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Long-term follow-up of residual disease in acute lymphoblastic leukemia
patients in complete remission using clonogeneic IgH probes and the
polymerase chain reaction
Y Nizet, S Van Daele, P Lewalle, JL Vaerman, M Philippe, C Vermylen, G Cornu, A Ferrant, JL Michaux and P Martiat
Department of Hematology, Cliniques Universitaires Saint-Luc, Brussels,
Belgium.
We sequentially studied bone marrow (BM) samples of 25 patients in complete
remission of an acute lymphoblastic leukemia (ALL) using a simplified
polymerase chain reaction (PCR) strategy (direct use of the PCR product as
a clonogenic probe recognizing rearranged Ig heavy chain sequences) as a
first approach. BM aspirates were serially investigated after obtention of
a complete response. When sensitivity was less than 1:10(4), the PCR
fragment was sequenced and a specific oligonucleotide was synthetized and
used as a probe (five cases). Cases in which minimal residual disease (MRD)
became undetectable were cross- controlled using either TCR delta
rearrangement or a specific translocation to circumvent the problem of
false-negative results arising from clonal evolution. The median follow-up
was 30 months (3 to 51 months). Within the first 3 months of complete
remission, MRD was detectable in 22 of 23 investigated patients and
remained so in 19 of 21 patients examined at 6 months, regardless of the
long-term clinical outcome. In patients remaining in complete remission at
30 months or more, two patterns of MRD emerged during the follow-up. Either
it continuously decreased to ultimately become undetectable (five patients)
or remained detectable (five patients) with an increase after
discontinuation of treatment in two. In the eight patients who relapsed,
MRD persisted throughout the clinical course, and eventually increased 3 to
12 months before relapse was clinically detectable. In one case, clonal
evolution of the VDJ heavy chain region was observed and recurrence of MRD
shown by the use of TCR delta rearrangement as a control. We conclude that
the use of this simplified methodology is a valuable tool for the follow-up
of MRD in a majority of ALL patients, though in a few cases, sequencing
needs to be performed to achieve a relevant sensitivity. The possibility of
clonal evolution requires a cross-control of any sample becoming negative
whatever the initial rearrangement used to generate a probe. In patients on
therapy, sequential search for MRD seems to be a good tool for predicting
the long-term outcome. In addition, patients remaining positive at the time
treatment is discontinued or with a high tumor burden after a few months
therapy may be at a higher risk of subsequent relapse, although a longer
follow-up is needed to answer this question.
Volume 82,
Issue 5,
pp. 1618-1625,
09/01/1993
Copyright © 1993 by The American Society of Hematology
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