Prognostic Value of Minimal Residual Disease Quantification Before Allogeneic Stem-Cell Transplantation in Relapsed Childhood Acute Lymphoblastic Leukemia: The ALL-REZ BFM Study Group
20 Jan 2009-Journal of Clinical Oncology (American Society of Clinical Oncology)-Vol. 27, Iss: 3, pp 377-384
TL;DR: Minimal residual disease (MRD) before allogeneic stem-cell transplantation was shown to predict outcome in children with relapsed acute lymphoblastic leukemia in retrospective analysis and is an important predictor for post-transplantation outcome.
Abstract: Purpose Minimal residual disease (MRD) before allogeneic stem-cell transplantation was shown to predict outcome in children with relapsed acute lymphoblastic leukemia (ALL) in retrospective analysis. To verify this, the Acute Lymphoblastic Leukemia Relapse Berlin-Frankfurt-Munster (ALL-REZ BFM) Study Group conducted a prospective trial. Patients and Methods Between March 1999 and July 2005, 91 children with relapsed ALL treated according to the ALL-REZ BFM 96 or 2002 protocols and receiving stem-cell transplantation in ≥ second remission were enrolled. MRD quantification was performed by real-time polymerase chain reaction using T-cell receptor and immunoglobulin gene rearrangements. Results Probability of event-free survival (pEFS) and cumulative incidence of relapse (CIR) in 45 patients with MRD ≥ 10−4 leukemic cells was 0.27 and 0.57 compared with 0.60 and 0.13 in 46 patients with MRD less than 10−4 leukemic cells (EFS, P = .004; CIR, P < .001). Intermediate-risk patients (strategic group S1) with MRD ...
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TL;DR: T cells engaged by blinatumomab seem capable of eradicating chemotherapy-resistant tumor cells that otherwise cause clinical relapse in patients with MRD-positive B-lineage ALL after intensive chemotherapy.
Abstract: Purpose Blinatumomab, a bispecific single-chain antibody targeting the CD19 antigen, is a member of a novel class of antibodies that redirect T cells for selective lysis of tumor cells. In acute lymphoblastic leukemia (ALL), persistence or relapse of minimal residual disease (MRD) after chemotherapy indicates resistance to chemotherapy and results in hematologic relapse. A phase II clinical study was conducted to determine the efficacy of blinatumomab in MRD-positive B-lineage ALL.
832 citations
Cites result from "Prognostic Value of Minimal Residua..."
...In children with B-lineage ALL, it was recently demonstrated that persisting MRD has a strong negative impact on the outcome of allogeneic HSCT.(16,17) Thus, in contrast to patients with MRD below the detection level, patients with positive MRD before allogeneic HSCT have an exceedingly high relapse rate....
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...In children with B-lineage ALL, it was recently demonstrated that persisting MRD has a strong negative impact on the outcome of allogeneic HSCT.16,17 Thus, in contrast to patients with MRD below the detection level, patients with positive MRD before allogeneic HSCT have an exceedingly high relapse rate....
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...According to similar analysis of adult B-lineage ALL, approximately 30% of patients with MRD-positive disease may be rescued by allogeneic HSCT....
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TL;DR: Genome-wide profiling of germline and leukaemic cell DNA has identified novel submicroscopic structural genetic changes and sequence mutations that contribute to leukaemogenesis, define new disease subtypes, affect responsiveness to treatment, and might provide novel prognostic markers and therapeutic targets for personalised medicine.
801 citations
TL;DR: It is concluded that blinatumomab can induce long-lasting complete remission in B-lineage ALL patients with persistent or recurrent MRD and of the subgroup of 6 Philadelphia chromosome-negative MRD responders with no further therapy after blinumomab, 4 are in ongoing hematologic and molecular remission.
434 citations
TL;DR: A high-throughput sequencing method that universally amplifies antigen-receptor gene segments and identifies all clonal gene rearrangements at diagnosis allows monitoring of disease progression and clonal evolution during therapy, allowing monitoring of treatment response in ALL and other lymphoid malignancies with great sensitivity and precision.
384 citations
Cites background from "Prognostic Value of Minimal Residua..."
...The prognostic power of MRD during treatment has been amply demonstrated in numerous correlative studies performed in patients with newly diagnosed childhood and adult ALL(6,7,17,28-37) or relapsed ALL(38-40), and in patients undergoing hematopoietic stem cell transplant.(27,41) Monitoring of MRD has become a central component of the modern managements of patients with ALL(7), and is beginning to be introduced as a criterion for testing novel anti-leukemic agents....
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TL;DR: Monitoring of minimal residual disease (MRD) has become routine clinical practice in frontline treatment of virtually all childhood acute lymphoblastic leukemia and in many adult ALL patients, and the efficacy of innovative drugs are currently being evaluated with MRD diagnostics within clinical trials.
380 citations
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TL;DR: In this paper, a class of tests developed for comparing the cumulative incidence of a particular type of failure among different groups is presented. The tests are based on comparing weighted averages of the hazards of the subdistribution for the failure type of interest.
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4,469 citations
TL;DR: The European Study Group on MRD detection in ALL (ESG-MRD-ALL), consisting of 30 MRD-PCR laboratories worldwide, has developed guidelines for the interpretation of real-time quantitative PCR-based MRD data.
Abstract: Most modern treatment protocols for acute lymphoblastic leukaemia (ALL) include the analysis of minimal residual disease (MRD). To ensure comparable MRD results between different MRD-polymerase chain reaction (PCR) laboratories, standardization and quality control are essential. The European Study Group on MRD detection in ALL (ESG-MRD-ALL), consisting of 30 MRD-PCR laboratories worldwide, has developed guidelines for the interpretation of real-time quantitative PCR-based MRD data. The application of these guidelines ensures identical interpretation of MRD data between different laboratories of the same MRD-based clinical protocol. Furthermore, the ESG-MRD-ALL guidelines will facilitate the comparison of MRD data obtained in different treatment protocols, including those with new drugs.
648 citations
TL;DR: In this paper, the authors developed a set of PCR primers and protocols for the detection of minimal residual disease (MRD) in acute lymphoblastic leukemia (ALL) using clone-specific junctional regions of immunoglobulin and T cell receptor gene rearrangements and TAL1 deletions as PCR targets.
Abstract: It is now widely accepted that the detection of minimal residual disease (MRD) has prognostic value in acute leukemia. However clinical MRD studies need standardized techniques. Therefore, several European laboratories have aligned their goals and performed comparative studies to achieve optimization and standardization of MRD techniques. This was achieved via the BIOMED-1 Concerted Action “Investigation of minimal residual disease in acute leukemia: International standardization and clinical evaluation.” This report describes the development of PCR primers and protocols for the detection of MRD in acute lymphoblastic leukemia (ALL) using clone-specific junctional regions of immunoglobulin and T cell receptor gene rearrangements and TAL1 deletions as PCR targets. A total of 54 primers was developed (1) to amplify rearrangements of the TCRD, TCRG, and IGK (Kde) genes as well as TAL1 deletions; (2) to sequence the junctional regions and breakpoint fusion regions; and (3) to perform MRD detection in bone marrow or peripheral blood samples during follow-up of ALL patients. Protocols were established to identify PCR targets at diagnosis by performing 25 PCR reactions per patient using appropriate positive and negative controls. Standardized protocols were developed for MRD monitoring via single amplification of the PCR target followed by dot blot hybridization with the corresponding patient-specific junctional region probe. In addition, alternative approaches were designed for cases where the target sensitivity of at least 10−4 was not obtained. The standardization described here of MRD-PCR techniques is essential for the process of translating MRD research into clinical practice.
338 citations