, RECRUITMENT, INFECTIONS, CHRONIC GVHD, SECONDARY, SYNDROMES, ADVERSE EFFECTS, RARE DISEASES, ALBERT, ANOREXIA
In this study, treosulfan-based conditioning showed a clinically meaningful trend towards improved freedom from TRM on Day +100 as well as reduced TRM at 12 months after transplantation. Also, OS and GvHD-free survival were increased, when compared to busulfan-based conditioning treatment. However, incidence of complete donor-type chimerism declined over time and an increased risk of secondary graft failure was observed after treosulfan. Accordingly, more treosulfan than busulfan treated children received second transplant procedures, donor lymphocyte infusions or stem cell boosts. Finally, all 9 patients who experienced secondary graft failure in the treosulfan arm were rescued and survived.Meanwhile, there already is ample published clinical experience with treosulfan-based conditioning in pediatric HSCT [However, the question of the optimal preparative regimen for a patient with a particular non-malignant disease is usually answered by retrospective registry analyses of populations with a single non-malignant condition. Due to the given heterogeneity of such rare diseases the conduct of prospectively randomized trials for single specific syndromes is not considered feasible. Nevertheless, most recently published, large retrospective analyses are in line with the findings reported in our prospective study.Albert et al. [Chiesa et al. [For beta-thalassemia major, Lüftinger et al. [In summary, these retrospective analyses suggest that outcome differences between treosulfan or busulfan based conditioning regimens partly depend on the specific disease entity. The results of our prospective randomized study are in line with these observations regarding an improved survival, lower toxicity and cGVHD incidence, but a potentially higher rate of mixed chimerism and graft failure after treosulfan-based conditioning. For instance, in our subgroup of 21 patients with beta-thalassemia major 0 out of 5 and 3 out of 16 patients experienced a graft failure after treatment with busulfan or treosulfan, respectively. However, 100% versus 93.8% engrafted and survived at least 12 months after transplant. In our small subgroup of 13 patients with chronic granulomatous disease (CGD) 0 out of 7 and 2 out of 6 patients experienced a graft failure after treatment with busulfan or treosulfan, respectively. Finally, 6 out of 7 versus 4 out of 6 patients engrafted and survived at least 12 months after transplant. As discussed below, the patient numbers with a disease-specific indication within our trial are too small for any firm safety or efficacy conclusion. Further well-designed comparative disease-specific real world data analyses are, therefore, highly warranted as referenced above.The PK sub-study on treosulfan included in our trials MC-FludT.16/NM and MC-FludT.17/M applied a BSA-adapted dose calculation. This was based on a Pop-PK model aiming at a comparative treosulfan exposure to all pediatric age (BSA) groups starting at 4 weeks of age [Despite the beneficial survival results of treosulfan based conditioning therapy as suggested by our prospective comparative trial, several limitations exist. Heterogeneity of the non-malignant transplant indications and the limited sample size affect treatment arm comparability. Randomized allocation was not stratified for underlying disease and resulted in an increased number of beta-thalassemia major in the treosulfan vs. the busulfan arm. Also, the overall study population consisted primarily of patients with PIDs and HBPs while IEMs and BMFs were underrepresented. The inclusion of patients with specific disease entities and selection of the conditioning intensity was at the investigators’ discretion. This resulted in 84% patients received the intensified treatment with thiotepa. Moreover, inclusion and exclusion criteria limited study recruitment by age, weight, body surface area, and organ function. For patients outside of these criteria, e.g., with obesity, anorexia or limited organ function the risk estimates may differ and potentially favor treosulfan. Patient numbers were too small for any potential analysis of conditioning drug exposure in subgroups.Treating physicians may prefer treosulfan over busulfan in patients with increased risk of TRM related to e.g., concomitant infections or pre-existing organ dysfunction. Although secondary graft failures were more common in the treosulfan group, these patients were rescued by second procedures. Moreover, there is strong evidence suggesting a reduced risk for impairment of gonadal function, acute and chronic GVHD, and other early and late adverse effects after treosulfan based conditioning [