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© 2000 American Society for Clinical Oncology
Osteonecrosis as a Complication of Treating Acute Lymphoblastic Leukemia in Children: A Report From the Children’s Cancer GroupFrom the Michigan State University/Kalamazoo Center for Medical Studies, Kalamazoo, MI; Children’s Cancer Group, Los Angeles, CA; Dupont Hospital for Children, Jefferson Medical College, Wilmington, DE; and University of Chicago Medical Center, Chicago, IL. Address reprint requests to Leonard A. Mattano, Jr, MD, Children’s Cancer Group, P.O. Box 60012, Arcadia, CA 91066-6012.
PURPOSE: To determine the incidence, risk factors, and morbidity for osteonecrosis (ON) in children with acute lymphoblastic leukemia (ALL) treated with intensive chemotherapy including multiple, prolonged courses of corticosteroid. PATIENTS AND METHODS: The occurrence of symptomatic ON was investigated retrospectively in 1,409 children ages 1 to 20 years old receiving therapy for high-risk ALL on Children’s Cancer Group (CCG) protocol CCG-1882.
RESULTS: ON was diagnosed in 111 patients (9.3% ± 0.9%, 3-year life-table incidence). The incidence was higher for older children ( CONCLUSION: Children ages 10 to 20 years who receive intensive ALL therapy, including multiple courses of corticosteroid, are at significant risk for developing ON.
OSTEONECROSIS (ON) is a well-recognized complication of corticosteroid use.1-19 Morbidity is caused by progressive joint damage and includes pain, limited range of motion, articular collapse, and arthritis. Weight-bearing joints are commonly affected, and total joint replacement is often necessary to restore function.12,20-27 Skeletal immaturity of children makes orthopedic management of ON more complex.12,28-30 Corticosteroids are integral to the management of childhood acute lymphoblastic leukemia (ALL).31 Improvements in event-free survival (EFS) have been achieved with the addition of dexamethasone to standard prednisone-based therapies.32-46 The increasing popularity of these regimens has been associated with a dramatic increase in the occurrence of ON and may be directly linked with dexamethasone, which is more potent than prednisone in both its antileukemic effects and toxic effects.31,47-66 However, this has not been evaluated in studies of appropriate size or study design to enable meaningful statistical analysis of ON incidence and predisposing factors. We have performed an extensive evaluation of symptomatic ON in a large cohort of children ages 1 to 20 years entered onto Children’s Cancer Group (CCG) protocol CCG-1882, a multiregimen protocol for patients with newly diagnosed high-risk ALL. The experimental design of CCG-1882 permitted the analysis of potential risk factors for the development of ON, including age, sex, corticosteroid exposure, and ethnicity. Patterns of joint involvement, surgical interventions, and morbidity associated with ON were delineated.
Patient Population Eligibility criteria for participation in CCG-1882 included children ages 1 to 9 years old with WBC  50 x 109/L and children 10 years old irrespective of WBC, excluding patients with lymphomatous features67-68 or French-American-British classification L3 blasts. Therapy is listed in Table 1. Cumulative corticosteroid doses are listed in Table 2. Patients demonstrating a rapid early response (RER) to therapy ( 25% marrow blasts on induction day 7) and successfully completing induction therapy were eligible for randomization to CCG-modified Berlin-Frankfurt-Munster therapy including a single delayed-intensification phase (SDI), with or without prophylactic cranial radiation (regimens A and B, respectively). Those with slow early response (SER, > 25% marrow blasts on induction day 7) initially all received augmented therapy (regimen C), including a second delayed-intensification phase (double delayed intensification [DDI]) and cranial radiation, to establish safety and preliminary efficacy of the treatment regimen before deciding to compare it with the less intensive regimen A. Thereafter, SER patients were eligible for randomization to either regimen A or regimen C.
A total of 1,541 patients were registered between May 8, 1989, and June 23, 1995, of whom 1,409 were included in this analysis. Informed consent was obtained from each patient and/or guardian according to institutional policy after protocol approval by the local human investigations committees. Reasons for exclusion included protocol ineligibility (n = 15), induction death (n = 22), induction failure (n = 26), patients observed for ALL outcome who received a nonprotocol regimen (n = 23), RER patients registered after March 22, 1995, from whom detailed therapy data were not collected (n = 44), and patients without follow-up information (n = 2). Patient characteristics are listed in Table 3.
Identification of ON Patients CCG-1882 end-of-phase data collection forms did not specifically request data regarding ON because, at the time of study development, the potential magnitude of this toxicity was not appreciated. In response to the spontaneous reporting by institutional investigators to the protocol committee of numerous ON cases among registered patients, a comprehensive group-wide assessment of this complication was undertaken. All 111 centers with patients registered on study participated in a survey in March 1996 to obtain detailed information regarding patients with ON. Fifty-six institutions identified a total of 111 study patients with ON. A detailed ON data questionnaire was obtained for each patient, including symptoms, joint involvement, diagnostic evaluations, modifications of ALL therapy, and orthopedic interventions. Additional data were obtained from the CCG-1882 computerized database and patient data records maintained at the CCG Group Operations Center.
Statistics
In the entire study population, 111 of 1,409 patients had ON, with a 3-year life-table estimated incidence of 9.3% (SD = 0.9%). There was only one occurrence of ON beyond 3 years from diagnosis of ALL. Occurrence of ON varied by age at diagnosis of ALL and sex (Table 4). Life-table analysis indicated a highly significant difference in age (log-rank, P < .0001), which was primarily caused by the very low rate in the less than 10–year age group (four of 516 patients) compared with the 10 to 15–year age group (85 of 736 patients) and the 16 to 20–year age group (22 of 157 patients), with 3-year ON incidence rates of 0.9% (SD = 0.4%), 13.5% (SD = 1.4%), and 18.0% (SD = 3.6%), respectively (Fig 1). Although the overall incidence rate was higher in the 16 to 20–year age group compared with the 10 to 15–year age group, it did not reach statistical significance (log-rank, P = .29).
Fifty-one of 790 males and 60 of 619 females had ON (male:female ratio = 0.67) (Table 4). ON occurred significantly more often in females than males (log-rank, P = .04; 3-year, P = .05), with 3-year incidence rates of 12.2% (SD = 1.4%) and 7.7% (SD = 1.1%), respectively. In children 10 to 20 years of age at diagnosis of ALL, this finding was more pronounced (log-rank, P = .03; 3-year, P = .03), with 3-year actuarial rates of 17.4% (SD = 2.1%) for females and 11.7% (SD = 1.6%) for males (Fig 2). This difference was greatest in the 10 to 15–year age group (log-rank, P = .003), with 3-year rates of 19.2% (SD = 2.3%) for females and 9.8% (SD = 1.6%) for males. However, among the much smaller group of young adults in the 16 to 20–year age range, the ON incidence was actually higher in males than females (3-year incidence rate, 20.7% [SD = 4.7%] v 13.2% [SD = 5.1%], respectively). Of interest, a more refined analysis of the older age range showed the incidence for females to be similar in the 10 to 11–, 12 to 13–, and 14 to 15–year age groups, with the highest level in the 14 to 15–year group (3-year incidence rate of 18.8%, SD = 4.6%). In males, the incidence was similar in the 14 to 15– and 16 to 20–year age groups, with the highest rate in the 16 to 20–year age group (20.7%); lower incidence rates were seen in the 10 to 11– and 12 to 13–year age groups (3-year incidence rates of 6.0% [SD = 2.1%] and 6.5% [SD = 2.4%], respectively).
ON patients ranged in age from 3.8 to 18.5 years at diagnosis of ALL. The mean age for ON patients was 13.6 years compared with 10.1 years for all CCG-1882 patients (males: 14.2 v 10.3 years, respectively, P < .001; females: 13.1 v 9.8 years, respectively, P < .001). In the 10 to 20–year age group, there was a significant difference in mean age for males who had ON compared with those who did not (14.6 v 13.7 years, respectively; P = .006), although no difference was seen for females (13.3 v 13.5 years, respectively; P = .48).
ON incidence was compared for randomized patients separately within both the RER and SER subsets for the
Other demographic and clinical characteristics (Table 3) were investigated for prognostic influence on ON incidence. In the 10–year age group, the only other prognostic factor identified was ethnic group (log-rank, P = .003). This was because of very different 3-year incidence rates in whites (16.7%, SD = 1.4%) compared with blacks (3.3%, SD = 2.3%) and other ethnic groups (6.7%, SD = 2.2%). Small cohort size may have hindered the identification of additional prognostic factors. To determine if there was a correlation between the occurrence of ON and overall EFS, Cox regression analysis used the time of diagnosis of ON as a time-dependent covariate. That analysis showed no evidence of any significant effect of ON on subsequent EFS in a multivariate analysis (P = .54), with a trend slightly in the direction of better outcome after occurrence of ON (relative hazard rate of EFS event = 0.84 for ON group compared with non-ON group). Small sample size precluded subgroup analysis. The diagnosis of ON was made by radiographic criteria in 108 of 111 patients. In the remaining three patients, surgical intervention was required for ON symptoms; however, radiographic data were not provided by the treating institutions. Plain radiographs were obtained in 86 patients and were the sole reported diagnostic study in 24 patients. The radiologic work-up included bone scintigraphy in 28 patients, computed tomography scan in four, and magnetic resonance imaging (MRI) scan in 68. Radiographs were not available for central review. Degree of osteonecrotic joint damage according to the Ficat staging system21 was not assessed. The interval between the diagnosis of ALL and the diagnosis of ON was estimated objectively, using the date of the earliest reported positive radiograph or surgical intervention as the date of ON diagnosis. Thirty-five patients (32%) were diagnosed with ON during year 1, 60 (54%) in year 2, and 15 (13%) in year 3, with only a single patient diagnosed at a later date (year 5). One patient was diagnosed with ON after induction but before dexamethasone exposure, 12 were receiving the first (n = 8) or second (n = 4) course of delayed intensification, and the remainder were in maintenance phase (n = 92) or had completed therapy (n = 6). Retrospective reporting did not enable determination of the time of ON symptom onset. All patients were in first marrow remission at the time of ON diagnosis. Joints affected by ON and associated morbidity are listed in Tables 5, 6 and 7. At the time of data collection, 17% of patients were categorized by the treating institution as having ON symptoms that were transient/resolved; whereas 83% had chronic symptoms (27% improving, 30% stable, and 26% worsening). Of note, ON was transient in all four children under 10 years of age.
The diagnosis of ON resulted in the discontinuation of further corticosteroid therapy in 60 patients and dose modifications in six patients. Therapy was not altered for 40 patients still on treatment. Three had completed ALL therapy at the time of ON diagnosis. Medication information was not available for two patients. The effect of corticosteroid dose changes on EFS could not be assessed, nor did our data review permit assessment if corticosteroid continuation worsened ON or if ON stabilized or improved while on continued corticosteroid. Orthopedic management of symptomatic ON varied. A period of non–weight-bearing (crutches and/or wheelchair) in combination with physical therapy was recommended for many patients. Orthopedic surgical procedures for symptomatic ON had been performed on 27 patients at the time of reporting, including 20 total hip arthroplasties (13 patients) and one knee arthroplasty. Other procedures included core decompression, revascularization, intertrochanteric osteotomy, and bone graft. An additional 17 total hip arthroplasties (12 patients) and six total knee arthroplasties (three patients) were planned. The effect of surgery on overall symptom course was not assessable because of the presence of multifocal ON in many patients.
This analysis represents the largest study of symptomatic ON in childhood ALL to date. Age greatly influenced the risk of developing ON, which was seen in 14.2% (SD 1.3%) of patients 10 to 20 years old at diagnosis of ALL and approximately 1% of those 1 to 9 years old. ON incidence in the 16 to 20–year age group was slightly higher than in the 10 to 15–year age group but not enough to reach a conventional statistical significance level in this study population. The maturing bone of adolescents may be more susceptible to the development of ON.72-73 With epiphyseal closure, corticosteroid-induced marrow fat-cell hypertrophy results in elevated intraosseous pressure followed by reduced intramedullary blood flow, marrow ischemia, and ultimately necrosis. In contrast, immature bone may buffer increased pressure at the epiphyseal plate.2,5-6,10-12,16,18 Even though older children and adolescents are at highest risk for ON, younger children are clearly not exempt from this toxicity, although their course may be transient and reversible, as in our four patients, or may be entirely without symptoms.54-56,74 The proposed mechanism of corticosteroid-induced ON predicts that females would become susceptible to this toxicity at a younger age than males because females progress through puberty earlier than males. The mean age of females with ON in our study was lower than that of males (13.2 v 14.6 years, respectively). Females also developed ON at a higher rate than males (11.2% v 7.7%, respectively). The peak female age group for ON was the 10 to 15–year age range (19.2%), with a lower incidence rate in the 16 to 20–year age range (13.2%). This finding may reflect the age distribution of these patients, 86% being in the 10 to 15–year age group and just 14% in the 16 to 20–year age group. Males showed a lower ON incidence rate in the 10 to 15–year age range (9.8%) and a higher rate in the 16 to 20–year age range (20.7%), with the increase in incidence actually beginning in the 14 to 15–year age subgroup. Pubertal stage, bone age, and hormone levels were not assessed. It is of interest whether the incidence of ON correlates with the amount of dexamethasone received. The CCG-1882 study design allowed direct comparison of ON incidences between SER patients randomized to receive either SDI (including one dexamethasone pulse) or DDI (including two dexamethasone pulses) phases. Patients 10 to 20 years old randomized to receive DDI exhibited a 1.4-fold higher incidence of symptomatic ON compared with those who received SDI, although this did not reach a conventional significance level. This effect was accentuated in females and in those 16 to 20 years of age at diagnosis of ALL. A larger randomized population in the at-risk age range would need to be studied to more definitively establish the comparative influence of DDI versus SDI treatment. However, if one assumes that exposure to delayed intensification is at least contributory to the development of ON, our results indicate that even a single course of delayed intensification increases the risk of ON compared with earlier studies that did not include such therapy. A recent MRI study implicating delayed intensification in the development of ON in a similar group of patients provides indirect support of this premise.56 Ethnicity was also found to be predictive of ON development, with a lower incidence in blacks, a somewhat higher incidence in nonwhites/nonblacks, and the highest incidence in whites. The relative incidence in whites was approximately five times more than in blacks, with only two cases of ON occurring in 68 blacks who were older than 9 years of age at diagnosis of ALL. The explanation for this finding is unclear. Ethnic differences have previously been identified in the incidence of bone tumors, with Ewing’s sarcoma rarely seen in blacks.75 Bone density may be influenced by genetic polymorphism of the vitamin D receptor in some populations, although this is under debate.76-79 Racial variation in pubertal development has not been evaluated in this patient population. Data analysis suggested a trend toward improved EFS among ON patients. Glucocorticoid sensitivity is known to vary between individuals.80 One may speculate that patients who are inherently more sensitive to the effects of glucocorticoid will not only have lymphoblasts that are more responsive to therapy, but will also have medullary bone that is more susceptible to toxicity. Future study is warranted and would enable more optimal use of corticosteroids in ALL therapy, with the goal of maximizing antileukemic benefit while minimizing the risk of potential toxicities. We were also interested in describing the spectrum of morbidities associated with ON in our patients. Multiple joints were affected in nearly 75% of the 111 patients. Weight-bearing joints were involved in 104 patients, severely limiting activity in 46. Nearly half of the patients required narcotic analgesia at some point in their course. Of note, all patients but one developed ON symptoms within 3 years of starting ALL therapy; 98 patients developed ON symptoms during or after the maintenance phase. Although this analysis did not include long-term follow-up and the percent who ultimately had a normal functional outcome is not known, at the time of data collection, the symptoms were considered chronic in 92 patients and stable or worsening in 62 patients. Of 86 affected hips, 37 were candidates for arthroplasty, as were six knee joints. Surgical options for ankle disease are limited and unsatisfactory. The impact of modifications in corticosteroid therapy on EFS could not be assessed, nor could the costs of managing this devastating complication be estimated. At the time of study onset, ON was considered a rare complication of ALL therapy. Its emergence was therefore unanticipated, and prospective data collection was not performed. Recognition of the increasing ON incidence prompted this investigation. Information was provided by the treating institution for each patient through completion of an ON data form, supplemented by use of the CCG computerized database and patient records. Nonetheless, the retrospective nature of this analysis imposed certain limitations. First, the reported ON incidence may underestimate the actual ON incidence because end-of-phase forms did not list ON as a reportable event, physician awareness of this toxicity was initially low, a uniform diagnostic approach was not used, and patient(s) who developed ON subsequent to this investigation were not included. Second, the estimated timing of symptom onset, degree of immobility, and pain severity were subject to error. Third, diagnosis was confirmed by institutional radiologists; films were not available for central review. And finally, the incidence of occult ON was not assessable, which would have required prospective MRI screening of asymptomatic patients. The incidence and age distribution of occult ON may differ somewhat from that of our patients.56 The current findings provide a stark contrast to the historical experience. ON has only recently arisen as a significant toxicity as increasing numbers of ALL patients have received dexamethasone-based delayed-intensification therapies with improved disease survival.32,48-52,54-56,58-66,74 Indeed, among the nearly 4,000 children who received prednisone-based treatment on CCG ALL protocols during the 1980s, the study chairs could not recall a single case of ON. Although dexamethasone may play a leading role in the development of ON, its marrow and bone effects may be additive or synergistic with those of prednisone administered during induction and maintenance. The potential role of other factors in the development of ON in these patients is uncertain. In CCG-1882, augmented therapy included additional doses of other agents including methotrexate, which has been shown to have metabolic effects resulting in osteoporosis.81-84 Osteopenia and associated vertebral fractures have been noted in newly diagnosed ALL patients, with an incidence as high as 1.6%,85-87 and are likely related to the bone-resorbing effects of lymphoblasts.88-91 However, an association between bone deossification and ON has not been documented, and bone-sparing interventions have yet to be investigated. Lastly, among solid tumor patients receiving chemotherapy without corticosteroid, ON has rarely been reported.92-94 As we continue to make remarkable progress in the treatment of childhood ALL, we must be mindful of the morbidity and toxicity associated with intensive therapies and strive to limit these without compromising antileukemic benefit. Based on the results of this investigation and our understanding of bone pathophysiology, the current CCG ALL protocol decreases by 40% the amount of dexamethasone administered to older children and adolescents receiving DDI, and patients are being monitored prospectively for the development of ON.
Supported by grants from the Division of Cancer Treatment, National Cancer Institute, National Institutes of Health, Department of Health and Human Services.
Contributing Children’s Cancer Group investigators, institutions, and grant numbers are listed in the Appendix.
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ABSTRACT
INTRODUCTION
2 tests for homogeneity of proportions, and comparison of patient groups for continuous variates (such as age) used t tests. Cox regression analysis, with the occurrence of ON as a time-dependent covariate, was used to investigate the effect of ON on subsequent EFS outcome.
