Int J Hematol DOI 10.1007/s12185-015-1790-4

ORIGINAL ARTICLE

Incidence, risk factors, and treatment outcome of symptomatic osteonecrosis in Taiwanese children with acute lymphoblastic leukemia: a retrospective cohort study of 245 patients in a single institution Shih‑Hsiang Chen1,4 · Tsung‑Yen Chang1,4 · Tang‑Her Jaing1,4 · Mel S. Lee2,4 · Chao‑Jan Wang3,4 · Iou‑Jih Hung1,4 · Chao‑Ping Yang1,4 

Received: 3 June 2014 / Revised: 18 March 2015 / Accepted: 25 March 2015 © The Japanese Society of Hematology 2015

Abstract  Osteonecrosis (ON) is a potentially disabling complication encountered in children who receive chemotherapy for acute lymphoblastic leukemia (ALL). Considering the possible effect of ethnic difference on the clinical features of symptomatic ON in pediatric ALL, we retrospectively evaluated 245 children with ALL who were treated at Chang Gung Memorial Hospital, Linkou, between 2002 and 2011. Six (2.4 %) patients developed symptomatic ON in a total of 17 sites during the follow-up period. Diagnosis of ON was confirmed by X-ray in seven, magnetic resonance imaging in two, and bone scan in three patients. The estimated cumulative incidence of symptomatic ON in newly diagnosed ALL was 3.4 % at 8 years. Four patients received ON-directed surgical interventions, including total hip replacement in three and arthroplasty in one. The incidence of ON was significantly higher among girls (P = 0.03), patients >10 years old (P = 2.2 × 10−4), and patients who had received more intensive chemotherapy regimen (P  = 0.02). These results indicate that the * Shih‑Hsiang Chen [email protected] Chao‑Ping Yang [email protected] 1

Division of Hematology/Oncology, Department of Pediatrics, Chang Gung Memorial Hospital, College of Medicine, Chang Gung University, 5 Fu‑Shin Street Kwei‑Shan 333, Taoyuan, Taiwan

2

Department of Orthopedic Surgery, Gung Memorial Hospital, Taoyuan, Taiwan

3

Department of Diagnostic Radiology, Chang Gung Memorial Hospital, Taoyuan, Taiwan

4

College of Medicine, Chang Gung University, Taoyuan, Taiwan





incidence and risk factors in our institute were similar to those observed in Western countries. Future studies surveying the impact on the quality of life of childhood ALL survivors in Taiwan are warranted. Keywords  Acute lymphoblastic leukemia · Chemotherapy · Children · Complication · Osteonecrosis

Introduction Recent advances in the intensive chemotherapy as well as adequate supportive care have made significant improvements in childhood acute lymphoblastic leukemia (ALL) so that approximately 80 % of children are able to be cured [1, 2]. As a drawback of more aggressive therapies, some late sequelae of treatment become more apparent. Osteonecrosis (ON) is a recognized complication of treatment for ALL and can occur in 10–15 % of ALL patients [3, 4]. The pathogenesis of ON is multifactorial. Suppression of osteoblasts and apoptosis of osteocytes, intra-medullary lipocyte proliferation resulting in reduced blood flow, and an effect of vascular endothelial and smooth muscle cells with further stasis and ischemia are reported [5]. Steroids are considered one main cause of ON. They are involved in lipocyte hypertrophy and direct toxicity to oseocytes, leading to ON [6–8]. ON can occur as a complication after hematopoietic stem cell transplantation (HSCT). The reported frequency is between 3.9 and 19 % [9, 10]. Graft-versus-host disease (GVHD) and total body irradiation (TBI) are two major risk factors for ON after HSCT [10]. It has been reported that white children have a higher incidence of ON than children from other races [3]. However, studies regarding ON focusing on Asian children with

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S.-H. Chen et al.

ALL are limited [11]. Herein, we performed an extensive evaluation of symptomatic ON in Taiwanese children younger than 18 years with newly diagnosed ALL who were treated in a single medical center. The aim of the present study was to assess the incidence, risk factors, and treatment outcome of symptomatic ON in Taiwanese children with ALL.

or subcondral cysts. Stage 3 is characterized by the subchondral lucency (crescent sign) and subcondral collapse. Stage 4 refers to collapse and degenerative change. The studies depended on the attending physician’s choice. Once ON was suspected or diagnosed, an orthopedic consultation was made for further intervention. Statistics

Materials and methods Patients and treatment of ALL Chang Gung Memorial Hospital, Linkou, is a nationally recognized tertiary referral center, serving northern Taiwan. About 22 % of Taiwanese children with cancer were treated in the Pediatric Hematology/Oncology Department at Chang Gung Memorial Hospital, Linkou. Children with newly diagnosed ALL from January 2002 to December 2011 were enrolled in the study. Standard morphological classification, immunophenotyping, cytogenetic analysis, and molecular studies were performed at initial diagnosis as described previously [12]. Patients with treatment abandonment or early loss before chemotherapy were excluded. According to the Taiwan Pediatric Oncology Group-ALL-2002 protocol, patients were stratified into three groups: standard-risk (SR), high-risk (HR), and veryhigh-risk (VHR) according to age, leukocyte counts, immunophenotype, and other prognostic factors at diagnosis. The details of the protocol were reported previously [13]. Patients treated on the SR protocol were randomly assigned to receive single (SR-B) or double reinduction (SR-A). On the basis of the efficacy-equivalence ration of 1:5.5 (1 mg/m2 dexamethasone = 5.5 mg/m2 prednisolone) [4], the cumulative dose of steroid was 7,500, 6,840, 10,030, and 5,971 mg/m2 for SR-A, SR-B, HR, and VHR groups, respectively. Clinical presentations, laboratory findings at diagnosis, and treatment outcome were retrospectively reviewed using medical records. This study was approved by the Chang Gung Institutional Review Board. Informed consent was obtained from the patients and/or guardians.

Fisher’s exact test was performed to make comparison between groups. The incidence of ON was estimated by Kaplan–Meier analysis. The time to ON was calculated from the initial diagnosis of ALL. Patients who underwent HSCT in first remission or had a treatment failure (refractory disease, relapse, or death in remission) before the onset of ON or did not develop ON were censored at that time. The Cox model was applied to analyze the effect of the variables on the risk of developing ON. Follow-up was updated as of July 31, 2013. Statistical analyses were performed using the software R version 2.9.1 for Windows (http://www.r-project.org/). In all analyses, P values were considered statistically significant at  right) and right distal femur

stationary. Case 5 presented with bilateral hip pain and difficulty in squatting when she was undergoing continuation chemotherapy of the TPOG ALL HR protocol. The X-ray showed stage 3 disease of bilateral femoral heads. Bilateral THR was performed after the conservative medical therapy failed to improve. Case 6 presented with right leg pain when she was undergoing continuation chemotherapy of the TPOG ALL HR protocol. The X-ray showed stage 3 disease of right femoral head. Her parents refused further chemotherapy, and she received no specific ON-directed treatment. She developed intermittent fever 8 months later. Follow-up X-ray showed collapse and sclerosis of right femoral head. She received arthrotomy, synovectomy, and debridement. The pathology showed avascular necrosis of bone and mycobacterial infection with necrotizing granulomatous inflammation of synovium. The culture eventually yielded Mycobacterium tuberculosis. She then took anti-tuberculosis therapy for 1 year. She still had limping gait without further surgical intervention at last followup. Collectively, 4 patients received ON-directed surgical intervention including total hip replacement in 3 and osteochondroplasty in 1. One patient (case 4) received medical therapy including hyperbaric oxygen therapy. The potential clinical risk factors were listed in Table 2. Compared to patients without ON, patients with ON were older age at diagnosis, female predominant, and treated with more intensive chemotherapy regimen. In univariate

analysis, these 3 factors were associated with cumulative incidence of ON. Older age (>10 years) and females remained independently associated with ON in multivariate analysis. However, the results for Cox model should be very cautious due to the low number of events in this study.

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Discussion The treatment results for childhood ALL in Taiwan has improved during the past decade [13]. Some treatment-related complications should be paid more attention to because the number of survivors is increasing. Osteonecrosis is not a fatal, but a serious complication, which may have marked effect on the quality of life. The overall 5-year cumulative incidence for symptomatic ON in newly diagnosed ALL was 3.6 % in the present study, which was within the range of 1.1 to 9.3 % as reported by other large retrospective studies [3, 14–16]. Higher incidence of ON was observed in patients treated with CCG-1882 protocol (3-year incidence of 9.3 %) and DFCI- consortium (5-year incidence of 7 %), while Arico et al. reported lower incidence in the AIEOP-ALL-95 study (5-year incidence of 1.6 %). The AIEOP-ALL-95 chemotherapy regimen included a lower cumulative dose of steroids (3250–6460 mg/m2) compared to that in the CCG (cumulative dose 5885–9050 mg/m2) and the DFCI (cumulative dose 7600–21240 mg/m2) studies. The cumulative dose of steroid

Incidence, risk factors, and treatment outcome… Table 2  Characteristics of patients with or without symptomatic osteonecrosis

Characteristics

No. of patients without ON (N = 239)

No. of patients with ON (N = 6)

2.2 × 10−4

Age (years)  

Incidence, risk factors, and treatment outcome of symptomatic osteonecrosis in Taiwanese children with acute lymphoblastic leukemia: a retrospective cohort study of 245 patients in a single institution.

Osteonecrosis (ON) is a potentially disabling complication encountered in children who receive chemotherapy for acute lymphoblastic leukemia (ALL). Co...
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