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Blood, 15 October 2000, Vol. 96, No. 8, pp. 2691-2696
CLINICAL OBSERVATIONS, INTERVENTIONS, AND THERAPEUTIC TRIALS
Clinical importance of minimal residual disease in childhood
acute lymphoblastic leukemia
Elaine Coustan-Smith,
Jose Sancho,
Michael L. Hancock,
James M. Boyett,
Frederick G. Behm,
Susana C. Raimondi,
John T. Sandlund,
Gaston K. Rivera,
Jeffrey E. Rubnitz,
Raul C. Ribeiro,
Ching-Hon Pui, and
Dario Campana
From the Departments of Hematology-Oncology,
Biostatistics and Epidemiology, and Pathology, St Jude Children's
Research Hospital, and University of Tennessee, Memphis, TN.
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.
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