The characteristics of the 16 patients who eventually developed ON are listed in Table 4. All patients showed typical imaging findings on MRI except 1 (case 941-3) who underwent only x-ray that showed bilateral flattened femoral head. The most commonly affected joints and bones were the hip joint (44%), the knee joint (25%), and the femur (13%). Three patients (19%) exhibited multiple lesions. Nine (56%) continued to receive the planned steroid therapy despite the diagnosis of ON, whereas the doses were decreased or withdrawn in 7 (44%). ON management varied for each patient depending on the physician discretion. Most patients (75%) received supportive care only and were advised to avoid lifting heavy weights (grade 2 according to Common Terminology Criteria for Adverse Event version 4.0). Three patients (19%) underwent surgical intervention (grade 3) and 1 was treated with oral bisphosphonates (grade 2). With the median follow-up times of 33 months (range, 4 to 194), the clinical outcomes of ON were as follows: 12 with amelioration of ON and 3 with stable disease, except 1 who suffered a relapse of leukemia.
In the 3 most recent JCCLSG ALL studies, we found that a significant number of patients developed ON during or after treatment. ALL2004 study was conducted to evaluate the efficacy of DEX usage as a corticosteroid in the context of intensification of reinduction phase, comparing with the preceding 2 studies wherein PSL was the only corticosteroid adopted. This strategy also enabled us to compare the DEX toxicity with that of PSL. The results clearly demonstrated the higher incidence of ON in ALL2004, indicating DEX exposure was the risk for ON in ALL chemotherapy.
The overall incidence of ON was 1.5% (16/1095), which was comparable with that in a previous study by the Japan Association of Childhood Leukemia Study (JACLS) (2.4%, Hiroki H, Yasushi I, Teruaki H, Makoto Y, Megumi O, Tooru K, Shinichiro N, Junichi H, Keizo H, Keiko Y, and Tatsutoshi N; unpublished data). In studies from Europe and the United states, the ON incidence was highly variable (1% to 2% up to 9%) and dependent on patient characteristics and treatment intensity.5–7 Furthermore, the detection methods of ON have significantly affected the incidence. Recent report from St Jude Total XV study showed that 17.6% of patients had the symptomatic ON, whereas the asymptomatic ON was detected in >50% of patients by the prospective screening with MRI test.15 With regard to the effects of race, the incidence of ON is reportedly higher in whites than in patients of African descent.7 Although it remains unclear whether the Asian race is related to an increased risk of ON, our results showed that the incidence of ON in Japanese children seemed to be comparable with that in European and American children. However, it should be taken into account the limitation of the present assessment: the possible missing of asymptomatic cases and the diagnosis partly depending on physician’s discretion.
In this study, female sex, age 10 years and above, and the use of DEX as a corticosteroid were significant risk factors for ON. Of the 33 female patients aged over 10 years who received DEX, 7 developed ON (cumulative incidence, 25.6%). This was the extremely higher incidence of ON comparing with the rest of patients. Although females were found to be at a higher risk of developing ON in the Children’s Cancer Study Group (CCG) and Italian studies,5,7 there was no such correlation in studies performed in the UK and Germany and at the Dana Farber Cancer Institute (Boston, MA).6,16,17 In addition, a Japanese study conducted by the JACLS failed to show a significant female predominance (male to female ratio, 7:9). Therefore, the effects of sex on ON pathogenesis remain unclear.
A significant contribution of age to ON onset has been robustly documented by most retrospective and prospective studies.5–7,9,16,18–21 Among children aged 10 years and above, those aged 16 to 20 years were at the highest risk of ON. The eligible patient age was 1 to 15 years in ALL941/2000 and 1 to 18 years in ALL2004; therefore, we may have underestimated the incidence of ON. Further monitoring is necessary when ALL treatment protocols designed for children are extended to adolescence and young adulthood.
The potential effect of DEX on ALL is 6.5 times that of PSL, resulting in an increase in the use of DEX for ALL treatment. Because DEX is more toxic to bone tissues,14,22 a higher incidence of ON has been a major concern in the design of treatment protocols. In ALL2004, DEX was incorporated only in the reinduction phase because an increased incidence of ON and mortality was reported with the use of DEX in the induction phase.23 Nonetheless, our data revealed a higher cumulative incidence of ON associated with DEX administration; this finding was comparable with the results of the Dana Farber Consortium study DFCI 00-01, wherein DEX was used in postremission intensification therapy and/or in the maintenance phase.24 Although the total corticosteroid dose (analyzed as PSL equivalents) at therapy completion were slightly lower in ALL2004 than in ALL941/2000 (Table 2), ON was most frequent in patients who had received only DEX in the HR group in ALL2004. These results suggest that DEX administration at any dose (as PSL equivalents) and in any treatment phase affects the incidence of ON. A recent report from the CCG found that DEX administration could influence the risk of ON21 and that alternate-week DEX administration during delayed intensification therapy decreased ON incidence compared with continuous DEX. In our ALL2004 protocol, DEX was administered continuously for 2 weeks, and it would have been beneficial to modify the DEX schedule from continuous administration to alternate-week administration.
Recently, biological and genetical basis for ON development has been extensively investigated. Children’s Oncology Group tested 12 polymorphisms of candidate genes and identified children with PAI-1 GA/AA genotypes were significantly associated with ON.25 Another study from St Jude Children’s Research Hospital showed polymorphisms of ACP1 were associated with risk of symptomatic ON as well as with lower serum albumin and higher cholesterol levels.15 These results suggest that some patients are prone to develop ON and individualized therapy should be needed in the future ALL studies.
In the present report, cases with ON were retrospectively collected by the questionnaire, and most of the ON patients were identified by symptoms and confirmed with imaging studies (x-ray/MRI) without central review. Despite such limitations, the clinical features of all 16 ON patients in our study were virtually comparable with those of patients in previous studies.6,7,16 Weight-bearing joints were commonly affected, whereas asymptomatic lesions might have been overlooked.15 Once ON is confirmed, the physician must decide whether steroids should be withheld or continued, considering that no consensus guideline is available thus far. Most of our patients were prescribed a planned dose of steroids without compromising functional outcomes after ON development. We believe that it may not be necessary to withhold steroids at the risk of leukemia relapse.
Bisphosphonates, which are structurally similar to pyrophosphates, inhibit osteoclast activity and bone turnover, thus exerting beneficial effects on bone mineralization.26 Alendronate, a third-generation bisphosphonate, is reportedly effective in the prevention of femoral head collapse in ON patients.27 Wiernikowski et al28 showed that alendronate-induced changes in bone mineral metabolism/homeostasis benefited bone mineralization in children with ALL or non-Hodgkin lymphoma with steroid-induced osteopenia. Another bisphosphonate, pamidronate, was shown to be effective in the management of pain and motor function recovery in symptomatic ON occurring in children with ALL.29 In the present study, alendronate was administered to 1 patient with symptomatic ON of the bilateral hip and knee joints; this resulted in no further deterioration of functional outcome and no treatment-induced side effects. However, further studies are required to clarify the potential benefits of concomitant bisphosphonate and steroid use for ON treatment.
In summary, the overall incidence of ON was 1.5% in the JCCLSG ALL studies, which was comparable with that reported in previous studies conducted in the Unites States and Europe. The known risk factors of age above 10 years, female sex, and DEX use were all significantly associated with an increase in the cumulative incidence of ON. In our future studies, we are intending to routinely screen for ON development with MRI test, especially those incorporating DEX in the treatment protocol. Although an ON management regimen remains to be established, steroids should not be withheld at the risk of ALL relapse.
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acute lymphoblastic leukemia; osteonecrosis; corticosteroid; dexamethasone
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