Treosulfan-Based Conditioning before Hematopoietic Stem Cell Transplantation: Analysis of Differences Between Children and Adults

OBJECTIVE: The published literature was reviewed to assess the impact of treosulfan for conditioning before allogeneic or autologous SCT to identify possible differences between children and adults with respect to toxicity, acute or chronic graft versus host disease (a/cGVHD), treatment related mortality (TRM), overall survival (OS), disease free survival (DFS). MATERIAL AND METHODS: Pediatric (patients aged <18 years) data originated from EBMT megafile report (EBMT Annual Meeting 2012) and 1 study of 28 patients from India. Adult data originated from 34 studies from European countries (Germany, Poland, Italy, France, Finland, Italy), Israel (4 studies, 119 patients) and USA (1 study, 60 patients). The analysis was performed based on data published before October, 1^st, 2013. Pediatric data included 604 (521 allo + 83 auto) evaluable patients out of total 871 patients reported. Data on adults included 644 (598 allo + 46 auto) evaluable patients out of total 835 patients reported. In pediatric cohort 165 patients suffered from malignancies, 356 patients were transplanted for non-malignant diseases; 437 underwent a first SCT, 87 had a subsequent transplant. In adult group 626 were treated for hematological malignancies and 18 for non-malignant diseases (SAA or thalassemia). No data on auto-SCT in adults were published after 2004. The majority of pediatric patients received treosulfan in dose 39-45 mg/m2 (332 patients, 62%). Most of adult patients treated after 2007 received dose of 42 mg/m2. RESULTS: The main indications for treosulfan use in pediatric population were non-malignant diseases (68%) or second SCT, while among adults older age (>50 years) and/or comorbidities disqualifying from myeloablative conditioning. No correlation between the given treosulfan dose and the grade III/IV toxicity was observed both in children and in adults. No association between dose and GVHD, OS, DFS, relapse incidence and TRM was found both in children and in adults.

Table: Results of treosulfan use in conditioning in children vs adults

	Children	Adults
Toxicity	Diarrhea (24%), stomatitis (22%), SGOT (25%)	Gastro-intestinal II (up to 33%), III-IV (10-29%)
aGVHD III-IV	10%	Median 23% (range 14-50)
Limited cGVHD	13%	Median 42% (range 16-72)
Extended cGVHD	6%	14-16%
3y OS	ALL-51%, AML-46%, inherited disorders-80%, hemoglobinopathies-93%	Median  61% (range 36-85)
Other	3y EFS  ALL-39% AML-40%	Median 2y DFS 55% (range 35-82), RI 25% (range 15-36), 100d TRM 11.8%.

CONCLUSIONS: Treosulfan-based conditioning with its low toxicity profile and dose-dependent myelotoxicity is a good option in children treated with non-malignant diseases. Additionally, both children and adults not eligible for conventional transplant regimen can be offered this treatment with acceptable results. Toxicity and survival were similar in children and adults, while acute and chronic GVHD incidence were higher in adult population.