Favorable Trisomies and ETV6-RUNX1 Predict Cure in Low-Risk B-Cell Acute Lymphoblastic Leukemia: Results From Children's Oncology Group Trial AALL0331

Abstract

Purpose: Children's Oncology Group (COG) AALL0331 tested whether pegaspargase intensification on a low-intensity chemotherapy backbone would improve the continuous complete remission (CCR) rate in a low-risk subset of children with standard-risk B-acute lymphoblastic leukemia (ALL).

Methods: AALL0331 enrolled 5,377 patients with National Cancer Institute standard-risk B-ALL (age 1-9 years, WBC < 50,000/μL) between 2005 and 2010. Following a common three-drug induction, a cohort of 1,857 eligible patients participated in the low-risk ALL random assignment. Low-risk criteria included no extramedullary disease, < 5% marrow blasts by day 15, end-induction marrow minimal residual disease < 0.1%, and favorable cytogenetics (ETV6-RUNX1 fusion or simultaneous trisomies of chromosomes 4, 10, and 17). Random assignment was to standard COG low-intensity therapy (including two pegaspargase doses, one each during induction and delayed intensification) with or without four additional pegaspargase doses at 3-week intervals during consolidation and interim maintenance. The study was powered to detect a 4% improvement in 6-year CCR rate from 92% to 96%.

Results: The 6-year CCR and overall survival (OS) rates for the entire low-risk cohort were 94.7% ± 0.6% and 98.7% ± 0.3%, respectively. The CCR rates were similar between arms (intensified pegaspargase 95.3% ± 0.8% v standard 94.0% ± 0.8%; P = .13) with no difference in OS (98.1% ± 0.5% v 99.2% ± 0.3%; P = .99). Compared to a subset of standard-risk study patients given identical therapy who had the same early response characteristics but did not have favorable or unfavorable cytogenetics, outcomes were significantly superior for low-risk patients (CCR hazard ratio 1.95; P = .0004; OS hazard ratio 5.42; P < .0001).

Conclusion: Standard COG therapy without intensified pegaspargase, which can easily be given as an outpatient with limited toxicity, cures nearly all children with B-ALL identified as low-risk by clinical, early response, and favorable cytogenetic criteria.

FIG 1.

CONSORT diagram for risk-stratified therapy. Reasons for ineligibility (n = 70) included missing or incorrect consent (n = 12), incorrect diagnosis (n = 12), incorrect timing to start of therapy (n = 12), no or insufficient samples (11), no testicular exam before enrollment (n = 5), ineligible for classification study (n = 4), prior therapy before enrollment (n = 3), institutional review board record issues (n = 3), started therapy before enrollment on classification study (n = 2), samples not sent to an approved cytogenetics lab (n = 2), no CNS status determined at enrollment (n = 2), no repeat diagnostic marrow within 1 week before enrollment (n = 1), and no signature on the short consent in patient's native language (n = 1). Regimens LRS and LRA include post-amendment patient cohorts LRS with IV methotrexate and LRA with IV methotrexate, respectively. Regimens SS, IS, SA, and IA include standard versus intensified consolidation and standard versus augmented interim maintenance. Regimen SS includes post-amendment patient cohort SS with IV methotrexate. COG, Children's Oncology Group; IA, intensified consolidation and augmented interim maintenance; IS, intensified consolidation and standard interim maintenance; IV, intravenous; LRA, low risk with intensified pegaspargase; LRS, low risk standard; LTFU, lost to follow-up; SA, standard consolidation and augmented interim maintenance; SMN, second malignant neoplasm; SR, standard risk; SS, standard consolidation.

FIG 2.

CCR and OS curves. (A) CCR and OS curves for the entire standard-risk (SR)-low population. Six-year CCR and OS rates were 94.7% ± 0.6% and 98.7% ± 0.3%, respectively. (B) CCR curves for standard (LRS, LRS with IV methotrexate [LRS-IV]) versus intensified pegaspargase (LRA, LRA with IV methotrexate [LRA-IV]) randomly assigned cohorts. Six-year CCR rates were 94.0% ± 0.8% and 95.3% ± 0.8%, respectively. (C) OS curves for standard (LRS, LRS-IV) versus intensified pegaspargase (LRA, LRA-IV) randomly assigned cohorts. Six-year OS rates were 99.2% ± 0.3% and 98.1% ± 0.5%, respectively. (D) CCR curves for LRS versus LRA randomly assigned regimens. Six-year CCR rates were 92.9% ± 1.1% and 95.3% ± 0.9%, respectively. (E) OS curves for LRS versus LRA randomly assigned regimens. Six-year OS rates were 99.0% ± 0.4% and 97.9% ± 0.6%, respectively. CCR, continuous complete remission; IV, intravenous; LRA, low risk with intensified pegaspargase; LRS, low risk standard; OS, overall survival.

FIG 3.

Survival comparisons for SR-low and SR-average cohorts. (A) CCR curves for SR-low (LRS and LRS-IV) versus SR-average (SS and SS-IV) randomly assigned standard therapy cohorts. Analysis only includes patients in the SR-average population who met all SR-low criteria except for favorable cytogenetics. Six-year CCR rates were 94.0% ± 0.8% versus 88.6% ± 1.7%, respectively. (B) OS curves for SR-low (LRS and LRS-IV) versus SR-average (SS and SS-IV) randomly assigned standard therapy cohorts. Six-year OS rates were 99.2% ± 0.3% versus 96.1% ± 1.0%, respectively. CCR, continuous complete remission; IV, intravenous; LRS, low risk standard; LRS-IV, LRS with IV methotrexate; OR, overall survival; SR, standard risk; SS, standard consolidation and standard interim maintenance.

FIG A1.

CCR in SR-low patients with day 8 versus day 15 M1 marrow and day 29 MRD < 0.1%. Six-year CCR for SR-low patients with day 8 M1/day 29 MRD < 0.1% versus day 15 M1/day 29 MRD < 0.1% were 95.7% ± 0.7% versus 93.8% ± 0.8%, respectively. CCR, continuous complete remission; MRD, minimal residual disease; SR, standard risk.

FIG A2.

CCR and OS in SR-low patients with day 8 PB MRD < 0.01% and day 29 marrow MRD < 0.01%. Six-year CCR and OS for SR-low patients with day 8 PB MRD < 0.01% were 96.3% ± 1.4% and 98.6% ± 0.8%, respectively. CCR, continuous complete remission; MRD, minimal residual disease; OS, overall survival; PB, peripheral blood; SR, standard risk.

FIG A3.

CCR and OS in SR-low patients with day 8 PB MRD ≥ 0.01% and day 29 marrow MRD < 0.01%. Six-year CCR and OS for SR-low patients with day 8 PB MRD ≥ 0.01% and day 29 MRD < 0.01% were 94.8% ± 0.9% and 99.1% ± 0.4%, respectively. CCR, continuous complete remission; MRD, minimal residual disease; OS, overall survival; PB, peripheral blood; SR, standard risk.