Outcome in Children With Standard-Risk B-Cell Acute Lymphoblastic Leukemia: Results of Children's Oncology Group Trial AALL0331

Abstract

Purpose: Children's Oncology Group (COG) AALL0331 tested whether intensified postinduction therapy that improves survival in children with high-risk B-cell acute lymphoblastic leukemia (ALL) would also improve outcomes for those with standard-risk (SR) ALL.

Patients and methods: AALL0331 enrolled 5,377 patients between 2005 and 2010. All patients received a 3-drug induction with dexamethasone, vincristine, and pegaspargase (PEG) and were then classified as SR low, SR average, or SR high. Patients with SR-average disease were randomly assigned to receive either standard 4-week consolidation (SC) or 8-week intensified augmented Berlin-Frankfurt-Münster (BFM) consolidation (IC). Those with SR-high disease were nonrandomly assigned to the full COG-augmented BFM regimen, including 2 interim maintenance and delayed intensification phases.

Results: The 6-year event-free survival (EFS) rate for all patients enrolled in AALL0331 was 88.96% ± 0.46%, and overall survival (OS) was 95.54% ± 0.31%. For patients with SR-average disease, the 6-year continuous complete remission (CCR) and OS rates for SC versus IC were 87.8% ± 1.3% versus 89.1% ± 1.2% (P = .52) and 95.8% ± 0.8% versus 95.2% ± 0.8% (P = 1.0), respectively. Those with SR-average disease with end-induction minimal residual disease (MRD) of 0.01% to < 0.1% had an inferior outcome compared with those with lower MRD and no improvement with IC (6-year CCR: SC, 77.5% ± 4.8%; IC, 77.1% ± 4.8%; P = .71). At 6 years, the CCR and OS rates among 635 nonrandomly treated patients with SR-high disease were 85.55% ± 1.49% and 92.97% ± 1.08%, respectively.

Conclusion: The 6-year OS rate for > 5,000 children with SR ALL enrolled in AALL0331 exceeded 95%. The addition of IC to treatment for patients with SR-average disease did not improve CCR or OS, even in patients with higher MRD, in whom it might have been predicted to provide more value. The EFS and OS rates are excellent for this group of patients with SR ALL, with particularly good outcomes for those with SR-high disease.

FIG 1.

CONSORT diagram. *Incorrect consent/missing informed consent at study entry (12), incorrect diagnosis (12), incorrect timing to the start of therapy (12), no/insufficient samples (11), no testicular exam prior to enrollment (5), ineligible for classification study (4), received prior therapy before enrolling on this study (3), IRB record issues (3), started therapy prior to enrolling on classification study (2), samples not sent to an approved cytogenetics lab (2), no CNS status determined at enrollment (2), no repeat diagnostic marrow within a week prior to enrollment (1), no signature on the short consent in patient’s native language (1). COG, Children’s Oncology Group; HR, high risk; IA, IC with AIM and ADI; IS, IC and standard IM/DI; LRA, low-risk with additional doses of pegaspargase; LRS, low-risk standard; LTFU, lost to follow-up; SA, SC with AIM and ADI; SMN, second malignant neoplasm; SS, SC and standard DI/IM.

FIG 2.

Event-free survival (EFS) and overall survival (OS; 6-year EFS, 88.96% ± 0.46%; 6-year OS, 95.54% ± 0.31%).

FIG 3.

Random assignment of patients in standard-risk average (SR-average) group by consolidation regimen. Comparison of (A) complete continuous remission (CCR; 6-year CCR for standard consolidation [SC], 87.8% ± 1.3% v 89.1% ± 1.2% for intensive consolidation [IC]; P = .52) and (B) overall survival (OS) rates (6-year OS, 95.78% ± 0.79% for SC v 95.15% ± 0.83% for IC; P = 1.0).

FIG 4.

In standard-risk high (SR-high) group, (A) complete continuous remission (CCR; 6-year CCR, 85.55% ± 1.49%) and (B) overall survival (OS) rates (6-year OS, 92.97% ± 1.08%).

FIG A1.

Standard-risk average group: limited to those with day-8 minimal residual disease (MRD) < 1% and day-29 MRD < 0.01% by consolidation regimen. (A) Complete continuous remission (CCR; 6-year CCR for standard consolidation [SC] v intensified consolidation [IC], 90.8% ± 1.9% v 91.6% ± 1.8%; P = .99) and (B) overall survival (OS) rates (6-year OS for SC v IC, 97.62% ± 1.01% v 97.36% ± 1.03%; P = .655).

FIG A2.

Standard-risk average group (6-year complete continuous remission [CCR] limited to those with day-8 minimal residual disease [MRD] < 1% and day-29 MRD < 0.01%) by (A) consolidation regimen before amendment 2C (88.48% ± 3.13% v 93.46% ± 2.33%; P = .31) and (B) consolidation regimen after amendment 2C (92.78% ± 2.35% v 90.05% ± 2.63%; P = .35).