scholarly journals Can Minimal Residual Disease Determination in Acute Myeloid Leukemia Be Used in Clinical Practice?

2017 ◽  
Vol 13 (8) ◽  
pp. 471-480 ◽  
Author(s):  
Marlise R. Luskin ◽  
Richard M. Stone
Keyword(s):  
Acute Myeloid Leukemia ◽  
Clinical Practice ◽  
Minimal Residual Disease ◽  
Myeloid Leukemia ◽  
Residual Disease ◽  
Multiparameter Flow Cytometry ◽  
Term Survival ◽  
The Impact ◽  
Minimal Residual ◽  
Acute Myeloid

In acute myeloid leukemia (AML) that is in complete remission, minimal residual disease (MRD) is presumed to be present, though not morphologically evident. Advances in diagnostics now permit the detection and quantification of MRD in AML by several techniques. The level of MRD after induction and consolidation therapy correlates with disease sensitivity to chemotherapy and has greater power to predict long-term survival than patient and disease characteristics that are available at diagnosis, including genetic information. A unique advantage of MRD is that it is an integrated measure of the impact and interaction of genetics, epigenetics, host immune milieu, bone marrow environment, and drug sensitivity on disease response to treatment. Here, we review the main techniques for MRD assessment in AML, including polymerase chain reaction, multiparameter flow cytometry, and next-generation sequencing, with a focus on method-specific and general limitations to the optimal employment of MRD techniques for the determination of AML prognosis. We also review the data that establish the prognostic and predictive value of MRD assessment in AML. Finally, we provide recommendations for the use of MRD in the care of patients with AML in clinical practice today, including whether it should influence treatment decisions.

Defining minimal residual disease in acute myeloid leukemia: which platforms are ready for “prime time”?

Blood ◽  
2014 ◽  
Vol 124 (23) ◽  
pp. 3345-3355 ◽  
Author(s):  
David Grimwade ◽  
Sylvie D. Freeman
Keyword(s):  
Acute Myeloid Leukemia ◽  
Minimal Residual Disease ◽  
Myeloid Leukemia ◽  
Residual Disease ◽  
Multiparameter Flow Cytometry ◽  
Molecular Heterogeneity ◽  
Prognostic Information ◽  
Reliable Determination ◽  
Minimal Residual ◽  
Acute Myeloid

Abstract The past 40 years have witnessed major advances in defining the cytogenetic aberrations, mutational landscape, epigenetic profiles, and expression changes underlying hematological malignancies. Although it has become apparent that acute myeloid leukemia (AML) is highly heterogeneous at the molecular level, the standard framework for risk stratification guiding transplant practice in this disease remains largely based on pretreatment assessment of cytogenetics and a limited panel of molecular genetic markers, coupled with morphological assessment of bone marrow (BM) blast percentage after induction. However, application of more objective methodology such as multiparameter flow cytometry (MFC) has highlighted the limitations of morphology for reliable determination of remission status. Moreover, there is a growing body of evidence that detection of subclinical levels of leukemia (ie, minimal residual disease, MRD) using MFC or molecular-based approaches provides powerful independent prognostic information. Consequently, there is increasing interest in the use of MRD detection to provide early end points in clinical trials and to inform patient management. However, implementation of MRD assessment into clinical practice remains a major challenge, hampered by differences in the assays and preferred analytical methods employed between routine laboratories. Although this should be addressed through adoption of standardized assays with external quality control, it is clear that the molecular heterogeneity of AML coupled with increasing understanding of its clonal architecture dictates that a “one size fits all” approach to MRD detection in this disease is not feasible. However, with the range of platforms now available, there is considerable scope to realistically track treatment response in every patient.

Allogeneic Hematopoietic Stem Cell Transplantation Overcomes the Adverse Prognostic Impact of Minimal Residual Disease in Acute Myeloid Leukemia

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 2027-2027
Author(s):  
Betul Oran ◽  
Timothy Singleton ◽  
Pablo A. Ramirez ◽  
Ryan Shanley ◽  
Claudio Brunstein ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Minimal Residual Disease ◽  
Myeloid Leukemia ◽  
Residual Disease ◽  
Prognostic Impact ◽  
Hematopoietic Stem ◽  
Disease Outcomes ◽  
The Impact ◽  
Minimal Residual ◽  
Acute Myeloid

Abstract Abstract 2027 BACKGROUND: The identification of minimal residual disease (MRD) can predict impending relapse in acute myeloid leukemia (AML) patients. Little data exists evaluating the prognostic impact of MRD, as determined by multiparametric flow cytometry (MFC), at the time of allogeneic (allo-HCT). Although disease outcomes may be worse for MRD positive (MRD+) patients, MRD is often associated with other adverse risk factors leaving it unclear whether MRD is an independent risk factor for relapse or a surrogate marker for underlying poor risk disease features. METHODS: We retrospectively analyzed 97 consecutive AML patients in complete morphological remission (CR) who underwent allo-HCT with a matched related donor (MRD, n=30, 31%), matched unrelated donor (MUD, n=4, 4%) or umbilical cord blood (UCB, n=63, 65%) at the University of Minnesota between January 2005 and June 2009. Presence of MRD at allo-HCT was determined by MFC. Analyses were done separately for myeloablative (MAC) and reduced intensity conditioning (RIC) patients, testing the impact of MRD along with conditioning intensity, age, donor type and disease status on allo-HCT outcomes. RESULTS: Of 97 patients, 41 (42%) had MAC; 57 (58%) had RIC. Sixty-six were in first CR (CR1) with the rest in CR2 or later remission (CR2+). MRD at allo-HCT was detected in 7 patients after MAC (17%) and 7 after RIC (12.5%); and this frequency was similar in patients in CR1 and CR2+ (13% vs. 16%, p=0.7). MRD+ and MRD- patients had similar median age (40 vs. 44 yrs), gender, donor source (MSD or MUD vs. UCB), CMV serostatus and diagnostic cytogenetic risk group. Six of 40 (15%) intermediate and 5 of 39 (13%) high risk cytogenetics patients had MRD+ (p=0.8). Only 3 of 53 patients with a cytogenetic abnormality at diagnosis had it detected prior allo-HCT and 1 of 3 had MRD. The median follow-up of survivors was 25 months. Two-year probabilities for MAC and RIC patients were similar: Overall survival (OS), 48% and 47 % and leukemia free survival (LFS) 43% and 41% respectively. When disease outcomes were analyzed separately by MRD status (table), OS and LFS were markedly worse in MRD+ patients receiving RIC, but this difference was not statistically significant. In multivariate analysis, MRD+ was not an independent prognostic factor for OS and LFS. Although we identified no adverse prognostic factors for MAC patients, patient with RIC in CR2+ had worse OS and LFS vs. CR1 (HR 2.6, p=0.04 and HR 2.7, p=0.04 respectively). CONCLUSION: The negative prognostic impact of MRD was overcome by allo-HCT with MAC, but outcomes with MRD+ were suggestively inferior after RIC. However due to limited sample size, MRD in patients with RIC should be further investigated. Disclosures: Weisdorf: Genzyme: Consultancy, Research Funding.

scholarly journals Defining minimal residual disease in acute myeloid leukemia: which platforms are ready for “prime time”?

Hematology ◽  
2014 ◽  
Vol 2014 (1) ◽  
pp. 222-233 ◽  
Author(s):  
David Grimwade ◽  
Sylvie D. Freeman
Keyword(s):  
Acute Myeloid Leukemia ◽  
Minimal Residual Disease ◽  
Myeloid Leukemia ◽  
Residual Disease ◽  
Multiparameter Flow Cytometry ◽  
Molecular Heterogeneity ◽  
Prognostic Information ◽  
Reliable Determination ◽  
Minimal Residual ◽  
Acute Myeloid

Abstract The past 40 years have witnessed major advances in defining the cytogenetic aberrations, mutational landscape, epigenetic profiles, and expression changes underlying hematological malignancies. Although it has become apparent that acute myeloid leukemia (AML) is highly heterogeneous at the molecular level, the standard framework for risk stratification guiding transplant practice in this disease remains largely based on pretreatment assessment of cytogenetics and a limited panel of molecular genetic markers, coupled with morphological assessment of bone marrow (BM) blast percentage after induction. However, application of more objective methodology such as multiparameter flow cytometry (MFC) has highlighted the limitations of morphology for reliable determination of remission status. Moreover, there is a growing body of evidence that detection of subclinical levels of leukemia (ie, minimal residual disease, MRD) using MFC or molecular-based approaches provides powerful independent prognostic information. Consequently, there is increasing interest in the use of MRD detection to provide early end points in clinical trials and to inform patient management. However, implementation of MRD assessment into clinical practice remains a major challenge, hampered by differences in the assays and preferred analytical methods employed between routine laboratories. Although this should be addressed through adoption of standardized assays with external quality control, it is clear that the molecular heterogeneity of AML coupled with increasing understanding of its clonal architecture dictates that a “one size fits all” approach to MRD detection in this disease is not feasible. However, with the range of platforms now available, there is considerable scope to realistically track treatment response in every patient.

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