Effects of Dexamethasone (DEX) Vs Prednisone (PDN) and High-Dose Methotrexate (HD-MTX) Vs Capizzi Methotrexate/Asparaginase (C-MTX/ASNase) On Osteonecrosis (ON) Incidence in Children and Young Adults with High Risk Acute Lymphoblastic Leukemia (HR-ALL): A Report From the Children's Oncology Group (COG) Study AALL0232

Abstract ⁶⁶⁵

Improved treatment outcomes for HR-ALL are associated with a significant risk of symptomatic ON, particularly in adolescents. Causes are multifactorial, including exposure to DEX, MTX and ASNase. This was first noted on CCG-1882 (1991–1995), which showed more ON in slow early responders (SER) given 2 vs 1 interim maintenance/delayed intensification (IM/DI) phases as part of therapy that included C-MTX/ASNase during IM and continuous DEX (d1-21) during DI (Mattano, JCO 2000). Since 1996 the COG has prospectively monitored the occurrence of symptomatic ON in HR ALL trials. CCG-1961 (1996–2002) showed that alternate-week DEX (AWD) (d1-7, 15–21) during 2 DIs reduced ON compared with continuous DEX during 1 DI in rapid early responders (RER) (Mattano, Lancet Oncol 2012). AALL0232 (2003–2011) enrolled a total of 3154 HR-ALL patients (pts) 1–30 yr and included COG augmented therapy with a 2×2 randomization to DEX (10 mg/M2 d1-14) vs PDN (60 mg/M2 d1-28) during induction (IND) and HD-MTX vs escalating-dose C-MTX plus pegaspargase during IM. RER pts received 1 IM/DI, SER pts received 2 IM/DI; all initially received monthly DEX maintenance (MTC) pulses (6 mg/M2 d1-5). To limit ON, pts 13+ yr received AWD during 1 or 2 DI, while pts <13 yr received continuous DEX. Based on interim analyses, the study was amended twice to address unexpectedly high ON rates. After 10/2006 all pts 10+ yr received AWD during DI; after 6/2008 all pts 10+ yr were non-randomly assigned to PDN during IND, and pts of all ages received AWD during DI and PDN pulses in MTC. Detailed analyses of 2701 pts with reportable data (1405 with 24+ month follow-up) showed ON in 249 pts (228 10+ yr, 21 1–9 yr; 119 males, 130 females). Symptom onset was pre-MTC in 17.7%, during MTC in 77.9%, after therapy completion in 4.4%, and within 36 months from ALL diagnosis in 98.0%. The 36-month cumulative ON incidence was 13.5±1.1%, was higher for pts 10+ yr (19.6±1.6 vs 3.1±0.9%, RHR 6.7, p<0.0001), and increased with age (1–9 yr 3.1±0.9%, 10–12 yr 17.2±2.5%, 13–15 yr 21.9±2.7%, 16+ yr 21.2±3.3%, p<0.0001). For pts 10+ yr, ON incidence was higher in females (22.2±2.5 vs 17.4±2.1%, RHR 1.4, p=0.01). Among randomized RER pts 10+ yr (Table), ON incidence was higher for DEX vs PDN (RHR 1.8); for pts 1–9 yr, rates were similarly low but modestly higher for PDN (borderline significance). There was no difference between C-MTX/ASNase vs HD-MTX overall. However, for pts 10+ yr randomized to PDN, pairwise comparison showed a higher ON rate for C-MTX/ASNase (17.2±3.8 vs 10.3±2.7%, RHR=1.7, p=0.01). Comparison of ON incidences between randomized RER regimens showed significant differences in pts 1–9 yr (DC 1.5±1.4, DH 0.7±1.0, PC 5.6±2.6, PH 1.9±1.6%, p=0.04) and 10+ yr (DC 23.9±4.0, DH 24.7±3.7, PC 20.9±4.0, PH 9.8±2.7%, p=0.0004). Comparison of ON incidences for pts 10–12 yr given continuous DEX vs AWD in DI (pre- vs post-2006 amendment) confirmed a significantly lower rate with AWD (28.9±3.8 vs 10.3±3.1%, RHR 3.1, p<0.0001). Maximum patient ON clinical severity (CTCAE v3.0) reported for 210 of 249 pts: 6.7% grade 1, 63.3% grade 2, 29% grade 3, 1.0% grade 4. The most common sites were knee > hip > ankle. In conclusion, DEX is associated with a higher incidence of ON among pts 10+ yr receiving augmented therapy. Children 1–9 yr appear to tolerate DEX and PDN during IND with similar low ON rates. ON risk can be significantly reduced by using AWD during DI, and by using HD-MTX rather than C-MTX/ASNase with PDN based regimens. Studies are presently underway that include prospective MRI screening to further define the natural history of ON in HR ALL and to identify additional risk factors for this common toxicity.