A Prospective Study on Incidence, Risk Factors and Long-Term Outcome of Osteonecrosis in 694 Patients with Pediatric Acute Lymphoblastic Leukemia,
Authors: te Winkel Mariël L. , Pieters Rob , Hop Wim C.J. , de Groot-Kruseman Hester A. , Lequin Maarten H. , van der Sluis Inge M. , Bökkerink Jos P.M. , Leeuw Jan A. , Bruin Marrie C. A. , Egeler R. Maarten , Veerman Anjo J.P. , van den Heuvel-Eibrink Marry M. 
Published: October 2019

Abstract
Abstract 3578

Purpose
As survival rates for pediatric acute lymphoblastic leukemia (ALL) have significantly improved, awareness of side effects such as osteonecrosis becomes increasingly important. We studied incidence, risk factors, therapeutic strategies and outcome of symptomatic osteonecrosis in pediatric ALL patients.

Methods
Prospectively, the cumulative incidence of osteonecrosis was assessed in 694 patients treated with the dexamethasone-based protocol of the Dutch Childhood Oncology Group (DCOG)-ALL9. Osteonecrosis was defined by development of symptoms (NCI grade 2–4) during treatment or within the year after treatment discontinuation, confirmed by magnetic resonance imaging. Using logistic multivariate regression, we evaluated the following putative risk factors for osteonecrosis: age at diagnosis, gender, risk group of ALL treatment and BMI at diagnosis. To describe outcome, we reviewed clinical and radiologic information after antileukemic treatment, ≥1 year after osteonecrosis diagnosis. To evaluate whether the occurrence of osteonecrosis is related to the EFS, Cox-regression was used with osteonecrosis as time-dependent variable.

Results
The estimated cumulative incidence of symptomatic osteonecrosis at 3 years was 6.1%. In 35 patients osteonecrosis became apparent during treatment (1 during induction phase, 1 during intensification phase, and 33 during maintenance phase) and in 3 patients symptoms of osteonecrosis became apparent during the first year after stop of therapy. The mean time-interval between diagnosis of ALL and presentation of osteonecrosis was 1.2 years (range:1 month–2.7 years). In all 38 patients the weight-bearing joints of the lower limb were the primary location (hip (n=11), knee (n=25), ankle (n=2)). In the majority of patients (n=34) multifocal symptomatic involvement was reported. Logistic multivariate regression identified age (OR=1.47, P <0.01) and female gender (OR=2.21, P =0.04) as independent risk factors after adjustment for treatment center. Median age at diagnosis of ALL was 13.5 in patients with osteonecrosis versus 4.7 in those without osteonecrosis. In 21 of 38 osteonecrosis patients (55%) chemotherapy was adjusted because of osteonecrosis. Seven patients (18%) underwent surgery. Clinical follow-up data of 35 patients were evaluated, median follow-up was 4.9 years. In 14 patients (40.0%) symptoms completely resolved, 14 (40.0%) had symptoms interfering with function but not with activities of daily living (ADL) (grade 2), seven (20.0%) had symptoms interfering with ADL (grade 3). In 24 patients radiologic follow-up was available; in six (25%) lesions improved/disappeared, in 13 (54%) lesions remained stable, five (21%) had progressive lesions. After adjustment for age, gender and risk group of ALL, multivariate Cox-regression showed no significant effect of osteonecrosis on subsequent EFS (P=0.75).

Conclusion
6% of pediatric ALL patients developed symptomatic osteonecrosis during/shortly after treatment. Older age and female gender were risk factors after adjustment for treatment center. After a median follow-up of five years, 60% of the survivors with osteonecrosis had persistent symptoms.

Disclosures:
No relevant conflicts of interest to declare.