Outstanding Outcome for Children with Standard Risk-Low (SR-Low) Acute Lymphoblastic Leukemia (ALL) and No Benefit to Intensified Peg-Asparaginase (PEG-ASNase) Therapy: Results of Children’s Oncology Group (COG) Study AALL0331
Authors: Mattano Leonard A. , Devidas Meenakshi , Friedmann Alison M. , Raetz Elizabeth A. , Loh Mignon , Buckley Patrick , Borowitz Michael J. , Carroll Andrew J. , Gastier-Foster Julie , Heerema Nyla A. , Kadan-Lottick Nina , Matloub Yousif , Marshall David T , Stork Linda C. , Wood Brent L. , Winick Naomi J. , Hunger Stephen , Carroll William L. , Maloney Kelly 
Published: October 2019

Introduction: Overall, children with new-onset SR (age 1-9 years (yr), WBC <50,000/microliter) B-ALL enrolled on COG AALL0331 achieved excellent 5-yr event free (EFS) (89%) and overall survival (OS) (96%) (Maloney, ASH 2013). AALL0331 utilized a common 3-drug induction (IND), with post-IND assignment into refined risk groups per clinical, cytogenetic, and early response criteria. The SR-Low group was defined by favorable cytogenetics (triple trisomies of chromosomes 4+10+17 or ETV6-RUNX1), no central nervous system or testicular leukemia, and rapid marrow response (<5% blasts by day (d) 15 and end-IND minimal residual disease (MRD) <0.1%). Given an expected EFS >90%, the study sought to improve outcome in this group without adding significant toxicity. Published data had shown that hyperdiploid B-ALL blasts and those with the ETV6-RUNX1 fusion have enhanced in vitro ASNase sensitivity, and ASNase intensification had been effective and well tolerated in several pediatric trials. Thus, AALL0331 randomized SR-Low patients (pts) to standard post-IND therapy with or without 4 additional doses of PEG-ASNase given at 3-week intervals during consolidation (CON) and interim maintenance (IM). We now report the efficacy results for this group.

Methods: AALL0331 enrolled 5377 SR-ALL pts from 4/2005-5/2010. All pts received standard IND (vincristine (VCR), dexamethasone (DEX), PEG-ASNase, intrathecal methotrexate (IT MTX)). At end-IND, 1857 pts meeting SR-Low criteria were randomized to one of two regimens, Low Risk Standard (LRS) or Low Risk ASNase (LRA), with identical CON (mercaptopurine (MP) 75 mg/M2 d1-28, VCR 1.5 mg/M2d1, IT MTX d1,8,15) and IM (DEX d1-5,29-33, MP d1-50, oral MTX weekly x8, IT MTX d29) phases except for additional PEG-ASNase (2500 IU/M2/dose) in LRA (CON d1,22 and IM d15,36). Subsequent delayed intensification (DI) and maintenance (MTC) phases were identical. After 6/2008, based on CCG-1991 SR-ALL efficacy analyses, the IM backbone was changed to escalating dose intravenous (IV) MTX (VCR d1,11,21,31,41, MTX d1,11,21,31,41, IT MTX d31) in both regimens (LRS-IV and LRA-IV).

Results: The 5-yr continuous complete remission (CCR) and OS rates (SE) for SR-Low pts (n=1857) were 95.2% (0.6) and 98.8% (0.3). Consistent with the results of CCG-1991, the 3-yr EFS was numerically higher with IV MTX (99.0% (0.4) vs 97.0% (0.5), p=0.16) but the difference did not reach statistical significance. PEG-ASNase intensification did not significantly improve outcome, with 5-yr CCR rates for LRA/LRA-IV vs LRS/LRS-IV of 96.0% (0.8) vs 94.4% (1.0) (p=0.1), and 5-yr OS rates of 98.3% (0.6) vs 99.3% (0.4) (p=0.05). Comparing pts randomized pre/post the IV MTX amendment, no advantage to PEG-ASNase intensification was observed with either the oral (5-yr EFS: LRA 96.0% (0.8) vs LRS 93.8% (1.0), p=0.2) or the IV MTX based IM regimens (3-yr EFS: LRA-IV 99.0% (0.6) vs LRS-IV 99.0% (0.6), p=0.9). Using more current COG MRD definitions for low risk ALL (d8 peripheral blood MRD <1% and d29 marrow MRD <0.01%), the 5-yr EFS/OS for SR-Low patients were 96.4% and 98.8%. Treatment-related adverse events were uncommon but occurred more frequently with PEG intensification. As of 12/31/2013 there were 72 relapses, 13 deaths in remission, and 4 second malignancies.

Conclusions: Data from AALL0331 show that, using sentinel genetic lesions and MRD response, about 35% of SR B-ALL patients meet LR criteria and are almost certain to be cured using a low intensity regimen comprised of a 3-drug IND and post-IND therapy without intensive consolidation or high dose MTX, an approach that limits the cumulative doses of anthracyclines (75 mg/m2) and alkylating agents (1000 mg/m2).

Disclosures

Borowitz: Becton Dickinson Biosciences: Research Funding. Hunger:Sigma Tau Pharmaceuticals: Honoraria; Jazz Pharmaceuticals: Honoraria.