Minimal residual disease prior to allogeneic hematopoietic cell transplantation in acute myeloid leukemia: a meta-analysis
TL;DR: A strong relationship between pre-transplant minimal residual disease and post-trans transplant relapse and survival is demonstrated and heterogeneity among studies using flow cytometry-based methods may underscore site-specific methodological differences or differences in test performance and interpretation.
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.
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VU University Medical Center1, Hannover Medical School2, University of Birmingham3, University of Rome Tor Vergata4, King's College London5, Cardiff University6, National Institutes of Health7, University of Texas MD Anderson Cancer Center8, Radboud University Nijmegen9, University of Oxford10, Fred Hutchinson Cancer Research Center11, University of Washington12, NewYork–Presbyterian Hospital13
TL;DR: The objective of this work was to identify key clinical and scientific issues in the measurement and application of MRD in AML, to achieve consensus on these issues, and to provide guidelines for the current and future use of MRd in clinical practice.
726 citations
National Institutes of Health1, Medical College of Wisconsin2, Harvard University3, Northside Hospital4, Fred Hutchinson Cancer Research Center5, Center for International Blood and Marrow Transplant Research6, Memorial Sloan Kettering Cancer Center7, West Virginia University8, Oregon Health & Science University9, University of Pennsylvania10, University of Minnesota11, Duke University12
TL;DR: Evidence is provided that MAC rather than RIC in patients with AML with genomic evidence of MRD before alloHCT can result in improved survival, and models of AML MRD also showed benefit for MAC over RIC for those who tested positive.
Abstract: PURPOSEPatients with acute myeloid leukemia (AML) in remission remain at risk for relapse even after allogeneic hematopoietic cell transplantation (alloHCT). AML measurable residual disease (MRD) s...
239 citations
TL;DR: Routine clinical use of MRD-testing requires further refinements and standardization/harmonization of assay platforms and results reporting, and convincing proof that a specific intervention will reduce relapse risk in persons with a positive MRd-test is lacking and needs testing in randomized trials.
Abstract: There is considerable interest in developing techniques to detect and/or quantify remaining leukaemia cells termed measurable or, less precisely, minimal residual disease (MRD) in persons with acute myeloid leukaemia (AML) in complete remission defined by cytomorphological criteria. An important reason for AML MRD-testing is the possibility of estimating the likelihood (and timing) of leukaemia relapse. A perfect MRD-test would precisely quantify leukaemia cells biologically able and likely to cause leukaemia relapse within a defined interval. AML is genetically diverse and there is currently no uniform approach to detecting such cells. Several technologies focused on immune phenotype or cytogenetic and/or molecular abnormalities have been developed, each with advantages and disadvantages. Many studies report a positive MRD-test at diverse time points during AML therapy identifies persons with a higher risk of leukaemia relapse compared with those with a negative MRD-test even after adjusting for other prognostic and predictive variables. No MRD-test in AML has perfect sensitivity and specificity for relapse prediction at the cohort- or subject levels and there are substantial rates of false-positive and -negative tests. Despite these limitations, correlations between MRD-test results and relapse risk have generated interest in MRD-test result-directed therapy interventions. However, convincing proof that a specific intervention will reduce relapse risk in persons with a positive MRD-test is lacking and needs testing in randomized trials. Routine clinical use of MRD-testing requires further refinements and standardization/harmonization of assay platforms and results reporting. Such data are needed to determine whether results of MRD-testing can be used as a surrogate end point in AML therapy trials. This could make drug-testing more efficient and accelerate regulatory approvals. Although MRD-testing in AML has advanced substantially, much remains to be done.
177 citations
TL;DR: The findings of this meta-analysis suggest that achievement of MRD negativity is associated with superior DFS and OS in patients with AML and support MRD status as an end point that may allow for accelerated evaluation of novel therapies in AML.
Abstract: Importance Measurable residual disease (MRD) refers to neoplastic cells that cannot be detected by standard cytomorphologic analysis. In patients with acute myeloid leukemia (AML), determining the association of MRD with survival may improve prognostication and inform selection of efficient clinical trial end points. Objective To examine the association between MRD status and disease-free survival (DFS) and overall survival (OS) in patients with AML using scientific literature. Data Sources Clinical studies on AML published between January 1, 2000, and October 1, 2018, were identified via searches of PubMed, Embase, and MEDLINE. Study Selection Literature search and study screening were performed according to the Preferred Reporting Items for Systematic Reviews and Meta-analyses guidelines. Studies that assessed DFS or OS by MRD status in patients with AML were included. Reviews, non–English-language articles, and studies reporting only outcomes after hematopoietic cell transplantation or those with insufficient description of MRD information were excluded. Data Extraction and Synthesis Study sample size, median patient age, median follow-up time, MRD detection method, MRD assessment time points, AML subtype, specimen source, and survival outcomes were extracted. Meta-analyses were performed separately for DFS and OS using bayesian hierarchical modeling. Main Outcomes and Measures Meta-analyses of survival probabilities and hazard ratios (HRs) were conducted for OS and DFS according to MRD status. Results Eighty-one publications reporting on 11 151 patients were included. The average HR for achieving MRD negativity was 0.36 (95% bayesian credible interval [CrI], 0.33-0.39) for OS and 0.37 (95% CrI, 0.34-0.40) for DFS. The estimated 5-year DFS was 64% for patients without MRD and 25% for those with MRD, and the estimated OS was 68% for patients without MRD and 34% for those with MRD. The association of MRD negativity with DFS and OS was significant for all subgroups, with the exception of MRD assessed by cytogenetics or fluorescent in situ hybridization. Conclusions and Relevance The findings of this meta-analysis suggest that achievement of MRD negativity is associated with superior DFS and OS in patients with AML. The value of MRD negativity appears to be consistent across age groups, AML subtypes, time of MRD assessment, specimen source, and MRD detection methods. These results support MRD status as an end point that may allow for accelerated evaluation of novel therapies in AML.
158 citations
TL;DR: A trial in which post-remission therapy of young patients with de novo AML was decided combining cytogenetics/genetics and post-consolidation levels of minimal residual disease, AuSCT may still have a role in FR and IR MRD-negative categories and ASCT prolongs OS and DFS to equal those of the FR category.
120 citations
References
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TL;DR: A new quantity is developed, I 2, which the authors believe gives a better measure of the consistency between trials in a meta-analysis, which is susceptible to the number of trials included in the meta- analysis.
Abstract: Cochrane Reviews have recently started including the quantity I 2 to help readers assess the consistency of the results of studies in meta-analyses. What does this new quantity mean, and why is assessment of heterogeneity so important to clinical practice?
Systematic reviews and meta-analyses can provide convincing and reliable evidence relevant to many aspects of medicine and health care.1 Their value is especially clear when the results of the studies they include show clinically important effects of similar magnitude. However, the conclusions are less clear when the included studies have differing results. In an attempt to establish whether studies are consistent, reports of meta-analyses commonly present a statistical test of heterogeneity. The test seeks to determine whether there are genuine differences underlying the results of the studies (heterogeneity), or whether the variation in findings is compatible with chance alone (homogeneity). However, the test is susceptible to the number of trials included in the meta-analysis. We have developed a new quantity, I 2, which we believe gives a better measure of the consistency between trials in a meta-analysis.
Assessment of the consistency of effects across studies is an essential part of meta-analysis. Unless we know how consistent the results of studies are, we cannot determine the generalisability of the findings of the meta-analysis. Indeed, several hierarchical systems for grading evidence state that the results of studies must be consistent or homogeneous to obtain the highest grading.2–4
Tests for heterogeneity are commonly used to decide on methods for combining studies and for concluding consistency or inconsistency of findings.5 6 But what does the test achieve in practice, and how should the resulting P values be interpreted?
A test for heterogeneity examines the null hypothesis that all studies are evaluating the same effect. The usual test statistic …
45,105 citations
TL;DR: It is concluded that H and I2, which can usually be calculated for published meta-analyses, are particularly useful summaries of the impact of heterogeneity, and one or both should be presented in publishedMeta-an analyses in preference to the test for heterogeneity.
Abstract: The extent of heterogeneity in a meta-analysis partly determines the difficulty in drawing overall conclusions. This extent may be measured by estimating a between-study variance, but interpretation is then specific to a particular treatment effect metric. A test for the existence of heterogeneity exists, but depends on the number of studies in the meta-analysis. We develop measures of the impact of heterogeneity on a meta-analysis, from mathematical criteria, that are independent of the number of studies and the treatment effect metric. We derive and propose three suitable statistics: H is the square root of the chi2 heterogeneity statistic divided by its degrees of freedom; R is the ratio of the standard error of the underlying mean from a random effects meta-analysis to the standard error of a fixed effect meta-analytic estimate, and I2 is a transformation of (H) that describes the proportion of total variation in study estimates that is due to heterogeneity. We discuss interpretation, interval estimates and other properties of these measures and examine them in five example data sets showing different amounts of heterogeneity. We conclude that H and I2, which can usually be calculated for published meta-analyses, are particularly useful summaries of the impact of heterogeneity. One or both should be presented in published meta-analyses in preference to the test for heterogeneity.
25,460 citations
"Minimal residual disease prior to a..." refers background in this paper
...5 (normalized to WT1 25 11 10 (3-22) 100%...
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...MFC (LAIP) BM MFC: limit of detection 110 20 26 (3-54) 100%...
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...or PCR (fusion genes, multiple) PCR: limit of detection MRD 19 (6-36)...
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...MFC (LAIP, 4-color) BM Limit of detection 21 32 MRD 31 (15-55) NR MRD 32 (16-58)...
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...PCR (WT1, multi-gene) PB Different for each gene 38 10 MRD 34 (12-59) 89% MRD MRD 34 (16-53) 100% MRD...
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TL;DR: This practical guide should improve the quality of the analysis and subsequent interpretation of systematic reviews and meta-analyses that include time-to-event outcomes and provide a corresponding, easy- to-use calculations spreadsheet, to facilitate the computational aspects.
Abstract: In systematic reviews and meta-analyses, time-to-event outcomes are most appropriately analysed using hazard ratios (HRs). In the absence of individual patient data (IPD), methods are available to obtain HRs and/or associated statistics by carefully manipulating published or other summary data. Awareness and adoption of these methods is somewhat limited, perhaps because they are published in the statistical literature using statistical notation. This paper aims to 'translate' the methods for estimating a HR and associated statistics from published time-to-event-analyses into less statistical and more practical guidance and provide a corresponding, easy-to-use calculations spreadsheet, to facilitate the computational aspects. A wider audience should be able to understand published time-to-event data in individual trial reports and use it more appropriately in meta-analysis. When faced with particular circumstances, readers can refer to the relevant sections of the paper. The spreadsheet can be used to assist them in carrying out the calculations. The methods cannot circumvent the potential biases associated with relying on published data for systematic reviews and meta-analysis. However, this practical guide should improve the quality of the analysis and subsequent interpretation of systematic reviews and meta-analyses that include time-to-event outcomes.
4,641 citations
"Minimal residual disease prior to a..." refers background in this paper
...5 (normalized to WT1 25 11 10 (3-22) 100%...
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...MFC (LAIP) BM MFC: limit of detection 110 20 26 (3-54) 100%...
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...or PCR (fusion genes, multiple) PCR: limit of detection MRD 19 (6-36)...
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...MFC (LAIP, 4-color) BM Limit of detection 21 32 MRD 31 (15-55) NR MRD 32 (16-58)...
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...PCR (WT1, multi-gene) PB Different for each gene 38 10 MRD 34 (12-59) 89% MRD MRD 34 (16-53) 100% MRD...
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University of Ulm1, University of Rome Tor Vergata2, Fred Hutchinson Cancer Research Center3, University of Münster4, University of Wales5, University of Chicago6, Nagoya University7, Leipzig University8, VU University Medical Center9, Northwestern University10, Erasmus University Medical Center11, Ohio State University12
TL;DR: An international expert panel is provided to provide updated evidence- and expert opinion-based recommendations for the diagnosis and management of AML, that contain both minimal requirements for general practice as well as standards for clinical trials.
3,000 citations
Additional excerpts
...5 (normalized to WT1 25 11 10 (3-22) 100%...
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...MFC (LAIP) BM MFC: limit of detection 110 20 26 (3-54) 100%...
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...PCR (WT1) PB or BM 5×10 normalized 17 23 MRD 4 (1-21) 100%...
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TL;DR: An International Working Group met to revise the diagnostic and response criteria for acute myelogenous leukemia originally published in 1990, as well as to provide definitions of outcomes and reporting standards to improve interpretability of data and comparisons among trials as mentioned in this paper.
Abstract: An International Working Group met to revise the diagnostic and response criteria for acute myelogenous leukemia originally published in 1990, as well as to provide definitions of outcomes and reporting standards to improve interpretability of data and comparisons among trials. Since the original publication, there have been major advances in our understanding of the biology and molecular genetics of acute leukemia that are clinically relevant and warrant incorporation into response definitions. Differences from the 1990 recommendations included a category of leukemia-free state, new criteria for complete remission, including cytogenetic and molecular remissions and remission duration. Storage of viable blasts for correlative studies is important for future progress in the therapy of these disorders.
2,474 citations