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Letters to the Editor
Figure 1. Cumulative incidence of symptomatic osteonecrosis for patients treated with long pulses dexamethasone (n=731) and patients treated with short pulses dexamethasone plus asparaginase (n=652) since start post-consolidation therapy (landmark). ASP: asparaginase; DEXA: dexamethasone.
In multivariable analysis including type of post-consol- idation treatment regimen, age at ALL diagnosis, sex and body mass index standard deviation score, age was the only significant independent risk factor (cause-specific hazard ratio [HRCS]=1.40; 95% CI=1.32-1.50; P<0.001, Table 1).
A statistically significant difference between the CION for different age categories at ALL diagnosis was observed (P<0.001, Figure 2). At 3 years since ALL diag- nosis, the CION was 1.2% (95% CI=0-2.3), 14.3% (95% CI=10.0-18.5) and 31.4% (95% CI=30.9-31.9%) for chil- dren aged (years) 1-9, 10-14, and 15-18, respectively.
Fifteen of 38 children (39%) with osteonecrosis in ALL- 10/11 MRG experienced severe osteonecrosis. Severe osteonecrosis occurred in none of the 6 children with osteonecrosis aged (years) 1-9, in 5 of the 15 (33%) aged 10-14, and in 10 of the 17 (59%) aged 15-18.
For detailed information on the site and management of osteonecrosis, refer to the Online Supplementary Appendix.
In this study, no statistically significant difference in the CION for children treated with short versus long pulses dexamethasone was found. Based on the findings of the CCG-1961 trial,5 we hypothesized that patients treated with short pulses dexamethasone would have a lower CION. This hypothesis was consistent with a recent preclinical study which showed that asparaginase added to a discontinuous dexamethasone regimen did not increase osteonecrosis occurrence in mice.10
We realized however, that to increase the survival of children with ALL over the past decades, asparaginase intensification has played an important role. Although the combined administration of dexamethasone and asparaginase in our protocols does not allow to prove the relative contribution of asparaginase to osteonecrosis development, we think it is conceivable that intensifica- tion of ALL treatment components other than dexam- ethasone regimens such as asparaginase may explain our
findings. There is evidence that asparaginase is associated with osteonecrosis, especially when administered con- currently with dexamethasone.1,7 We have previously shown that in patients with osteonecrosis, a hypercoag- ulable state may result from a lower dexamethasone- related increase of anticoagulants in combination with a subsequent decline of these anticoagulants after asparag- inase introduction.1 Furthermore, asparaginase increases the plasma concentration of dexamethasone, and in par- ticular PEG-asparaginase may increase triglyceride levels (associated with osteonecrosis) especially in combination with dexamethasone.7,11,12 In a controlled pre-clinical model, mice receiving asparaginase plus continuous dex- amethasone experienced osteonecrosis more often than those receiving dexamethasone alone.13 Furthermore, dis- continuous dexamethasone reduced the risk of osteonecrosis compared to continuous dexamethasone in the CCG-1961 trial more in patients who received inten- sified versus standard treatment, also suggesting that other treatment components may play a role in the effect of dexamethasone pulses duration.5 Other explanations for our finding could be that the long pulses dexametha- sone in the DCOG ALL-9 protocol were already shorter than the continuous dexamethasone in the CCG-1961 trial, and administered throughout maintenance com- pared to during delayed intensification only, respectively.
Our results highlight the relevance of therapeutic con- text when interpreting results of treatment-related toxic- ity. Further research addressing the effect of dexametha- sone and asparaginase schedules on osteonecrosis occur- rence is needed. This is of interest since older children who are at highest risk of (severe) osteonecrosis are also most likely to have an unfavorable leukemia outcome, which raises serious cautiousness towards ALL treatment reduction because of toxicity.14 Furthermore, adequate treatment of osteonecrosis remains an issue: overall suc- cess of conservative treatment is limited since about 50% of patients reported persistent symptoms after 5 years of
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