Excellent Event Free (EFS) and Overall Survival (OS) For Children With Standard Risk Acute Lymphoblastic Leukemia (SR ALL) Despite The Absence Of a Significant Impact On Outcome With The Addition Of An Intensified Consolidation: Results Of Children’s Oncology Group (COG) AALL0331

The EFS/OS for SR (age 1-9.99 yrs and initial white blood cell count <50,000/microliter) B-cell precursor (B-ALL) patients (pts) has steadily improved over time. The COG AALL0331 SR ALL trial utilized a 3 drug induction without anthracylines, with post-induction assignment into refined risk groups (SR-Low, SR-Average (Av), SR-High) based on leukemia genetics and early response. COG studies have shown that intensified post-induction therapy improved EFS/OS in NCI high risk ALL patients <10 yrs of age; however, the relative value of individual components is uncertain. AALL0331 included a 2 X 2 randomization at end-induction to standard (SC) vs. intensified consolidation (IC) and standard interim maintenance (IM) / delayed intensification (DI) vs. intensified IM/DI for SR-Av (not Low or High) pts, defined as those whose leukemic blasts did not show triple trisomies (TT) of chromosomes 4+10+17, ETV6-RUNX1, or very high risk features and had an excellent early response based on day 8 (or 15) M1 (<5% blasts) bone marrow (BM) and end-induction minimal residual disease (MRD) <0.1%. The IM/DI randomization was closed in 2008 due to superior results of escalating IV methotrexate (MTX) during IM for SR ALL pts treated on CCG 1991; all pts subsequently received escalating IV MTX during IM.

AALL0331 enrolled 5311 SR B-ALL pts from 4/2005-5/2010. All patients received a 3 drug induction (dexamethasone, vincristine (VCR), PEG-asparaginase (PEG), intrathecal (IT) MTX). SR-Av pts were randomized at end-induction between SC (mercaptopurine (MP) 75 mg/m² d 1-28, VCR 1.5 mg/m² d 1, IT MTX d 1, 8, 15) vs. IC (cyclophosphamide 1000 mg/m² d 1,29, cytarabine 75 mg/m² d 1-4, 8-11, 29-32, 36-39, MP 60 mg/m² d 1-14, 29-42, VCR 1.5 mg/m² d 15, 22, 43, 50, PEG 2500 units/m² d 15, 43, IT MTX d 1, 8, 15, 22). Therapy following consolidation was the same for all SR-Av pts after 2008.

The 5-yr EFS/OS for all evaluable SR B-ALL pts was 89% and 96% (see Table 1). IC did not significantly improve outcome for SR Av pts, with 5-yr continuous complete remission (CCR) rates for SC vs. IC of 88% (1.6%) vs. 89.3% (1.5%) (p=0.13) and 5-yr OS rates for SC vs. IC of 95.8% (1.0%) vs. IC 95.7% (1.0%) (p=0.93). Because COG has now shown that end-induction MRD of 0.01% is a better discriminator of poor outcome than the 0.1% level used in AALL0331, we examined overall outcome and the results of the randomized intervention in two different MRD defined subsets of SR-Av pts (Table 1). The 5-yr CCR rates for pts with MRD 0.01%-<0.1% were 77% (6%) and 76% (6%) for SC and IC (p=0.31) and 89% (1.6%) vs 91.5% (1.5%) for IC (p=0.08) for MRD <0.01%.

The outcome for the 1857 SR-Low pts (TT or ETV6-RUNX1 plus d 8 (or 15) M1 BM and d 29 MRD <0.1%) was outstanding, with 5-yr EFS/OS of 95% and 99%. SR-High pts (d 15 BM ≥5% blasts and/or d 29 MRD ≥0.1%) who were non-randomly assigned to IC and 2 intensified IM/DI phases did very well with 5-yr EFS/OS 85% and 94%. The 5-yr EFS for this group (85%) was much better than that of SR Av pts (77%) with MRD 0.01-<0.1% who received less intensive therapy, emphasizing the benefit of intensifying treatment for pts with MRD >0.01% that is now part of all COG protocols. COG AALL0331 is the largest trial of SR B-ALL pts ever conducted and establishes the value of risk directed treatment intensification.