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Blood, 15 March 2002, Vol. 99, No. 6, pp. 1952-1958
CLINICAL OBSERVATIONS, INTERVENTIONS, AND THERAPEUTIC TRIALS
Prognostic significance and modalities of flow cytometric minimal
residual disease detection in childhood acute lymphoblastic
leukemia
Michael N. Dworzak,
Gertraud Fröschl,
Dieter Printz,
Georg Mann,
Ulrike Pötschger,
Nora Mühlegger,
Gerhard Fritsch, and
Helmut Gadner for the Austrian
Berlin-Frankfurt-Münster Study Group
From the Children's Cancer Research Institute, St Anna
Kinderspital, Vienna, Austria.
Detection of minimal residual disease (MRD) in acute lymphoblastic
leukemia (ALL) predicts outcome. Previous studies were invariably based
on relative quantification and did not investigate sample-inherent
parameters that influence test accuracy, which makes comparisons and
clinical conclusions cumbersome. Hence, we conducted a prospective,
population-based MRD study in 108 sequentially recruited children with
ALL uniformly treated with the ALL-Berlin-Frankfurt-Münster
(ALL-BFM) 95 protocol in Austria (median follow-up of 40 months). Using
sensitive, limited antibody panel flow cytometry applicable to 97% of
patients, we investigated 329 bone marrow samples from 4 treatment time
points. MRD was quantified by blast percentages among nucleated cells
(NCs) and by absolute counts (per microliter). Covariables such as NC
count, normal B cells, and an estimate of the test sensitivity were
also recorded. Presence and distinct levels of MRD correlated with a
high probability of early relapse at each of the time points studied.
Sequential monitoring at day 33 and week 12 was most useful for
predicting outcome independently from clinical risk groups: patients
with persistent disease ( 1 blast/µL) had a 100% probability of
relapse, compared to 6% in all others. Absolute MRD quantification was
more appropriate than relative, due to considerable variations in total
NC counts between samples. Regeneration of normal immature B cells
after periods of rest from treatment limited the test sensitivity. In
conclusion, MRD detection by flow cytometry is a strong and independent
outcome indicator in childhood ALL. Standardization regarding absolute
quantification on the basis of NCs and assessment during periods of
continuous treatment promise to increase the accuracy, simplicity, and
cost efficiency of the approach.
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