Methotrexate Therapy in Childhood Acute Lymphoblastic Leukemia (ALL)

In childhood acute lymphoblastic leukemia (ALL), major improvements in therapy and supportive care have led to increased survival rates. In current treatment protocols, patients are assigned to multi-agent chemotherapy regimens of different intensities based on the patient’s individual risk profile and probability to encounter relapse. However, 20% of patients relapse or do not respond well to therapy. Methotrexate (MTX) is an essential drug in the treatment of childhood ALL. In addition to systemic control of leukemia, it is crucial for prophylaxis and treatment of sanctuary sites, including the CNS. The main targets of polyglutamylated MTX are dihydrofolate reductase (DHFR—also inhibited by MTX monoglutamates), thymidylate synthase (TS), and several enzymes involved in purine synthesis. However, MTX can cause acute, subacute, and long-term neurotoxicities. The mechanism of neurotoxicity is likely through disruption of CNS folate homeostasis and/or direct neuronal damage. Methotrexate is a critical component of ALL therapy and plays an important role in CNS prophylaxis. Worldwide, two different methotrexate intensification strategies have been studied: High-dose methotrexate (HD-MTX) regimens of 2 to 5 g/m2 administered over 24 hours followed by leucovorin rescue and the Capizzi regimen with lower, escalating doses of intravenous methotrexate (C-MTX) of 100 to 300 mg/m2 through short infusions, without leucovorin rescue, followed by asparaginase. As treatment outcome has improved substantially, more research focuses on strategies to reduce toxic side effects from drugs such as methotrexate (MTX). Identifying risk factors of high-dose methotrexate (HD-MTX)-induced adverse events, such as oral mucositis, would be valuable to develop preventive interventions.

Methotrexate Therapy in Childhood Acute Lymphoblastic Leukemia (ALL) Keywords:

childhood acute lymphoblastic leukemia , Methotrexate , dose methotrexate , neurotoxicities , Therapeutic mechanism , Clinical treatment.