Clinical significance of low levels of minimal residual disease at the end of remission induction therapy in childhood acute lymphoblastic leukemia

Abstract

Minimal residual disease (MRD) at the end of remission-induction therapy predicts relapse in acute lymphoblastic leukemia (ALL). We examined the clinical significance of levels below the usual threshold value for MRD positivity (0.01%) in 455 children with B-lineage ALL, using polymerase chain reaction amplification of antigen-receptor genes capable of detecting at least 1 leukemic cell per 100 000 normal mononucleated cells (0.001%). Of the 455 clinical samples studied on day 46 of therapy, 139 (30.5%) had MRD 0.001% or more with 63 of these (45.3%) showing levels of 0.001% to less than 0.01%, whereas 316 (69.5%) had levels that were either less than 0.001% or undetectable. MRD measurements of 0.001% to less than 0.01% were not significantly related to presenting characteristics but were associated with a poorer leukemia cell clearance on day 19 of remission induction therapy. Patients with this low level of MRD had a 12.7% (+/- 5.1%; SE) cumulative risk of relapse at 5 years, compared with 5.0% (+/- 1.5%) for those with lower or undetectable MRD (P < .047). Thus, low levels of MRD (0.001%-< 0.01%) at the end of remission induction therapy have prognostic significance in childhood ALL, suggesting that patients with this finding should be monitored closely for adverse events.

Figure 1

Day 19 MRD levels by flow cytometry in 3 patient cohorts defined according to day 46 MRD levels by PCR. The size of each cohort is given within the diagram. Horizontal bars represent median values. Levels of minimal residual disease (MRD) on day 19 were significantly different in the 3 groups (P < .001 by Kruskal-Wallis 1-way analysis of variance test).

Figure 2

Cumulative incidence of relapse (mean ± SE) among 379 children with B-lineage ALL whose MRD levels were less than 0.01% on day 46 (end of remission induction therapy). Patients with MRD 0.001% to less than 0.01% had a significantly higher incidence of relapse than those with lower levels or undetectable MRD by PCR.