Authors' reply

Abstract

Authors' reply Sir—Tomoko Matsumura and colleagues raise several questions about the relevance of PCR-based detection of MRD in childhood ALL. First, they remark that, unlike fusion gene transcripts, the used targets are not oncogenic and therefore less suitable for MRD monitoring. We believe that this is a misconception, because the Ig/TCR gene rearrangements are highly specific fingerprint-like markers of leukaemic cells and are applicable as PCR targets in virtually all ALL cases, implying that no patient selection occurs.1van Dongen JJM Szczepański T DeBruijn MAC et al.Detection of minimal residual disease in acute leukemia patients.Cytokines Mol Ther. 1996; 2: 121-133PubMed Google Scholar, 2Pongers-Willemse MJ Seriu T Stolz F et al.Primers and protocols for standardized detection of minimal residual disease in acute lymphoblastic leukemia using immunoglobulin and T cell receptor gene rearrangements and TAL1 deletions as PCR targets.Report of the BIOMED-1 Concerted Action investigation of minimal residual disease in acute leukemia. Leukemia. 1998; 13: 110-118Google Scholar This broad applicability is in contrast with fusion gene transcripts such as BCR-ABL, which occur only in about 40% of childhood ALL cases. Besides, several types of chromosomal aberrations are also detected in healthy individuals.3Biernaux C Loos M Sels A Huez G Stryckmans P Detection of major bcr-abl gene expression at a very low level in blood cells of some healthy individuals.Blood. 1995; 86: 3118-3122PubMed Google Scholar For MRD detection in ALL, we prefer PCR targets at the DNA level, since this is more accurate than reverse transcriptase (RT)-PCR analysis of fusion gene transcripts, which is dependent on the RT efficiency and mRNA expression. Second, Matsumura and co-workers doubt whether detection of MRD provides additional prognostic information to risk factors at diagnosis, especially chromosomal aberrations. Our extensive Cox-regression analyses of the MRD results at the various follow-up time points showed that MRD information is a risk factor independent of known prognostic indices at diagnosis. This result was also shown in Coustan-Smith and colleagues4Coustan-Smith E Behm FG Sanchez J et al.Immunological detection of minimal residual disease in children with acute lymphoblastic leukaemia.Lancet. 1998; 351: 550-554Summary Full Text Full Text PDF PubMed Scopus (374) Google Scholar flow cytometric immunophenotyping MRD study, which included MLL and BCR-ABL aberrations in the multivariate analyses. Furthermore, our results clearly show that information about the kinetics of tumour reduction during the first 3 months of treatment allow identification of an unprecedented large group of low-risk patients (43% of all patients) with a 4-year relapse rate of only 2%, and a high-risk group (15% of all patients) with a 4-year relapse rate of 80%. The remaining intermediate-risk group had an overall relapse rate of 23%, but at a later stage during maintenance treatment this group could be divided into an MRD-negative group with 10% relapse rate and an MRD-positive group with 67% relapse rate. Although we could not include chromosomal aberrations in our Cox-regression analyses, it is obvious that the MRD-based risk group classification cannot be equalled by any other prognostic factor, including chromosomal aberrations. For instance, the so-called poor-prognosis MLL gene aberrations and BCR-ABL aberrations identify only 5–8% of childhood ALL cases having a relapse rate of about 60%, whereas the so-called good-prognosis TEL-AML1 aberrations are found in about 25% of patients with a relapse rate of roughly 15%.5Pui C-H Evans WE Drug therapy: acute lymphoblastic leukemia.N Engl J Med. 1998; 339: 605-615Crossref PubMed Scopus (795) Google Scholar These results also show that patients carrying the same type of chromosomal aberrations in fact still form a heterogeneous group with different outcome, which might profit from MRD monitoring. Most importantly, it should be emphasised that MRD studies during follow-up measure a different event from prognostic factors at diagnosis. Information about the kinetics of tumour reduction during the first months of follow-up gives insight into the in-vivo drug resistance of the leukaemic cells, which apparently is independent from the prognostic factors at initial presentation. Prognostic value of minimal residual disease in acute lymphoblastic leukaemia in childhoodThe detection of residual leukaemia by competitive PCR may be a beneficial prognostic factor in childhood acute lymphoblastic leukaemia (ALL) as documented by Jacques van Dongen and colleagues (Nov 28, p 1731),1 especially because specific molecular markers have not yet been identified in most of these children. Full-Text PDF