General AML,   DNMT3A,  NPM1

ESH 2018 | MRD assessment in AML

The European School of Hematology (ESH) Clinical Updates in Acute Leukemia Meeting took place on 4–6 May 2018, in Budapest, Hungary. At this meeting, Gert Ossenkoppele (chair of our Global and European Steering Committee) from the VU University Medical Center, Amsterdam, Netherlands,  gave a talk titled “Measurable residual disease in AML”. Measurable residual disease (MRD) is an important independent prognostic factor for outcomes in acute myeloid leukemia (AML). At the ESH meeting, Gert Ossenkoppele discussed the different approaches used to detect MRD in AML and how it can define the treatment algorithm for patients. At present, there are several methods used to evaluate MRD in various settings including multiparameter flow cytometry (MFC), real-time quantitative polymerase chain reaction (RQ-PCR), next-generation sequencing (NGS), and Digital PCR. 1,2

RQ-PCR approach for the detection of MRD has an established high sensitivity and it is recommended by the EuropeanLeukemia Net (ELN) MRD Working Party.2 Gert Ossenkoppele discussed a study by Ivey et al. published in the New England Journal of Medicine (NEJM) in 2016. In this study, RQ-PCR was used to detect MRD in 2,569 samples obtained from 346 patients with NPM1-mutated AML who had undergone intensive treatment in the National Cancer Research Institute AML17 trial. Findings of this study demonstrated that the presence of MRD, determined by quantification of NPM1-mutated transcripts, predicted increased risk for relapse and survival among patients with standard-risk AML.3

Next, Gert Ossenkoppele discussed the prospective detection of MRD using flow cytometry. He discussed a study by Terwijn et al. published in the Journal of Clinical Oncology in 2012. In this study, the value of immunophenotypically assessed MRD was investigated in a multicenter clinical trial comprising of 517 AML patients (younger than 60 years old). MRD was evaluated in bone marrow samples in complete remission (CR). MRD percentage was found to be an independent prognostic factor for OS and RFS when assessed in a post-induction or post-consolidation single-center setting. However, immunophenotypic measurement of MRD is limited by sensitivity and specificity.4

Then, the speaker discussed the role of NGS for the detection of MRD. He presented data from a large study which was published in the NEJM  by  Mojca Jongen-Lavrencic from the Erasmus University Medical Center, Rotterdam, Netherlands, and colleagues. In this study, targeted NGS was performed on bone marrow or peripheral blood samples (at diagnosis and after induction therapy) from 482 AML patients (median age = 51 years; range, 18–66) who were treated with two cycles of standard induction chemotherapy followed by consolidation in HOVON-SAKK clinical trials. At diagnosis, at least one single mutation was detected in 89.2% of patients (430/482). After induction therapy, persistent mutations remained in 51.4% of patients in CR (n = 430) at various allele frequencies (range, 0.02–47%). Most common persistent mutations comprise DTA mutations including DNMT3A (78.7%), TET2 (54.2%) and ASXL1 (51.6%).  Persisting DTA mutations did not associate with an increased incidence of relapse. Interestingly, it was observed that the detection of persistent non-DTA mutations at any allele frequency strongly associated with an increased relapse risk, reduced relapse-free survival and overall survival.5 More results from this study were reported by the AML global portal (AGP) here.

Professor Ossenkoppele concluded his talk by highlighting the importance of measuring MRD and how it can be used to tailor therapy in AML. Firstly, MRD monitoring is important for better defining complete remission (CR) which is more reliable than morphological assessment. MRD can also be used in refining outcome predictions and risk stratification, informing treatment decisions, identifying potential for relapse and enable early intervention. Lastly, in the future, MRD can serve as a surrogate endpoint for survival which would be really important for early drug development.

References
  1. Ossenkoppele G. Measurable Residual Disease in AML. ESH Clinical Updates in Acute Leukemias. May 4–6 2018, Budapest, Hungary.
  2. Schuurhuis G. J. et al. Minimal/measurable residual disease in AML: consensus document from ELN MRD Working Party. Blood. 2018 Jan 12. DOI: 10.1182/blood-2017-09-801498. [Epub ahead of print].
  3. Ivey A. et al. Assessment of Minimal Residual Disease in Standard-Risk AML. N Engl J Med. 2016; 374: 422–433. DOI: 10.1056/NEJMoa1507471.
  4. Terwijn M. et al. High Prognostic Impact of Flow Cytometric Minimal Residual Disease Detection in Acute Myeloid Leukemia: Data From the HOVON/SAKK AML 42A Study. J Clin Oncol. 2013 Nov 1; 31(31): 3889–3897. DOI: 10.1200/JCO.2012.45.9628
  5. Jongen-Lavrencic M. et al. Molecular Minimal Residual Disease in Acute Myeloid Leukemia. N Engl J Med. 2018 Mar 29; 378(13): 1189–1199. DOI: 10.1056/NEJMoa1716863.
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