Blog | Aug. 30, 2023

MRD in AML: the next step in fighting leukemia

Modern treatment of hematological cancers allows for oncologists to routinely track the amount of cancer present in the patient, allowing the treatment to be tailored to the patient, ensuring the best outcome. If the cancer is non-responsive to first-line treatments, doctors may try a more aggressive second-line option. On the other hand, if the treatment is successfully eradicating the cancer, they may begin to lower the dosage to limit adverse events associated with the medication. But, what happens when the amount of cancer is so low, it cannot be detected by current technology, yet is still present? This phenomenon is known as measurable residual disease (MRD) and refers to the small number of cancer cells that may be present in the body following anti-cancer treatment. and the ability to detect MRD can be an important biomarker for prognostic, predictive, monitoring, and efficacy-response assessments. If we are able to detect MRD then it is evidence that the cancer is either still present or has progressed since treatment concluded. In several studies, the presence of MRD has correlated with worse survival outcomes and higher rates of relapse.^1,2,3 The information gained by detecting MRD would allow doctors to modify patient’s treatment by more accurately assessing their cancer status.

Significance of MRD quantification

The significance of MRD quantification in relation to acute lymphoblastic leukemia (ALL) was first investigated in the 1990s in multiclinic centers in Europe and the U.S.⁴ The research at that time indicated that, in ALL cases, MRD assessment should be done early during treatment. Other studies in that same period highlighted the utility of MRD status as a reliable indicator of future relapse risk.^5,6,7 At the time, flow cytometry and PCR were used to monitor MRD status in patients. In the decades since, the methods to determine MRD status have grown to include PCR and next generation sequencing (NGS), as have the number of disease-states that we can monitor with MRD. While commonly looked for in blood cancers, MRD can also potentially be useful in the monitoring of solid tumors as well including non-small cell lung tumor (NSCLC), breast cancer, and neuroblastomas.^8,9,10,11

The detection of MRD as a predictor of relapse and its integration into clinical trials for acute myeloid leukemia (AML) are problems currently being investigated by the Foundation for the National Institutes of Health (FNIH) Biomarkers consortium, of which Sysmex Inostics is one of the private sector partners. AML is one of the deadliest blood cancers, resulting in more than 10,000 lives lost in the U.S. each year.¹² Because AML has a high rate of relapse and poor prognosis, it’s necessary to test patients for MRD after initial treatment as a prognostic indicator of therapeutic effectiveness and relapse risk. However, assessment of MRD in AML remains to be a challenge due to a lack of standardization and comparability of the different methods used to detect MRD. It has been shown that patients with a positive MRD result can clear the residual disease with additional therapy.^13,14 However, there is also a lack of consensus as to what defines MRD, a problem that is being researched by the FNIH AML consortium. This has led to conflicting reports as to the utility of treating AML patients with positive MRD result.^15,16,17 Thus there is limited application of MRD information clinically because of the lack of consensus. However, MRD detection by any method, be it flow cytometry, PCR, or NGS, remains a strong predictor of relapse and shorter survival in AML patients.¹⁸

Flow cytometry relies on the presence of leukemia-associated immunophenotypes (LAIPs). Flow cytometry is widely accessible to AML patients and many labs have experience analyzing flow cytometry. However, analysis of the tests is still very subjective, making standardization more difficult. PCR can be used to detect AML MRD and is able to detect MRD with much higher sensitivity than flow cytometry. However, each PCR assay needs to be designed for specific mutations observed in AML, and thus has less utility if the mutation is not known prior to testing. NGS can be applied to virtually all AML patients and has a higher sensitivity than flow cytometry. However, due to error-rates introduced in sequencing it can be difficult to separate positive results from background noise. Each of the testing methods identifying AML MRD has its pros and cons, however, a method that allows for high sensitivity, specificity, and high throughput would be extremely desirable to maximize the utility of testing for MRD in AML. To this end, the FINH MRD in AML project is investigating the use of genetic tests to improve the accuracy of MRD detection approaches, helping establish MRD as a validated biomarker in AML, and generating important molecular information about AML.

Improving AML outcomes

AML-MRD-SEQ may potentially be a useful tool in the detection of MRD in AML patients. With sensitivity to detect as few as 7 mutant molecules with 0.035% mutant allele frequency, high specificity, and a quick turnaround AML-MRD-SEQ could help improve AML outcomes at all levels of clinical practice. Additionally, other Plasma-Safe-SeqS panels may help advance the understanding of the use of MRD assessment in other cancers such as breast (BC-SEQ) or NSCLC (RAS-RAF-SEQ). Through the partnership with the Foundation for the National Institutes of Health (FNIH) on the MRD in AML project, Sysmex Inostics received its first set of standards to test FLT3-ITDs which are likely to be elevated in future AML MRD guidance. These technologies represent a promising future for understanding and utilizing this powerful prognostic tool.

References

1. Hochhaus, A. et al. IRIS Investigators. Long-term outcomes of imatinib treatment for chronic myeloid leukemia. N Engl J Med. 2017;376(10):917-27.
2. Böttcher, S. et al. Minimal residual disease quantification is an independent predictor of progression-free and overall survival in chronic lymphocytic leukemia: a multivariate analysis from the randomized GCLLSG CLL8 trial. J Clin Oncol. 2012;30(9):980-88.
3. Bassan, R. et al. Improved risk classification for risk-specific therapy based on the molecular study of minimal residual disease (MRD) in adult acute lymphoblastic leukemia (ALL). Blood. 2009;113(18):4153-62.
4. Kruse, A. et al. Minimal Residual Disease Detection in Acute Lymphoblastic Leukemia. Int J Mol Sci. 2020 Feb 5;21(3):1054.
5. Cave, H. et al. Clinical significance of minimal residual disease in childhood acute lymphoblastic leukemia. European Organization for Research and Treatment of Cancer—Childhood Leukemia Cooperative Group. N. Engl. J. Med. 1998;339:591-98.
6. Coustan-Smith, E. et al. Immunological detection of minimal residual disease in children with acute lymphoblastic leukaemia. Lancet. 1998;351:550-54.
7. van Dongen, J.J. et al. Prognostic value of minimal residual disease in acute lymphoblastic leukaemia in childhood. Lancet. 1998;352:1731-38.
8. Tachtsidis, A. et al. Minimal residual disease in breast cancer: an overview of circulating and disseminated tumour cells. Clin Exp Metastasis. 2016 Aug;33(6):521-50.
9. Pellini, B., Chaudhuri, A.A. Circulating Tumor DNA Minimal Residual Disease Detection of Non-Small-Cell Lung Cancer Treated with Curative Intent. J Clin Oncol. 2022 Feb 20;40(6):567-75.
10. Uemura, S. et al. Dynamics of Minimal Residual Disease in Neuroblastoma Patients. Front Oncol. 2019 Jun 4;9:455.
11. Heuser, M. et al. 2021 Update on MRD in acute myeloid leukemia: a consensus document from the European LeukemiaNet MRD Working Party. Blood. 2021 Dec 30;138(26):2753-67.
12. https://www.cancer.net/cancer-types/leukemia-acute-myeloid-aml/statistics
13. Heuser, M. et al. Posttransplantation MRD monitoring in patients with AML by next-generation sequencing using DTA and non-DTA mutations. Blood Adv. 2021;5(9):2294-2304.
14. Paras, G. et al. Conditioning intensity and peritransplant flow cytometric MRD dynamics in adult AML. Blood. 2022;139(11):1694-1706.
15. Freeman, S.D. et al. Measurable residual disease at induction redefines partial response in acute myeloid leukemia and stratifies outcomes in patients at standard risk without NPM1 mutations. J Clin Oncol. 2018;36(15):1486-97.
16. 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;31(31):3889-97.
17. Balsat, M. et al. Postinduction minimal residual disease predicts outcome and benefit from allogeneic stem cell transplantation in acute myeloid leukemia with NPM1 mutation: a study by the Acute Leukemia French Association Group. J Clin Oncol. 2017;35(2):185-93.
18. Short, N.J. et al. Association of Measurable Residual Disease with Survival Outcomes in Patients with Acute Myeloid Leukemia: A Systematic Review and Meta-analysis. JAMA Oncol. 2020;6(12): 1890-99.