An unanticipated consequence of the successful treatment of childhood ALL has been the emergence of osteonecrosis as a significant toxicity with unacceptable morbidity.4, 6, 9, 10
Our prospective findings in this trial demonstrate that the use of alternate-week rather than continuous dexamethasone during delayed intensification results in a two-fold reduction in the relative risk of symptomatic ON among rapid responder patients ≥10 years old, particularly those 16+ years old, and a four-fold reduction among those randomized to intensified therapy, even though those treated with alternate week dexamethasone received a higher total dexamethasone exposure (-). Additionally, osteonecrosis incidence was lower among slow responder patients ≥10 years old assigned to double delayed intensification with alternate-week dexamethasone on this study, as compared to a similar historical cohort treated on the prior CCG-1882 trial who received two delayed intensification phases with continuous dose dexamethasone (11·8% versus 23·2%).10
These results establish that dexamethasone dosing manner supersedes cumulative exposure as a key factor in the development of treatment-related osteonecrosis and can be modified to limit osteonecrosis risk while achieving superior ALL outcomes.18
The alternate-week dexamethasone schedule was devised based on the pathophysiology of glucocorticoid-induced osteonecrosis, which is associated with marrow lipid infiltration and osteocyte lipid hypertrophy. Such changes are dramatic and occur early during glucocorticoid exposure, causing increased intramedullary pressure and consequent blood flow stasis, which is exacerbated by pubertal bone growth and epiphyseal closure.4, 23, 24
Liver-to-marrow lipid emboli contribute to the development of thrombotic ischemia.25
Glucocorticoids are also directly toxic to osteocytes, inducing apoptosis and exacerbating bone necrosis.26
Alternate-week dosing may moderate these effects, allow for dissipation of intramedullary pressure, and avert osteocyte death. The positive effect of a “steroid holiday” was demonstrated in a mouse model.13
Bone toxicity may also occur with methotrexate and asparaginase due to hypercoagulability, vascular endothelial damage, and perturbations of bone formation, possibly influenced by host genetic polymorphisms.5, 12, 14, 27-29
While the pathogenesis of treatment-related osteonecrosis is presumed multifactorial, it is significant that dexamethasone dose modification was sufficient to reduce osteonecrosis incidence despite exposure to intensified therapy and two interim maintenance and delayed intensification phases (). The magnitude of osteonecrosis risk reduction associated with alternate-week dexamethasone was greater among patients receiving intensified therapy, which included additional vincristine, pegaspargase, and escalating-dose methotrexate, than among those receiving standard therapy; this benefit was especially notable in both groups for patients ≥16 years. Although patients assigned to continuous dexamethasone during single delayed intensification entered maintenance somewhat earlier than those assigned to alternate-week dexamethasone during double delayed intensification, we believe that an uninterupted three-week dexamethasone exposure constitutes a greater ON risk than four additional monthly prednisone pulses. In addition to the physiologic, pharmacologic, and pharmacogenomic factors discussed earlier, it is notable that males had significantly less ON than females despite receiving an additional year of maintenance, including approximately 13 prednisone pulses. There are many potential reasons for the difference in ON rates between the genders, but our findings do not provide compelling evidence that the prednisone pulses are a major factor.
Interestingly, among patients ≥10 years given continuous dexamethasone the osteonecrosis incidence was significantly higher with intensified versus standard therapy (21·4 versus 12·4%, p=0·018). In contrast, for patients given alternate-week dexamethasone the osteonecrosis incidence trended lower on the intensified than the standard regimen (6·9 versus 10·8%, p=0·18). Bone toxicity is likely initiated during induction by prednisone and exacerbated during delayed intensification by dexamethasone. It is plausible that the longer scheduled glucocorticoid-free interval between induction and delayed intensification on the intensified regimens (17 versus 13 weeks) was able to provide partial protection against the degree of additional toxicity associated with alternate-week but not that of continuous dexamethasone. These and other potential interactions between glucocorticoid schedule and components of intensified therapy are being further evaluated in the COG successor trial AALL0232 (http://clinicaltrials.gov/ct/show/NCT00075725
Dexamethasone exposure is influenced by host drug clearance, and poor clearance is strongly associated with ON risk.5
Reduced clearance is also associated with older age and concurrent asparaginase treatment, which would predict increased dexamethasone levels and toxicity among older patients and among those receiving intensive asparaginase therapy. Our findings substantiate this prediction, and suggest that alternate-week dexamethasone may ameliorate these effects. In addition, because intensified therapy includes more potentially hepatotoxic agents during interim maintenance, it is possible that residual hepatotoxicity leading to altered dexamethasone metabolism and increased host exposure during delayed intensification contributed to the observed differences in osteonecrosis between regimens, particularly with continous dexamethasone dosing.
Osteonecrosis incidence strongly correlated with age at ALL diagnosis and female gender, despite females receiving one year less of maintenace therapy than males. The median age of symptom onset was younger in females than males and among those receiving continuous dexamethasone, suggesting a contribution of growth and hormonal factors in the development of osteonecrosis. Pubertal status was not assessed in this trial.
The burden of osteonecrosis was substantial. While only seven patients younger than ten years developed osteonecrosis, all but one had multiple joints diagnosed; 15 of the 18 joints were weight bearing, with three total hip arthroplasties having been performed in two patients. Of note, four of seven received alternate-week dexamethasone, and all became symptomatic relatively early, either during delayed intensification (two) or within the first six months of maintenance therapy (five). This warrants further study since young children who develop osteonecrosis during ALL therapy may possess unique pharmacogenetic or other predisposing factors. Almost all (95%) of the 136 patients ≥10 years with osteonecrosis had symptomatic involvement of weight-bearing joints. While there were no clinical or therapy-related features predictive of surgical need, more patients ≥16 years at ALL diagnosis underwent surgical procedures than those younger (61 versus 35%). However, this may reflect physician preference to delay surgery pending skeletal maturity and therapy completion rather than osteonecrosis severity. While the protocol provided corticosteroid dose modification guidelines for patients who developed osteonecrosis, surgical and other management approaches were at institutional discretion. Although initial osteonecrosis symptom onset was within two years of ALL diagnosis in 88% of patients, in many cases additional symptomatic and asymptomatic sites were identified over time; in fact, across the trial, 10% of joints were diagnosed after the last patient had completed protocol therapy. The trial was not designed to assess long-term functional outcome, nor was presymptomatic MRI screening performed. As observed by others, the ultimate outcome of asymptomatic osteonecrosis is variable.1, 4
An intriguing finding was the apparent event-free survival advantage among older patients of both genders diagnosed with osteonecrosis compared to those without osteonecrosis. This may be attributable to the superior outcomes achieved with intensified therapy and/or the fact that all slow responder patients, who had an inferior event-free survival compared to rapid responder patients, were non-randomly assigned to receive double interim maintenance and delayed intensification phases including alternate-week dexamethasone. However, we believe that these explanations are unlikely to account fully for this difference given the similar osteonecrosis incidence rates observed between standard and intensified therapy cohorts, and the absence of therapeutic advantage for double vs single delayed intensification as previously reported.18
Further subset comparisons are limited by patient numbers. Instead, this finding may reflect inherent differences of host glucocorticoid metabolism and/or response that might impact both anti-leukemia efficacy and toxicity.10, 30
These observations are noteworthy given that maintenance corticosteroid discontinuation or modification was allowed for patients diagnosed with osteonecrosis, and suggest that this practice does not compromise ALL outcome.
One limitation of our study was to allow institutional choice of imaging modality used to confirm each osteonecrosis site. While this was a prudent approach from the perspective of patient management and health economics, it is acknowledged that the true osteonecrosis incidence may have been underestimated due to the variability in diagnostic imaging sensitivity. A second limitation was that data were not captured on acquired or underlying clotting abnormalities that may have contributed to osteonecrosis risk, the potential significance of which was yet to be elucidated when the study was designed in the mid-1990s. Finally, the study was neither designed nor did it have adequate power to directly compare osteonecrosis incidences between individual rapid response regimens within age and gender subsets; statistical analyses are thus limited to overall comparisons as reported ().
In conclusion, this study provides new insight into patient- and treatment-related risk factors for osteonecrosis, highlights the burden of this toxicity among affected patients, and identifies simple dose modifications of dexamethasone administration that can significantly decrease the incidence of osteonecrosis in the context of highly effective chemotherapy.18
Alternate-week dexamethasone dosing during delayed intensification has been incorporated into successor COG ALL clinical trials with prospective toxicity monitoring. Further studies to better characterize the natural history and predisposing factors for osteonecrosis in ALL are ongoing by the COG.