DiNardo, Courtney D.; Luger, Selina M.
Assessment of remission status in acute myeloid leukemia (AML) has traditionally relied on morphology. Although cytogenetics has provided a method for detection of minimal residual disease (MRD) for over 20 years, this methodology has been restricted to approximately 50% of patients with known abnormal cytogenetics at diagnosis [1,2]. Over the past decade, increasingly sensitive methods to identify leukemic clones and detect MRD have been developed. In the current era of genomic medicine, the ability to assign a ‘leukemic signature’ is now possible in almost all patients due to the ability to detect molecular abnormalities and leukemia-associated immunophenotypes (LAIPs). With molecular screening, genetic alterations such as FLT3 and NPM1 mutations are now detectable in more than 85% of patients with normal cytogenetics , and up to 95% of patients have identifiable LAIPs by multiparameter flow cytometry (MFC) .
The availability of these methodologies has been useful in allowing us to define a patient's leukemic clone, and in some cases to risk-stratify treatment based on findings at disease presentation. The clinical significance of persistent clonal abnormalities in remission is less well understood. Multiple studies have identified that the presence or absence of MRD after treatment, or before hematopoietic stem cell transplant, is prognostic for relapse-free survival and overall survival (OS). More recently, data suggest that MRD detection should be used as a tool not only in risk assessment, but also in guiding treatment decisions, such as whether or not to proceed to allogeneic transplant in morphologic remission to improve outcomes. However, the assays that are used vary in their sensitivity, specificity, interpretation, and reproducibility. As we move toward a personalized approach to AML treatment, it will be imperative to establish standardized methods of MRD analysis to allow for accurate and reproducible results among various laboratories and institutions.
The focus of this article is to review the current methods of MRD detection and the utility of MRD assessment in the treatment of AML. Potential algorithms in clinical practice and avenues for future research will be discussed.
MOLECULAR MINIMAL RESIDUAL DISEASE ASSESSMENT
The recent development of real-time quantitative PCR (RQ-PCR) allows for monitoring of patients with known fusion transcripts, genetic mutations, and/or overexpressed genes. RQ-PCR has improved the sensitivity of MRD detection of fusion transcripts to 1 leukemic cell in 1000 to 100 000 normal cells (i.e. 0.1–0.001%) [5,6], and the quantification of results now allows for serial molecular monitoring to determine trends in transcript levels.
MRD detection of the common and favorable risk reciprocal rearrangements, most notably t(15;17), led the way for the role of MRD assessment in AML. In acute promyelocytic leukemia (APML), persistent detection of the t(15;17) PML-RARA fusion transcript following consolidation therapy or recurrently positive PML-RARA was shown to be the most powerful predictor of relapse-free survival . In the landmark AML15 trial of the UK Medical Research Council (MRC), RQ-PCR monitoring of MRD was used to deliver preemptive therapy for APML patients with subclinical disease after anthracycline-based treatment, to prevent overt morphologic relapse. Therapy with arsenic trioxide (ATO) based on sequential RQ-PCR analysis led to a 3-year cumulative incidence of clinical relapse (CIR) of 5% in this trial, compared to a 12% 3-year CIR in the historical AML12 control population, a group in which MRD monitoring was not performed. Initiation of ATO prevented progression to overt relapse in the majority of patients with molecular relapse and is one of the first studies in an AML cohort to show that treatment based on MRD results can affect patient outcomes.
In AML with inv(16) or t(16;16), the pathologic CBFB-MYH11 fusion transcript can be detected via RQ-PCR. In an analysis of 53 patients treated by the German–Austrian AML Study Group, prospective MRD monitoring was obtained at predetermined time points throughout treatment [8▪▪]. Persistently positive fusion transcripts postconsolidation provided a statistically significant difference in relapse-free survival (RFS), with a 2-year RFS of 79% in MRD-negative patients compared to 54% in MRD-positive patients. The cut-off level of 10 detectable copies after treatment, identified in a previous study , was validated and demonstrated that RQ-PCR levels below 10 copies (normalized to abl transcripts) after treatment are a prerequisite for relapse-free and long-term survival. Moreover, in patients with RQ-PCR negativity immediately postconsolidation who became positive on subsequent RQ-PCR analysis, the median time to CIR was 6 months (range 3–18 months), demonstrating that there is an adequate amount of time to intervene in a state of minimal disease burden. This study also performed paired peripheral blood and bone marrow MRD analyses and determined that whereas bone marrow samples were more sensitive during treatment, peripheral blood samples were adequate for subsequent MRD monitoring in patients who were MRD-negative by bone marrow at the end of consolidation, which is likely to increase compliance.
In a retrospective French study of 59 AML patients with inv(16)/t(16;16) who achieved a first complete remission (CR1) on cooperative group trials , the presence of any detectable MRD in peripheral blood samples at the end of consolidation was associated with a 2-year continuous complete remission of 13%, compared to 85% if MRD was undetectable (P = 0.0001). The 2-year OS for patients who achieved a decrease in transcript levels greater than 3 logs, after the first consolidation course compared to their diagnostic specimen, was 100%, while the 2-year OS was 57% if the transcript level decrease was less than 3 logs (P = 0.017). These findings have led to an ongoing prospective clinical trial (CBF-2006) in which matched related donor allogeneic transplant is offered to patients in CR1 who do not achieve a 3-log reduction of CBFB-MYH11 transcript level after the first course of consolidation therapy.
Somewhat surprisingly, there is still a lack of data proving the utility of MRD monitoring in t(8;21) and t(9;11) AML, although this is likely due to the small numbers of these patients in AML cohorts and not a manifestation of the ineffectiveness of MRD analysis of these subsets [11,12].
Although the above studies rely on identification of defined cytogenetic abnormalities seen in a minority of patients with AML, recently identified recurrent molecular mutations such as NPM1 and FLT3 now provide a substrate for PCR-based MRD techniques in the cytogenetically normal, intermediate-risk AML subgroups.
Use of RQ-PCR to monitor MRD in NPM1-mutated patients is well elucidated in a recent study by Krönke et al. [13▪▪] as part of the German–Austrian AML Study Group. As approximately 45–60% of cytogenetically normal AML patients have NPM1 mutations , monitoring of this mutation has implications in a large number of AML patients. In a cohort of 245 patients under age 60, achievement of RQ-PCR negativity after induction therapy identified patients with a 4-year CIR of 6.4%, compared to 53% in MRD-positive patients (P < 0.001), and OS of 90 vs. 51% (P = 0.001), respectively (see Figure 1 in [13▪▪]). In this study, all 36 patients with 200 NPM1 mutant transcript levels per 104 ABL copies, obtained (at any point) after completion of therapy, experienced relapse. Peripheral blood and bone marrow were similar in the posttreatment period in the ability to determine this clinically significant copy number. The dramatically low CIR rate of 6.5% at 4 years in the MRD-negative group provides important implications for personalized treatment decisions and argues against proceeding to transplant in this population.
The role of MRD monitoring for FLT3-ITD-mutated patients has been more difficult to establish. Although some studies have reported FLT3-ITD instability rates of less than 5% , FLT3-ITD mutations have generally been found to be less reliable during the course of disease for accurate MRD assessments . A recent study assessed the stability of FLT3-ITD by comparing 30 paired samples of FLT3-ITD-positive AML at initial diagnosis and at relapse [17▪]. Seven of 30 (23.3%) patients lost the original mutation at disease relapse as measured by RQ-PCR. Interestingly, two of these seven patients acquired new FLT3-ITDs at relapse as identified by GeneScan assay, and RQ-PCR methodology was then able to detect the ‘new’ ITD in the initial diagnostic specimen at a level previously undetectable by GeneScan. Despite this relative instability, this study was able to show that a more than 3 log reduction of FLT3-ITD after first postinduction chemotherapy independently predicted a better disease-free survival (OS not statistically significant) on multivariate analysis.
Although the use of RQ-PCR-based MRD technology seems promising, the complex methodology of MRD assays, and differences in standardized data analysis and presentation have complicated its widespread clinical use. To address this concern, Ostergaard et al. [18▪▪] have designed a highly flexible MRD-reporting software program through the European LeukemiaNet that provides efficient handling and harmonization of RQ-PCR data from various RQ-PCR platforms, and provides uniform and intuitive reports. This program is currently in use for the reporting of MRD data in the UK AML17 trial. Figure 1 displays the highly concordant MRD results obtained between eight participating laboratories using this MRD software. This software package facilitates the comparison of results obtained between trial groups, which could provide much needed standardization of MRD result reporting.
MULTIPARAMETER FLOW CYTOMETRY AND MINIMAL RESIDUAL DISEASE
MFC is a distinctly different method of MRD detection that uses multicolor flow cytometry to identify LAIPs. Recent studies suggest LAIPs can be detected in approximately 95% of patients with newly diagnosed AML  with a sensitivity of 0.1–0.01% . When measured postconsolidation for patients in a morphologic complete remission, MRD status by MFC (using a previously established cut-off of 3.5 × 104 residual leukemia cells) predicts clinical outcome in a consistent manner [21,22].
In 284 AML patients enrolled in European Organization of Research and Treatment of Cancer/Gruppo Italiano Malattie EMatologiche dell’Adulto protocols from 1998 to 2008, LAIPs were detected prospectively by MFC in 245 of 284 (86%) patients [23▪▪]. The LAIP was then used to track residual leukemia cells after each treatment step and during subsequent follow-up. In a subset of 143 patients who achieved a morphologic complete remission after induction and had available cytogenetic information, 115 patients (80%) were in the intermediate-risk group, 22 (16%) in good-risk, and six (4%) in poor-risk cytogenetic categories. Overall, relapse rate was significantly higher among the MRD-positive patients (74 vs. 27%, P < 0.001). In intermediate-risk patients, MRD-negative patients had a 4-year RFS of 63 vs. 17% (P < 0.001) and improved OS (67 vs. 23%, P = 0.002). In the good-risk karyotype group, MRD-negative patients had a 4-year RFS of 70 vs. 15% (P = 0.001) and improved OS (84 vs. 38%, P = 0.006). On the basis of their results, they identified two categories of risk with distinct prognosis: low risk (good or intermediate-risk karyotype with MRD-negative status) and high risk (including poor-risk cytogenetics, FLT3-ITD-mutated cases, and good or intermediate-risk karyotype with MRD-positive status). The low-risk patients had a 4-year RFS of 58%, OS of 73%, and CIR of 15%. The high-risk group had a 4-year RFS of 22%, OS of 17%, and CIR of 77% (P < 0.001 for all comparisons; see Fig. 2).
In the high-risk group, allogeneic transplant in CR1 conferred a superior outcome to autologous transplant (RFS 47 vs. 13%, P = 0.029). This study suggests that MFC-determined MRD status at the end of consolidation, in conjunction with molecular data and cytogenetics, can be used to develop an algorithm to identify patients who may derive benefit from allogeneic stem cell transplantation.
In pediatric studies of AML, MRD measurements have been used for risk assessment and treatment decisions [24▪▪]. In the AML02 trial, 204 of 215 patients (95%) had LAIPs to allow for MFC MRD studies (with a sensitivity at least 0.1%), and MRD analysis was successful in 99% of the samples received. Patients, aged 2 days to 21 years, with identified blasts or MRD-positive status after induction I (daunorubicin, etoposide, and high or low-dose cytarabine) received subsequent chemotherapy with intensified timing, including the addition of gemtuzumab ozogamicin, and patients with persistent morphologic disease or MRD were candidates for allogeneic transplant. High-dose (total of 18 g/m2) vs. low-dose (total of 2 g/m2) cytarabine did not affect the rate of MRD detection after induction I. With this risk-adapted treatment approach, the outcome for patients with low levels (0.1–1%) of MRD was identical to that of patients with MRD-negative status, suggesting that treatment intensification may benefit patients with low levels of MRD after initial chemotherapy. In the group of high-risk patients with MRD levels more than 1% after induction I, there was a nonsignificant trend toward improved OS among those who underwent allogeneic transplant (43.5 vs. 23.1 months, P = 0.14). Using the risk-adapted therapy approach, children with AML achieved a 3-year event-free survival (EFS) of 63% and an OS of 71%, a marked improvement in outcomes compared to historical pediatric AML controls, including the St Jude AML97 (EFS 44%, OS 50%) , Children's Cancer Group 2961 (EFS 42%, OS 52%) , and MRC (EFS 48%, OS 56%) .
A major criticism of flow cytometry-based MRD assays is that results are highly operator-dependent , and erroneous interpretation can occur if the interpreter has a less than extensive knowledge of normal hematopoietic immunophenotypic analysis. One suggestion by the international community has been development of software that allows for automated analysis of flow cytometric data to provide accurate gating strategies. Currently, no consensus exists for standardized AML antibody panels or specimen processing techniques, which make reproducibility and generalizability difficult [28,29].
WILMS’ TUMOR GENE AND MINIMAL RESIDUAL DISEASE
A particularly interesting proposed marker for MRD detection is the Wilms’ tumor gene (WT1), a transcription factor overexpressed in most patients with AML and other hematologic malignancies. WT1 transcript levels can be detected and quantified using RQ-PCR technology in both bone marrow and peripheral blood samples . Although quantification of WT1 expression levels can vary extensively among laboratories, the utility of WT1 gene transcript levels was recently acknowledged in the European LeukemiaNet consortium guidelines . A recent study identified that rising WT1 transcript levels alone can predict imminent relapse, in particular in the postallogeneic transplant setting [31▪], in which the median interval between rising WT1 levels and overt morphologic relapse was 2 months.
In a phase I/II clinical trial of a WT1 antigen-targeted autologous dendritic cell vaccination, longitudinal control of AML MRD, as measured by peripheral blood WT1 expression, was attained with repetitive dendritic cell vaccinations [32▪]. Dendritic cell vaccination was associated with the achievement of molecular remission in five of 10 patients who exhibited elevated WT1 mRNA expression levels before vaccination therapy. Three of those five patients remain in clinical remission with undetectable WT1 mRNA levels 3 years later. This preliminary study suggests that MRD detection can be used to direct therapy with impact on clinical outcome.
MINIMAL RESIDUAL DISEASE ASSESSMENT AND STEM CELL TRANSPLANTS
In the posttransplant setting, early recognition of disease relapse via MRD techniques allows for the application of immunotherapeutic interventions such as reductions in immunosuppression, donor lymphocyte infusions (DLIs), and use of novel therapy such as DNA methyltransferase inhibitors, before overt morphologic relapse . To that end, MRD detection in conjunction with posttransplant chimerism analysis is gaining increasing importance in the posttransplant period, although the specific techniques, timing, frequency, and actual clinical utility in terms of patient outcomes for MRD monitoring remain poorly defined .
In addition to posttransplant monitoring, a recent study from the Fred Hutchinson Cancer Research Center revealed the impact of MRD positivity in the pretransplant setting for allogeneic transplant patients [34▪▪]. In a retrospective review of 99 patients receiving a myeloablative transplant for AML in first morphologic remission, 24 patients were determined to be MRD-positive as determined by MFC (any level of residual disease detected was considered positive). Two-year OS was 30.2 and 76.6% in the MRD-positive and MRD-negative subgroups, respectively. MRD-positive patients were more likely to have AML with poor-risk cytogenetics and had a higher prevalence of secondary AML. Interestingly, they were also less likely to have received consolidation therapy with high-dose cytarabine containing regimens. Surprisingly, 2-year nonrelapse mortality was also higher for MRD-positive patients, at 26 vs. 10.1%. An obvious unanswered question is whether additional pretransplant therapy could improve outcomes in this high-risk, MRD-positive cohort.
Although the past decade has seen dramatic progress in the understanding of AML biology, improvements in patient outcomes have often failed to parallel these scientific advances. The sensitivity afforded by MRD detection offers a promising role in this setting, in which improved prognostication can lead to personalized therapeutic decisions to maximize treatment, with the dual goals of improving survival and minimizing toxicity.
Although MRD-based assessments have been clearly shown to provide prognostic information, use of MRD as a risk factor to subsequently influence treatment is a more novel concept. Current goals should, thus, focus on integrating serial MRD assessments into cytogenetic and molecular results for optimized risk stratification and appropriately standardizing MRD technologies to allow for reproducibility and multiinstitutional collaboration.
Conflicts of interest
There are no conflicts of interest.
REFERENCES AND RECOMMENDED READING
Papers of particular interest, published within the annual period of review, have been highlighted as:
▪ of special interest
▪▪ of outstanding interest
Additional references related to this topic can also be found in the Current World Literature section in this issue (pp. 126–127).
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