Clinical significance of minimal residual disease in childhood acute lymphoblastic leukemia and its relationship to other prognostic factors: a Children's Oncology Group study

Abstract

Minimal residual disease (MRD) is an important predictor of relapse in acute lymphoblastic leukemia (ALL), but its relationship to other prognostic variables has not been fully assessed. The Children's Oncology Group studied the prognostic impact of MRD measured by flow cytometry in the peripheral blood at day 8, and in end-induction (day 29) and end-consolidation marrows in 2143 children with precursor B-cell ALL (B-ALL). The presence of MRD in day-8 blood and day-29 marrow MRD was associated with shorter event-free survival (EFS) in all risk groups; even patients with 0.01% to 0.1% day-29 MRD had poor outcome compared with patients negative for MRD patients (59% +/- 5% vs 88% +/- 1% 5-year EFS). Presence of good prognostic markers TEL-AML1 or trisomies of chromosomes 4 and 10 still provided additional prognostic information, but not in National Cancer Institute high-risk (NCI HR) patients who were MRD(+). The few patients with detectable MRD at end of consolidation fared especially poorly, with only a 43% plus or minus 7% 5-year EFS. Day-29 marrow MRD was the most important prognostic variable in multi-variate analysis. The 12% of patients with all favorable risk factors, including NCI risk group, genetics, and absence of days 8 and 29 MRD, had a 97% plus or minus 1% 5-year EFS with nonintensive therapy. These studies are registered at www.clinicaltrials.gov as NCT00005585, NCT00005596, and NCT00005603.

Figure 1

EFS of all patients enrolled on 9900 series therapeutic studies with satisfactory end-induction MRD. The 5-year EFS values plus or minus SE are shown for patients with varying levels of MRD. The outcome of those with high levels of MRD is very poor, but even those with 0.01% to 0.1% MRD have only a 59% plus or minus 5% 5-year EFS.

Figure 2

Relapse-free survival showing the effect of end-induction MRD on early and late relapse. (A) Early relapse. (B) Late relapse. MRD positivity is defined as greater than .01%. (A) All patients were censored at 3 years from diagnosis. In addition, all nonrelapse events occurring during the first 3 years were censored. (B) Only patients who were in remission at 3 years from diagnosis are included in the analysis and again, all nonrelapse events are censored.

Figure 3

EFS of NCI SR patients with favorable genetic features. (A) TEL-AML1. (B) Double trisomies. The very few patients with both lesions are included in panel A as a function of end-induction MRD. Outcome of MRD⁺ patients in both groups is much worse than those who are MRD⁻. The 5-year EFS is indicated on each curve as appropriate.

Figure 4

EFS of all patients enrolled in therapeutic studies as a function of level of day-8 PB MRD. There is a stepwise decrement in 5-year EFS at each 10-fold increase in MRD level.

Figure 5

Prognostic significance of day-8 blood MRD in patients who are free of MRD in bone marrow by day 29. Patients with high levels (defined as > 1%) MRD at day 8 fare worse (5-year EFS of 79% ± 4%) than those with lower levels (90% ± 1%), even if they become MRD⁻ by day 29. This difference was especially important in NCI HR patients (see “Results”).

Figure 6

EFS among variably defined groups of good-prognosis patients. NCI SR patients with favorable genetic features who were MRD⁻ at both day 8 and day 29 were the best group, with a 97% plus or minus 1% 5-year EFS. They had statistically better outcomes than either patients without the genetic features who had the same MRD characteristics (92% ± 3%; P = .020) or end-induction MRD⁻, favorable genetic patients who were day-8 MRD⁺ (93% ± 2%; P = .024).

Figure 7

EFS of all patients as a function of level of end-consolidation MRD. Patients who were MRD⁺ (> .01%) had a significantly inferior outcome, with a 5-year EFS of 43% plus or minus 7%. This effect was seen on each of the 3 therapeutic studies (see text). Prognostic significance of end-consolidation MRD in all patients enrolled on therapeutic studies.