Personalization of dexamethasone therapy in childhood acute lymphoblastic leukaemia

Abstract

Dexamethasone is a key component in the treatment of childhood acute lymphoblastic leukaemia (ALL). Despite playing a key role in the improved survival of ALL over several decades, intensification of dexamethasone therapy has also contributed to the increased toxicity associated with treatment, which is now seen to be at unacceptable levels given the favourable disease prognosis. Therefore the focus for treatment is now shifting towards reducing toxicity whilst maintaining current survival rates. As approximately 50% of patients were successfully treated on less intensive protocols of the 1980s, it has been questioned whether therapy intensification is necessary in all patients. Furthermore, there remains a subset of children who are still not cured of their disease. New strategies are therefore needed to identify patients who could benefit from dose reduction or intensification. However, adjusting a potentially life threatening therapy is a challenging task, particularly given the heterogeneous nature of ALL. This review focuses on the potential for patient stratification based on our current knowledge of dexamethasone pharmacokinetics, pharmacogenetics and the action of dexamethasone at the cellular level. A carefully designed, combined approach is needed if we are to achieve the aim of improved personalization of dexamethasone therapy for future patients.

Pharmacogenomic markers of glucocorticoid response in the initial phase of remission induction therapy in childhood acute lymphoblastic leukemia

“…However, many children experience severe toxicity associated with treatment with dangerous side effects, while some of them are not cured. 33 So, it could be argued that these groupings are not yet comprehensive enough. 34 As for induction remission phase of ALL treatment, it is essential to find as many potential markers of GC resistance as possible.…”

Hipomanía y corticoides en pacientes oncológicos. Reporte de un caso y revisión de la literatura

“…Inhiben también la bradicinina y sus efectos inflamatorios, además de estabilizar la membrana de los lisosomas disminuyendo su acción fagocítica. Todo esto ha hecho de los corticoides una herramienta terapéutica fundamental para el tratamiento de la inflamación y de aquellas enfermedades que afectan al sistema inmunológico e incluso todo este efecto antiinflamatorio que afecta la expresión de determinados genes ha permitido el uso de los corticoides como un agente antineoplásico 3,12 .…”

“…que se pretende palear, como pérdida de masa ósea, glaucoma, diabetes, infecciones y trastornos psiquiátricos entre otros 2 . Mención especial requieren aquellos casos en que los corticoides son utilizados como agentes antineoplásicos como ocurre en algunos tipos de leucemias 3 , en donde muchas veces, pese a los efectos adversos, la terapia esteroidal no se suspende.…”

Inhibition of cell growth by cellular differentiation into adipocyte-like cells in dexamethasone sensitive cancer cell lines

“…Therefore, it has been suggested that exposure to GCs for prolonged time seems to be one of factors inducing cancers via malfunction of immune system induced with stress (Godbout and Glaser 2006 ). Meanwhile, the inhibition of cell growth and induction of apoptotic cell death are observed in several type of cancer cells after being exposed to GCs (Bailly-Maitre et al 2001 ; Qian et al 2011 ; Buxant et al 2015 ; Jackson et al 2016 ). Therefore, GCs are often considered a potential alternative chemotherapeutic drug for cancer treatment and reducing cancer pains in solid tumors and acute lymphoid leukemia by their cytotoxic effects, such as cellular apoptosis (Yennurajalingam et al 2013 ; Jackson et al 2016 ).…”