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Letters to the Editor
Figure 2. Cumulative incidence of symptomatic osteonecrosis for children aged 1-9 years (n=1,124), 10-14 years (n=260) and 15-18 years (n=86) since acute lymphoblastic leukemia diagnosis. ALL: acute lymphoblastic leukemia.
follow-up.2 Hence, prevention of osteonecrosis by treat- ment scheduling modification seems preferable since it could possibly decrease osteonecrosis associated morbid- ity without jeopardizing leukemia outcome.
The association between age and the risk of osteonecrosis has been thoroughly studied. Adolescents are disproportionally affected by this toxicity relative to younger children and adults.15 We here confirmed find- ings from other large studies,5,16 and showed in addition that the 3-year CION was significantly different in chil- dren aged (years) 1-9 (1.2%), 10-14 (14.3%), and 15-18 (31.4%). This means that among children older than 10 years, an age group that most studies have focused on,4,7,15 children aged 15-18 seem to develop osteonecrosis most often, even relative to children aged 10-14 years. This is especially important since our study for the first time shows that in these 15-18-year-old patients, the osteonecrosis is more often severe. Of all patients affect- ed by severe osteonecrosis, 67% ultimately required joint replacement and 20% still experienced chronic pain at follow-up, indicating the clinical relevance of this compli- cation. Our finding is in line with previous studies that showed an increased risk of severe osteonecrosis and hip replacement among older children.5,17 More studies are needed to better understand the occurrence of severe and progressive osteonecrosis.
The results of our study must be interpreted in light of several limitations. We did not perform a randomized controlled trial, so differences between the cohorts other than those adjusted for may exist. We think limiting our analysis to the MRG in ALL-10/11 was justified, but could have introduced bias. However, an overall analysis comparing the CION of ALL-9 versus the entire ALL- 10/11 cohort showed similar results. Although we attempted to rule out differences in induction therapy by employing a landmark analysis, this protocol variation, as well as differences in asparaginase formulation, should be
appreciated. Furthermore, all patients in ALL-10/11 received both short pulses dexamethasone and asparagi- nase, so assessing the effect of each treatment compo- nent separately was not possible.
We conclude that no statistically significant difference in the CION for children treated with short pulses dex- amethasone plus asparaginase versus long pulses of dex- amethasone alone during ALL post-consolidation therapy was found. We postulate that the protective effect of shorter pulses dexamethasone on osteonecrosis occur- rence may be attenuated by recent intensification of other treatment components such as asparaginase. Among children older than 10 years, especially children aged 15-18 years developed symptomatic, in particular severe osteonecrosis.
Jenneke E. van Atteveld,1 Hester A. de Groot-Kruseman,2 Marta Fiocco,1,3,4 Maarten H. Lequin,1,5 Sebastian J.C.M.M. Neggers,1 Saskia M.F. Pluijm,1 Inge M. van der Sluis,1
Rob Pieters1 and Marry M. van den Heuvel-Eibrink1
1Princess Máxima Center for Pediatric Oncology, Utrecht; 2Dutch Childhood Oncology Group (DCOG), Utrecht; 3Medical Statistics Unit, Department of Biomedical Data Science, Leiden University Medical Center, Leiden; 4Mathematical Institute, Leiden University, Leiden and 5Department of Radiology, University Medical Center Utrecht, Utrecht, the Netherlands
Correspondence: JENNEKE E. VAN ATTEVELD j.e.vanatteveld@prinsesmaximacentrum.nl
doi:10.3324/haematol.2020.257550
Disclosures: no conflicts of interest to disclose.
Contributions: JEvA study design, data collection, data analysis, data interpretation, manuscript writing; HAdG-K data collection, data analysis, data interpretation, manuscript writing; MF data analysis, data interpretation, manuscript writing; MHL data interpretation, manuscript writing; SJCMMN data interpretation, manuscript writing; SMFP data interpretation, manuscript writing;
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haematologica | 2021; 106(4)