Effect 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

Summary

Background

Acute lymphoblastic leukaemia (ALL) is curable in more than 80% of children and adolescents who exhibit high-risk features. However, treatments are associated with symptomatic osteonecrosis that disproportionately affects adolescents. Based on the findings from the CCG-1882 trial, the CCG-1961 trial was designed to assess whether dexamethasone dose modification would reduce the risk of osteonecrosis. We therefore compared use of continuous versus alternate-week dexamethasone within standard and intensified post-induction treatments.

Methods

In the CCG-1961 trial, a multicohort cooperative group trial, 2056 patients (aged 1–21 years) with newly diagnosed high-risk ALL (age ≥10 years, white blood cell count ≥50×10⁹ per L, or both) were recruited. To address osteonecrosis, a novel alternate-week schedule of dexamethasone (10 mg/m² per day on days 0–6 and 14–20) was compared with standard continuous dexamethasone (10 mg/m² per day on days 0–20) in computer-generated randomised regimens with permuted blocks within double or single delayed intensification phases, respectively. Masking was not possible because of the differences in the treatments. Analysis was by intention to treat. This study is registered with ClinicalTrials.gov, number NCT00002812.

Findings

Symptomatic osteonecrosis was diagnosed in 143 patients at 377 confirmed skeletal sites, resulting in 139 surgeries. In patients aged 1–21 years, the overall cumulative incidence of osteonecrosis at 5 years was 7·7% (SE 0·9), correlating with age at ALL diagnosis (1–9 years, 1·0% [0·5]; 10–15 years, 9·9% [1·5], hazard ratio 10·4 [4·8–22·5]; 16–21 years, 20·0% [4·3], 22·2 [10·0–49·3]; p<0·0001) and sex of the patients aged 10–21 years (girls 15·7% [2·5] vs boys 9·3% [1·7], 1·7 [1·2–2·4]; p=0·001). For patients aged 10 years and older with a rapid response to induction treatment, the use of alternate-week dexamethasone during phases of delayed intensification significantly reduced osteonecrosis incidence compared with continuous dexamethasone (8·7% [2·1] vs 17·0% [2·9], 2·1 [1·4–3·1]; p=0·0005), especially in those aged 16 years and older (11·3% [5·3] vs 37·5% [11·0], p=0·0003; girls 17·2% [8·1] vs 43·9% [14·1], p=0·05; boys 7·7% [5·9] vs 34·6% [11·6], p=0·0014).

Interpretation

Alternate-week dexamethasone during delayed intensification phases, a simple dose modification, reduces the risk of osteonecrosis in children and adolescents given intensified treatment for high-risk ALL. Its use is being evaluated in children with standard risk ALL.

Funding

US National Cancer Institute at the National Institutes of Health.

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.