ArticlesEffect of alternate-week versus continuous dexamethasone scheduling on the risk of osteonecrosis in paediatric patients with acute lymphoblastic leukaemia: results from the CCG-1961 randomised cohort trial
Introduction
With treatment, more than 80% of children and adolescents with acute lymphoblastic leukaemia (ALL) will be cured, but osteonecrosis is an adverse event that has become a major cause of acute and long-term morbidity, particularly in adolescents.1, 2, 3, 4, 5, 6 In patients aged 10 years and older at diagnosis of ALL, the incidence of osteonecrosis has risen from anecdotal reports to 7·4–44·6%.1, 5, 7, 8, 9, 10, 11 The weight-bearing joints are affected in 95% of patients who develop osteonecrosis and operative interventions are needed for management of symptoms and impaired mobility in more than 25% of cases.10
The rising incidence of osteonecrosis in patients with ALL is often attributed to the increasing use of dexamethasone in the treatment regimens, although increased systemic exposure to methotrexate and asparaginase might also contribute to the pathogenesis.12, 13, 14 Dexamethasone is 6·5 times more potent and more readily penetrates the blood–brain barrier than does prednisone: advantageous for the treatment of ALL but harmful to bones.15, 16 Identification of ways to preserve efficacy while reducing the risk of osteonecrosis is a huge challenge in the treatment of ALL in childhood.
The Children's Oncology Group (COG) first identified a high risk of osteonecrosis in the CCG-1882 trial10 in which augmented treatment—which included two 21-day courses of dexamethasone—was compared with standard treatment including one course for patients with a slow early response to initial therapy. Augmented treatment was associated with better event-free and overall survival. Although both regimens were associated with unacceptably high 3-year cumulative incidence of osteonecrosis in patients aged 10 years and older at diagnosis, a higher incidence was noted with augmented treatment (23·2% [SE 4·8] vs 16·4% [4·3] at 3 years; p=0·27), although this was not significant.10, 17 Since the augmented regimen included two phases of delayed intensification and interim maintenance rather than one phase, we postulated that the additional dexamethasone exposure and perhaps other components of treatment contributed to the increased risk of osteonecrosis.
Based on the findings from the CCG-1882 trial, the CCG-1961 trial was designed to assess whether components of augmented treatment would benefit patients with high-risk ALL who had a rapid early response to treatment, and whether dexamethasone dose modification would reduce the risk of osteonecrosis. The treatment efficacy results of the CCG-1961 trial showed that intensified post-induction treatment was better than standard intensity treatment, and the results obtained with one versus two phases of interim maintenance and delayed intensification were equivalent.18 In an effort to reduce the risk of osteonecrosis, all patients randomly assigned to regimens with two phases of interim maintenance and delayed intensification were given dexamethasone on an experimental alternate-week basis (days 0–6 and 14–20) during each delayed intensification and those assigned to regimens with one phase of interim maintenance and delayed intensification were given the standard continuous dexamethasone (days 0–20). We report the results of this comparison of osteonecrosis risk in the CCG-1961 trial.
Section snippets
Patients and treatment
Children and adolescents aged 1–21 years with newly diagnosed high-risk ALL were enrolled in the CCG-1961 trial between Sept 16, 1996, and May 1, 2002, at more than 100 local CCG centres throughout the USA, Canada, Australia, and New Zealand. High-risk ALL was defined as patients having an initial white blood cell count greater or equal to 50×109 per L or as being 10 years or older, or both. Eligibility criteria, baseline characteristics of patients, and details of treatment have been reported
Results
Figure 1 shows the randomisation of the rapid and slow early responders to the different treatments in the CCG-1961 trial. Among patients who had a slow early response, no difference in osteonecrosis incidence was noted between the randomly assigned regimens. Baseline characteristics of the patients who had a rapid early response and were assigned to continuous or alternate-week dexamethasone were similar (table 1) with no substantial differences between the two groups except for platelet count.
Discussion
Our findings show that alternate-week rather than continuous dexamethasone during delayed intensification is associated with a two-times reduction in the relative risk of symptomatic osteonecrosis in rapid early responders aged 10 years and older, particularly those aged 16 years and older, and a reduction in children randomly assigned to intensified treatment, even though children given alternate-week dexamethasone were exposed to a higher total dose of dexamethasone (figure 4A–C).
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Prof Nachman died in June, 2011