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

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.

Richard Dillon | EHA 2019

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