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My paper of the month - Treosulfan vs busulfan conditioning for allogeneic bmt in children with nonmalignant disease: a randomized phase 2 trial

Paediatric Diseases Working Party (PDWP)

Professor Krzysztof Kałwak* comments on the publication titled "Treosulfan vs busulfan conditioning for allogeneic bmt in children with nonmalignant disease: a randomized phase 2 trial" published in Bone Marrow Transplantation.  

* Head of the Department and Clinic of Bone Marrow Transplantation, Pediatric Oncology and Hematology, Medical University of Wrocław, Poland. Chair of the EBMT Paediatric Diseases Committee

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

Karl-Walter Sykora et al.

Published in Bone Marrow Transplantation November 04, 2023 DOI:

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is considered a potentially curative treatment for pediatric patients suffering from a variety of non-malignant diseases. However, the question of the optimal preparative regimen(s) for this heterogeneous condition is subject of ongoing research. Feasibility of a treosulfan / fludarabine conditioning in adults was initially reported by Casper et al., 2004. This was transferred into therapeutic attempts for children considered ineligible to standard conditioning treatments by Wachowiak et al., 2002. After a prospective phase 2 trial in children with malignant diseases (Kalwak et al., 2020) and the more recent prospective comparative evaluation of busulfan and treosulfan in adult patients with AML and MDS (Beelen et al., 2022) the article of Sykora et al., 2023 now presents safety, pharmacokinetic and efficacy results of a multi-center, prospective, randomized, phase 2 trial which compared full-dosed busulfan with myeloablative treosulfan conditioning (3 x 10, 12, or 14 g/m²; individual dose adapted to actual body surface area). All children in both treatment arms received fludarabine and additional thiotepa at the investigator’s discretion declared prior to randomization. The trial was conducted on the basis of an EMA/PDCO-granted Pediatric Investigational Plan (PIP) for treosulfan in the European Community.

In this study a total of 106 patients were randomized of which 101 children (50 busulfan; 51 treosulfan) received the study drug and were included in the safety and efficacy analyses. Pediatric patients 28 days to less than 18 years of age with non-malignant disease including Inborn Error of Metabolism (IEM), Primary Immunodeficiency Disease (PID), Hemoglobinopathy (HBP), and Bone Marrow Failure syndrome (BMF) indicated for a first allo-HSCTs were eligible. Descriptive by nature, the primary objective of the trial was to compare freedom from transplantation (treatment)-related mortality (freedom from TRM) until Day +100 after transplantation. Explorative comparative analyses included TRM, overall survival (OS), GvHD at 12 months and others. Covariates were additionally considered to examine efficacy and safety in pre-specified subgroups or in multivariate analyses (disease groups, age group, donor type, thiotepa, and serotherapy).

The main results of the trial revealed improvement of Kaplan-Meier estimates of TRM at 12 months of 12.0% vs. 3.9% after busulfan and treosulfan, respectively (HR: 0.29 [95% CI: 0.06, 1.41]). After a median follow-up of 25 months the 12-month estimate of OS was 88.0% in the busulfan arm versus 96.1% in the treosulfan arm (HR: 0.29 [95% CI: 0.06, 1.41]). The conditional cumulative neutrophil engraftment was comparable between the treatment arms (busulfan: 100.0% and treosulfan: 97.3%). However, cumulative incidences of primary and secondary graft failures at 12 months were significantly different: 4.0% after busulfan (95% CI: 0.0%, 9.4%) versus 15.8% (95% CI: 5.8%, 25.9%) after treosulfan (P = 0.0366). 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. In addition, incidence of mixed donor type chimerism at 12 months was lower in the busulfan arm while moderate/severe chronic GvHD was lower in the treosulfan arm. Toxicity was comparable in the different treatment arms, while incidence of HSOS (all grades) was 10% after busulfan and 2% after treosulfan. The pharmacokinetic substudy demonstrated a comparable treosulfan exposure in all dose groups with a trend for somewhat increased AUCs in the higher BSA categories.

Despite the beneficial survival results of treosulfan-based conditioning therapy as suggested by the prospective, comparative trial results limitations include the overall low patient number and the heterogeneity of patient population. Randomized allocation to treatment arms was not stratified for underlying disease and resulted in an imbalanced, increased number of beta-thalassemia major in the treosulfan arm. Patient numbers were too small for firm analysis of conditioning drug exposure in the pre-specified subgroups.

In conclusion, the reported prospective trial data provide evidence for an improved survival of treosulfan conditioned children with non-malignant diseases due to a reduction of TRM. Different to allo-HSCT after treosulfan-based conditioning in children or adults with malignant diseases an increased risk for secondary graft failures is to be considered for children with non-malignant transplant indications. This observation is in line with more recent large retrospective comparative analyses by Chiesa et al., 2020, Albert et al., 2022 and Lüftinger et al. 2022.   


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  6. Chiesa R, Wang J, Blok H-J, Hazelaar S, Neven B, Moshous D, et al. Hematopoietic cell transplantation in chronic granulomatous disease: a study of 712 children and adults. Blood. 2020;136:1201–11.
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