Minimal Residual Disease in Acute Myeloid Leukemia: Still a Work in Progress?
Abstract
:1. Introduction
2. Has MRD Evaluation Superseded Baseline Risk Assessment and Disease Staging?
3. Molecular Biology Techniques
3.1. RUNX1/RUNX1T1 and CBFB/MYH11
3.2. NPM1
3.3. WT1
3.4. Other Molecular Markers
4. Multiparameter Flow Cytometry
5. Combined Approaches
6. Issues in the Implementation of MRD Assessment as the New Standard to Evaluate Clinical Response
6.1. Inter-Laboratory Standardization
6.2. Choice of Methodology
6.3. Best Source for MRD and Sample Quality
6.4. Significance of MRD Evaluation as a Decision-Making Tool
6.5. Safety and Efficacy of Treatment Alternatives
6.6. Effectiveness of allo-HSCT in Eradicating MRD
6.7. Best Time-Points for MRD Evaluation
7. “Real-Life” Use of MRD as a Decision-Making Tool in 2017
8. Some Final Considerations about Future Developments
Acknowledgments
Author Contributions
Conflicts of Interest
References
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Molecular Markers | Frequency (% of All) | Occurrence in Leukemogenesis | Predictive Power for Clinical Relapse | Technique |
---|---|---|---|---|
Fusion products | ||||
RUNX1/RUNX1T1 | 7–10% | Early | Very good | RT-qPCR |
CBFB/MYH11 | 5–8% | Early | Very good | RT-qPCR |
MLL/MLLT3 | 2% | Probably late | Good | RT-qPCR |
Mutations | ||||
FLT3-ITD | 25–30% | Late | Poor | RT-qPCR/NGS |
NPM1 | 30% (50% in normal-karyotype) | Late | Very good | RT-qPCR/NGS |
DNMT3A | 10–15% | Early | Poor | NGS |
RUNX1 | 10% | Early | Possibly good | NGS |
IDH1/IDH2 | 8–9% each | Early | Possibly good | NGS |
Overexpression | ||||
WT1 | 85–90% | Unknown | Good | RT-qPCR |
Trial | Nation | ID | MRD-Related Endpoints | Type | Age Limits |
---|---|---|---|---|---|
MRC AML 17 | UK | ISRCTN55675535 | Assess the prognostic value of minimal residual disease monitoring (randomization: monitoring vs. not monitoring) | Phase 3 | <60 years |
MRC AML 19 | UK | ISRCTN31682779 | Assess the prognostic value of minimal residual disease monitoring (randomization: monitoring vs. not monitoring) | Phase 3 | 18–60 years |
MRC AML 18 | UK | ISRCTN78449203 | Treatment intensification in MRD+ patients after the first cycle, chemotherapy randomization | Phase 3 | >60 years |
GIMEMA AML1310 | Italy | NCT01452646 | MRD stratification of intermediate-risk karyotype; risk-adapted, MRD-directed therapy (autoSCT vs. SCT) after first consolidation | Phase 2 | 18–60 years |
CETLAM AML-03 | Spain | NCT01723657 | MRD stratification of intermediate-risk karyotype; risk-adapted, MRD-directed therapy (autoSCT vs. SCT) after first consolidation | Phase 2 | 18–70 years |
PETHEMA LMA10 | Spain | NCT01296178 | Risk-adapted, MRD-directed therapy(study arms not provided) | Phase 3 | <65 years |
PETHEMA | Spain | NCT00390715 | Prospective study on the prognostic value of baseline cytogenetics and MRD monitoring | Observational (prospective) | <65 years |
Nanfang Hospital of Southern Medical University, Guangzhou | China | NCT02870777 | MRD-directed therapy for low- and intermediate-risk AML. Front-line allo-HSCT intensification is programmed for MRD+ patients | Phase 3 | 18–60 years |
Rochester University | USA | NCT01311258 | Identification by MPFC, among all MRD cells, of the clones eventually responsible for clinical relapse (LIC) | Observational (prospective) | >18 years |
Az. Ospedaliera Città della Salute e della Scienza Torino | Italy | NCT02714790 | Assess the prognostic role of MRD defined as BM expression of WT1 | Observational (retrospective) | >18 years |
Medical College of Wisconsin | USA | NCT02349178 | Estimating the efficacy of Clofarabine, Cyclophosphamide and Etoposide in eliminating MRD in AML patients, otherwise in clinical remission, before allo-HSCT | Phase 2 | <40 years |
Technische Universitat of Dresden RELAZA2 | Germany | EudraCT 2010-022388-37 | 5-Azacitidinetreatment of patients with MDS or AML with significant residual disease or an increase of MRD | Phase 2 | >18 years |
Ulm University | Germany | NCT01770158 | Maintenance Therapy with Histamine Dihydrochloride and Interleukin-2 in AML MRD+ patients post consolidation therapy | Observational (prospective) | >18 years |
Washington University | USA | NCT00863434 | Clofarabine and Cytarabine in treating MRD+ (by MPFC) AML patients | Phase 2 | 18–75 years |
Singapore General Hospital | Singapore | NCT00394381 | Autologous Cytokine-induced Killer cell adoptive immunotherapy for MRD+ patients post autologous HSCT | Phase 1/2 | 12–75 years |
Institute of Hematology & BloodDisease Hospital, Tianjin | China | NCT03021395 | Efficacy of maintenance Decitabine (after consolidation chemotherapy) in clearing MRD in patients in clinical remission | Phase 1/2 | 14–55 years |
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Mosna, F.; Capelli, D.; Gottardi, M. Minimal Residual Disease in Acute Myeloid Leukemia: Still a Work in Progress? J. Clin. Med. 2017, 6, 57. https://doi.org/10.3390/jcm6060057
Mosna F, Capelli D, Gottardi M. Minimal Residual Disease in Acute Myeloid Leukemia: Still a Work in Progress? Journal of Clinical Medicine. 2017; 6(6):57. https://doi.org/10.3390/jcm6060057
Chicago/Turabian StyleMosna, Federico, Debora Capelli, and Michele Gottardi. 2017. "Minimal Residual Disease in Acute Myeloid Leukemia: Still a Work in Progress?" Journal of Clinical Medicine 6, no. 6: 57. https://doi.org/10.3390/jcm6060057