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Letters to the Editor
Effect of post-consolidation regimen on symptomatic osteonecrosis in three DCOG acute lymphoblastic leukemia protocols
Symptomatic osteonecrosis is a serious side effect of childhood acute lymphoblastic leukemia (ALL) treat- ment. In affected children, the blood supply to especially the epiphysis of weight-bearing bones is insufficient.1 Osteonecrosis may resolve completely with conservative treatment or may result in debilitating long-term seque- lae such as articular collapse, ultimately leading to joint replacement at an early age.2,3
Corticosteroids, used to treat ALL, largely contribute to osteonecrosis development.4 Moreover, higher cumula- tive corticosteroid doses may be associated with an ele- vated risk of osteonecrosis. A large trial from the Children’s Oncology Group (CCG-1961) showed that shorter corticosteroid pulses decreased the risk of osteonecrosis despite a higher cumulative dose in adoles- cents.5 This strategy has been widely adopted in other pediatric ALL protocols.6 However, asparaginase has been shown to increase the risk of osteonecrosis especial- ly when administered concurrently with corticos- teroids,1,7 and its administration has been intensified in recent ALL protocols, which contributed to increased sur- vival rates.8 The benefit of shorter pulses dexamethasone on osteonecrosis development in the context of recent asparaginase intensified regimens remains unclear.
The primary aim of this study was to compare the cumulative incidence of osteonecrosis (CION) in children treated with long (Dutch Childhood Oncology Group [DCOG] ALL-9) versus short pulses dexamethasone (asparaginase intensified ALL-10/11 medium risk group [MRG]). The secondary aim was to investigate the asso- ciations between risk factors and osteonecrosis and to assess the characteristics of patients with severe osteonecrosis.
Children aged 1-18 years with newly diagnosed ALL between January 1997 to March 2015 treated according to the DCOG ALL-9 or ALL-10/11 MRG protocol were eligible for this study. Detailed information on patient selection and data collection is provided in the Online Supplementary Appendix. For our primary aim, the CION was estimated from start post-consolidation (landmark analysis), since dexamethasone pulses started from this timepoint onwards. Consent from patients and/or legal guides for data collection had been previously obtained.
Patients were treated with dexamethasone during induction and with long pulses dexamethasone (14 days 6 mg/m2/day every 7 weeks, cumulative dose non-high risk group, 1,370 mg/m2; high risk group, 1,244 mg/m2)
without concurrent asparaginase during post-consolida- tion in ALL-9 (Online Supplementary Table S1). Patients in ALL-10/11 MRG were treated with prednisone during induction and with short pulses dexamethasone (5 days 6 mg/m2/day every 3 weeks, cumulative dose, 1,115 mg/m2) with 18 or 30 weeks concurrent PEG-asparagi- nase (2,500 IU/m2 [ALL-10] or an individualized dose [ALL-11] every 2 weeks) during post-consolidation, resulting in six or ten dexamethasone pulses that were administered concomitantly with PEG-asparaginase.
Osteonecrosis was defined as persistent pain in joints and/or limbs (not resulting from vincristine neuropathy) developed during or in the first year after ALL treatment and confirmed by magnetic resonance imaging (and/or X- ray, see the Online Supplementary Appendix). Severe osteonecrosis was defined as Ponte di Legno (PdL) grade 4 (Online Supplementary Table S2) in ALL-10/11 MRG.9
The CION since start post-consolidation therapy was estimated for patients treated in ALL-10/11 MRG versus ALL-9 using competing risk models with stem cell trans- plantation, second malignancy, relapse and death as com- peting event. In this analysis, only the subset of patients who reached post-consolidation per protocol was includ- ed. The CION since ALL diagnosis was estimated for dif- ferent age categories in the total cohort. Fine and Gray’s test was used to assess the difference between the CION. A univariable and multivariable Cox proportional hazard regression model was used to estimate the effect of risk factors on osteonecrosis (see the Online Supplementary Appendix for details).
Of 1,612 patients eligible for ALL-9 (n=886) and ALL- 10/11 MRG (n=726), 1,470 (91%) were included in this study (Online Supplementary Figure S1). Thirteen hundred eighty-four (94%) of these patients reached the start of post-consolidation therapy per protocol and were includ- ed in the landmark analysis. The baseline characteristics of patients treated in ALL-9 versus ALL-10/11 MRG were not significantly different (Online Supplementary Table S3).
In total, 79 (5%) of 1,470 patients developed osteonecrosis during the study. Thirty-six (5%) of 731 children in ALL-9 and 38 (6%) of 652 children in ALL- 10/11 MRG who were included in the landmark analysis developed osteonecrosis, respectively. No statistically significant difference between the CION since start post- consolidation therapy for the two groups was found (P=0.54, Figure 1); at 3 years since the start of post-con- solidation therapy, the CION was 4.9% (95% Confidence Interval [CI]=3.4-6.5) and 5.4% (95% CI=3.6-7.1) in ALL-9 versus ALL-10/11 MRG, respective- ly. In addition, the CION since ALL diagnosis was esti- mated, which showed no statistically significant differ- ence (P=0.80, Online Supplementary Figure S2).
Table 1. Cause-specific hazard ratio estimates along with their 95% Confidence Intervals for the risk of symptomatic osteonecrosis since start post-consolidation therapy from a univariable and multivariable Cox proportional hazard regression model.
Univariable model n=1,383
HRcs 95% CI
1.21 0.76-1.92
1.38 1.30-1.46
1.18 0.75-1.87
1.01 0.82-1.24
P HRcs 0.416 0.69
<0.001 1.40
0.479 1.53
0.942 0.90
Multivariable model n=1,383
95%CI P
Post-consolidation regimen (ALL-10/11 MRG vs. ALL-9) Age (yrs)
Sex (male vs. female)
BMI (SDS)
0.43-1.11
1.32-1.49
0.97-2.44
0.73-1.10
0.123
<0.001
0.070
0.289
1198
ALL: acute lymphoblastic leukemia; BMI: body mass index; CI: Confidence Interval; DEXA: dexamethasone; HRCS: cause-specific hazard ratio; MRG: medium risk group; SDS: standard deviation score; yrs: years.
haematologica | 2021; 106(4)