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Brent L. Wood - One of the best experts on this subject based on the ideXlab platform.

  • Ultrasensitive detection of acute myeloid leukemia Minimal Residual Disease using single molecule molecular inversion probes
    Haematologica, 2017
    Co-Authors: Adam Waalkes, Kelsi Penewit, Brent L. Wood, Stephen J. Salipante
    Abstract:

    The identification of Minimal Residual Disease is the primary diagnostic finding which predicts relapse in patients treated for acute myeloid leukemia. Ultrasensitive detection of Minimal Residual Disease would enable better patient risk stratification and could open opportunities for early therapeutic intervention. Herein we apply single molecule molecular inversion probe capture, a technology combining multiplexed targeted sequencing with error correction schemes based on molecular barcoding, in order to detect mutations identifying Minimal Residual Disease with ultrasensitive and quantitative precision. We designed a single molecule molecular inversion probe capture panel spanning >50 kb and targeting 32 factors relevant to acute myeloid leukemia pathogenesis. We demonstrate linearity and quantitative precision over 100-fold relative abundance of mutant cells (1 in 100 to 1 in 1,500), with estimated error rates approaching 1 in 1,200 base pairs sequenced and maximum theoretical limits of detection exceeding 1 in 60,000 mutant alleles. In 3 of 4 longitudinally collected specimens from patients with acute myeloid leukemia, we find that single molecule molecular inversion probe capture detects somatic mutations identifying Minimal Residual Disease at substantially earlier time points and with greater sensitivity than clinical diagnostic approaches used as current standard of care (flow cytometry and conventional molecular diagnosis), and identifies persisting neoplastic cells during clinical remission. In 2 patients, single molecule molecular inversion probe capture detected heterogeneous, subclonal acute myeloid leukemia populations carrying distinct mutational signatures. Single molecule molecular inversion probe technology uniquely couples scalable target enrichment with sequence read error correction, providing an integrated, ultrasensitive approach for detecting Minimal Residual Disease identifying mutations.

  • Minimal Residual Disease prior to allogeneic hematopoietic cell transplantation in acute myeloid leukemia a meta analysis
    Haematologica, 2017
    Co-Authors: Sarah A Buckley, Brent L. Wood, Christopher S. Hourigan, Megan Othus, Celalettin Ustun, Michael A Linden, Todd E Defor, Michele Malagola, Chloe Anthias
    Abstract:

    Minimal Residual Disease prior to allogeneic hematopoietic cell transplantation has been associated with increased risk of relapse and death in patients with acute myeloid leukemia, but detection methodologies and results vary widely. We performed a systematic review and meta-analysis evaluating the prognostic role of Minimal Residual Disease detected by polymerase chain reaction or multiparametric flow cytometry before transplant. We identified 19 articles published between January 2005 and June 2016 and extracted hazard ratios for leukemia-free survival, overall survival, and cumulative incidences of relapse and non-relapse mortality. Pre-transplant Minimal Residual Disease was associated with worse leukemia-free survival (hazard ratio=2.76 [1.90-4.00]), overall survival (hazard ratio=2.36 [1.73-3.22]), and cumulative incidence of relapse (hazard ratio=3.65 [2.53-5.27]), but not non-relapse mortality (hazard ratio=1.12 [0.81-1.55]). These associations held regardless of detection method, conditioning intensity, and patient age. Adverse cytogenetics was not an independent risk factor for death or relapse. There was more heterogeneity among studies using flow cytometry-based than WT1 polymerase chain reaction-based detection (I2=75.1% vs. <0.1% for leukemia-free survival, 67.8% vs. <0.1% for overall survival, and 22.1% vs. <0.1% for cumulative incidence of relapse). These results demonstrate a strong relationship between pre-transplant Minimal Residual Disease and post-transplant relapse and survival. Outcome heterogeneity among studies using flow-based methods may underscore site-specific methodological differences or differences in test performance and interpretation.

  • Cord-Blood Transplantation in Patients with Minimal Residual Disease
    The New England journal of medicine, 2016
    Co-Authors: Filippo Milano, Brent L. Wood, Ted Gooley, Ann E. Woolfrey, Mary E.d. Flowers, Kristine Doney, Robert P. Witherspoon, Marco Mielcarek, J. Deeg, Mohamed L. Sorror
    Abstract:

    BackgroundThe majority of patients in need of a hematopoietic-cell transplant do not have a matched related donor. Data are needed to inform the choice among various alternative donor-cell sources. MethodsIn this retrospective analysis, we compared outcomes in 582 consecutive patients with acute leukemia or the myelodysplastic syndrome who received a first myeloablative hematopoietic-cell transplant from an unrelated cord-blood donor (140 patients), an HLA-matched unrelated donor (344), or an HLA-mismatched unrelated donor (98). ResultsThe relative risks of death and relapse between the cord-blood group and the two other unrelated-donor groups appeared to vary according to the presence of Minimal Residual Disease status before transplantation. Among patients with Minimal Residual Disease, the risk of death was higher in the HLA-mismatched group than in the cord-blood group (hazard ratio, 2.92; 95% confidence interval [CI], 1.52 to 5.63; P=0.001); the risk was also higher in the HLA-matched group than in t...

  • Principles of Minimal Residual Disease detection for hematopoietic neoplasms by flow cytometry
    Cytometry. Part B Clinical cytometry, 2015
    Co-Authors: Brent L. Wood
    Abstract:

    Flow cytometry has become an indispensible tool for the diagnosis and classification of hematopoietic neoplasms. The ability to rapidly distinguish cellular subpopulations via multiparametric assessment of quantitative differences in antigen expression on single cells and enumerate the relative sizes of the resulting subpopulations is a key feature of the technology. More recently, these capabilities have been expanded to include the identification and enumeration of rare subpopulations within complex cellular mixtures, for example, blood or bone marrow, leading to the application for post-therapeutic monitoring or Minimal Residual Disease detection. This review will briefly present the principles to be considered in the construction and use of flow cytometric assays for Minimal Residual Disease detection including the use of informative antibody combinations, the impact of immunophenotypic instability, enumeration, assay sensitivity, and reproducibility.

  • Detection of Minimal Residual Disease in NPM1-mutated acute myeloid leukemia by next-generation sequencing
    Modern Pathology, 2014
    Co-Authors: Stephen J. Salipante, Jonathan R Fromm, Jay Shendure, Brent L. Wood
    Abstract:

    Detection of Minimal Residual Disease predicts adverse outcome in patients with acute myeloid leukemia. Currently, Minimal Residual Disease may be detected by RQ-PCR or flow cytometry, both of which have practical and diagnostic limitations. Here, we describe a next-generation sequencing assay for Minimal Residual Disease detection in NPM1 -mutated acute myeloid leukemia, which encompasses ∼60% of patients with normal karyotype acute myeloid leukemia. Exon 12 of NPM1 was PCR amplified using sequencing adaptor-linked primers and deep sequenced to enable detection of low-prevalence, acute myeloid leukemia-specific activating mutations. We benchmarked our results against flow cytometry, the standard of care for acute myeloid leukemia Minimal Residual Disease diagnosis at our institution. The performance of both approaches was evaluated using defined dilutions of an NPM1 mutation-positive cell line and longitudinal clinical samples from acute myeloid leukemia patients. Using defined control material, we found this assay sensitive to approximately 0.001% mutant cells, outperforming flow cytometry by an order of magnitude. Next-generation sequencing was precise and semiquantitative over four orders of magnitude. In 22 longitudinal samples from six acute myeloid leukemia patients, next-generation sequencing detected Minimal Residual Disease in all samples deemed negative by flow cytometry. Further, in one-third of patients, sequencing detected alternate NPM1 mutations in addition to the patient’s index mutation, consistent with tumor heterogeneity. Next-generation sequencing provides information without prior knowledge of NPM1 mutation subtype or validation of allele-specific probes as required for RQ-PCR assays, and without generation and interpretation of complex multidimensional flow cytometry data. This approach may complement current technologies to enhance patient-specific clinical decision-making.

Jerry Radich - One of the best experts on this subject based on the ideXlab platform.

  • Minimal Residual Disease in Allogeneic Recipients
    Allogeneic Stem Cell Transplantation, 2003
    Co-Authors: Jerry Radich
    Abstract:

    Relapse after stem cell transplant (SCT) is a major obstacle to cure. Sensitive methods can identify patients that harbor Minimal Residual Disease (MRD) while appearing in morphological remission after myeloablative therapy. Often, the detection of MRD is the harbinger of relapse in these patients. The study of MRD aims to differentiate patients with Residual leukemia destined for relapse as opposed to patients with stable or declining Residual Disease. Once identified, patients with a high risk of relapse could potentially undergo additional preemptive therapy to abort relapse.

  • Detection of Minimal Residual Disease in acute leukemia.
    Current opinion in hematology, 2000
    Co-Authors: Eric L. Sievers, Jerry Radich
    Abstract:

    A significant proportion of patients with acute leukemia who achieve remission subsequently experience frank relapse of their Disease, and their ultimate prognosis is typically poor. Although such Disease recurrences have been impossible to predict using standard laboratory techniques, new methods have been studied that identify patients destined to relapse. Sensitive polymerase chain reaction analyses of unique breakpoint fusion regions, and, in cases of acute lymphoblastic leukemia, patient-specific gene rearrangements have been used to detect Minimal Residual Disease. Multiparameter flow cytometry has also been used to identify rare leukemia cells among populations of predominantly normal cells. Because these types of studies in pediatric acute lymphoblastic leukemia have convincingly demonstrated that patients with evidence of Minimal Residual Disease during remission have a much higher incidence of relapse, therapeutic protocols have been initiated that intensify therapy for patients with Minimal Residual Disease detected during remission.

  • Advances in the detection of Minimal Residual Disease
    Current opinion in hematology, 1997
    Co-Authors: Jerry Radich, Blythe Thomson
    Abstract:

    The study of Minimal Residual Disease (MRD) is an attempt to detect and define the significance of leukemia invisible to normal morphologic examination. In many circumstances the clinical significance of MRD detection is unclear, because the technical ability to detect and quantify it has outpaced studies demonstrating its clinical significance. The detection of Minimal Residual Disease most consistently has been associated with relapse in acute lymphoblastic leukemia, t(15;17) acute myeloid leukemia, and chronic myeloid leukemia post-transplant, especially after T-cell depletion. But, in many types of leukemia, including acute myeloid leukemia and acute lymphoblastic leukemia, MRD can be detected in long-term remission patients without subsequent relapse. The study of MRD is evolving from detecting Residual Disease and predicting relapse to the study of the mechanisms that explain how minimum Residual Disease can coexist in a "cured" patient.

  • Detection of Minimal Residual Disease in acute and chronic leukemias.
    Current opinion in hematology, 1996
    Co-Authors: Jerry Radich
    Abstract:

    The study of Minimal Residual Disease is an attempt to redefine the concept of remission. Opinion as to the clinical utility of Minimal Residual Disease is still in evolution. It has become clear that the ability to merely detect Minimal Residual Disease by the polymerase chain reaction amplification of the molecular "fingerprint" of a leukemia does not always foretell relapse. Rather, careful consideration must be taken of the context of the type of Disease, the molecular lesion itself, and the type of therapy employed. Thus although the detection of Minimal Residual Disease in acute lymphoblastic leukemia or acute promyelocytic leukemia has a high correlation with relapse, detection of Minimal Residual Disease in t(8;21) acute myelogenous leukemia has little correlation with relapse. In some Diseases (eg. chronic myeloid leukemia) the clinical relevance of Minimal Residual Disease detection may be strengthened by quantification, although this in itself introduces another level of complexity and potential pitfalls. Nevertheless, we are moving toward the day when the molecular definition of Disease status will guide therapy.

  • Minimal Residual Disease.
    Current opinion in hematology, 1995
    Co-Authors: Jerry Radich
    Abstract:

    The study of Minimal Residual Disease has been fueled by the technologic advent of the polymerase chain reaction and basic developments identifying the genetic lesions involved in human malignancies. Thus far advances in identifying, cloning, and the subsequent polymerase chain reaction amplification of relevant genes have outpaced clinical studies designed to tell us the significance of Minimal Residual Disease. It has become clear that the mere detection of Minimal Residual Disease does not foretell relapse; thus, although the presence of Minimal Residual Disease in acute lymphoblastic leukemia and acute prolymphocytic leukemia appears to be associated with a high risk of relapse, the presence of Minimal Residual Disease in t(8;21) acute myeloid leukemia, chronic myeloid leukemia, and t(14;18) non-Hodgkin's lymphoma is not clearly associated with impending relapse. In most situations there is clearly a need for carefully controlled studies to evaluate the predictive value of Minimal Residual Disease.

Roland B. Walter - One of the best experts on this subject based on the ideXlab platform.

Alexander A. Morley - One of the best experts on this subject based on the ideXlab platform.

  • Application of the polymerase chain reaction to detection of Minimal Residual Disease
    Pathology, 1992
    Co-Authors: Alexander A. Morley
    Abstract:

    The exquisite sensitivity of the polymerase chain reaction makes it potentially possible to detect a small population of neoplastic cells provided that they contain DNA or RNA which differs from the nonneoplastic population. For haemopoietic cells, this situation obtains for translocations, for the rearranged immunoglobulin and T-cell receptor genes of B or T disorders, for mutated oncogenes such as ras, and for repetitive segments of DNA. In this presentation the technical aspects of detection of Minimal Residual Disease will be discussed using examples from the above areas. The clinical value of detection of Minimal Residual Disease is a separate issue which will be resolved over the next few years. However, it does seem likely that important information on the biology, treatment and prognosis of haematological neoplasms will be obtained.

Sarah A Buckley - One of the best experts on this subject based on the ideXlab platform.

  • Minimal Residual Disease prior to allogeneic hematopoietic cell transplantation in acute myeloid leukemia a meta analysis
    Haematologica, 2017
    Co-Authors: Sarah A Buckley, Brent L. Wood, Christopher S. Hourigan, Megan Othus, Celalettin Ustun, Michael A Linden, Todd E Defor, Michele Malagola, Chloe Anthias
    Abstract:

    Minimal Residual Disease prior to allogeneic hematopoietic cell transplantation has been associated with increased risk of relapse and death in patients with acute myeloid leukemia, but detection methodologies and results vary widely. We performed a systematic review and meta-analysis evaluating the prognostic role of Minimal Residual Disease detected by polymerase chain reaction or multiparametric flow cytometry before transplant. We identified 19 articles published between January 2005 and June 2016 and extracted hazard ratios for leukemia-free survival, overall survival, and cumulative incidences of relapse and non-relapse mortality. Pre-transplant Minimal Residual Disease was associated with worse leukemia-free survival (hazard ratio=2.76 [1.90-4.00]), overall survival (hazard ratio=2.36 [1.73-3.22]), and cumulative incidence of relapse (hazard ratio=3.65 [2.53-5.27]), but not non-relapse mortality (hazard ratio=1.12 [0.81-1.55]). These associations held regardless of detection method, conditioning intensity, and patient age. Adverse cytogenetics was not an independent risk factor for death or relapse. There was more heterogeneity among studies using flow cytometry-based than WT1 polymerase chain reaction-based detection (I2=75.1% vs. <0.1% for leukemia-free survival, 67.8% vs. <0.1% for overall survival, and 22.1% vs. <0.1% for cumulative incidence of relapse). These results demonstrate a strong relationship between pre-transplant Minimal Residual Disease and post-transplant relapse and survival. Outcome heterogeneity among studies using flow-based methods may underscore site-specific methodological differences or differences in test performance and interpretation.

  • Prognostic and therapeutic implications of Minimal Residual Disease at the time of transplantation in acute leukemia.
    Bone marrow transplantation, 2012
    Co-Authors: Sarah A Buckley, Roland B. Walter
    Abstract:

    Prognostic and therapeutic implications of Minimal Residual Disease at the time of transplantation in acute leukemia