Deoxyribonucleic acid (DNA) methyltransferase 3A (DNMT3A) mutation testing should be included as a biomarker test in cytogenetically normal acute myeloid leukemia (AML) patients.
Acute myeloid leukemia (AML)
To determine if testing for deoxyribonucleic acid (DNA) methyltransferase 3A (DNMT3A) mutation in cytogenetically normal patient population with acute myeloid leukemia (AML) determines prognosis with standard indication and consolidation therapy, as a guide to choosing alternative treatment if appropriate
Acute myeloid leukemia (AML) patients with a normal cytogenetic profile
Deoxyribonucleic acid (DNA) methyltransferase 3A (DNMT3A) mutation testing
- Overall survival
- Disease-free survival
- Relapse-free survival
- Event-free survival
- Complete remission
Hand-searches of Published Literature (Primary Sources)
Hand-searches of Published Literature (Secondary Sources)
Searches of Electronic Databases
Searches of Unpublished Data
Literature Search Strategy
The primary search is up to date as of July 26, 2012. Published literature was retrieved via searching the following electronic databases: MEDLINE (1946 to July Week 3, 2012) with in-process records and other non-indexed citations and daily updates via Ovid (July 25, 2012); EMBASE (1980 to Week 29, 2012) via Ovid; and The Cochrane Central Register of Controlled Trials (2012, Issue 7) via Ovid. Terms used were related to AML (acute myeloid leukemia OR acute myelogenous leukemia OR acute myelocytic leukemia) and DNMT3A (DNA methyltransferase 3A OR DNA [cytosine-5]-methyltransferase 3A human OR DNMT3A protein).
Study Selection Criteria and Protocol
Studies must have included cytogenetically normal (CN) patients stratified to the intermediate-risk group. Pediatric AML was not included for analysis (<15 years of age); no upper age limit was specified. Comparators under investigation were normal cytogenetic risk groups defined with the DNMT3A mutation versus normal cytogenetic risk groups without the DNMT3A mutation (wild type). The exact nature of the treatment administered was not of primary interest but was documented if the study provided the information. Primary outcomes of interest include overall survival (OS), complete remission (CR), cumulative incidence of relapse (CIR) and relapse-free survival (RFS). Co-occurring molecular aberrations, along with where the mutation was located in the gene, were documented for further research. Inclusion criteria encompassed systematic reviews, meta-analyses, clinical practice guidelines, randomized control trials, cohort studies (prospective and retrospective) or case-control studies with an analysis or subgroup analysis of DNMT3A biomarker status and investigated DNMT3A in patients with previously treated or untreated AML. Exclusion criteria was applied to articles published in a language other than English, were non-systematic reviews, letters, editorials, commentaries, or historical articles, or if patients had secondary AML.
- Eight studies met the inclusion criteria and were included in the review.
- Six of the eight studies were included in quantitative synthesis (meta‐analysis).
Review of Published Meta-Analyses
Systematic Review with Evidence Tables
Data Extraction and Assessment of Study Quality and Potential for Bias
One reviewer went through the various databases that were mentioned in the search strategy (see the "Description of Methods Used to Collect/Select the Evidence" field) to identify relevant guidelines and articles. The same reviewer conducted title and abstract screening, and duplicates were removed. For each eligible study, the same reviewer would extract all the study data (including study design features, patient population, interventions, molecular exons sequenced and analyzed, co-occurring molecular aberrations with deoxyribonucleic acid [DNA] methyltransferase 3A [DNMT3A], and clinical outcomes).
Synthesizing the Evidence
When clinically homogenous results from two or more trials were available, a meta-analysis would be conducted using the Review Manager software. For time-to-event outcomes, hazard ratios (HRs), rather than the number of events at a certain time point, would be the preferred statistic for meta-analysis, and would be used as reported. If the HR and/or its standard error were not reported, they would be derived from other information reported in the study, if possible, using the methods described by Parmar et al., 1998. For all outcomes, the generic inverse variance model with random effects, or other appropriate random effects models in Review Manager, would be used.
Statistical heterogeneity would be calculated using the χ2 test for heterogeneity and the I2 percentage. A probability level for the χ2 statistic less than or equal to 10% (p≤0.10) and/or an I2 greater than 50% would be considered indicative of statistical heterogeneity.
The response data from six of the eight studies were pooled for a meta-analysis. See Figure 1 in the original guideline document for forest plot of effect size for overall survival.
A formal cost analysis was not performed and published cost analyses were not reviewed.
Internal Peer Review
Almost all Program in Evidence-based Care (PEBC) documents undergo internal review. With recommendation reports, this review is conducted by the Director of the PEBC. The Working Group is responsible for considering the changes, and if those changes could be made without substantially altering the recommendations, the altered draft would not need to be resubmitted for approval again.
The recommendations are supported by prospective and retrospective studies.
Assessing deoxyribonucleic acid (DNA) methyltransferase 3A (DNMT3A) mutational status provides important prognostic information for acute myeloid leukemia (AML) patients with a normal karyotype.
- The recommendation is based on evidence currently available. Despite the heterogeneous nature of the studies included, the likelihood of having a series of large homogenous studies done in this patient population is low due to the nature of the disease and its management.
- Care has been taken in the preparation of the information contained in this report. Nonetheless, any person seeking to apply or consult the report is expected to use independent medical judgment in the context of individual clinical circumstances or seek out the supervision of a qualified clinician. Cancer Care Ontario makes no representation or guarantees of any kind whatsoever regarding the report content or use or application and disclaims any responsibility for its application or use in any way.
An implementation strategy was not provided.
Quick Reference Guides/Physician Guides
|Leber B, Ismaila N, Kamel-Reid S, Rutherford M, Molecular Oncology Advisory Committee. The prognostic value of the DNMT3A biomarker in cytogenetically normal patients with acute myeloid leukemia. Toronto (ON): Cancer Care Ontario (CCO); 2013 Nov 27. 17 p. (Recommendation report; no. MOAC-1). [23 references]|
Not applicable: The guideline was not adapted from another source.
2013 Nov 27
Program in Evidence-based Care - State/Local Government Agency [Non-U.S.]
The Program in Evidence-based Care (PEBC) is a Province of Ontario initiative sponsored by Cancer Care Ontario and the Ontario Ministry of Health and Long-Term Care.
The Program in Evidence-based Care (PEBC) is a provincial initiative of Cancer Care Ontario supported by the Ontario Ministry of Health and Long-Term Care. All work produced by the PEBC is editorially independent from the Ontario Ministry of Health and Long-Term Care.
Molecular Oncology Advisory Committee
Authors: B. Leber, N. Ismaila, S. Kamel-Reid, M. Rutherford
In accordance with the Program in Evidence-based Care (PEBC) Conflict of Interest (COI) Policy, the guideline authors, Molecular Oncology Advisory Committee (MOAC) members, and internal and external reviewers were asked to disclose potential conflicts of interest.
The authors, members, and reviewers reported that they had no conflicts of interest.
This is the current release of the guideline.
The RECOMMENDATION report, initially the full original Guideline, over time will expand to contain new information emerging from their reviewing and updating activities.
Please visit the Cancer Care Ontario Web site for details on any new evidence that has emerged and implications to the guidelines.
Electronic copies: Available in Portable Document Format (PDF) from the Cancer Care Ontario Web site .
The following are available:
- The prognostic value of the DNMT3A biomarker in cytogenetically normal patients with acute myeloid leukemia. Summary. Toronto (ON): Cancer Care Ontario (CCO); 2013 Nov 27. 5 p. Electronic copies: Available in Portable Document Format (PDF) from the Cancer Care Ontario Web site .
- Program in Evidence-based Care handbook. Toronto (ON): Cancer Care Ontario (CCO); 2012. 14 p. Available in PDF from the Cancer Care Ontario Web site .
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