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.
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 ≥50×10(9) per L, or both) were recruited. To address osteonecrosis, a novel alternate-week schedule of dexamethasone (10 mg/m(2) per day on days 0-6 and 14-20) was compared with standard continuous dexamethasone (10 mg/m(2) 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.


RESULTS
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).


CONCLUSIONS
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.


BACKGROUND
US National Cancer Institute at the National Institutes of Health.
Michigan State University College of Human Medicine, Michigan State University Kalamazoo Center for Medical Studies, Kalamazoo, MI 49008, USA. mattano@umich.edu
Leonard A
LA
Mattano
Meenakshi
M
Devidas
James B
JB
Nachman
Harland N
HN
Sather
Stephen P
SP
Hunger
Peter G
PG
Steinherz
Paul S
PS
Gaynon
Nita L
NL
Seibel
D000293:Adolescent; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D001215:Asparaginase / Q000008:administration & dosage; D002648:Child; D002675:Child, Preschool; D015331:Cohort Studies; D003561:Cytarabine / Q000008:administration & dosage; D003630:Daunorubicin / Q000008:administration & dosage; D003907:Dexamethasone / Q000008:administration & dosage* / Q000009:adverse effects*; D018572:Disease-Free Survival; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D015994:Incidence; D007223:Infant; D008297:Male; D008727:Methotrexate / Q000008:administration & dosage; D010020:Osteonecrosis / Q000139:chemically induced* / Q000175:diagnosis / Q000453:epidemiology / Q000517:prevention & control*; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy* / Q000401:mortality; D011241:Prednisone / Q000008:administration & dosage; D017678:Sex Distribution; D012737:Sex Factors; D015996:Survival Rate; D016896:Treatment Outcome; D014750:Vincristine / Q000008:administration & dosage; D055815:Young Adult
D003561:Cytarabine; D014750:Vincristine; D003907:Dexamethasone; D001215:Asparaginase; D011241:Prednisone; D008727:Methotrexate; D003630:Daunorubicin