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MRD in AML
used platforms, due largely to the intrinsic error rate of sequencing. This lack of sensitivity is often because the assays are designed for identification of mutations in base- line samples (for which high sensitivity is generally not needed) and then repurposed for assessment of MRD (for which adequate sensitivity is imperative). However, depending on the NGS platform used and the amount of input DNA, NGS can theoretically achieve a sensitivity of 10-6, making it an attractive potential option for very sen- sitive MRD detection. Advances in NGS technologies, including molecular barcoding and duplex sequencing, may improve the sensitivity of NGS and allow for the identification of very low levels of residual leukemia.50,51
Prognostic Impact of measurable residual disease in acute myeloid leukemia
Achievement of MRD negativity has been shown to be a powerful prognostic factor in numerous studies of patients undergoing frontline AML therapy. Based on the consistent impact of MRD on long-term outcomes across multiple studies and AML subtypes, consensus guidelines from the European LeukemiaNet support “complete remission without MRD” as an official AML response cri- terion.2 There are also ongoing efforts in the USA and else- where to validate MRD as a surrogate endpoint for accel- erated regulatory approval of novel drugs and combina- tions. Here we review some of the major studies support- ing the clinical use of MRD to provide prognostic and pre- dictive information in AML.
Multiparameter flow cytometry-based measurable residual disease studies
MRD as assessed by MFC is highly prognostic when measured at various time points, including after induction, during and after consolidation, and peri-transplant.12,13,16,18,52- 56 While studies have used varied cutoffs to define MRD “negativity,” many have used levels of ≤0.1% to define negativity, both because this level of sensitivity can be reli- ably achieved with flow-based assays and because this level appears to provide the best discrimination for relapse risk at most time points.13,56 However, it is important to note that some studies have also suggested that even lev- els of residual leukemia below the 0.1% threshold may be associated with worse outcomes than lack of detectable MRD.12,53 Several studies in younger adults ≤60 years of age with newly diagnosed AML undergoing standard frontline chemotherapy have shown that achievement of MRD negativity is associated with a significantly lower risk of relapse and better survival.13,16,18 The impact of MRD status consistently adds additional prognostic information beyond that provided by pretreatment characteristics, such as cytogenetics and genetic mutations. Notably, most studies have evaluated MRD in younger adults and the data regarding the impact of MRD in patients >60 years are relatively scant. However, the available data suggest that achievement of MRD negativity in the older popula- tion may be predictive for lower relapse risk whether the patients are treated with intensive chemotherapy or hypomethylating agents.12,57 Because most older patients with AML will not be candidates for allogeneic HSCT, the potential therapeutic implications of persistent MRD in these patients is less clear than in their younger counter- parts.
The National Cancer Research Institute AML17 trial is the largest study of MRD in AML to date and provides some key insights into the impact of MRD in AML.18 This study enrolled 1,874 adults <60 years of age with AML who received standard daunorubicin plus cytarabine- based induction, followed by risk-adapted chemotherapy consolidation, with or without allogeneic HSCT. Patients with MRD positivity (defined as ≥0.1% by MFC assay) after cycle 1 had similar 5-year overall survival as patients who only achieved a partial response (51% vs. 46%, respectively), highlighting the poor outcomes associated with persistent MRD. Given the large size of this popula- tion, subgroup analyses were possible, including those among patients with standard-risk AML without NPM1 mutations. Of note, this is a particularly important group to refine prognosis using MRD, since there is controversy as to whether standard-risk patients (as determined by pretreatment characteristics) should routinely undergo HSCT in first remission; it is also a population in which MFC-based MRD assessment plays an integral role given the absence of a reliable molecular MRD target (e.g. mutant NPM1).1,22 Among patients with standard-risk AML without NPM1 mutation, the 5-year overall survival rates for patients who achieved MRD negativity after two cycles and for patients who remained MRD-positive were 63% and 33%, respectively (P=0.003), with the difference being driven by a significantly higher relapse rate in the MRD-positive group. Thus, MRD status after induction or in early consolidation may be able to stratify standard-risk patients according to risk of relapse and, consequently, help to determine the potential benefit from consolidative allogeneic HSCT.
Detectable MRD immediately prior to HSCT was also associated with increased risk of post-HSCT relapse and worse overall survival in several studies.52-55 These obser- vations are further supported by a meta-analysis of 19 studies evaluating pre-HSCT MRD (the majority of which assessed MRD by MFC).58 In one study of patients with AML who underwent HSCT, those in complete remission but with detectable MRD had a similar post-HSCT relapse rate and overall survival as those transplanted when not in morphological remission.54 The 3-year overall survival rates for patients who were in complete remission but MRD-positive versus those with active AML at the time of HSCT were 26% and 23%, respectively, compared to 73% for patients who were MRD-negative. The impact of post-HSCT MRD status is, however, less clear.55,59 While patients with persistent or recurrent MRD after HSCT appear to have relatively poor outcomes, one analysis sug- gests that pre-HSCT MRD status carries relatively more prognostic information than post-HSCT MRD status.55 In this study, only pre-HSCT MRD was independently asso- ciated with long-term outcomes. The 3-year overall sur- vival rate for patients with pre-HSCT MRD that persisted after the transplant was 19% and only slightly higher for those with pre-HSCT MRD that cleared with transplanta- tion (3-year overall survival rate: 29%).
Polymerase chain reaction-based measurable residual disease studies
The prognostic impact of MRD detected by PCR has been shown primarily in acute promyelocytic leukemia, core-binding factor leukemias, and NPM1-mutated AML, as the target alterations in these AML subtypes represent stable, foundational genomic lesions that become unde-
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