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© 2001 American Society for Clinical Oncology Bony Morbidity in Children Treated for Acute Lymphoblastic LeukemiaFrom the Department of Pediatrics, Massachusetts General Hospital; Quality Control Center and Departments of Pediatric Oncology and Biostatistical Science, Dana-Farber Cancer Institute; and Division of Hematology/Oncology, Children’s Hospital, and Department of Pediatrics, Harvard Medical School, Boston, MA. Address reprint requests to Lewis B. Silverman, MD, Dana-Farber Cancer Institute, 44 Binney St, Boston, MA 02115; email: lewis_ silverman{at}dfci.harvard.edu
PURPOSE: Corticosteroids are widely used in the treatment of acute lymphoblastic leukemia (ALL). To determine the frequency of corticosteroid-associated bony morbidity in children with ALL, we retrospectively evaluated the incidence of fractures and osteonecrosis (ON) on two consecutive pediatric ALL protocols. PATIENTS AND METHODS: One hundred seventy-six consecutive children were treated for ALL between 1987 and 1995 at the Dana-Farber Cancer Institute and Children’s Hospital. Prednisone was used as the corticosteroid during postremission therapy from 1987 to 1991, and dexamethasone was used from 1991 to 1995. Medical records for all patients were reviewed to assess the occurrence of fractures and ON. RESULTS: With a median follow-up of 7.6 years, the 5-year cumulative incidence (CI) ± SE of any bony morbidity for the 176 patients was 30% ± 4%, with a 5-year CI of fractures of 28% ± 3% and of ON of 7% ± 2%. With multivariate analysis, independent predictors of bony morbidity included age 9 to 18 years at diagnosis (P < .01), male sex (P < .01), and treatment with dexamethasone (P = .01). Dexamethasone was associated with a higher risk of fractures (5-year CI, 36% ± 5% v 20% ± 4% with prednisone; P = .04), but not ON (P = .40). The 5-year event-free survival for the 176 patients was 79% ± 3%. CONCLUSION: Children treated for ALL had a high incidence of fractures and ON. Older children, boys, and patients receiving dexamethasone were at increased risk for the development of bony morbidity. Future studies should attempt to minimize corticosteroid-associated bony morbidity without compromising clinical efficacy.
OVER THE LAST 50 years, outcome for children with acute lymphoblastic leukemia (ALL) has significantly improved, with recent reports estimating event-free survival (EFS) rates of 78% to 83%.1-3 As cure rates have improved, research has focused on the recognition and reduction of treatment-related morbidity. For instance, corticosteroids, a major component of therapy for ALL, have been associated with development of bony morbidity, such as osteopenia and fractures. The magnitude of this toxicity has not been fully elucidated. Many investigators have demonstrated that children with ALL have reduced bone mineral density during and even many years after the completion of therapy,4-8 but there are few published reports regarding the incidence of fractures in this patient population.4 Osteonecrosis (ON), also known as avascular necrosis, is another disabling bony toxicity attributed to corticosteroid usage.9,10 It frequently involves multiple joints and can lead to significant pain and loss of function, sometimes necessitating total joint replacement.11-13 Mattano et al14 recently reported a 3-year ON cumulative incidence (CI) of 9% in children treated for higher risk ALL, with the highest frequency observed in adolescents. Twenty-four percent of affected patients in that series underwent an orthopedic procedure to relieve symptoms.14 The diagnosis of ON after development of symptoms may underestimate its prevalence. In one series, screening magnetic radiographic imaging studies detected ON in nine (38%) of 24 patients, six of whom were asymptomatic.15 The clinical significance of asymptomatic findings remains unclear. Historically, prednisone has been the corticosteroid used most often in the treatment of ALL. Recently, dexamethasone has been used by many investigators because of its increased bioavailability, superior in vitro antileukemia activity, and enhanced CNS penetration.16-19 Little is known about the relative bony morbidity of prednisone and dexamethasone. To determine the incidence of fractures and ON in children treated for ALL, we performed a retrospective study of patients treated at Dana-Farber Cancer Institute (DFCI)/Children’s Hospital (CH) between 1987 and 1995 on two consecutive protocols—one using prednisone during postremission therapy and the other, dexamethasone. We report here the frequency and predictors of corticosteroid-associated bony morbidity.
Patient Selection Between November 1987 and December 1995, 176 children, ages 0 to 18 years, with newly diagnosed ALL were enrolled onto two consecutive DFCI ALL Consortium protocols (protocols 87-01 and 91-01) at DFCI/CH. The institutional review board at each institution approved each protocol before patient enrollment, and informed consent was obtained from parents or guardians before therapy started. Medical records were available for all patients and were reviewed for information regarding bony morbidity. All diagnoses of fracture and ON were confirmed by at least one radiographic imaging study. For each fracture and diagnosis of ON, the following were recorded: date of diagnosis, phase of antileukemia therapy, anatomic location, method of diagnosis, and any surgical intervention. Bony morbidity was evaluated until any of the following occurred: induction failure, induction death, relapse, remission death, or time of stem-cell transplant (during first remission).
Antileukemia Therapy Each protocol consisted of four phases of treatment: remission induction, CNS treatment, intensification, and continuation therapy. Details have previously been published and are listed in Table 1.20 Therapy on protocol 91-01 (1991 to 1995) was similar to that on protocol 87-01 (1987 to 1991), with the following exceptions: on protocol 91-01, dexamethasone was used instead of prednisone during postremission therapy at bioequivalent dosing, on the basis of anti-inflammatory potency21; patients received 30 instead of 20 weeks of asparaginase during intensification therapy; and SR boys received 18 Gy cranial radiation instead of intrathecal therapy alone as CNS prophylaxis. Patients were also eligible to participate in different, protocol-specific randomizations, listed in Table 1. On both protocols, corticosteroids were transiently held when a patient experienced a fracture and restarted after it healed. Corticosteroids were permanently discontinued at the time of diagnosis of ON.
Corticosteroid Dose Total intended corticosteroid doses differed according to protocol and risk group assignment (Table 2). On protocol 87-01, SR and HR patients received a total of 7,600 mg/m2 and 21,240 mg/m2 of prednisone, respectively. Dexamethasone was not administered on protocol 87-01. On protocol 91-01, all patients received 1,120 mg/m2 of prednisone during remission induction, in addition to dexamethasone at total doses of 1,020 mg/m2 for SR patients and 3,060 mg/m2 for HR patients. Dexamethasone doses were converted to prednisone equivalents by multiplying the dexamethasone dose by a conversion factor of 6.67; this is based on the relative anti-inflammatory properties of the two drugs.21 By using this conversion, total prednisone equivalents for patients on protocol 91-01 were 7,920 mg/m2 for SR patients and 21,530 mg/m2 for HR patients.
Statistical Analysis The primary end point was 5-year CI of the first occurrence of ON, fracture, or both.22,23 Induction failure, induction death, leukemia relapse, and remission death were competing events. Patients with neither bony morbidity nor a competing event were censored at the time of most recent follow-up. The median follow-up was 9.5 and 5.2 years for patients enrolled on protocols 87-01 and 91-01, respectively (7.6 years for the total group). Tests of significance for differences in CI of bony morbidity between patient subgroups were conducted by using the method of Gray.24 EFS was the time from complete remission to the first outcome event; induction failure and induction deaths were considered events at time zero. Other outcome events included death during remission and relapse. EFS was estimated with the Kaplan-Meier method,25 and Greenwood’s formula26 was used to calculate SEs.
Patient Characteristics The characteristics of the 176 patients evaluated are listed in Table 3. Eighty-seven patients (49%) were treated on protocol 87-01, and the remaining 89 patients (51%) on protocol 91-01. Fifty-four percent of patients were boys. One hundred twenty-five children (71%) were classified as HR, 39 of whom (22% of total) were 9 to 18 years old at diagnosis. There was no significant difference in presenting features when comparing the two protocols (data not shown).
Bony Morbidity The 5-year CI of any bony morbidity (fracture, ON, or both) for all 176 patients was 30% ± 4% (Table 3 and Fig 1). The 5-year CI of developing bony morbidity for patients 9 to 18 years old at diagnosis was 51% ± 8%, significantly higher (P < .01) than for patients less than 9 years old (5-year CI, 24% ± 4%). Boys were more likely to experience bony morbidity than girls (5-year CI of 38% ± 5% v 21% ± 5%, respectively; P < .01). There was a trend toward increased bony morbidity in HR compared with SR patients (P = .09); however, there was no statistically significant difference between risk groups when only patients less than 9 years old at diagnosis (P = .45) were considered.
Fractures Eighty-seven fractures occurred in 51 children, with a 5-year CI of 28% ± 3% (Table 4). Although no fractures were noted during the first 2 months of treatment, 74 (85%) occurred either during continuation therapy or after cessation of treatment. Median time from diagnosis of ALL to first fracture was 15 months (interquartile range, 10 to 24 months). Forty fractures (46%) occurred in long bones and 47 (54%) in the digits, clavicle, vertebrae, and facial bones. Presenting characteristics associated with the greatest risk of fracture included male sex (5-year CI of 37% ± 5% compared with 16% ± 4% for girls; P < .01), and age  9 nine years (5-year CI of 46% ± 8%, compared with 22% ± 4% for children < 9 years old; P < .01). There was no significant difference in the incidence of fractures on the basis of risk group or presenting WBC.
ON Thirty-three sites of ON were diagnosed in 13 patients (Table 4). All but three patients developed ON at multiple sites (mean, 2.5; range, one to four sites). The 5-year CI of ON was 7% ± 2%. Four of the 13 patients (31%) required surgical intervention, and eight (62%) also developed bone fractures. Diagnosis of ON was most common during the continuation phase (45% of diagnoses) or after the cessation of therapy (33%). Median time from diagnosis of ALL to first diagnosis of ON was 14 months (interquartile range, 10 to 24 months). ON was diagnosed most frequently in the weight-bearing bones of the lower extremities (82% of cases). The highest risk of ON was observed in children 9 to 18 years old at diagnosis (5-year CI, 21% ± 7% v 4% ± 2% for patients < 9 years old). There was no significant difference in ON rates by risk group (P = .80), sex (P = .98), or presenting WBC (P = .56).
Comparison of Dexamethasone and Prednisone
Prognostic Factors With univariate analysis, male sex (P < .01), age 9 to 18 years at diagnosis (P < .01), and treatment with dexamethasone on protocol 91-01 (P = .01) were associated with increased risk of developing bony morbidity. These three factors were associated with an increased risk of fractures (P < .01, P < .01, and P = .04, respectively), but only age was a significant predictor of ON (P < .01). In multiple regression models, including age, risk group, sex, and treatment protocol, older age at diagnosis (P < .01), male sex (P < .01), and treatment with dexamethasone on protocol 91-01 (P = .01) were independent risk factors for the development of bony morbidity.
EFS and Bony Morbidity
We report here a high incidence of bony morbidity as a complication of treatment for childhood ALL. There have been few previously published reports of fracture rates in children treated for ALL and none in such a large study cohort. The fracture rate of our cohort (5-year CI of 28%) far exceeded the rates of 1.6% to 2.1% observed in healthy children.27,28 The 5-year CI of ON was 7%, within the range reported by others for intensively treated pediatric ALL patients.14 ON was diagnosed in multiple locations in most patients and usually in weight-bearing bones, consistent with prior reports.9,13,14 Patients treated on Protocol 87-01 and 91-01 received relatively high cumulative doses of corticosteroids (Table 2), which may have contributed both to excellent antileukemia efficacy (5-year EFS of 79%) and the high incidence of bony morbidity. Patients treated on protocol 91-01 (dexamethasone during postremission therapy) had a much higher risk of fractures than those treated on protocol 87-01 (prednisone during postremission therapy) (P = .04). Other than postremission corticosteroids, therapy on the two protocols was nearly identical (Table 1). Thus, our data suggest that dexamethasone, administered at presumably equipotent anti-inflammatory doses, was more toxic to the skeletal system than prednisone. We have previously reported increased toxicity when dexamethasone was substituted for prednisone in the treatment of childhood ALL, including a higher incidence of septic episodes and deaths during remission induction and more severe neurocognitive late effects.29,30 Dexamethasone’s relatively increased toxicity might result from its longer half-life and increased bioavailability. Although results of protocols substituting dexamethasone for prednisone in the treatment of childhood ALL have been promising in terms of enhanced antileukemia efficacy,1,17,31 a prospective, randomized study is necessary to determine the relative efficacy and toxicity of the two agents. The Children’s Cancer Group conducted such a trial, enrolling children with lower risk ALL. Preliminary results suggested that dexamethasone was associated with an improved 3-year EFS and also higher morbidity, but longer follow-up is necessary.32 Currently, we are prospectively randomizing all children with ALL to receive either dexamethasone or prednisone during postremission therapy. In addition to corticosteroids, other aspects of therapy and even the disease process itself might have contributed to bony morbidity. Radiographic evidence of osteopenia has been reported in approximately 10% of children with ALL at the time of diagnosis, before the initiation of chemotherapy.33 Methotrexate has been implicated in the development of osteopathy, including osteoporosis and fractures.34 The most severe osteopathy has been observed after high-dose methotrexate, to which patients on protocols 87-01 and 91-01 were minimally exposed (no doses or one dose). In animal and in vitro studies, doxorubicin has been shown to have inhibitory effects on bone formation, although the clinical relevance of these findings has not been established.34 Some authors have suggested that cranial radiation may also contribute to bony morbidity, although this finding has not been confirmed by others.35 However, of all the agents used in the treatment of childhood ALL, corticosteroids have been most strongly associated with the development of bony morbidity. Age at diagnosis and sex affected the risk of developing bony morbidity. Older children (9 to 18 years old) were twice as likely to suffer a bone fracture (P < .01) and were more than five times as likely as younger patients to be diagnosed with ON (P < .01). Other studies have also suggested that older children were at higher risk for bony complications during treatment for ALL, especially ON, perhaps because of physiologic differences between adolescents and younger children, such as epiphyseal closure and circulating hormone levels.9,14,35 We also observed an increased risk for developing a fracture in boys (P < .01), consistent with reports that male survivors of childhood ALL have more severe osteopenia than female survivors.5 Fracture rates in healthy children are higher in adolescents and boys, perhaps because of increased participation in organized sports and risk-taking behaviors.27,36 These factors may have contributed to the higher fracture rates observed in boys and adolescents with ALL. We did not observe any difference in ON rates when comparing boys and girls, although others have reported that ON is more common in female ALL patients.14 Given the high rate of fractures and ON in children with ALL, future studies should focus on defining the effect of bony morbidity on quality of life, as well as investigating strategies to reduce these toxicities. We are currently studying whether a decrease in the cumulative corticosteroid dose administered to HR patients (which includes all older children) might decrease toxicity without compromising antileukemia efficacy. Bisphosphonates are another therapeutic option that might reduce the rate of pathologic fractures, because they have been shown to reduce corticosteroid-induced osteoporosis in adults with nonmalignant conditions.37,38 However, the safety and efficacy of bisphosphonates in pediatric ALL patients have yet to be determined. Future studies should also evaluate whether early and intensive screening for ON by magnetic resonance imaging or other radiographic modalities prevents significant functional impairment.15 The recognition of bony morbidity as a significant problem in childhood ALL highlights the challenge of treating these patients: administering therapy which is effective enough to maximize cure rates yet not associated with unacceptable toxicities.
Supported in part by grants no. CA68484 and CA06516 from the National Institutes of Health. We thank the patients, families, physicians, nurses, data managers, and all others who participated in these trials. We acknowledge the fundamental contributions of Mia Donnelly, Jennifer Peppe, and Sharon Thornhill.
1. Silverman LB, Gelber RD, Dalton VK, et al: Improved outcome for children with acute lymphoblastic leukemia: Results of Dana-Farber Consortium Protocol 91-01. Blood 97: 1211-1218, 2001
2.
Schrappe M, Reiter A, Ludwig WD, et al: Improved outcome in childhood acute lymphoblastic leukemia despite reduced use of anthracyclines and cranial radiotherapy: Results of trial ALL-BFM 90. German-Austrian-Swiss ALL-BFM Study Group. Blood 95: 3310-3322, 2000
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Pui CH, Mahmoud HH, Rivera GK, et al: Early intensification of intrathecal chemotherapy virtually eliminates central nervous system relapse in children with acute lymphoblastic leukemia. Blood 92: 411-415, 1998 4. Halton JM, Atkinson SA, Fraher L, et al: Altered mineral metabolism and bone mass in children during treatment for acute lymphoblastic leukemia. J Bone Miner Res 11: 1774-1783, 1996[Medline] 5. Arikoski P, Komulainen J, Voutilainen R, et al: Reduced bone mineral density in long-term survivors of childhood acute lymphoblastic leukemia. J Pediatr Hematol Oncol 20: 234-240, 1998[Medline] 6. Warner JT, Evans WD, Webb DK, et al: Relative osteopenia after treatment for acute lymphoblastic leukemia. Pediatr Res 45: 544-551, 1999[Medline] 7. Brennan BM, Rahim A, Adams JA, et al: Reduced bone mineral density in young adults following cure of acute lymphoblastic leukaemia in childhood. Br J Cancer 79: 1859-1863, 1999[Medline]
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Arikoski P, Komulainen J, Riikonen P, et al: Reduced bone density at completion of chemotherapy for a malignancy. Arch Dis Child 80: 143-148, 1999 9. Murphy RG, Greenberg ML: Osteonecrosis in pediatric patients with acute lymphoblastic leukemia. Cancer 65: 1717-1721, 1990[Medline] 10. Chang CC, Greenspan A, Gershwin ME: Osteonecrosis: Current perspectives on pathogenesis and treatment. Semin Arthritis Rheum 23: 47-69, 1993[Medline] 11. Hanif I, Mahmoud H, Pui CH: Avascular femoral head necrosis in pediatric cancer patients. Med Pediatr Oncol 21: 655-660, 1993[Medline] 12. Thornton MJ, O’Sullivan G, Williams MP, et al: Avascular necrosis of bone following an intensified chemotherapy regimen including high dose steroids. Clin Radiol 52: 607-612, 1997[Medline] 13. Wei SY, Esmail AN, Bunin N, et al: Avascular necrosis in children with acute lymphoblastic leukemia. J Pediatr Orthop 20: 331-335, 2000[Medline]
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Mattano LA Jr, Sather HN, Trigg ME, et al: Osteonecrosis as a complication of treating acute lymphoblastic leukemia in children: A report from the Children’s Cancer Group. J Clin Oncol 18: 3262-3272, 2000 15. Ojala AE, Paakko E, Lanning FP, et al: Osteonecrosis during the treatment of childhood acute lymphoblastic leukemia: A prospective MRI study. Med Pediatr Oncol 32: 11-17, 1999[Medline] 16. Balis FM, Lester CM, Chrousos GP, et al: Differences in cerebrospinal fluid penetration of corticosteroids: Possible relationship to the prevention of meningeal leukemia. J Clin Oncol 5: 202-207, 1987[Abstract] 17. Jones B, Freeman AI, Shuster JJ, et al: Lower incidence of meningeal leukemia when prednisone is replaced by dexamethasone in the treatment of acute lymphocytic leukemia. Med Pediatr Oncol 19: 269-275, 1991[Medline] 18. Ito C, Evans WE, McNinch L, et al: Comparative cytotoxicity of dexamethasone and prednisolone in childhood acute lymphoblastic leukemia. J Clin Oncol 14: 2370-2376, 1996[Abstract] 19. Kaspers GJ, Veerman AJ, Popp-Snijders C, et al: Comparison of the antileukemic activity in vitro of dexamethasone and prednisolone in childhood acute lymphoblastic leukemia. Med Pediatr Oncol 27: 114-121, 1996[Medline] 20. Silverman LB, Declerck L, Gelber RD, et al: Results of Dana-Farber Cancer Institute Consortium protocols for children with newly diagnosed acute lymphoblastic leukemia (1981-1995). Leukemia 14: 2247-2256, 2000[Medline] 21. Haynes RC Jr, Murad F: Adrenocorticotropic hormone; adrenocortical steroids and their analogs; inhibitors of adrenocortical steroid biosynthesis, in Gilman AG, Goodman LS, Rall TW, et al (eds): The Pharmacological Basis of Therapeutics ( ed 7 ). New York, NY: Macmillan Publishing Company, 1985, pp 1459-1489 22. Kalbfeisch JD, Prentice RL: The Statistical Analysis of Failure Time Data. New York, NY: John Wiley, 1980 23. Gooley TA, Leisenring W, Crowley J, et al: Estimation of failure probabilities in the presence of competing risks: New representations of old estimators. Stat Med 18: 695-706, 1999[Medline] 24. Gray RJ: A class of K-sample tests for comparing the cumulative incidence of a competing risk. Ann Stat 16: 1141-1154, 1988 25. Kaplan EL, Meier P: Nonparametric estimation from incomplete observations. J Am Stat Assoc 53: 457-481, 1958 26. Greenwood M: The Natural Duration of Cancer: Reports on Public Health and Medical Subjects. London, United Kingdom: Her Majesty’s Stationary Office, 1926 27. Landin LA: Fracture patterns in children: Analysis of 8,682 fractures with special reference to incidence, etiology and secular changes in a Swedish urban population 1950-1979. Acta Orthop Scand Suppl 202: 1-109, 1983[Medline] 28. Worlock P, Stower M: Fracture patterns in Nottingham children. J Pediatr Orthop 6: 656-660, 1986[Medline] 29. Hurwitz CA, Silverman LB, Schorin MA, et al: Substituting dexamethasone for prednisone complicates remission induction in children with acute lymphoblastic leukemia. Cancer 88: 1964-1969, 2000[Medline] 30. Waber DP, Carpentieri SC, Klar N, et al: Cognitive sequelae in children treated for acute lymphoblastic leukemia with dexamethasone or prednisone. J Pediatr Hematol Oncol 22: 206-213, 2000[Medline]
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Veerman AJ, Hahlen K, Kamps WA, et al: High cure rate with a moderately intensive treatment regimen in non-high-risk childhood acute lymphoblastic leukemia: Results of protocol ALL VI from the Dutch Childhood Leukemia Study Group. J Clin Oncol 14: 911-918, 1996 32. Bostrom B, Gaynon PS, Sather H, et al: Dexamethasone decreases central nervous system relapse and improves event-free survival in lower risk acute lymphoblastic leukemia. Proc Am Soc Clin Oncol 17: 527a, 1998 (abstr) 33. Halton JM, Atkinson SA, Fraher L, et al: Mineral homeostasis and bone mass at diagnosis in children with acute lymphoblastic leukemia. J Pediatr 126: 557-564, 1995[Medline]
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Pfeilschifter J, Diel IJ: Osteoporosis due to cancer treatment: Pathogenesis and management. J Clin Oncol 18: 1570-1593, 2000 35. Barr RD, Halton J, Willan A, et al: Impact of age and cranial irradiation on radiographic skeletal pathology in children with acute lymphoblastic leukemia. Med Pediatr Oncol 30: 347-350, 1998[Medline] 36. Cheng JC, Shen WY: Limb fracture pattern in different pediatric age groups: A study of 3,350 children. J Orthop Trauma 7: 15-22, 1993[Medline]
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Adachi JD, Bensen WG, Brown J, et al: Intermittent etidronate therapy to prevent corticosteroid-induced osteoporosis. N Engl J Med 337: 382-387, 1997
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Saag KG, Emkey R, Schnitzer TJ, et al: Alendronate for the prevention and treatment of glucocorticoid-induced osteoporosis: Glucocorticoid-Induced Osteoporosis Intervention Study Group. N Engl J Med 339: 292-299, 1998 Submitted January 8, 2001; accepted March 15, 2001. This article has been cited by other articles:
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Copyright © 2001 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
