Glucocorticoid use in acute lymphoblastic leukaemia

Abstract

Glucocorticoids (prednisone and dexamethasone) play an essential part in the treatment of acute lymphoblastic leukaemia (ALL), but their optimum doses and bioequivalence have not been established. Results of preclinical studies have shown that dexamethasone has a longer half-life and better CNS penetration than does prednisone. In prospective randomised trials, dexamethasone improved control of CNS leukaemia. At a prednisone-to-dexamethasone dose ratio of less than seven, dexamethasone (6-18 mg/m(2) per day) resulted in a better event-free survival than did prednisone (40-120 mg/m(2) per day), and high-dose dexamethasone (10-18 mg/m(2) per day) improved the outcome of T-cell ALL and high-risk ALL. However, dexamethasone caused more adverse effects, including infection, bone fracture, osteonecrosis, mood and behaviour problems, and myopathy. At a dose ratio greater than seven, the two drugs showed no difference in efficacy. Therefore, the efficacy of prednisone and dexamethasone is dose dependent and needs to be carefully assessed against the toxic effects. Moreover, although dexamethasone generally showed increased activity in ALL cells in vitro, the dose ratio of the two drugs that exerted equivalent cytotoxic effects differed substantially in samples from individuals. The selection of the type and dose of glucocorticoid should be based on the risk of relapse, treatment phase, and the chemotherapeutic drugs used concomitantly.

Figure 1. Glucocorticoid receptor signaling

Extracellular glucocorticoid released from circulating steroid-binding protein (SBP) enters the cell by passive transport due to its relatively small size and lipophilicity. The unbound glucocorticoid receptor (GR) forms heterocomplexes with chaperone heat shock proteins (hsp) 90 and 70 and co-chaperone immunophilin FK506 binding protein (FKBP) 52, which are required for optimal binding of glucocorticoid. After binding, the GR dissociates from its (co-) chaperone proteins, unmasking the GR domain responsible for nuclear translocation. GRs can homodimerize and interact with glucocorticoid response elements (GRE) to induce gene transcription (transactivation) or they can remain monomers and interact with transcription factors such as activating protein-1 (AP-1) or nuclear factor-κB (NF-κB) (transrepression). Both mechanisms produce clinically observed effects of glucocorticoids.

Figure 2

Chemical structures of cortisol and of the synthetic glucocorticoids prednisone, prednisolone, and dexamethasone.