Glucocorticoid use in acute lymphoblastic leukaemia

Summary

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/m² per day) resulted in a better event-free survival than did prednisone (40–120 mg/m² per day), and high-dose dexamethasone (10–18 mg/m² 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.

Introduction

Glucocorticoids were among the first drug classes used in the treatment of patients with acute lymphoblastic leukaemia (ALL) and are still essential components of treament.1, 2 They seem to exert their cytotoxic effects by binding to glucocorticoid receptors in the cytoplasm (figure 1).³ These receptors can then form dimers, translocate to the nucleus, and interact with glucocorticoid-response elements to transactivate gene expression, or they can remain as monomers and repress the activity of transcription factors such as the activating protein-1 (AP-1) or nuclear factor-κB (NFκB).4, 5, 6 Both pathways inhibit cytokine production,⁷ change the expression of various oncogenes,⁸ and induce cell-cycle arrest⁹ and apoptosis.¹⁰

In vivo and in vitro, glucocorticoid resistance is an adverse prognostic factor in ALL, and several mechanisms have been reported.¹ Glucocorticoid exposure induces upregulation of the glucocorticoid receptor in ALL cells, and about half of 51 responsive genes identified have been functionally linked to three major pathways: cell proliferation and survival (mitogen-activated protein kinase [MAPK] pathways), NFκB signalling, and glucose metabolism.11, 12 Glucocorticoid resistance has been associated with upregulation of the genes involved in glucose metabolism, and increased glucose uptake into the cells.11, 13, 14 Glucocorticoids also induce release of calcium ions from the endoplasmic reticulum into the cytosol; the resulting increase in mitochondrial calcium ions induces cytochrome-c release and triggers apoptosis. Raised expression of the calcium-binding proteins (CBP) S100A8 and S100A9, and of the antiapoptotic B-cell lymphoma 2 (BCL-2) protein family member myeloid cell leukaemia sequence 1 (MCL-1), inhibit signalling mediated by free cytosolic and mitochondrial calcium ions signals, respectively, causing glucocorticoid resistance.15, 16, 17

Traditionally, prednisone has been the glucocorticoid most commonly used in the treatment of patients with ALL; it is typically given for 4 consecutive weeks in combination with vincristine, an anthracycline, asparaginase, and intrathecal chemotherapy. In the past few years, dexamethasone, another glucocorticoid, has been used increasingly to treat ALL. These two glucocorticoids are synthetic analogues of cortisol that differ molecularly in several important aspects (figure 2).18, 19, 20, 21 Dexamethasone differs from prednisolone (active metabolite of prednisone) only by a fluorine atom at the 9α position of ring B and a methyl group at the C16 position of ring D. The 9α fluorine slows the metabolism of dexamethasone, thereby extending its plasma half-life (200 min vs 60 min for prednisolone) and biological half-life (36–54 h vs 24–36 h).19, 21 The C16 methyl group reduces the sodium-retention effect of dexamethasone to a minimum. Prednisone is thought to have half the mineral corticoid activity of cortisol, whereas dexamethasone is thought to have little or none.²¹

Results from bioequivalence studies of dexamethasone and prednisone have often been discordant. Generally, 1 mg of dexamethasone is equivalent to 5–10 mg of prednisone in reducing inflammation.20, 21, 22 However, this equivalence has not been firmly established in antileukaemic treatment. We review the use of prednisone and dexamethasone in the treatment of ALL, assessing evidence from in-vitro studies, preclinical models, and clinical studies; comparing the benefits and adverse effects of the drugs, and discussing their optimum uses.