At the 46 th Annual Meeting of the European Society for Blood and Marrow Transplantation (EBMT), the AML Hub will hold a satellite symposium ( August 30, 2020, 8:30 A.M. CEST ) on how measurable residual disease (MRD) impacts the outcome of stem cell transplantation (SCT) in patients with acute myeloid leukemia (AML). During this satellite symposium, five international experts—Gert Ossenkoppele, Jacqueline Cloos, Christian Thiede, Adriano Venditti, and Charles Craddock—will discuss the latest developments and remaining challenges of MRD assessments in the context of SCT. Here, we present an introductory overview of the theme, which will be explored in more depth at the satellite symposium.
What is MRD testing?
MRD denotes the presence of leukemic cells at levels of 1:10 4to 1:10 6white blood cells, compared with morphologic-based tests that only detect down to 1:20. MRD has been a hot topic in the last year as it has been identified as having the potential to predict patients at higher risk of relapse after transplant and, therefore, may allow earlier intervention, improving survival. It could also act as a surrogate endpoint to accelerate the clinical trial and approval process. 1
How should MRD be measured?
Currently, MRD is commonly measured by multiparameter flow cytometry (MFC) or by real-time qPCR (RT-qPCR), but digital PCR and next-generation sequencing (NGS) are starting to be used more frequently. In this video , Peter Valk talks about NGS and its implementation in molecular diagnostics.
The European LeukemiaNet has issued guidelines for the measurement of MRD that recommend RT-qPCR due to its high sensitivity. 1They acknowledge, however, that its application is limited to ~40% of AML patients, therefore, the use of MFC is advised is advised in the remaining 60% of cases. The guidelines also indicate that the use of NGS has a potentially broader application, but standardization is required before widespread clinical use can proceed.
How is MRD currently being used in clinical trials?
Updates from recent trials that assessed MRD as part of their design
At the virtual 2020 American Society of Clinical Oncology (ASCO) Annual Meeting, Curtis Lachowiez reported an interim analysis from a phase Ib/II trial ( NCT03471260 ) evaluating the venetoclax and ivosidenib combination with or without azacitidine inpatients with isocitrate dehydrogenase-1 gene ( IDH1), in which MRD was used as an assessment of the efficacy of the treatment.
This trial found that all patients who achieved MRD negativity, as assessed by flow cytometry, had better outcomes compared to patients who were MRD positive (MRD+). Patients who achieved complete remission (CR) and were MRD negative (MRD−) across all treatment groups were found not to have relapsed and remained event-free up to a median follow-up of 11 months. Read the full article here .
Update of the AML18 trial ( NCT02272478)
The interim results of the AML18 trial were presented in June at EHA 2020. This trial assessed overall survival (OS) in elderly patients (> 60 years) without adverse risk cytogenetics at diagnosis randomized between a fractionated or single dose of gemtuzumab ozogamicin. Nigel Russell reported that MRD was used to guide further treatment of patients following Course 1 of therapy. Patients who were MRD− at this stage received further daunorubicin (DA), whereas patients who were MRD+ were randomized between:
- fludarabine, high-dose cytarabine, idarubicin, and granulocyte-colony stimulating factor or
- DA and cladribine
View the video here .
Update of the magrolimab phase Ib trial
During the virtual ASCO Annual Meeting, the results from a phase Ib trial ( NCT03248479 ) were presented by David Sallman . This trial investigated the use of azacitidine with magrolimab in patients with myelodysplastic syndromes or AML. MRD status was recorded, and it was found that 22% of patients with myelodysplastic syndromes and 50% of patients with AML in CR or CR with incomplete hematologic recovery were MRD− by flow cytometry . For further information, please click here .
What are the benefits of using MRD?
Richard Dillon discussed how MRD status impacts outcome following transplant at EHA 2019. Being able to identify patients at risk of relapse is very important for clinicians treating AML. Currently, patients who relapse have a very poor survival rate, with fewer than 20% achieving long-term survival—this is where MRD may add value as a prognostic indicator.
PCR, which is more sensitive at measuring MRD than flow cytometry, was used in the AML17 trial to identify patients at high risk of relapse. MRD− patients were associated with a good prognosis regardless of the presence of FMS-like tyrosine kinase 3 ( FLT3) internal tandem duplication mutations. There was a subset of patients who were demonstrated to be MRD+ using RT-qPCR but still fell below defined thresholds for presence of leukemic cells. These patients were shown to have a low risk of relapse. However, another subset of patients was identified as having a very high risk of relapse: MRD+ patients with FLT3 mutations. This group demonstrated only 17% survival 2 years after transplant. Watch the discussion here .
What challenges still exist with respect to the use of MRD as a surrogate endpoint?
The phase III PETHEMA-FLUGAZA trial( NCT02319135 ), which evaluated the quality of CR after induction and consolidation by MRD status, found that OS was similar for patients who were MRD− and for patients in partial remission. This issue may stem from the fact that a gold standard treatment for the measurement of MRD in AML does not exist. Read more about this here .
How does MRD impact the clinical outcome of SCT in AML now?
The GIMEMA AML1310 trial ( NCT01452646 ) used risk-adapted MRD assessment to guide SCT. Based on 2009 guidelines, patients (18–61 years old) were stratified for risk and those in the intermediate-risk group were given allogeneic (allo)-SCT or autologous-SCT, dependent on their MRD status. In the intermediate-risk group, it was shown that allo-SCT can be avoided if patients are MRD− following induction therapy. Additionally, in patients who were MRD+, it was demonstrated that OS is improved and disease-free survival is prolonged following allo-SCT. Read more about the details here .
Two studies presented at the 2019 American Society of Hematology (ASH) Annual Meeting & Exposition showed the benefits of MRD monitoring before and after SCT. Jorge Sierra presented the final results of the AML12 trial, which used risk-adapted therapy based on AML genetics at diagnosis and MRD status following consolidation chemotherapy. It was shown that MRD was useful for predicting relapse and chemotherapy and that allo-SCT was possible in intermediate- and adverse-risk groups based on MRD positivity and/or genetics. In addition, a study presented by Felicitas Thol showed that monitoring MRD by NGS after SCT is highly predictive for relapse and OS in AML. Read more about both these presentations here .