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Molecular Detection of Minimal Residual Disease Is a Strong Predictive Factor of Relapse in Childhood B-Lineage Acute Lymphoblastic Leukemia with Medium Risk Features

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Molecular Detection of Minimal Residual Disease Is a Strong Predictive Factor of Relapse in Childhood B-Lineage Acute Lymphoblastic Leukemia with Medium Risk Features Leukemia (2000) 14, 1939–1943 2000 Macmillan Publishers Ltd All rights reserved 0887-6924/00 $15.00 www.nature.com/leu Molecular detection of minimal residual disease is a strong predictive factor of relapse in childhood B-lineage acute lymphoblastic leukemia with medium risk features. A case control study of the International BFM study group A Biondi1, MG Valsecchi2, T Seriu3, E D’Aniello1, MJ Willemse4, K Fasching5, A Pannunzio1, H Gadner5, M Schrappe3, WA Kamps6, CR Bartram3, JJM van Dongen4 and ER Panzer-Gru¨mayer5 1Clinica Pediatrica Universita` di Milano-Bicocca, Ospedale S Gerardo, Monza, Italy; 2Department of Medicine and Public Health, Universita` di Verona, Italy; 4Department of Immunology, Erasmus University Rotterdam, Rotterdam, The Netherlands; 3Institute of Human Genetics, University of Heidelberg, Heidelberg, Germany; 5Children’s Cancer Research Institute, St Anna Kinderspital, Vienna, Austria; and 6Dutch Childhood Leukemia Study Group (DCLSG), The Hague, The Netherlands The medium-risk B cell precursor acute lymphoblastic leuke- abnormalities) features at diagnosis3,4 and the evaluation of mia (ALL) accounts for 50–60% of total childhood ALL and early response to pre-phase treatment.5,6 comprises the largest number of relapses still unpredictable with diagnostic criteria. To evaluate the prognostic impact of The medium-risk group (MRG) represents a rather hetero- 1,7 minimal residual disease (MRD) in this specific group, a case genous cohort of patients. In the recently closed national control study was performed in patients classified and treated studies of the Austrian and German Berlin–Frankfurt–Mu¨nster as medium (or intermediate)-risk according to the criteria of (BFM) group (ALL-BFM 90),8 the Associazione Italiana di national studies (ALL-BFM 90, DCLSG protocol ALL-8, Ematologia e Oncologia Pediatrica (AIEOP-ALL 91)9 or the AIEOP-ALL 91), which includes a good day 7 treatment response. Standardized polymerase chain reaction (PCR) Dutch Childhood Leukemia Study Group (DCLSG, protocol 10 analysis of patient-specific immunoglobulin and T cell receptor ALL-8), the patients were stratified into standard-risk (SR), gene (TCR) rearrangements were used as targets for semi- medium-risk (MR) and high-risk (HR) treatment groups, mainly − − − quantitative estimation of MRD levels: >10 2,103, <10 4. according to the presenting features, ie leukemic cell mass Twenty-nine relapsing ALL patients were matched with the and prednisone response.2 The medium-risk group covers same number of controls by using white blood cell count (WBC), age, sex, and time in first complete remission, as more than half of newly diagnosed ALL and has 20–25% of 8–10 matching factors. MRD was evaluated at time-point 1 (end of children relapsing at 4–5 years from diagnosis. Compared protocol Ia of induction treatment, ie 6 weeks from diagnosis) to high risk patients, the percentage of failures is relatively and time-point 2 (before consolidation treatment, ie 3 months low, but they account for more than half of all relapses in > −3 from diagnosis). MRD-based high risk patients ( 10 at both most studies.8–10 Identification of the children who are likely time-points) were more frequently present in the relapsed cases than in controls (14 vs 2), while MRD-based low risk to relapse, should be sufficiently early to allow intensification patients (MRD negative at both time-points) (1 vs 18) showed of their treatment schedule and thereby improve their the opposite distribution. MRD-based high risk cases experi- outcome. enced a significantly higher relapse rate than all other patients, We and others have recently shown that monitoring of according to the estimated seven-fold increase in the odds of minimal residual disease (MRD) by highly sensitive molecular failure, and a much higher rate than MRD-based low risk patients (OR = 35.7; P = 0.003). Using the Cox model, the predic- or immunological approaches, gives clinically relevant insight 11–15 tion of the relapse-free interval at 4 years was 44.7%, 76.4% and into the effectiveness of treatment. Combined information 97.7% according to the different MRD categories. MRD-based on MRD from the first 3 months of treatment identified risk group classification demonstrate their clinical relevance patients at different risk of relapse and it has been proposed within the medium-risk B cell precursor ALL which account for to be relevant for tailored treatment.11–14 The series of the the largest number of unpredictable relapses, despite the cur- rent knowledge about clinical and biological characteristics at International BFM Study Group (I-BFM-SG) on MRD rep- 14 diagnosis. Therefore, MRD detection during the first 3 months resents the largest so far reported, and 65% of this series of follow-up can provide the tools to target more intensive ther- consisted of patients with medium-risk features, but the evalu- apy to those patients at true risk of relapse. Leukemia (2000) ation of the prognostic impact of MRD for these medium risk 14, 1939–1943. patients was hampered by the relatively small number of Keywords: childhood ALL; B cell precursor ALL; minimal residual disease; immunoglobulin; T cell receptor; gene rearrangements events and by the heterogeneity of the group with regard to MRD information. This prompted us to design a matched case-control study, Introduction by focussing on the medium-risk patients already included in the I-BFM-SG MRD study,14 and by increasing the number of The attempt to tailor the intensity of treatment to patient’s risk medium-risk relapsed cases analyzed for MRD, with the same of relapse, represents one of the major issues in the current modalities and in the same countries which participated in therapeutic strategy of childhood acute lymphoblastic leuke- the previous study. This is an efficient type of study design, mia (ALL).1 Risk classification comprises the use of both clini- which provides an estimate of the impact of MRD on the odds cal (age, liver and spleen size),2,3 and biological (leukocyte or of failure, and adjusts for heterogeneity in presenting features blast count, phenotype, DNA index, chromosomal by matching.16 In addition, the study allowed us to explore different types of MRD classification and, under certain assumptions, to project the impact of early detection of MRD Correspondence: A Biondi, Centro Ricerca ‘M Tettamanti’, Clinica positivity in relapse-free interval. Pediatrica, Universita` di Milano-Bicocca, Ospedale S Gerardo, Via Donizetti 106, 20052 Monza (MI), Italy; Fax: 39 039 233 2167 Received 30 December 1999; accepted 5 July 2000 MRD as a predictive factor for childhood ALL A Biondi et al 1940 Materials and methods complete remission to relapse; in case no relapsed occurred, the time is censored at the last follow-up or at death in Patients and cell samples remission), we resorted to the background hazard function as estimated, according to Cox,18 in the prospective cohort, and Bone marrow samples were taken at diagnosis and during fol- made the following assumptions: proportional hazards low-up times (time-point 1 corresponds to the end of phase between MRD-based risk groups and the OR estimate as an la of the induction, ie 5–6 weeks from diagnosis; time-point approximation of the hazard ratio. Further, we should be 2 before consolidation treatment, ie 3 months from aware in interpreting results, of possible biases that could have diagnosis),8–10 in 29 relapsing ALL patients and in the same occurred in the cohort and in the case-control study, had the number of matched controls (see below). Out of the 29 cases, preserved samples been disproportionately available for differ- 17 relapses in the MRG were already included in I-BFM-SG ent types of patients. MRD series14 and 12 cases were additionally analyzed for MRD. All relapses occurred in the bone marrow. All controls were from the I-BFM-SG MRD series. All children were Identification of PCR targets at diagnosis enrolled in the ALL-BFM 90, the AIEOP-ALL 91, or the DCLSG ALL-8 protocols8–10 which shared the same BFM-based criteria The procedure for the identification of the patient-specific for risk definition and intensive chemotherapy.2 We con- probe according to the junctional regions of the T cell recep- sidered patients with B cell precursor phenotype and age tor (TCR) gamma (TCRG), delta (TCRD) and kappa deleting greater than 1 year, who were classified as medium risk elements (Kde) recombinations has been described in detail.19 according to the following criteria: BFM risk factor (RF) >0.8 Briefly, the rearrangements were detected by Southern blot (and ,1.7 only for AIEOP-ALL 91);2 good prednisone analysis and confirmed by PCR analysis and direct sequencing response (as defined if the peripheral blood blast cell count/µl of the junctional regions with standardized sets of oligonucle- at day 8 is ,1000);2 CR at day 35 or 42; absence of t(9;22) otide primers. On the basis of the sequence data of the junc- and t(4;11) translocations and no CNS disease (only for tional regions, patient-specific oligonucleotides were AIEOP-ALL 91).9 designed for each identified MRD-PCR target, using OLIGO Mononuclear cells were isolated from the bone marrow 5.0 software (National Biosciences, Plymouth, MN, USA).19 samples and stored in liquid nitrogen or at −70°C for DNA extraction. Of the 58 patients included in the analysis: 10 were from Austria, 13 from Germany, 28 from Italy and seven MRD detection during follow-up from the Netherlands. They fulfilled the following criteria: (1) preferably, two PCR targets at least one of which reached a The MRD-PCR analyses of bone marrow samples during fol- sensitivity of 10−4; (2) MRD data known at the two predefined low-up were done by single PCR analysis of 1 µg of DNA time points.14 In those cases (three), where MRD data only at (equivalent to 105–106 cells) with the standardized primer time-point 2 were available, patients were included if MRD sets, followed by dot blotting and hybridization with the corre- level was .10−4, as we assumed the same or higher MRD sponding 32P-labelled patient-specific junctional region level at the previous time-point.
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