How I investigate minimal residual disease in acute lymphoblastic leukemia

Abstract

Minimal Residual Disease (MRD) is the most important independent prognostic factor in acute lymphoblastic leukemia (ALL) and refers to the deep level of measurable disease in cases with complete remission by conventional pathologic analysis, especially by cytomorphology. MRD can be detected by multiparametric flow cytometry, molecular approaches such as quantitative polymerase chain reaction for immunoglobulin and T‐cell receptor (IG/TR) gene rearrangements or fusion genes transcript, and high‐throughput sequencing for IG/TR. Despite the proven clinical usefulness in detecting MRD, these methods have differences in sensitivity, specificity, applicability, turnaround time and cost. Knowing and understanding these differences, as well as the principles and limitations of each technology, is essential to laboratory standardization and correct interpretation of MRD results in line with treatment time points, therapeutic settings, and clinical trials. Here, we review the methodological approaches to measure MRD in ALL and discuss the advantages and limitations of the most commonly used techniques.

Measurable residual disease in acute lymphoblastic leukemia: methods and clinical context in adult patients

“…In addition to its laborious and time-consuming methodology, ASO-qPCR may be limited by the loss or emergence of new V(D)J sequences, leading to false negative MRD results. 38 …”

“…In addition to its laborious and time-consuming methodology, ASO-qPCR may be limited by the loss or emergence of new V(D)J sequences, leading to false negative MRD results. 38 In a study in which both BCR-ABL1 level and IG/TR ASO-qPCR were monitored in the bone marrow of Ph + B-ALL patients, overall concordance between the two methods was ~70%, 39 but IG/TR was found to be more reliable at predicting outcomes. However, another study investigating the discrepancy between the two methods showed that some patients with persistent BCR-ABL1 transcript levels may in fact contain the fusion gene in myeloid cells, indicating a chronic myeloid leukemia-like stem cell disease, which may be missed by ASO/qPCR.…”

Deciphering stage 0 hematogones by flow cytometry in follow‐up bone marrow samples of pediatric B—Acute lymphoblastic leukemia cases: A potential mimicker of residual disease after anti CD19 therapy

“…It is also used as a gating marker in flow cytometry (FCM) for diagnosis and residual disease detection posttreatment in B cell malignancies for the above reason. FCM is the most commonly used technique for detecting residual disease in ALL due to its advantage over molecular methods (Brüggemann & Kotrova, 2017; Correia et al, 2021). Currently, there are four groups of drugs that have been developed to target CD19, (i) unconjugated monoclonal antibodies like Inebilizumab and Tafasitamab, (ii) antibody drug conjugates like Denintuzumab mafodotin and Loncastuximab tesirine, (iii) molecules that recruit T cells to kill CD19+ cells by antibody dependent cellular cytotoxicity called bi‐specific T cell engager (BiTE) like Blinatumomab, and (iv) chimeric antigen receptor (CAR) T cell therapy like tisagenlecleucel, axicabtagene ciloleucel, and lisocabtagene maraleucel (Gambella et al, 2022; Yin et al, 2021).…”

Comparison of Multiparameter Flow Cytometry and ClonoSEQ Studies for Precursor B-Lymphoblastic Leukemia Minimal Residual Disease Detection on Bone Marrow Samples

“…Precursor B-lymphoblastic leukemia (B-ALL) patients in morphologic remission may still have measurable disease detected by highly sensitive methods. The choice of an optimal method for MRD measurement depends on the test characteristics and clinical scenarios [2]. MRD values are reported to have a Center (RPCC) during the time from October 2020 to April 2022.…”