Defining consensus leukemia-associated immunophenotypes for detection of minimal residual disease in acute myeloid leukemia in a multicenter setting

Feller, N; Velden, Vincent H.J. van der; Brooimans, Rik A.; Boeckx, Nancy; Preijers, Frank; Kelder, Angèle; Greef, Inge de; Westra, Guus; Marvelde, Jeroen G. te; Aerts, Patrik; Wind, Henk; Leenders, Marij; Gratama, Jan-Willem; Schuurhuis, Gerrit Jan

doi:10.1038/bcj.2013.27

Cited by 65 publications

(59 citation statements)

References 18 publications

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“…It is likely that stronger standardization of MFC-MRD assays will evolve from networked centralized laboratories such as in European initiatives (eg, Feller et al 35 ), taking into account the differences between pediatric and adult AML for the specificity and frequency of aberrancies. Improved selection and analysis of leukemic aberrancies could be achieved by Web-based access to international interlaboratory shared resources of the most useful robust LAIPs/ different-from-normal profiles/analysis strategy, together with agreement to test newer combinations.…”

Section: Standardization Of Mfc-mrdmentioning

confidence: 99%

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

Grimwade

Freeman

2014

Blood

232

212

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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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Section: Standardization Of Mfc-mrdmentioning

confidence: 99%

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

Grimwade

Freeman

2014

Blood

232

212

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“…4, [40][41][42][43][44] In light of these limitations, we would highly encourage the research community to work toward standardized methods for the detection and monitoring of MRD levels and use them as soon as they become available, and to conduct well controlled, ideally randomized trials for evaluating the value of MRD-directed treatment escalation or de-escalation in AML. Recent studies in acute lymphoblastic leukemia demonstrate that such trials are feasible and can provide definitive evidence that modification of postremission treatment intensity based on MRD status can optimize treatment outcomes.…”

Section: Resultsmentioning

confidence: 99%

Minimal residual disease–directed therapy in acute myeloid leukemia

Käyser

Schlenk

Grimwade

et al. 2015

Blood

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Case 1: A 35-year-old man with a normal white blood cell (WBC) count (9.3 3 10 9 /L) was diagnosed with acute myeloid leukemia (AML) with a t(8;21)(q22;q22) translocation in 25/25 metaphases. The RUNX1-RUNX1T1 fusion gene was detected by real-time quantitative polymerase chain reaction (PCR), whereas studies for mutations involving KIT and FLT3 were negative. After 1 cycle of induction therapy with cytarabine/idarubicin according to the "713" schema, he achieved a morphologic complete remission (CR) with a 2-log reduction of RUNX1-RUNX1T1 transcript levels. The patient has an excellent performance status and no comorbidities. Should you recommend allogeneic hematopoietic cell transplantation (HCT)?Case 2: A 43-year-old woman was diagnosed with cytogenetically normal AML; molecular studies for gene mutations involving NPM1, CEBPA, and FLT3 were negative. After standard induction chemotherapy, she achieved a morphologic CR and then underwent 1 cycle of consolidation therapy with high-dose cytarabine. During the pre-HCT work-up in anticipation of matched related donor transplant, she is found to have evidence of minimal residual disease (MRD) by multiparameter flow cytometry (MFC); no prior MFC studies are available. She has no comorbidities other than arterial hypertension, and her performance status is excellent. Are you recommending additional cycle(s) of chemotherapy to attempt MRD eradication before HCT? IntroductionIn recent years, several methods have been developed to detect submicroscopic MRD in AML patients in morphologic remission.1-4 The existence of small numbers of leukemic cells among normal hematopoietic cells can be identified based on numeric or structural chromosomal changes, gene mutations, antigen receptor rearrangements, abnormal gene expression, altered cell growth, and immunophenotypic abnormalities. Thus far, most exploited for MRD detection and quantification in AML are MFC-and PCR-based approaches, which can achieve sensitivities up to 10 25 to 10 26. 1-5 MFC has gained popularity for the detection of MRD in AML because it can be applied to the vast majority of AML patients, although the identification of immunophenotypic abnormalities can be challenging, especially if a diagnostic specimen is not available or the disease has evolved over time. PCR-based approaches are typically limited to specific patient subsets, but recent methodologic advances (eg, based on next generation sequencing or digital PCR) allow leukemia-associated mutations to be tracked more comprehensively, thereby broadening the scope of molecular MRD detection (defined in this study as the detection of chimeric fusion genes, somatic mutations, or aberrant gene expression).For several reasons, including variations in health care provision and laboratory infrastructures between countries and, perhaps, the fluidity with which MRD detection methodologies are evolving, implementation of standardized MRD assessments into clinical practice has remained a major challenge. Nevertheless, increasing evidence indicates that the pre...

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“…However, interpretation of MFC for MRD detection is technically demanding and highly individualized, since it is dependent on the expertise and experience of the reference laboratory [8•,15,18]. Increased accuracy and sensitivity of MRD detection can be obtained by incorporation of more antibodies and automated analysis algorithms for the detection of an abnormal cell [18]; albeit cost-effectiveness has so far not been systematically evaluated. Leukemic cells are quantified relative to other cells in the specimen; hence, the smallest cell cluster, judged as MRD positive, depends on the total number of analyzed cells.…”

Section: Mrd Detection By Mfcmentioning

confidence: 99%

Minimal Residual Disease in Acute Myeloid Leukemia—Current Status and Future Perspectives

Käyser

Walter

Stock

et al. 2015

Curr Hematol Malig Rep

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In acute myeloid leukemia (AML), the achievement of a morphological complete remission (CR) is an important milestone on the road to cure. Still, the majority of patients who achieve a morphological CR will eventually relapse. Thus, morphological means are not sensitive enough to detect clinically relevant tumor burdens left behind after therapy. Over the last years, several methodologies, particularly multiparameter flow cytometry and polymerase chain reaction, have emerged that can detect, quantify, and monitor submicroscopic amounts of leukemia cells ("minimal residual disease", MRD). Newer techniques, such as next-generation sequencing, have not only changed our understanding of the molecular pathogenesis and clonal heterogeneity of AML but may also be used for MRD detection. Increasing evidence indicates that MRD could play an important role in dynamically refining disease risk and, perhaps, serve to fine-tune post-remission therapy in a risk-adapted manner, although the latter concept awaits validation through well-controlled trials. In this review, we discuss the current use of MRD measurements during AML treatment and highlight future perspectives.

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Defining consensus leukemia-associated immunophenotypes for detection of minimal residual disease in acute myeloid leukemia in a multicenter setting

Cited by 65 publications

References 18 publications

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

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

Minimal residual disease–directed therapy in acute myeloid leukemia

Minimal Residual Disease in Acute Myeloid Leukemia—Current Status and Future Perspectives

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