MRD monitoring and clinical guidance for AML: An introduction to this month educational theme

This month the AML Global Portal (AGP) is focusing on measurable residual disease (MRD; previously known as minimal residual disease) and its role in guiding treatment for acute myeloid leukemia (AML). This article will introduce the benefit and latest advances of MRD monitoring in AML and will provide an introduction to content that will be published in the AGP over the following weeks.

Approximately 50% of patients with AML will relapse after achieving complete remission (CR) with induction chemotherapy.1 MRD has significant clinical value as it measures the number of leukemic cells that persist following therapy and can eventually lead to relapse. Accumulating evidence has shown that MRD is a strong prognostic marker for relapse and patient outcomes1 in various hematological malignancies.

Prof. David Grimwade was one of the pioneers establishing the value of MRD for treatment management. He was one of the first to extend the use of MRD from other malignancies like acute promyelocytic leukemia (APL) to AML. His belief in tailoring therapy in AML had a global impact and provided a prime example that advances in basic science could rapidly be applied to clinical practice. Today, multiple clinical investigations are underway to determine the exact MRD protocols needed to successfully guide post-treatment therapeutic strategies in AML.

1st NCRI AML academy meeting | The David Grimwade Memorial Lecture
MRD detection

There are different methods for assessing MRD that differ in their sensitivity and the genetic aberrations they detect. The most commonly used techniques so far are multiparameter flow cytometry (MFC; 1:10-4 to 10-5 sensitivity) or quantitative PCR (1:10-3 to 10-5 sensitivity). A more recent approach involves next-generation sequencing (NGS) with a sensitivity of one leukemia cell per 10-3 to 10-5 white blood cells.1 These techniques are all currently used for MRD assessment in AML depending on local availability and based on the recently published guidelines from the European LeukemiaNet (ELN) MRD Working Party2 and the National Comprehensive Cancer Network (NCCN).3

A challenge with NGS MRD detection is the existence of an almost 1% sequencing error that occurs at each nucleotide position. This issue makes it difficult to distinguish patients with true AML mutations of low allelic frequency from sequencing errors. To address this, a group of German researchers adapted an error-corrected sequencing approach in the NGS MRD assay and examined its ability to predict relapse and survival in patients with AML following allogeneic stem cell transplantation (allo-SCT). The results from 160 patients showed that error-corrected NGS MRD has high sensitivity and can be successfully used for the majority of patients with AML. Moreover, error-corrected NGS MRD was highly prognostic of patient outcomes (overall survival, Relapse-free survival, cumulative incidence of relapse) following allo-SCT and could be used to guide treatment at that stage. For more information on this study read our published summary here.

Gert Ossenkoppele | ISAL 2019 | Using MRD for clinical decision making in AML
MRD status in standard-risk patients

MRD has the potential to predict outcomes in standard-risk AML patients. This was validated by the NCRI AML17 trial that was summarized by the AGP Hub here. In this study, patients without high-risk factors like FLT3 duplication or NPM1 mutation were prospectively analysed for MRD status by MFC. Standard risk patients received either one (C1) or two (C2) courses of daunorubicin plus cytosine arabinoside induction, following which MRD was assessed. MRD status was more prognostic of relapse and overall survival (OS) after C2 than C1 in this patient population. Following C2, MRD-positivity was associated with poorer overall survival (OS) and higher relapse incidence. This study showed that MRD can improve outcome stratification in standard-risk patients with AML and may help identify standard-risk patients who may benefit from allo-SCT after the first round of induction therapy.

 MRD status in older patients

 The phase III Pethema-Flugaza trial provided evidence on the role of MRD status in elderly patients with AML who were treated with semi-intensive chemotherapy. The results of the study were presented at the 2018 ASH meeting and have been summarized by the AGP here. Patients aged over 65 years (n= 285) were randomized to receive either a) induction with fludarabine, cytarabine, and G-CSF (FLUGA) followed by consolidation with reduced-intensity FLUGA or b) induction therapy with 5-azacitidine (AZA) followed by consolidation with AZA. After consolidation, if MRD ≥ 0.01% patients continued treatment or stopped if MRD < 0.01%. MRD was prospectively evaluated by MFC following both induction and consolidation stages. The results of this study indicated that MRD-negativity is an independent prognostic factor in elderly patients treated with less intensive therapies.

The phase III ECOG-ACRIN E2906 trial also prospectively evaluated the role of MRD status in older patients (³ 60 years) with AML. The results of this trial have been summarized by the AGP here. MRD was assessed by MFC in n=147 patients randomized 1:1 to either a) daunorubicin induction plus intermediate-dose cytarabine consolidation or b) clofarabine induction and consolidation. The results of this study showed that MRD-positivity (³ 0.1%) occurred commonly in this patient population (60.5%) and was significantly associated with the worst OS and disease-free survival. These results were very different from those seen in younger patients, who with similar treatment, achieved a much higher MRD negativity rate (70-80%) amongst patients in CR. Nevertheless, MRD status was still highly prognostic of outcomes in this patient population too.

MRD status in patients with recurrent genetic abnormalities

The AMLSG study sought to assess the prognostic value of MRD in 155 adult patients with t(8;21) AML and has been summarized by the AGP here. The investigators showed that MRD negativity post-treatment was an independent prognostic factor with improved OS and reduced cumulative incidence of relapse. Moreover, the results indicated that both MRD-negativity and the reduction of RUNX1-RUNX1T1 transcript levels at specific time points were significant prognostic markers. Multiple MRD assessments were performed during follow-up, allowing for the definition of cut-offs predicting relapse. However, since almost all relapses occurred within one year after treatment, the authors highlighted the need for more regular MRD assessments at shorter intervals within the first year, in the real-world setting.  

MRD status in patients undergoing allo-SCT

MRD can be very informative and could help guide clinicians towards the use of transplantation or other treatment in different patient risk groups. The AML17 study aimed to evaluate whether pre-transplant MRD status can predict patient outcomes following allo-SCT. They examined 107 young patients with the NPM1 mutation who were eligible for intensive chemotherapy. The median follow-up of the study was 4.9 years after allo-SCT. Interestingly, MRD-negativity pre-transplant was associated with good outcomes regardless of FLT3 aberrations or transplant type. Donor source, conditioning regimen or T-cell depletion were not associated with patient outcomes in those with MRD-negative status. In patients with positive MRD, only T-cell depletion was associated with worse survival compared to those who did not undergo T-cell depleted transplantation. The study concluded that these results may help with treatment management prior to and after transplantation in such AML patient populations. For more information on this trial read our AGP Hub summary here.

EHA 2019 | What impact does MRD status have on the outcomes of patients with AML undergoing allo-SCT?
MRD feasibility in developing countries

An interesting point on the feasibility of MRD assessment in developing countries was highlighted by Dr. Isolda Fernandez in her interview with the AGP during the EHA 2018 meeting. Despite the indisputable clinical value of MRD, its assessment is considered a luxury in developing countries like Argentina. The lack of specialized laboratories and trained personnel to run and interpret MRD assays creates barriers in its clinical use. Dr. Fernardez stated that it is crucial for MRD assessment to become standard of care for patients with AML so that it can start to be considered as an invaluable part of therapy in developing countries too.

Isolda Fernandez | EHA 2018 | What is the feasibility of MRD detection in developing countries?
Conclusions

It is evident that MRD has a strong clinical value for all AML patient populations and it helps clinicians decide between the use of further treatment or transplant in patients with AML who relapse after initial treatment. Due to its prognostic value, MRD-directed therapy should become a clinical reality for patients with AML. In this way, clinicians will be able to create personalized treatments for each patient and use intensive, highly toxic therapies only for those that have the potential to benefit from them.

1st NCRI AML academy meeting | The benefits of MRD monitoring in clinical practice and research?

 

References
  1. Ravandi F. et al., Evaluating measurable residual disease in acute myeloid leukemia. Blood Advances, 2(11), 1356–1366. DOI:10.1182/bloodadvances.2018016378
  2. Schuurhuis G. J. et al. (2018). Minimal/measurable residual disease in AML: a consensus document from the European LeukemiaNet MRD Working Party. Blood, 131(12), 1275–1291. DOI:10.1182/blood-2017-09-801498
  3. NCCN. NCCN Guidelines. https://www.nccn.org/about/news/ebulletin/ebulletindetail.aspx?ebulletinid=3683 [Accessed 2019 Oct  2019]
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