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MRD in AML
NGS-based technologies, the sensitivity of these assays is generally no better than ~1%, limiting their discrimina- tion for small amounts of residual disease. In a study of patients with AML undergoing HSCT, an error-corrected, molecular barcoded NGS MRD assay was able to detect residual mutations prior to HSCT with a median variant allelic frequency of 0.33% (range, 0.016%-4.91%), sug- gesting that such an assay can detect lower levels of MRD than can standard NGS MRD assays.51 Among the 96 evaluable patients, 45% were MRD-positive prior to HSCT using this approach. The 5-year cumulative inci- dence of relapse was 66% for those who were MRD-pos- itive versus 17% for those who were MRD-negative (HR 5.58; P<0.001). On multivariate analysis, MRD remained an independent predictor of relapse and also overall sur- vival (HR 3.0; P=0.004). Further studies of these more sen- sitive, error-corrected NGS technologies in other contexts are warranted.
Practical considerations for the evaluation of measurable residual disease in clinical practice
While MRD response has been reliably shown to be predictive for better outcomes, there is significant hetero- geneity across studies depending on the specific popula- tion of patients, regimen used, AML subtype, MRD method and target, timing of MRD assessment, and threshold to define adequate response, among other fac- tors. All of these variables must be considered when inter- preting study results and attempting to generalize to a patient in clinical practice. Despite these challenges, we routinely assess MRD in our clinical practice, as this infor- mation helps to refine prognostic assessment and, in some cases, informs therapeutic decisions (e.g. identifies patients who may be candidates for MRD-directed clinical trials or HSCT). Consensus recommendations from the European LeukemiaNet support this approach of routine MRD assessment in AML.6 We also routinely discuss the findings with our patients, particularly when this informa- tion is used for clinical decision-making. However, despite the strong association of MRD with clinical outcomes, it is imperative to remember (and to convey to the patient) that “MRD-negativity” does not equate to “cure,” as cumulative incidences of relapse of approximately 20- 50% are still observed in “MRD-negative” patients, depending on the assay and clinical context. In contrast, while “MRD-positive” patients almost invariably relapse without subsequent therapy, this is also not an absolute certainty. Thus, an acknowledgment of the limitations of our current MRD technologies is required by the clinician to avoid “over-interpreting” MRD information.
When using MRD in clinical practice, it is important to choose a complementary MRD assay tailored to the AML subtype of a particular patient. For patients with an appro- priate target (e.g. those with acute promyelocytic leukemia, core-binding factor AML or NPM1-mutated AML), PCR is preferred to MFC since the clinical data in these populations are more robust for the former and it also has a higher sen- sitivity.2,6,22 When MFC is used, it is imperative that it is per- formed in a laboratory with extensive experience in inter- pretation to ensure accuracy of the assessment.
Whether peripheral blood can replace bone marrow for MRD testing is an area of controversy, although it is gen- erally agreed that an accurate and sensitive peripheral
blood-based MRD assay would be welcome to both clini- cians and patients, given the less invasive nature of this approach. While some studies have suggested similar find- ings with these two sources of assay material,74,75 most of the available clinical data on the prognostic and predictive impact of MRD were derived from bone marrow speci- mens. Furthermore, bone marrow likely provides addi- tional sensitivity, with detectable MRD levels approxi- mately 1-log higher than those in the peripheral blood.6 For example, in core-binding factor AML, a “negative” peripheral blood MRD assay could miss positive bone marrow MRD in up to 40% of cases during therapy and 10-15% of cases during follow up.33 Conversely, in a study of PCR-based MRD in NPM1-mutated AML, discrimina- tion for survival was better when peripheral blood was used than when bone marrow was used.15 Thus, the opti- mal source for MRD assessment is likely dependent on assay, regimen, and time. Future studies of peripheral blood MRD monitoring are needed across MRD technolo- gies and treatment contexts, and should include investiga- tion of the potential use of circulating cell-free DNA as a source for MRD assays similarly to what has been achieved for some solid tumors.76,77 Initial efforts are already underway in AML.78,79
While the optimal prognostic time point of MRD assessment varies slightly based on the specific regimen and other factors, most studies have shown that detectable MRD is associated with worse outcomes regardless of when it is measured. For patients treated with intensive chemotherapy in the frontline setting, we routinely assess for MRD, at a minimum, at the end of induction and consolidation. It is reasonable to assess MRD at the end of the first cycle of consolidation as well, particularly in patients who remained MRD-positive after induction. In several studies, this time point (i.e. after 2 cycles of chemotherapy) is the most discriminatory for relapse and long-term survival.15,18 MRD status before transplantation is also highly associated with risk of post- HSCT relapse and may identify patients who may be candidates for investigational post-HSCT maintenance strategies.52-55
Therapeutic implications of measurable resid- ual disease in acute myeloid leukemia
While it is important to obtain MRD information for prognostic purposes, ultimately the goal of developing MRD assays that can more accurately determine risk of relapse in an individual patient with AML is so that post- remission therapies can be tailored accordingly. Currently, risk stratification in AML is largely based on cytogenetic and molecular alterations present at the time of diagnosis; these factors are currently the primary dis- ease-related considerations for deciding to pursue HSCT in first remission.2 In contrast, in acute lymphoblastic leukemia, the decision to pursue HSCT in first remission is determined in large part by MRD status, particularly in the pediatric population.7-9 Furthermore, the CD3-CD19 bispecific T-cell engaging antibody blinatumomab is highly effective in eradicating MRD in patients with acute lymphoblastic leukemia and is approved by the United States Food and Drug Administration for this use.80 While some data support the use of MRD to guide therapeutic decisions in AML, the role of MRD-guided
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