Association Between Measurable Residual Disease in Patients With Intermediate-Risk Acute Myeloid Leukemia and First Remission, Treatment, and Outcomes.
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SUBMITTER: Yu S
PROVIDER: S-EPMC8264648 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:We aimed to investigate outcomes of different post-remission treatment (PRT) choices based on dynamic measurable residual disease (MRD) by multiparameter flow cytometry in favorable-risk AML (FR-AML). Four hundred and three younger patients with FR-AML in first complete remission (CR1) were enrolled in this registry-based cohort study, including 173 who received chemotherapy (CMT), 92 autologous stem cell transplantation (auto-SCT), and 138 allogeneic SCT (allo-SCT). The primary endpoint was the 5-year overall survival (OS). Subgroup analyses were performed based on dynamic MRD after the 1st, 2nd, and 3rd courses of chemotherapy. In subgroups of patients with negative MRD after 1 or 2 course of chemotherapy, comparable OS was observed among the CMT, auto-SCT, and allo-SCT groups (p = 0.340; p = 0.627, respectively). But CMT and auto-SCT had better graft-versus-host-disease-free, relapse-free survival (GRFS) than allo-SCT in both subgroups. For patients with negative MRD after three courses of chemotherapy, allo-SCT had better disease-free-survival than CMT (p = 0.009). However, OS was comparable among the three groups (p = 0.656). For patients with persistently positive MRD after 3 courses of chemotherapy or recurrent MRD, allo-SCT had better OS than CMT and auto-SCT (p = 0.011; p = 0.029, respectively). Dynamic MRD might improve therapy stratification and optimize PRT selection for FR-AML in CR1.
| S-EPMC8648754 | biostudies-literature
Project description:ObjectivesThis study retrospectively investigated in which cycle measurable residual disease (MRD) is associated with prognosis in patients in first complete remission (CR1) of intermediate-risk acute myeloid leukemia (AML).MethodsThe study enrolled 235 younger patients with intermediate-risk AML. MRD was evaluated by multiparameter flow cytometry after the 1st, 2nd, and 3rd chemotherapy cycles (MRD1-3, respectively).ResultsNo significant association was detected after the 1st and 2nd cycles. However, the 5-year incidence of relapse was higher in the MRD3-positive group (n = 99) than in the negative group (n = 136) (48.7% vs. 13.7%, P = 0.005), while 5-year disease-free survival (DFS) and overall survival (OS) were lower in the MRD3-positive group than in the negative group (43.2% vs. 81.0% and 45.4% vs. 84.1%; P = 0.003 and 0.005, respectively). Allogeneic hematopoietic stem cell transplantation led to a lower 5-year relapse, and higher DFS and OS rates than chemotherapy in the MRD3-positive group (22.3% vs. 71.5%, 65.9% vs. 23.0%, and 67.1% vs. 23.9%; P < 0.001, 0.002, and 0.022, respectively), but did not affect the MRD-negative group.ConclusionsMRD3 could serve as an indicator for post-remission treatment choice and help improve outcomes for intermediate-risk AML in CR1.
| S-EPMC9668963 | biostudies-literature
Project description:Mounting evidence suggests measurable residual disease (MRD) assessments are prognostic in acute myeloid leukemia (AML). High-risk AML encompasses a subset of AML with poor response to therapy and prognosis, with features such as therapy-related AML, an antecedent hematologic disorder, extramedullary disease (in adults), and selected mutations and cytogenetic abnormalities. Historically, few patients with high-risk AML achieved deep and durable remission with conventional chemotherapy; however, newer agents might be more effective in achieving MRD-negative remission. CPX-351 (dual-drug liposomal encapsulation of daunorubicin/cytarabine at a synergistic ratio) demonstrated MRD-negativity rates of 36-64% across retrospective studies in adults with newly diagnosed high-risk AML and 84% in pediatric patients with first-relapse AML. Venetoclax (BCL2 inhibitor) demonstrated MRD-negativity rates of 33-53% in combination with hypomethylating agents for high-risk subgroups in studies of older adults with newly diagnosed AML who were ineligible for intensive therapy and 65% in combination with chemotherapy in pediatric patients with relapsed/refractory AML. However, there is no consensus on optimal MRD methodology in AML, and the use of different techniques, sample sources, sensitivity thresholds, and the timing of assessments limit comparisons across studies. Robust MRD analyses are needed in future clinical studies, and MRD monitoring should become a routine aspect of AML management.
| S-EPMC8909238 | biostudies-literature
Project description:PURPOSE:Measurable residual disease (MRD) has prognostic importance for patients with acute myeloid leukemia (AML). How leukemia providers incorporate MRD into routine practice remains undefined. PATIENTS AND METHODS:A survey was developed and distributed to a large sample of leukemia physicians. Demographic information was collected along with details concerning MRD practices. A multivariable logistic regression model evaluated provider characteristics predictive of MRD utilization. RESULTS:268 responses were received (response rate of 41%). 69% of providers reported routine use of MRD in management of AML, most commonly (90%) for its role in guiding therapy; providers who did not use MRD routinely most frequently cited inadequate resources (58%). Providers utilized flow cytometry- more than polymerase chain reaction-based assays with nucleophosmin-1 being the most common target with the latter. We found substantial variability in how MRD affected clinical decision making, particularly in pre- and post-transplant scenarios. CONCLUSIONS:MRD was frequently used in making treatment decisions and in estimating prognosis. However, there was lack of uniformity in these practices. Standardization of assays, adoption of requisite technology, and dissemination of data about the value of MRD use would likely increase usage of MRD in the care of patients with AML.
| S-EPMC7029617 | biostudies-literature
Project description:ImportanceMeasurable 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.ObjectiveTo examine the association between MRD status and disease-free survival (DFS) and overall survival (OS) in patients with AML using scientific literature.Data sourcesClinical studies on AML published between January 1, 2000, and October 1, 2018, were identified via searches of PubMed, Embase, and MEDLINE.Study selectionLiterature 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 synthesisStudy 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 measuresMeta-analyses of survival probabilities and hazard ratios (HRs) were conducted for OS and DFS according to MRD status.ResultsEighty-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 relevanceThe 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.
| S-EPMC7545346 | biostudies-literature
Project description:Quantification of measurable residual disease (MRD) provides critical prognostic information in acute myeloid leukemia (AML). A variety of platforms exist for MRD detection, varying in their sensitivity and applicability to individual patients. MRD detected by quantitative polymerase chain reaction, multiparameter flow cytometry, or next-generation sequencing has prognostic implications in various subsets of AML and at various times throughout treatment. While it is overwhelmingly evident that minute levels of remnant disease confer increased risk of relapse and shortened survival, the therapeutic implications of MRD remain less clear. The use of MRD as a guide to selecting the most optimal post-remission therapy, including hematopoietic stem cell transplant or maintenance therapy with hypomethylating agents, small molecule inhibitors, or immunotherapy is an area of active investigation. In addition, whether there are sufficient data to use MRD negativity as a surrogate endpoint in clinical trial development is controversial. In this review, we will critically examine the methods used to detect MRD, its role as a prognostic biomarker, MRD-directed therapeutics, and its potential role as a study endpoint.
| S-EPMC8417965 | biostudies-literature
Project description:Curative-intent therapy leads to complete remissions in many adults with acute myeloid leukemia (AML), but relapse remains common. Numerous studies have unequivocally demonstrated that the persistence of measurable ('minimal') residual disease (MRD) at the submicroscopic level during morphologic remission identifies patients at high risk of disease recurrence and short survival. This association has provided the impetus to customize anti-leukemia therapy based on MRD data, a strategy that is now routinely pursued in acute promyelocytic leukemia (APL). While it is currently uncertain whether this approach will improve outcomes in AML other than APL, randomized studies have validated MRD-based risk-stratified treatment algorithms in acute lymphoblastic leukemia. Here, we review the available studies examining MRD-directed therapy in AML, appraise their strengths and limitations, and discuss avenues for future investigation.
| S-EPMC4968046 | biostudies-literature
Project description:Assessment of measurable residual disease (MRD) upon treatment of acute myeloid leukemia (AML) remains challenging. It is usually addressed by highly sensitive PCR- or sequencing-based screening of specific mutations, or by multiparametric flow cytometry. However, not all patients have suitable mutations and heterogeneity of surface markers hampers standardization in clinical routine. In this study, we propose an alternative approach to estimate MRD based on AML-associated DNA methylation (DNAm) patterns. We identified four CG dinucleotides (CpGs) that commonly reveal aberrant DNAm in AML and their combination could reliably discern healthy and AML samples. Interestingly, bisulfite amplicon sequencing demonstrated that aberrant DNAm patterns were symmetric on both alleles, indicating that there is epigenetic crosstalk between homologous chromosomes. We trained shallow-learning and deep-learning algorithms to identify anomalous DNAm patterns. The method was then tested on follow-up samples with and without MRD. Notably, even samples that were classified as MRD negative often revealed higher anomaly ratios than healthy controls, which may reflect clonal hematopoiesis. Our results demonstrate that targeted DNAm analysis facilitates reliable discrimination of malignant and healthy samples. However, since healthy samples also comprise few abnormal-classified DNAm reads the approach does not yet reliably discriminate MRD positive and negative samples.
| S-EPMC8727289 | biostudies-literature
Project description:Measurable residual disease (MRD) detected by multiparametric flow cytometry (MFC) is associated with unfavorable outcome in patients with AML. A simple, broadly applicable eight-color panel was implemented and analyzed utilizing a hierarchical gating strategy with fixed gates to develop a clear-cut LAIP-based DfN approach. In total, 32 subpopulations with aberrant phenotypes with/without expression of markers of immaturity were monitored in 246 AML patients after completion of induction chemotherapy. Reference values were established utilizing 90 leukemia-free controls. Overall, 73% of patients achieved a response by cytomorphology. In responders, the overall survival was shorter for MRDpos patients (HR 3.8, p = 0.006). Overall survival of MRDneg non-responders was comparable to MRDneg responders. The inter-rater-reliability for MRD detection was high with a Krippendorffs α of 0.860. The mean time requirement for MRD analyses at follow-up was very short with 04:31 minutes. The proposed one-tube MFC approach for detection of MRD allows a high level of standardization leading to a promising inter-observer-reliability with a fast turnover. MRD defined by this strategy provides relevant prognostic information and establishes aberrancies outside of cell populations with markers of immaturity as an independent risk feature. Our results imply that this strategy may provide the base for multicentric immunophenotypic MRD assessment.
| S-EPMC9417981 | biostudies-literature
Project description:Considerable progress has been made in the past several years in the scientific understanding of, and available treatments for, acute myeloid leukemia (AML). Achievement of a conventional remission, evaluated cytomorphologically via small bone marrow samples, is a necessary but not sufficient step toward cure. It is increasingly appreciated that molecular or immunophenotypic methods to identify and quantify measurable residual disease (MRD) - populations of leukemia cells below the cytomorphological detection limit - provide refined information on the quality of response to treatment and prediction of the risk of AML recurrence and leukemia-related deaths. The principles and practices surrounding MRD remain incompletely determined however and the genetic and immunophenotypic heterogeneity of AML may prevent a one-sizefits- all approach. Here, we review the current approaches to MRD testing in AML, discuss strengths and limitations, highlight recent technological advances that may improve such testing, and summarize ongoing initiatives to generate the clinical evidence needed to advance the use of MRD testing in patients with AML.
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