Effect of Busulfan and Treosulfan on Gonadal Function after Allogeneic Stem Cell Transplantation in Children and Adolescents with Nonmalignant Diseases Is Not Exposure-Dependent.

With an increasing number of young patients surviving into adulthood after hematopoietic stem cell transplantation (HSCT), gonadal dysfunction becomes an important late effect with significant impact on quality of life. In this retrospective study, we evaluated the exposure of busulfan (Bu) and treosulfan (Treo) in relation to gonadal function in pediatric patients who underwent HSCT for a nonmalignant disease between 1997 and 2018. In the Bu group, 56 patients could be evaluated, and gonadal dysfunction was found in 35 (63%). Lower Bu exposure (ie, cumulative area under the curve [AUC] <70 mg*h/L) was not associated with a reduced risk of gonadal dysfunction (odds ratio [OR], .92; 95% confidence interval [CI], .25 to 3.49; P = .90). In the Treo cohort, 32 patients were evaluable and gonadal insufficiency occurred in 9 patients (28%). Lower Treo exposure (AUC <1750 mg*h/L on day 1) was not associated with a reduced risk of gonadal dysfunction (OR, 1.6; 95% CI, .16 to 36.6; P = .71). Our data do not support the premise that reduced-intensity Bu-based conditioning reduces the risk for gonadal toxicity, and it is unlikely that therapeutic drug monitoring-based reduced treosulfan exposure will further limit the risk of gonadal dysfunction.

Therapeutic Drug Monitoring of Conditioning Agents in Pediatric Allogeneic Stem Cell Transplantation; Where do We Stand?

Allogeneic hematopoietic stem cell transplantation (HSCT) is an established curative treatment that has significantly improved clinical outcome of pediatric patients with malignant and non-malignant disorders. This is partly because of the use of safer and more effective combinations of chemo- and serotherapy prior to HSCT. Still, complications due to the toxicity of these conditioning regimens remains a major cause of transplant-related mortality (TRM). One of the most difficult challenges to further improve HSCT outcome is reducing toxicity while maintaining efficacy. The use of personalized dosing of the various components of the conditioning regimen by means of therapeutic drug monitoring (TDM) has been the topic of interest in the last decade. TDM could play an important role, especially in children who tend to show greater pharmacokinetic variability. However, TDM should only be performed when it has clear added value to improve clinical outcome or reduce toxicity. In this review, we provide an overview of the available evidence for the relationship between pharmacokinetic parameters and clinical outcome or toxicities of the most commonly used conditioning agents in pediatric HSCT.

Impact of Treosulfan Exposure on Early and Long-Term Clinical Outcomes in Pediatric Allogeneic Hematopoietic Stem Cell Transplantation Recipients: A Prospective Multicenter Study.

Treosulfan-based conditioning has gained popularity in pediatric allogeneic hematopoietic stem cell transplantation (HSCT) because of its presumed favorable efficacy and toxicity profile. Treosulfan is used in standardized dosing regimens based on body surface area. The relationships between systemic treosulfan exposure and early and long-term clinical outcomes in pediatric patients undergoing allogeneic HSCT for nonmalignant diseases remain unclear. In this a multicenter, prospective observational study, we assessed the association between treosulfan exposure and early and, in particular, long-term clinical outcomes. Our study cohort comprised 110 pediatric patients with nonmalignant diseases who underwent HSCT between 2011 and 2019 in Leiden, The Netherlands and Rome, Italy. Blood samples were collected, and treosulfan area under the receiver operating characteristic curve (AUC0-∞) was estimated as a measure of exposure. Cox proportional hazard survival analyses were performed to assess the relationships between treosulfan exposure and overall survival (OS) and event-free survival (EFS). The predictive value of systemic treosulfan exposure for the occurrence of toxicity within 28 days was evaluated using a multivariable logistic regression analysis. In the overall cohort, OS and EFS at 2 years were 89.0% and 75.3%, respectively, with an excellent OS of 97% in children age <2 years. The occurrence of grade II-IV acute graft-versus-host disease, the level of 1-year whole blood chimerism, and 2-year OS and EFS were not correlated with treosulfan exposure. The occurrence of skin toxicity (odds ratio [OR], 3.97; 95% confidence interval [CI], 1.26-13.68; P = .02) and all-grade mucositis (OR, 4.43; 95% CI, 1.43-15.50; P = .02), but not grade ≥2 mucositis (OR, 1.51; 95% CI, 0.52 to 4.58; P = .46) was related to high treosulfan exposure (>1750 mg*h/L). Our study demonstrates that standardized treosulfan-based conditioning results in a favorable OS and EFS in infants and children with nonmalignant diseases, independent of interindividual variation in treosulfan exposure. These outcomes can be achieved without the need for therapeutic drug monitoring, thereby emphasizing the advantage of treosulfan use in this category of patients. Although higher treosulfan exposure increases the risk of skin toxicity, there is no absolute necessity for therapeutic drug monitoring if proper preventive skin measures are taken. More research is needed to assess whether deescalation of treosulfan doses is possible to minimize early and long-term toxicity without compromising efficacy.

Treosulfan-induced myalgia in pediatric hematopoietic stem cell transplantation identified by an electronic health record text mining tool.

Treosulfan is increasingly used as myeloablative agent in conditioning regimen prior to allogeneic hematopoietic stem cell transplantation (HSCT). In our pediatric HSCT program, myalgia was regularly observed after treosulfan-based conditioning, which is a relatively unknown side effect. Using a natural language processing and text-mining tool (CDC), we investigated whether treosulfan compared with busulfan was associated with an increased risk of myalgia. Furthermore, among treosulfan users, we studied the characteristics of given treatment of myalgia, and studied prognostic factors for developing myalgia during treosulfan use. Electronic Health Records (EHRs) until 28 days after HSCT were screened using the CDC for myalgia and 22 synonyms. Time to myalgia, location of pain, duration, severity and drug treatment were collected. Pain severity was classified according to the WHO pain relief ladder. Logistic regression was performed to assess prognostic factors. 114 patients received treosulfan and 92 busulfan. Myalgia was reported in 37 patients; 34 patients in the treosulfan group and 3 patients in the busulfan group (p = 0.01). In the treosulfan group, median time to myalgia was 7 days (0-12) and median duration of pain was 19 days (4-73). 44% of patients needed strong acting opiates and adjuvant medicines (e.g. ketamine). Hemoglobinopathy was a significant risk factor, as compared to other underlying diseases (OR 7.16 95% CI 2.09-30.03, p = 0.003). Myalgia appears to be a common adverse effect of treosulfan in pediatric HSCT, especially in hemoglobinopathy. Using the CDC, EHRs were easily screened to detect this previously unknown side effect, proving the effectiveness of the tool. Recognition of treosulfan-induced myalgia is important for adequate pain management strategies and thereby for improving the quality of hospital stay.

High interpatient variability of treosulfan exposure is associated with early toxicity in paediatric HSCT: a prospective multicentre study.

Treosulfan-based conditioning is increasingly employed in paediatric haematopoietic stem cell transplantation (HSCT). Data on treosulfan pharmacokinetics in children are scarce, and the relationship between treosulfan exposure, toxicity and clinical outcome is unresolved. In this multicentre prospective observational study, we studied treosulfan pharmacokinetics and the drug's relationship with regimen-related toxicity and early clinical outcome in 77 paediatric patients. Treosulfan dose was 30 g/m2 , administered over 3 consecutive days in infants <1 year old (n = 12) and 42 g/m2 in children ≥1 year old (n = 65). Mean day 1 treosulfan exposure was 1744 ± 795 mg*h/l (10 g/m2 ) and 1561 ± 511 mg*h/l (14 g/m2 ), with an inter-individual variability of 56 and 33% in the respective groups. High treosulfan exposure (>1650 mg*h/l) was associated with an increased risk of mucosal [Odds ratio (OR) 4·40; 95% confidence interval (CI) 1·19-16·28, P = 0·026] and skin toxicity (OR 4·51; 95% CI 1·07-18·93, P = 0·040). No correlation was found between treosulfan exposure and the early clinical outcome parameters: engraftment, acute graft-versus-host disease and donor chimerism. Our study provides the first evidence in a large cohort of paediatric patients of high variability in treosulfan pharmacokinetics and an association between treosulfan exposure and early toxicity. Ongoing studies will reveal whether treosulfan exposure is related to long-term disease-specific outcome and late treatment-related toxicity.