Clinical importance of minimal residual disease in childhood acute lymphoblastic leukemia

Abstract

By using rapid flow cytometric techniques capable of detecting one leukemic cell in 104 normal cells, we prospectively studied minimal residual disease (MRD) in 195 children with newly diagnosed acute lymphoblastic leukemia (ALL) in clinical remission. Bone marrow aspirates (n = 629) were collected at the end of remission induction therapy and at 3 intervals thereafter. Detectable MRD (ie, ≥0.01% leukemic mononuclear cells) at each time point was associated with a higher relapse rate (P < .001); patients with high levels of MRD at the end of the induction phase (≥1%) or at week 14 of continuation therapy (≥0.1%) had a particularly poor outcome. The predictive strength of MRD remained significant even after adjusting for adverse presenting features, excluding patients at very high or very low risk of relapse from the analysis, and considering levels of peripheral blood lymphoblasts at day 7 and day 10 of induction therapy. The incidence of relapse among patients with MRD at the end of the induction phase was 68% ± 16% (SE) if they remained with MRD through week 14 of continuation therapy, compared with 7% ± 7% if MRD became undetectable (P = .035). The persistence of MRD until week 32 was highly predictive of relapse (all 4 MRD+patients relapsed vs 2 of the 8 who converted to undetectable MRD status; P = .021). Sequential monitoring of MRD by the method described here provides highly significant, independent prognostic information in children with ALL. Recent improvements in this flow cytometric assay have made it applicable to more than 90% of all new patients.

Determination of minimal residual disease in leukaemia patients

“…In the studies outlined above, the prognostic value of MRD was independent of that of other known clinical and biological prognosticators of outcome. In our study, MRD remained a significant predictor in analyses that excluded patients at very high or very low risk of relapse by St Jude criteria, or that focused on patients with high risk of relapse by the criteria defined by the National Cancer Institute (Coustan-Smith et al, 2000;Pui et al, 2001). In the International BFM (I-BFM) study, MRD was also a strong predictor of outcome in children with medium-risk features (Biondi et al, 2000).…”

“…Cumulative incidence of relapse according to MRD in childhood ALL. MRD was measured by flow cytometry at d 19 of remission induction therapy, at the end of remission induction therapy (d 46), and at weeks 14 and 32 of continuation therapy(Coustan-Smith et al, 2000. Solid lines indicate patients with residual disease detectable by flow cytometry; broken lines indicate residual-disease-negative patients.…”

Augmented Berlin‐Frankfurt‐Münster therapy in adolescents and young adults (AYAs) with acute lymphoblastic leukemia (ALL)

“…Molecular or flow cytometry studies measuring MRD have strongly predicted for relapse in pediatric ALL studies. [19][20][21][22][23][24][25] In AYAs with ALL, MRD status at the end of induction therapy also has been associated with differences in survival. 26,27 In our study, a negative MRD status by multicolor flow cytometry on days 29 and day 84 was associated with improved survival (Table 3).…”

Prognostic impact of absolute lymphocyte counts at the end of remission induction in childhood acute lymphoblastic leukemia

“…6 The level of minimal residual disease (MRD) during and after remission induction chemotherapy is the strongest prognostic factor in childhood ALL. [10][11][12][13] MRD is an independent predictor of outcome and can define risk subgroups among clinically or genetically defined ALL subtypes. In the St. Jude Total XV study for children and adolescents with newly diagnosed ALL, we incorporated MRD measurements in risk-classification algorithms and used them to guide therapy, a strategy that resulted in 5-year EFS and OS rates of 85.6% and 93.5%, respectively.…”