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Current Opinion in Hematology:
doi: 10.1097/MOH.0b013e3283543d5c

Minimal residual disease monitoring in childhood acute lymphoblastic leukemia

Campana, Dario

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Department of Paediatrics, Yong Loo Lin School of Medicine, National University of Singapore, Singapore

Correspondence to Dario Campana, MD, PhD, Department of Paediatrics, Yong Loo Lin School of Medicine, National University of Singapore, Centre for Translational Medicine,14 Medical Drive, Level 9 South, Singapore 117599, Singapore. Tel: +65 6601 2666; fax: +65 6779 7486; e-mail:

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Purpose of review: This review summarizes recent advances in the application of minimal residual disease (MRD) testing in childhood acute lymphoblastic leukemia (ALL).

Recent findings: Polymerase chain reaction amplification of antigen receptor genes, one of the two main methods to study MRD in ALL, could be made more rapid, sensitive and informative by the application of next-generation sequencing technologies. Advances in flow cytometric detection of MRD, the other main method, include the identification of new immunophenotypic markers to recognize ALL cells, the development of computerized approaches to automate data analysis, and the generation of instruments that can rapidly screen large number of cells for immunophenotypic abnormalities while visualizing their morphology. Recent data further corroborate the prognostic value of MRD at early time points during therapy, demonstrate the prognostic significance of MRD among ALL subtypes, and indicate that presenting features can complement the prognostic utility of MRD.

Summary: MRD is replacing morphology to measure treatment response in ALL and is being used, with promising results, for risk-stratification in clinical protocols. Recent studies provide further evidence of its prognostic significance and point to possible strategies to increase the reliability, applicability and sensitivity of MRD testing.

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In patients with leukemia, minimal residual disease (MRD) signifies leukemic cells undetectable by morphologic examination of bone marrow smears. Acute lymphoblastic leukemia (ALL) has been at the forefront of the development of MRD methods [1]. Progress in introducing MRD testing into the clinic was not initially widely supported as some investigators were concerned that the distribution of leukemic cells during treatment might be too heterogeneous for MRD testing to be accurate. In fact, the strong correlation between levels of MRD and relapse risk suggests that, at least at the early stages of therapy, ALL distribution is quite homogeneous [1]. Other investigators insisted that progress in ALL prognostication could only occur by focusing on the genetics of leukemic cells. However, MRD measurements should be inherently more informative than any leukemic cell features as they reflect the effect of several other variables that influence treatment response and outcome, including variations in drug dosage, pharmacogenomics and pharmacodynamics factors, the effect of the microenvironment, and patient compliance [1]. Ultimately, confidence in the clinical utility of MRD has grown with improvements in methodology and the strength of many correlative studies, and MRD testing is gradually superceding morphology as the best means to assess treatment response and define ‘remission’ in patients with ALL. This article provides an update on recent advances in the application of MRD studies to childhood ALL.

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Two main approaches have been demonstrated to provide clinically meaningful MRD results: PCR amplification of immunoglobulin and T-cell receptor (TCR) genes, and flow cytometric detection of aberrant immunophenotypes [2,3]. PCR amplification of oncogenic fusion transcripts can only be applied to a subset of patients, that is, those with the most prevalent gene fusions, and suffers from lack of quantitative power [4▪]; hence, it is used less frequently.

Clonal rearrangements of immunoglobulin and TCR genes occur in approximately 90% of patients with ALL. By targeting these genes, after identifying them at diagnosis, MRD monitoring with a sensitivity of one leukemic cell in 100 000 normal bone marrow cells (or 0.001%) can be attained [2,4▪,5]. Because of the extensive efforts of the investigators participating in the BIOMED-2 Concerted Action BMH4-CT98–3936 project, the methods have been extensively optimized and standardized, thus facilitating their implementation in other laboratories [2,4▪]. This approach, however, requires sequencing of diagnostic DNA, identification of suitable rearrangements (often more than one), synthesis of corresponding primers and development of PCR conditions that are optimal for each rearrangement [2]. This process is time consuming and usually precludes analysis of MRD at early time points (e.g., day 15) in a timely fashion. The advent of massive parallel sequencing technologies, and their decreasing cost, has opened the possibility of using consensus primers (a set of primers that can be used to amplify all possible rearranged immunoglobulin or TCR segments) and parallel sequencing to identify the most prevalent rearrangement at diagnosis [6]. These rearrangements are then searched among those amplified in the same way in the follow-up samples, obviating the need to develop reagents and PCR conditions for each patient. The specificity and sensitivity of this approach is potentially very high and, if sufficient DNA is available for study, it can reach 1 in 106 and beyond [6]. In initial tests of this method applied to ALL, Faham et al.[7] studied diagnostic and follow-up samples from 10 patients using a comprehensive set of consensus primers: they could identify all five samples that were MRD-positive according to established flow cytometry and PCR methods, with highly concordant estimates of MRD levels between the established and the new method. Interestingly, one of the five samples that were MRD-negative by both flow cytometry and conventional PCR had unambiguous leukemia-derived sequences in the range of one in a million. This approach holds potential for greatly facilitating molecular MRD studies in ALL and it may well supplant the current method.

Leukemia-associated immunophenotypes that can be monitored by flow cytometry are expressed by leukemic lymphoblasts in the majority of patients and allow MRD detection with a sensitivity of 0.01%. However, identifying the immunophenotypic difference between ALL and normal cells takes much training and experience. The greater the difference between the overall immunophenotypic profiles of leukemic and normal cells, the easier it is to recognize ALL cells. On the basis of this principle, we sought to identify additional markers that would make ALL cells more distinct. This task traditionally relied on a heuristic approach, largely based on trial and error [8–10]. Encouraged by the promising results of a pilot study that identified CD58 as a useful marker for MRD studies [11], we compared genome-wide gene expression of lymphoblasts from 270 patients with newly diagnosed childhood ALL to that of sorted normal CD19+CD10+ B-cell progenitors from four healthy donors, that is, cells with immunophenotypic features similar to those of leukemic lymphoblasts [12▪]. Among genes differentially expressed by genome-wide expression array analysis, we selected a group of 30 for further studies based on their highly abnormal expression at the mRNA level in a substantial proportion of ALL cases and on the availability of specific antibodies suitable for routine flow cytometric studies [12▪]. We then tested their expression by flow cytometry in 200 B-lineage ALL and 61 nonleukemic bone marrow samples, including in the analysis recovering bone marrow samples, which are particularly challenging in MRD studies of ALL because of their high proportion of normal immature lymphoid cells. Of the 30 markers, 22 were differentially expressed in up to 81% of ALL cases [12▪], including markers also found by other investigators to be differentially expressed in ALL such as CD304 [13] and CD123 [14]. The reliability of the new markers was further corroborated by comparisons using paired diagnosis–relapse samples, which demonstrated that their expression remained stable during leukemia progression [12▪]. The addition of these new markers considerably improved existing MRD panels by allowing reliable MRD monitoring by flow cytometry in all patients with a potential sensitivity of one in 100 000 [12▪]. Other markers recently reported to hold potential for MRD studies include CD81 [15], CD49f [10], and CD11b [16], the latter also having been found to be overexpressed in a substantial number ALL cases in our gene expression array comparison [12▪].

Attempts to automate the interpretation of flow cytometric MRD data are now being made [17]. Fiser et al.[18] developed a method based on hierarchical clustering analysis which yielded MRD results that correlated well with standard procedures. These new approaches, if incorporated into easily accessible software, should be a useful aid and may ultimately automate the interpretation process entirely. These efforts should take into account the fact that the intensity of marker expression may change during chemotherapy [19]. Dworzak et al.[20] recently reported a study of some of the markers in patients who were MRD positive through sequential testing. They found that downregulation of CD10 and CD34 expression observed early during chemotherapy reverted to the levels recorded at diagnosis after glucocorticoids were stopped. Glucocorticoids were also linked to upregulation of CD20 and changes in CD45 expression, whereas changes in CD11b expression occurred later [20].

A recent study tested the potential of an entirely different approach to immunophenotypic analysis of MRD, based on high-speed cell imaging scanning technology [21]. This method has the potential to identify immunophenotypically aberrant cells among 1 million or more normal cells and then determine their morphology to ensure that the signals detected are not artifacts but originate from viable lymphoblasts [21].

Because current MRD tests are complex and require specific expertise, they should be performed in specialized laboratories. PCR studies are typically performed in reference laboratories but flow cytometric studies, which require instruments and reagents widely available for leukemia immunophenotyping, are often attempted by investigators without the necessary specialized skills, which may lead to erroneous results. Recognizing the potentially disastrous consequences of this, cooperative groups generally submit samples to reference laboratories with demonstrated expertise [22–24], or share the workload among a larger number of laboratories after extensive cross-testing and standardization efforts [25–27].

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The prognostic significance of MRD in childhood ALL is unquestionable and has been demonstrated in numerous correlative studies using either PCR or flow cytometry, measuring MRD at various intervals during therapy, in the context of different chemotherapy regimens, and including children with first-relapse ALL who achieve a second remission [5,22,23,28–36,37▪,38–44]. In addition to predicting outcome in the context of chemotherapy, MRD also provides valuable information when measured prior to and after allogeneic hematopoietic stem cell transplant (HSCT) [45–48].

A large study by Conter et al.[37▪] illustrates the prognostic importance of MRD. These authors used PCR to obtain MRD measurements on days 33 and 78 in 3184 patients with newly diagnosed B-lineage ALL enrolled in the Associazione Italiana Ematologia Oncologia Pediatrica – Berlin Frankfurt Münster (AIEOP-BFM) ALL 2000 protocol, and identified three risk-categories based on MRD levels. Patients with MRD less than 0.01% on days 33 and 78 (42%) had a 5-year event-free survival (EFS) of 92.3%, those with MRD at least 0.1% on day 78 (6%) had an EFS of 50.1% and the remaining patients (52%) had an EFS of 77.6% (1.3). MRD was a better predictor of outcome than leukocyte count, age, early response to prednisone and genetic subtype. Importantly, MRD was predictive of outcome even among subsets of patients defined by TEL-AML1, high hyperdiploidy, or BCR-ABL1. In a recently reported study, Schrappe et al.[49▪] used similar methodology to measure MRD in 464 patients with T-ALL. Using the same cut-off levels applied by Conter et al. in the B-lineage ALL cohort, they found that only 16% were MRD less than 0.01% on days 33 and 78, 21% had MRD at least 0.1% on day 78 and 63% had intermediate MRD levels. MRD less than 0.01% at the end of induction was the best indicator of a favorable prognosis, whereas patients with MRD at least 0.1% on day 78 had a high risk of relapse. Notably, patients converting to MRD negativity on day 78 (32%) had a favorable outcome. Among 99 infants with ALL enrolled in the Interfant-99 protocol, Van der Velden et al.[50] found that all those with MRD at least 0.01% at the end of induction and/or consolidation (26%) relapsed, whereas relapse occurred in only 13% of those with MRD less than 0.01% at both time points (44%); the remaining patients had a relapse rate of 31%. Finally, Bowman et al.[51▪] recently reported that MRD measured in peripheral blood on day 8 and in the bone marrow on day 29 were strong prognostic factors in children with B-lineage ALL and high-risk presenting clinical features who received augmented therapy.

Studies performed during remission induction therapy are emerging as being particularly informative. Sutton et al.[36] used PCR to measure MRD at various time points during treatment in 108 patients enrolled on the Australian and New Zealand Children's Cancer Study Group Study VII and found that day 15 was the best early MRD time point to predict risk of relapse. Basso et al.[23] used flow cytometry to examine bone marrow samples from 830 children with ALL collected on day 15 of treatment, after 14 days of steroids and one dose of vincristine, daunorubicin, and asparaginase, as well as intrathecal methotrexate. One group of patients, representing 42% of the cohort, had less than 0.1% ALL cells, and had a 5-year cumulative incidence of relapse of 7.5%. A second group (47%) had MRD of 0.1% to less than 10% and a relapse rate of 17.5%. Finally, 11% of patients had high MRD of 10% or more and a relapse rate of 47.2%. In a multivariate analysis, MRD was the strongest prognostic factor among those available by day 15; even when MRD detected by PCR at later time points was added to the model, MRD on day 15 retained prognostic significance.

The informative potential of MRD measured at early time points has practical implications because these can be performed with a simplified, low-cost, flow cytometry assay. To this end, we found that bone marrow normal lymphoid progenitors (CD19+, CD10+, and/or CD34+) are exquisitely sensitive to corticosteroids and other antileukemic drugs [52]. In patients with B-lineage ALL, cells with this phenotype detected early in treatment indicate residual disease. MRD detection by this simplified assay correlated well with those of more complex flow cytometric and molecular MRD tests [52]. On the basis of these results, we have initiated treatment protocols relying on the simplified test to identify good early responders who are offered less intensive chemotherapy (R. Ribeiro, G. Rivera, D. Campana, E. Coustan-Smith, F. Pedrosa, I. Sidhom, K. Shaaban, et al., unpublished results). Other investigators have also recently confirmed the informative value of this approach [53]. Such studies represent a good starting point for laboratories interested in implementing MRD studies and are particularly well suited for centers with limited resources, because they require only a very small antibody panel and basic instrumentation.

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MRD testing has changed the definition of remission in ALL and set a new standard by which the efficacy of antileukemia therapy can be measured. MRD levels are now used for risk-assignment in several treatment protocols for childhood ALL. In the now closed St Jude Total XV study for children and adolescents with ALL, MRD was measured on days 19 and 46 of treatment and chemotherapy, and the data were used to determine a final risk classification [24], resulting in outstanding overall cure rates. Regardless, in this study, high MRD levels (≥1%) at the end of induction (a criterion for HSCT in first remission) remained an adverse predictor of outcome and the only independent prognostic factor (in addition to CNS3 status at diagnosis or traumatic lumbar puncture). Lankester et al. [54] stratified 48 children with ALL undergoing HSCT according to the MRD levels before transplant. Those with MRD at least 0.01% (n = 18) were eligible for early tapering of cyclosporine post-HSCT and donor lymphocyte infusions. Relapses appeared to occur later and several presented at extramedullary sites, suggesting some modulatory effect from the intervention [54]. Although event-free survival in this study (19%) was ultimately not better than that of previous trials, further attempts are warranted to reduce the relapse rate post-HSCT for patients with MRD prior to transplant, and/or strive for a further reduction of MRD before beginning the transplant conditioning regimen [47].

The relative weight of different prognostic factors in ALL changes as therapy improves and new prognostically significant subsets, such as B-lineage ALL with abnormalities of the IKZF1 gene [55] or early T-cell precursor [56], must now be taken into account. Although MRD measurements will most likely remain central to the modern treatment of ALL, their predictive power might be improved by integrating it with that of other factors. To this end, Rabin et al.[57] found that absolute lymphocyte counts on day 29 could improve MRD-based predictions in children treated in the Children's Oncology Group P9900 protocols. Lonnerholm et al.[58] reported data suggesting that results of vincristine and doxorubicin resistance determined in vitro might add to MRD measurements on day 29. Finally, Waanders et al.[59] integrated MRD and IKZF1 gene status to predict 79% of the relapses (with 93% specificity) occurring in a group of 131 B-lineage ALL patients.

In sum, MRD studies have revolutionized risk-stratification in childhood ALL and have multiple applications in the management of patients. MRD is also beginning to be used to determine the efficacy of new anti-ALL agents [60▪], and should be a valuable tool to accelerate the discovery of agents with the highest antileukemic effect.

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Conflicts of interest

There are no conflicts of interest.

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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. 341–342).

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This study demonstrated the prognostic significance of MRD in B-lineage ALL regardless of presenting features in a large cohort of patients.

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This study demonstrated the prognostic significance of MRD in T-lineage ALL.

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This study demonstrated the clinical significance of MRD in patients with high-risk ALL treated with augmented therapy.

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60▪. Topp MS, Kufer P, Gokbuget N, et al. Targeted therapy with the T-cell-engaging antibody blinatumomab of chemotherapy-refractory minimal residual disease in B-lineage acute lymphoblastic leukemia patients results in high response rate and prolonged leukemia-free survival. J Clin Oncol 2011; 29:2493–2498.

An excellent example of using MRD as an eligibility criteria for a trial with a novel agent.

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acute lymphoblastic leukemia; flow cytometry; minimal residual disease; polymerase chain reaction; prognosis; remission

© 2012 Lippincott Williams & Wilkins, Inc.


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