Prognostic significance of minimal residual disease in high risk B-ALL: a report from Children's Oncology Group study AALL0232

Abstract

Minimal residual disease (MRD) is highly prognostic in pediatric B-precursor acute lymphoblastic leukemia (B-ALL). In Children's Oncology Group high-risk B-ALL study AALL0232, we investigated MRD in subjects randomized in a 2 × 2 factorial design to receive either high-dose methotrexate (HD-MTX) or Capizzi methotrexate (C-MTX) during interim maintenance (IM) or prednisone or dexamethasone during induction. Subjects with end-induction MRD ≥0.1% or those with morphologic slow early response were nonrandomly assigned to receive a second IM and delayed intensification phase. MRD was measured by 6-color flow cytometry in 1 of 2 reference labs, with excellent agreement between the two. Subjects with end-induction MRD <0.01% had a 5-year event-free survival (EFS) of 87% ± 1% vs 74% ± 4% for those with MRD 0.01% to 0.1%; increasing MRD amounts was associated with progressively worse outcome. Subjects converting from MRD positive to negative by end consolidation had a relatively favorable 79% ± 5% 5-year disease-free survival vs 39% ± 7% for those with MRD ≥0.01%. Although HD-MTX was superior to C-MTX, MRD retained prognostic significance in both groups (86% ± 2% vs 58% ± 4% for MRD-negative vs positive C-MTX subjects; 88% ± 2% vs 68% ± 4% for HD-MTX subjects). Intensified therapy given to subjects with MRD >0.1% did not improve either 5-year EFS or overall survival (OS). However, these subjects showed an early relapse rate similar to that seen in MRD-negative ones, with EFS/OS curves for patients with 0.1% to 1% MRD crossing those with 0.01% to 0.1% MRD at 3 and 4 years, thus suggesting that the intensified therapy altered the disease course of MRD-positive subjects. Additional interventions targeted at the MRD-positive group may further improve outcome. This trial was registered at www.clinicaltrials.gov as #NCT00075725.

Figure 1

Schematic of study design for treatment on AALL0232. See text for details.

Figure 2

EFS of subjects with HR ALL treated on AALL0232 as a function of MRD levels at end of induction. (A) Five-year EFS for patients with <0.01% MRD was 87% ± 1%, 74% ± 4% for those between 0.01% and 0.1%, 63% ± 4% for those between 0.1% and 1%, 44% ± 9% for those between 1% and 10%, and 26% ± 9% for those >10%. The early outcome for subjects with 0.1% to 1% MRD is superior to that of subjects with lower levels of MRD, likely reflecting the effect of intensified therapy, though the curves cross at ∼3 years (dotted line), and the overall outcome of this group is inferior to those with less MRD. (B) OS of subjects whose EFS was shown in panel A. The curves for OS in the cohort of subjects with 0.1% to 1% MRD again crosses that of those with lower MRD levels, but the time of the cross is delayed by ∼1 year. (C) EFS of subjects with 0.1% to 1% MRD as a function of the location of their MRD testing. The unusual shape of this curve is identical in the 2 sites.

Figure 3

DFS of patients with HR ALL as a function of MRD at end of consolidation. This figure displays DFS instead of EFS, because only those patients continuing on protocol therapy after induction (or extended induction) are included. Only subjects who were slow early responders at end induction had a second sample obtained, but this graph displays results only for those who were MRD positive at day 29. The 5-year DFS of subjects who cleared their MRD was quite good at 79% ± 5%, whereas those who were persistently positive had only a 39% ± 7% 5-year DFS.

Figure 4

Prognostic significance of very low levels of MRD. In ∼10% of cases that were considered MRD negative (at 0.01%), a few events with an abnormal phentoype were detected, though quantitation of such a small population is not accurate. The EFS of such subjects was slightly poorer than that of those who were completely negative by flow cytometry (5-year EFS, 81% ± 3% vs 88% ± 1%).