Elevated Plasma Ferritin and Busulfan Pharmacodynamics During High-dose Chemotherapy Regimens in Children with Malignant Solid Tumors

Abstract

Hepatic veno-occlusive disease (HVOD) is a frequent complication during hematopoietic stem-cell transplantation (HSCT). A strong relationship has been demonstrated between busulfan exposure and HVOD for busulfan-cyclophosphamide and allogeneic HSCT in adults. Busulfan disposition after the first intake was studied in 77 children treated for solid malignancies with high-dose busulfan-containing regimens and autologous HSCT. Busulfan was combined with cyclophosphamide and melphalan (n=30), melphalan (n=27), and thiotepa (n=20). No relationship was observed between busulfan exposure and HVOD. In contrast, plasma ferritin at baseline was higher in patients with HVOD (750 ng/ml (20-3,110)) compared with those without HVOD (189 ng/ml (8-3,967), P=0.012). Multivariate analysis showed that a ferritin level exceeding 300 ng/ml was the only risk factor for HVOD with an odds ratio of 4.0 (confidence interval 95% (1.5-11.2), P=0.0071). A high ferritin level at baseline was explained by the diagnosis of neuroblastoma, related treatments and transfusions.

Hepatic Veno-Occlusive Disease following Stem Cell Transplantation: Incidence, Clinical Course, and Outcome

“…dosing of busulfan in children, have been associated with more VOD rather than less, suggesting that such measures are not uniformly protective in all SCT populations [105]. Other contributing factors have included extension of the age limit for transplantation by more widespread use of RIC protocols, the use of multiple alkylating regimens in certain pediatric populations (eg, neuroblastoma), reservation of SCT for patients with relapsed or resistant disease due to advances in novel remission induction therapy, introduction of promising but potentially toxic new agents for graft-versus-host disease prophylaxis (eg, sirolimus, everolimus), second or third SCT in patients encountering secondary malignancies after cure of their first, and the increasing use of mismatched donors [37,38,104,106–109]. …”

Risk factors for hepatic veno-occlusive disease: a retrospective unicentric study in 116 children autografted after a high-dose BU-thiotepa regimen

“…This high ferritin level could be related to the higher number of RBC transfusions administered to these patients. Bouligand et al 33 however, showed that a high level of ferritin was a major risk factor for HVOD. The lack of significance of a high ferritin level in our multivariate analysis could be explained by the different types of tumors (brain tumors vs neuroblastoma) and/or the different conditioning regimens 21,22,30 or by the fact that our study was simply too underpowered to corroborate Bouligand's result.…”

Children's Oncology Group's 2013 blueprint for research: Neuroblastoma

“…The variability in the efficacy and toxicity has been due, in part, to interpatient differences in busulfan clearance and the narrow therapeutic range of busulfan systemic exposure [95]. However, no clear pharmacodynamic association exists between busulfan AUC and hepatotoxicity in children receiving BuMel for conditions other than neuroblastoma [96,97]. Worse mucositis and longer hospitalization was associated with elevated plasma total and unbound melphalan AUC in adults diagnosed with myeloma receiving melphalan [98] although similar studies have not been performed in patients with neuroblastoma.…”