Effect of High-Dose Methotrexate (HD-MTX) Vs Capizzi Methotrexate/Pegaspargase (C-MTX/ASNase) on Osteonecrosis (ON) Incidence in Children and Young Adults with T-Acute Lymphoblastic Leukemia (T-ALL): Results of Children’s Oncology Group (COG) Study AALL0434
Authors: Mattano Leonard A. , Devidas Meenakshi , Chen Si , Esiashvili Natia , Asselin Barbara , Winick Naomi J. , Loh Mignon , Raetz Elizabeth A , Hunger Stephen , Carroll William L. , Winter Stuart S. , Dunsmore Kimberly P. 
Published: October 2019

Introduction: Augmented post-induction (IND) intensification therapy improved event free (EFS) and overall survival (OS) among patients (pts) 1-20 years (yr) with NCI high-risk (HR) B- and T-ALL on CCG-1961 (Seibel, Blood 2008) but was associated with significant ON (Mattano, Lancet Oncol 2012). Successor COG trials for HR B-ALL (AALL0232) and T-ALL (AALL0434) have investigated modifications of augmented therapy to further improve outcome and reduce ON risk. HD-MTX delivered during interim maintenance (IM) provided an EFS advantage over escalating dose (Capizzi) MTX/ASNase on AALL0232 (Larsen, ASCO 2011) and confirmed a lower ON incidence with alternate-week (AWD) vs continuous (CD) dexamethasone (DEX) during delayed intensification (DI) (Mattano, ASH 2012). Additionally, ON incidence was lower among pts 10+ yr receiving IND prednisone (PDN) vs DEX, especially those randomized to HD-MTX. We now report results for ON incidence among T-ALL pts receiving comparable therapy on AALL0434.

Methods: AALL0434 opened 1/2007 and completed accrual 7/2014, with 1155 evaluable T-ALL pts 1-30 yr included in this report (data freeze 6/30/2014). All pts received standard 4-drug IND (vincristine, PDN 60 mg/M2 days 1-28, pegaspargase, daunorubicin, intrathecal MTX). Following IND, pts received augmented therapy with a 2x2 randomization to HD-MTX vs C-MTX/ASNase (during a single IM phase) with or without six 5-day (d) courses of nelarabine (NEL) (during consolidation (CON), DI, and MTC cycles 1-3). Pts meeting low-risk (LR) criteria (age 1-9 yr, WBC <50,000/microliter, no central nervous system or testicular leukemia, and rapid marrow response (<5% blasts by d15 and end-IND minimal residual disease <0.1%)) were not eligible for the NEL randomization. Initially, pts 1-9 yr received CD (10 mg/M2 d1-21) during DI, and all pts received DEX pulses (6 mg/M2 d1-5) every 28d during MTC. After 9/2008, based on AALL0232 ON interim analyses, all pts received AWD (d1-7,15-21) during DI and PDN pulses (40 mg/M2 d1-5) during MTC. To accommodate drug scheduling, pegaspargase dose intervals were increased on NEL regimens during CON and DI by 7-14d, CON was extended by 21d, and 3 fewer steroid pulses were given during MTC cycles 1-3. MTC duration was 1 yr longer for males.

Results: Among 1155 evaluable pts (617 with 36+ months follow-up), 69 (6%) developed imaging-confirmed ON (58/527 (11%) 10+ yr, 11/628 (2%) 1-9 yr; 54/861 (6%) males, 15/294 (5%) females). Symptom onset was pre-MTC in 13%, during MTC in 86%, after therapy completion in 1%, and within 36 months in 93%. Maximum reported ON clinical severity (CTCAE v4.0) was 11.6% grade 1, 60.9% grade 2, 27.5% grade 3. The overall 36-month ON cumulative incidence was 8.0±1.2% and was higher for pts 10+ yr (14.6±2.3 vs 2.6±1.0%, RHR 5.7, p<0.0001). Males 10+ yr had a numerically higher ON incidence that was not statistically significant (15.5±2.7 vs 10.9±4.8, RHR 1.4, p=0.4). Higher ON rates were seen among pts randomized to C-MTX/ASNase or HD-MTX without NEL (Table). Among pts 13+ yr treated without NEL, ON rates for C-MTX/ASNase (26.4±5.8%) and HD-MTX (23.0±6.2%) were similar to those seen in comparably treated B-ALL pts on AALL0232 regimens PC (18.9±2.7%) and PH (17.3±2.5%).

Conclusions: T- and B-lineage ALL pts are at similar overall risk for developing ON when given comparable therapy, particularly those age 10+ yr. Increased pegaspargase exposure likely contributes to the increased ON rates seen with C-MTX/ASNase in both populations, whereas longer intervals between pegaspargase doses and fewer steroid pulses during early MTC appear associated with significantly lower rates for T-ALL pts on NEL regimens. Unlike B-ALL, the observed higher rate among males may be due to the expected T-ALL gender imbalance and resulting low numbers of female pts. AWD during DI is now considered standard care for all ALL populations on COG ALL trials. ON will continue to be closely monitored through completion of this trial.

Table: Randomized Regimens, 36-Month Cumulative Incidence Rate (% ± SE) Without Nelarabine With Nelarabine Age (yr) C-MTX/ASNase HD-MTX C-MTX/ASNase HD-MTX P* 1-30 11.6±2.2 8.2±1.9 5.2±4.0 3.2±3.5 0.04 n=363 n=442 n=138 n=171 10-30 20.6±4.0 16.0±3.7 10.2±7.7 6.1±6.2 0.07 n=158 n=185 n=71 n=93

*P value for 4-way comparison of regimens by age cohort

Disclosures

Hunger: Sigma Tau Pharmaceuticals: Honoraria; Jazz Pharmaceuticals: Honoraria.