Advances in measurable residual disease monitoring for adult acute lymphoblastic leukemia

Abstract

Adult acute lymphoblastic leukemia management has traditionally relied upon pretreatment conventional risk factors for treatment decisions. Despite using intensive multiagent chemotherapy followed by a prolonged maintenance or allogeneic stem cell transplantation, these patients remain at a high risk of relapse. Improved techniques for detection of measurable residual disease (MRD) have tremendously changed the posttreatment disease burden assessment and evolved as a powerful predictor of relapse and survival superseding historical prognostic factors. Moreover, MRD measurement has become an integral part of risk stratification, prognosis assessment, intensification or de‐escalation of treatment, monitoring of disease burden, and an endpoint in clinical trials. With existing approaches like allogeneic hematopoietic stem cell transplantation and emergence of novel agents (eg, blinatumomab, inotuzumab ozogamicin, and chimeric antigen receptor [CAR] T cells) that are highly effective in eradicating residual disease, understanding the role of MRD in treatment decisions is getting more and more important and complex. This review will highlight the advances that have been achieved in MRD monitoring over the years and the practical applications in different time points of treatment to provide a framework for rational management decisions by practicing hematologists and oncologists.

Consensus Recommendations for MRD Testing in Adult B-Cell Acute Lymphoblastic Leukemia in Ontario

“…Regardless of the methodology used, a certain volume of testing is necessary to achieve the required level of expertise in MRD testing. For example, accurate flow cytometry assessment is highly dependent on the expertise of the interpreting Hematopathologist [ 26 ]. In addition, assay sensitivity for a standardized reverse transcription real-time quantitative PCR (RT-qPCR) MRD assay for the BCR-ABL1 transcript in Ph-positive ALL is related to the laboratory’s level of experience with the specific protocol [ 29 ].…”

“…Flow cytometry is currently the most widely used technique in North America for assessing MRD in Ph-negative B-ALL patients. Modern flow cytometry techniques using 6 or more fluorochromes are capable of detecting MRD with a sensitivity of approximately 10 −4 (assuming an adequate sample), and there is the potential for even greater sensitivity with more than 8 fluorochromes and a higher number of input cells, although such sensitivity is not achieved routinely [ 26 ]. MRD assessment by flow cytometry is affordable and has a quick turnaround time.…”

“…MRD assessment by flow cytometry is affordable and has a quick turnaround time. However, the interpretation of flow cytometry results for MRD assessment requires substantial expertise from the Hematopathologist [ 26 ]. Currently, Ontario laboratories performing flow cytometry for MRD assessment in adult B-ALL are not all using standardized protocols.…”

“…Sensitivity of this method varies based on the amount of input DNA: a sensitivity of 10 −4 to 10 −5 can be reached with 500 ng to 1 μg of input DNA. In comparison with flow cytometry and RQ-PCR, NGS generally shows better sensitivity [ 26 ]. However, the quantification of MRD levels by NGS can be challenging.…”

“…Flow cytometry for MRD analysis involves identifying and tracking aberrant leukemia-associated immunophenotypes (LAIP) found on leukemic cells [ 25 ]. Molecular genetic methods include quantitative polymerase chain reaction (qPCR), droplet digital PCR (ddPCR), or next generation sequencing (NGS) to detect the presence of leukemia-specific gene fusions, such as BCR-ABL1 , or clonal rearrangements in the immunoglobulin ( Ig ) and T-cell receptor ( TCR ) gene families [ 26 ].…”