Dana-Farber Cancer Institute ALL Consortium. Quantitative analysis of minimal residual disease predicts relapse in children with B-lineage acute lymphoblastic leukemia in DFCI ALL Consortium Protocol 95-01

Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.
Blood (Impact Factor: 10.45). 10/2007; 110(5):1607-11. DOI: 10.1182/blood-2006-09-045369
Source: PubMed


In a prospective trial in 284 children with B-lineage acute lymphoblastic leukemia (ALL), we assessed the clinical utility of real-time quantitative polymerase chain reaction analysis of antigen receptor gene rearrangements for detection of minimal residual disease (MRD) to identify children at high risk of relapse. At the end of induction therapy, the 5-year risk of relapse was 5% in 176 children with no detectable MRD and 44% in 108 children with detectable MRD (P < .001), with a linear association of the level of MRD and subsequent relapse. Recursive partitioning and clinical characteristics identified that the optimal cutoff level of MRD to predict outcome was 10(-3). The 5-year risk of relapse was 12% for children with MRD less than one leukemia cell per 10(3) normal cells (low MRD) but 72% for children with MRD levels greater than this level (high MRD) (P < .001) and children with high MRD had a 10.5-fold greater risk of relapse. Based upon these results we have altered our treatment regimen for children with B-lineage ALL and children with MRD levels greater than or equal to 10(-3) at the end of 4 weeks of multiagent induction chemotherapy now receive intensified treatment to attempt to decrease their risk of subsequent relapse.

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Available from: John G Gribben
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    • "PCR-based MRD assays have been tested clinically in childhood acute lymphoblastic leukemia (ALL) by targeting IgH gene rearrangements with sensitivities on the order of one leukemic cell in 104–106 normal cells. Rapid reduction of MRD following induction therapy was associated with a 3-year relapse rate less than 5%, while children with detectable MRD had a 3-year relapse rate of 23%–75% [25]. In ALL, MRD was the most powerful prognostic factor of outcome, independent of other risk factors (age, leukocyte count, cytogenetic abnormalities, prednisone response), with similar results in children undergoing BM transplantation [26, 27]. "
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    ABSTRACT: Assessing molecular persistent or minimal residual disease (PD/MRD) in childhood Burkitt lymphoma (BL) is challenging because access to original tumor is usually needed to design patient-specific primers (PSPs). Because BL is characterized by rearranged immunoglobulin heavy chain (IgV(H)) genes, IgV(H) primer pools from IgV(H1)-IgV(H7) regions were tested to detect PD/MRD, thus eliminating the need for original tumor. The focus of the current study was to assess the feasibility of using IgV(H) primer pools to detect disease in clinical specimens. Fourteen children diagnosed with B-NHL had follow-up repository specimens available to assess PD/MRD. Of the 14 patients, 12 were PD/MRD negative after 2 months of therapy and remained in remission at the end of therapy; 2/14 patients were PD/MRD positive at 2-3 months and later relapsed. PSP-based assays from these 14 patients showed 100% concordance with the current assay. This feasibility study warrants further investigation to assess PD/MRD using IgV(H) primer pools, which could have clinical significance as a real-time assessment tool to monitor pediatric BL and possibly other B-cell non-Hodgkin lymphoma therapy.
    Full-text · Article · Apr 2009 · Advances in Hematology
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    • "Minimal residual disease (MRD), as measured by reverse transcription-polymerase chain reaction (RT-PCR) or flow cytometry, has been shown to be useful for predicting prognosis in paediatric (Brisco et al, 1994; Cave et al, 1998; Coustan-Smith et al, 1998; van Dongen et al, 1998; Dworzak et al, 2002; Nyvold et al, 2002; Zhou et al, 2007) and adult ALL patients (Brisco et al, 1996; Mortuza et al, 2002; Vidriales et al, 2003; Bruggemann et al, 2006; Raff et al, 2007). However , the utility of MRD as a prognostic indicator has been established on the basis of data from patients treated with chemotherapy alone, and it remains to be determined whether it is useful in patients treated with chemotherapy in combination with imatinib. "
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    ABSTRACT: The clinical significance of minimal residual disease (MRD) is uncertain in patients with Philadelphia chromosome-positive acute lymphoblastic leukaemia (Ph+ ALL) treated with imatinib-combined chemotherapy. Here we report the results of prospective MRD monitoring in 100 adult patients. Three hundred and sixty-seven follow-up bone marrow samples, collected at predefined time points during a uniform treatment protocol, were analysed for BCR-ABL1 transcripts by quantitative reverse transcription polymerase chain reaction. Ninety-seven patients (97%) achieved complete remission (CR), and the relapse-free survival (RFS) rate was 46% at 3 years. Negative MRD at the end of induction therapy was not associated with longer RFS or a lower relapse rate (P = 0.800 and P = 0.964 respectively). Twenty-nine patients showed MRD elevation during haematological CR. Of these, 10 of the 16 who had undergone allogeneic haematopoietic stem cell transplantation (HSCT) in first CR were alive without relapse at a median of 2.9 years after transplantation, whereas 12 of the 13 who had not undergone allogeneic HSCT experienced a relapse. These results demonstrate that, in Ph+ ALL patients treated with imatinib-combined chemotherapy, rapid molecular response is not associated with a favourable prognosis, and that a single observation of elevated MRD is predictive of subsequent relapse, but allogeneic HSCT can override its adverse effect.
    Full-text · Article · Dec 2008 · British Journal of Haematology
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    • "At the end of induction, 51% of samples had levels of MRD ‡0AE01%. In other large prospective studies, this value ranged from 24% to 60%, reflecting method sensitivity and differences in treatment protocols (Cave et al, 1998; van Dongen et al, 1998; Coustan-Smith et al, 2000; Dworzak et al, 2002; Nyvold et al, 2002; Zhou et al, 2007) (Table SVII). In addition, levels of MRD detected at <0AE01% by other studies varied greatly Fig 2. Kaplan–Meier curves for the three minimal residual disease (MRD) risk groups show significant differences with a log rank trend value <0AE01 (P = 0AE0091). "
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    ABSTRACT: In this single centre study of childhood acute lymphoblastic leukaemia (ALL) patients treated on the Medical Research Council UKALL 97/99 protocols, it was determined that minimal residual disease (MRD) detected by real time quantitative polymerase chain reaction (RQ-PCR) and 3-colour flow cytometry (FC) displayed high levels of qualitative concordance when evaluated at multiple time-points during treatment (93·38%), and a combined use of both approaches allowed a multi time-point evaluation of MRD kinetics for 90% (53/59) of the initial cohort. At diagnosis, MRD markers with sensitivity of at least 0·01% were identified by RQ-PCR detection of fusion gene transcripts, IGH/TRG rearrangements, and FC. Using a combined RQ-PCR and FC approach, the evaluation of 367 follow-up BM samples revealed that the detection of MRD >1% at Day 15 (P = 0·04), >0·01% at the end of induction (P = 0·02), >0·01% at the end of consolidation (P = 0·01), >0·01% prior to the first delayed intensification (P = 0·01), and >0·1% prior to the second delayed intensification and continued maintenance (P = 0·001) were all associated with relapse and, based on early time-points (end of induction and consolidation) a significant log-rank trend (P = 0·0091) was noted between survival curves for patients stratified into high, intermediate and low-risk MRD groups.
    Full-text · Article · Nov 2008 · British Journal of Haematology
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