Analysis of Long-Term Outcomes, Management and Prevalence of Osteonecrosis in UKALL 2003: 3.5% of Adolescents and Young Adults over 10 Years of Age with Acute Lymphoblastic Leukaemia Required Hip Replacement
Authors: Amin Nadia L , Kinsey Sally , Feltbower Richard , Vora Ajay J. , Goulden Nicholas , Wade Rachel , Mitchell Chris , Hough Rachael , Rowntree Clare , James Beki 
Published: October 2019

Abstract
Introduction: As the majority of children and young people now survive acute lymphoblastic leukaemia (ALL), the challenge has shifted to minimising treatment related toxicity. Osteonecrosis is one of the most serious complications of treatment, and can result in significant long term morbidity.
In UKALL2003, which recruited patients between Oct 1, 2003 and June 30, 2011, all patients received dexamethasone 6mg/m2 for 29 days during induction and again for 5 days each month during maintenance in combination with Vincristine. Standard and intermediate risk patients were randomised to 1 or 2 delayed intensifications, each of which contained dexamethasone 10mg/m2 for 14 days in an alternate week schedule.
Aim: To report the prevalence, management and long term outcomes of patients who developed osteonecrosis among 3126 patients aged 1-24 years old entered into UKALL2003.
Methods: Patients with reported bone toxicity were identified by the central trials unit, which also provided information regarding age, sex, ethnicity and treatment. A questionnaire for each patient was sent to the relevant primary treatment centres (n=40) requesting information on patient demographics, diagnosis, management and outcomes of patients with osteonecrosis. Each primary treatment centre was also asked for details of previously unreported patients known to have osteonecrosis. Statistical analysis was undertaken using Chi-squared tests to identify significant differences in the prevalence of osteonecrosis according to age, sex, ethnicity, and treatment. Percentages were calculated as simple percentages.
Results: We received an 83% response rate from primary treatment centres. 153 patients (5%) were reported as having developed osteonecrosis at some point after the start of treatment for ALL (including relapse therapy or stem cell transplant if required (n=5)), of which 38 were previously unreported to the clinical trials unit. Age demonstrated the strongest association with risk of osteonecrosis (p=0.01). Of patients aged <10 years at diagnosis (n=2287), only 0.7% of patients developed osteonecrosis, compared with 16% of patients aged 10 to 15 years, and 15% of patients aged 16 years and over. 17% of those over the age of 18 years developed osteonecrosis. Only 11 of those affected were less than 10 years of age when symptoms began. There was no significant difference in prevalence by ethnic group (White/ British, South Asian, Black), sex or 1 versus 2 delayed intensifications (p=0.85, p=0.86 and p=0.38 respectively).
Median time between onset of symptoms and diagnosis of osteonecrosis was 1 month, with 83% of patients diagnosed with MRI. The median time between diagnosis of ALL and onset of osteonecrosis symptoms was 14 months (range: minus 3 to 73 months). There were 438 areas of reported osteonecrosis in the 153 patients, with hips (157), knees (131), shoulders (61) and ankles (42) most commonly reported. Fractures were reported in 34 (22%) of patients who developed osteonecrosis.
In the 153 patients with osteonecrosis, steroids were reported to have been discontinued in 93 (61%), bisphosphonates were given to 35 (23%), 10 of whom had also had fractures, 52 were given vitamin D (34%) and 64 (42%) required surgery. Hip replacements were required in 30 patients and of these, 29 were age >10 years at diagnosis of ALL (with a total of 839 patients aged >10 years in UKALL2003). There were 130 patients aged>18 years at diagnosis in UKALL2003, and of these, 4 required a hip replacement.
With a median follow up of 70 months (range 27-124 months), 57 patients were reported to have no long term effects, 59 patients had minimal disability (able to carry out activities of daily living), 16 had significant disability, and 5 patients required a wheelchair at the time of response. 9 patients died from disease relapse, progression of ALL, sepsis or acute graft versus host disease. Outcome information was not available for a further 9 patients.
Conclusion: This work highlights the impact of osteonecrosis as a cause of considerable morbidity for patients treated for ALL, with important implications for quality of life. Further, this work confirms that the greatest impact is on those aged over 10 years at diagnosis, with 1 in 30 patients in this group requiring hip replacement. Better strategies to monitor for and manage this condition are required to reduce the incidence, whilst maintaining overall and event free survival.

Disclosures
No relevant conflicts of interest to declare.