(Epi)genetic and biochemical determinants of methotrexate-induced oral mucositis in pediatric acute lymphoblastic leukemia

Abstract

Acute Lymphoblastic Leukemia (ALL) is the most frequently occurring type of cancer in childhood affecting 120 – 130 patients per year in The Netherlands. High-dose Methotrexate (HD-MTX) is an important component of pediatric ALL treatment. Children with ALL receiving HD-MTX and folinic acid rescue (Leucovorin – LV) therapy show a large interpatient variety in pharmacokinetics of MTX and the occurrence of side effects. Better understanding of this heterogeneous response would aid in developing more personalized therapy regimens. Despite administration of LV rescue therapy, 20% of patients develop severe MTX-induced oral mucositis leading to treatment delays and an impaired quality of life. In this thesis, we aimed to determine both the role of several (epi)genetic and biochemical determinants of HD-MTX induced oral mucositis as well as to elucidate the role of folinic acid. We showed that when it comes to determinants of MTX-induced oral mucositis, genetic polymorphisms do not seem to play a large and clinically relevant role in the development of MTX-induced oral mucositis. We showed in an in vitro model the first preclinical data that patients might benefit from earlier start of LV or a pre-treatment before start of HD-MTX with local LV to reduce oral mucositis. Based on our observation that LV is able to restore the intracellular folate pool after HD-MTX treatment, we would plead for a reserved use of extra, increased or prolonged doses of systemic LV outside of current standard protocols as treatment efficacy may potentially be affected.