Prognostic value of minimal residual disease in acute lymphoblastic leukaemia in childhood

Prognostic value of minimal residual disease in acute lymphoblastic leukaemia in childhood

Prognostic value of minimal residual disease in acute lymphoblastic leukaemia in childhood Sir—The detection of residual leukaemia by competitive PCR ...

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Prognostic value of minimal residual disease in acute lymphoblastic leukaemia in childhood Sir—The 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. van Dongen and co-workers used the rearrangement of T-cell receptor or immunoglobulin heavy-chain genes as clonal markers. However, these genetic changes are not pathogenic causes of these diseases, but represent manifestations of clonal expansion of the lymphoid cells. This finding is in contrast with previous studies of chimeric mRNA such as AML1/MTG8,2 and BCR/ABL,3 in which the chimeric products were principal causes of these malignant changes. In these studies, the usefulness of minimal residual disease (MRD) monitoring was examined in homogeneous groups, but in this study they treated children with a specific form of ALL. These workers may also have overestimated the efficacy of MRD monitoring because children with ALL with different prognoses are analysed together. In high-risk patients, it is difficult to achieve complete remission by conventional induction therapies, and leukaemic cells may exist at molecular levels even on complete remission. Positive results of MRD monitoring after induction therapy might predict prognosis, indicating the high probability of subsequent relapse in these patients. On the other hand, goodrisk patients have a high probability of complete remission and cure even by conventional chemotherapies. It is not surprising that van Dongen and colleagues’ PCR results remained negative after remission induction. When such groups are analysed en masse, the presence of residual leukaemia detected by PCR assays may seem to be correlated with subsequent relapses, but probably gives no more information than the initial evaluation of the patients’ risk factors. To eliminate such effects, van Dongen undertook a multivariate analysis after stratification of the classic prognostic factors. Yet, chromosomal characteristics, the most powerful prognostic factors for leukaemia, were excluded from the stratified log-rank test because of the prevalence of patients in whom they could not be evaluated. We

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therefore believe that a patient group with uniform prognostic risk factors is required to determine the true efficacy of MRD monitoring with the competitive PCR of rearrangement of T-cell-receptor or immunoglobulin heavy chain genes. Tomoko Matsumura, *Masahiro Kami, Toshiki Saito, Hisashi Sakamaki, Hisamaru Hirai Department of Haematology, Tokyo Metropolitan Komagome Hospital, Tokyo; *Department of Haematology and Oncology, Faculty of Medicine, University of Tokyo, Bunkyoku, Tokyo 113-8655, Japan e-mail: [email protected] 1

van Dongen JJM, Seriu T, Panzer-Grimayer ER, et al. Prognostic value of minimal residual disease in acute lympholastic leukaemia in childhood. Lancet 1998; 352: 1731–38. 2 Tobal K, Yin JA. Monitoring of minimal residual disease by quantitative reverse transcriptase-polymerase chain reaction for AML1-MTG8 transcripts in AML-M2 with t(8; 21). Blood 1996; 88: 3704–09. 3 Preudhomme C, Henic N, Cazin B et al. Good correlation between RT-PCR analysis and relapse in Philadelphia (Ph1)-positive acute lymphoblastic leukemia (ALL). Leukemia 1997; 11: 294–97.

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.1,2 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.3 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

flow cytometric colleagues 4 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 lowrisk 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 MRDbased 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%.5 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. *J J M van Dongen, M J Pongers-Willemse, A Biondi, E R Panzer-Grümayer, C R Bartram *Department of Immunology, University Hospital Rotterdam/Erasmus University Rotterdam, 3000 DR Rotterdam, PO Box 1738, Netherlands; Department of Paediatrics, Universitá Milano, Ospedale San Gerardo, Monza, Italy; Department of Paediatrics, Children’s Cancer Research Institute, St Anna Kinderspital, Vienna, Austria; and Institute of Human Genetics, University of Heidelberg, Heidelberg, Germany ( e-mail: [email protected]) 1

van Dongen JJM, Szczepa´nski T, D eB r u i j n MAC, et al. Detection of minimal residual disease in acute leukemia patients. Cytokines Mol Ther 1996; 2: 121–33. 2 Pongers-Willemse MJ, Seriu T, Stolz F, et al. Primers and protocols for standardized

THE LANCET • Vol 353 • February 27, 1999