Abstract
Measurable (minimal) residual disease (MRD) is an established, key prognostic factor in adult B-cell acute lymphoblastic leukemia (B-ALL), and testing for MRD is known to be an important tool to help guide treatment decisions. The clinical value of MRD testing depends on the accuracy and reliability of results. Currently, there are no Canadian provincial or national guidelines for MRD testing in adult B-ALL, and consistent with the absence of such guidelines, there is no uniform Ontario MRD testing consensus. Moreover, there is great variability in Ontario in MRD testing with respect to where, when, and by which technique, MRD testing is performed, as well as in how the results are interpreted. To address these deficiencies, an expert multidisciplinary working group was convened to define consensus recommendations for improving the provision of such testing. The expert panel recommends that MRD testing should be implemented in a centralized manner to ensure expertise and accuracy in testing for this low volume indication, thereby to provide accurate, reliable results to clinicians and patients. All adult patients with B-ALL should receive MRD testing after induction chemotherapy. Philadelphia chromosome (Ph)-positive patients should have ongoing monitoring of MRD during treatment and thereafter, while samples from Ph-negative B-ALL patients should be tested at least once later during treatment, ideally at 12 to 16 weeks after treatment initiation. In Ph-negative adult B-ALL patients, standardized, ideally centralized, protocols must be used for MRD testing, including both flow cytometry and immunoglobulin (Ig) heavy chain and T-cell receptor (TCR) gene rearrangement analysis. For Ph-positive B-ALL patients, MRD testing using a standardized protocol for reverse transcription real-time quantitative PCR (RT-qPCR) for the BCR-ABL1 gene fusion transcript is recommended, with Ig/TCR gene rearrangement analysis done in parallel likely providing additional clinical information.
Highlights
The overall incidence of acute lymphoblastic leukemia (ALL) in Canada is 0.8 per100,000 person years
The working group recognizes that flow cytometry and Ig/T-cell receptor (TCR) gene rearrangement analysis are both widely accepted approaches for MRD testing in Philadelphia chromosome (Ph)-negative B-cell acute lymphoblastic leukemia (B-ALL) patients, provided that the minimum sensitivity requirement of 10−4 is met by a standardized protocol (Table 1)
Given the advantages of next generation sequencing (NGS) compared to real-time quantitative PCR (RQ-PCR) for MRD detection, and its increased adoption and standardization in Europe, as Canadian laboratories develop molecular assays for MRD detection in Ph-negative ALL, the working group recommends that molecular MRD testing be performed in a central laboratory in Ontario
Summary
The overall incidence of acute lymphoblastic leukemia (ALL) in Canada is 0.8 per. 100,000 person years. Leukemias with this translocation, Ph-positive ALL, comprise about 25% of cases of adult ALL overall, but with an increasing incidence with age, reaching 40 to 50% of adult ALL cases above age 50 [4,5,6]. Patients who achieve MRD negativity after induction, or at a later time point, have improved relapse-free survival as well as improved overall survival. These outcomes are noted across all subgroups, including both. To be optimally useful clinically, MRD assessment requires accurate, reproducible, and sensitive detection of very low levels of residual leukemia. This can be done using either flow cytometry, or molecular genetic methods. An expert multidisciplinary working group was convened to discuss the status of MRD testing in Ontario, and to define recommendations for improving the delivery of MRD testing in adult B-ALL
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