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Blood, 1 April 2002, Vol. 99, No. 7, pp. 2315-2323
CLINICAL OBSERVATIONS, INTERVENTIONS, AND THERAPEUTIC TRIALS
Comparative analysis of Ig and TCR gene rearrangements at
diagnosis and at relapse of childhood precursor-B-ALL provides
improved strategies for selection of stable PCR targets for monitoring
of minimal residual disease
Tomasz Szczepa ski,
Marja J. Willemse,
Bas Brinkhof,
Elisabeth R. van
Wering,
Mirjam van der Burg, and
Jacques J. M. van Dongen
From the Department of Immunology, University Hospital
Rotterdam/Erasmus University Rotterdam, The Netherlands; Department of
Pediatric Hematology and Chemotherapy, Silesian Medical Academy,
Zabrze, Poland; and Dutch Childhood Leukemia Study Group, The Hague,
The Netherlands.
Immunoglobulin (Ig) and T-cell receptor (TCR) gene rearrangements
are excellent patient-specific polymerase chain reaction (PCR) targets
for detection of minimal residual disease (MRD) in acute lymphoblastic
leukemia (ALL), but they might be unstable during the disease course.
Therefore, we performed detailed molecular studies in 96 childhood
precursor-B-ALL at diagnosis and at relapse (n = 91) or at
presumably secondary acute myeloid leukemia (n = 5). Clonal Ig and
TCR targets for MRD detection were identified in 94 patients, with 71%
of these targets being preserved at relapse. The best stability was
found for IGK-Kde rearrangements (90%), followed by
TCRG (75%), IGH (64%), and incomplete
TCRD rearrangements (63%). Combined Southern blot and PCR
data for IGH, IGK-Kde, and TCRD
genes showed significant differences in stability at relapse between
monoclonal and oligoclonal rearrangements: 89% versus 40%,
respectively. In 38% of patients all MRD-PCR targets were preserved at
relapse, and in 40% most of the targets ( 50%) were preserved. In
22% of patients most targets (10 cases) or all targets (10 cases) were
lost at relapse. The latter 10 cases included 4 patients with secondary
acute myeloid leukemia with germline Ig/TCR genes. In 5 other patients
additional analyses proved the clonal relationship between both disease
stages. Finally, in 1 patient all Ig/TCR gene rearrangements were
completely different between diagnosis and relapse, which is suggestive
of secondary ALL. Based on the presented data, we propose stepwise
strategies for selection of stable PCR targets for MRD monitoring,
which should enable successful detection of relapse in most (95%) of childhood precursor-B-ALL.
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