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

Abstract

Measurable residual disease (MRD) is the most powerful independent predictor of risk of relapse and long-term survival in adults and children with acute lymphoblastic leukemia (ALL). For almost all patients with ALL there is a reliable method to evaluate MRD, which can be done using multi-color flow cytometry, quantitative polymerase chain reaction to detect specific fusion transcripts or immunoglobulin/T-cell receptor gene rearrangements, and high-throughput next-generation sequencing. While next-generation sequencing-based MRD detection has been increasingly utilized in clinical practice due to its high sensitivity, the clinical significance of very low MRD levels (<10-4) is not fully characterized. Several new immunotherapy approaches including blinatumomab, inotuzumab ozogamicin, and chimeric antigen receptor T-cell therapies have demonstrated efficacy in eradicating MRD in patients with B-ALL. However, new approaches to target MRD in patients with T-ALL remain an unmet need. As our MRD detection assays become more sensitive and expanding novel therapeutics enter clinical development, the future of ALL therapy will increasingly utilize MRD as a criterion to either intensify or modify therapy to prevent relapse or de-escalate therapy to reduce treatment-related morbidity and mortality.

ZNF384 fusion transcript levels for measurable residual disease monitoring in adult B‐cell acute lymphoblastic leukemia

“…Measurement of measurable residual disease (MRD) plays an important role in outcomes prediction, risk stratification, and treatment decisions. Fusion transcript levels detected by real‐time quantitative polymerase chain reaction (RQ‐PCR) is an ideal MRD marker with high sensitivity and specificity 8–10 . Ravandi et al.…”

“…Fusion transcript levels detected by real-time quantitative polymerase chain reaction (RQ-PCR) is an ideal MRD marker with high sensitivity and specificity. [8][9][10] Ravandi et al assessed MRD in Ph-positive ALL patients treated with combination of chemotherapy and TKIs, demonstrating better outcomes of patients with BCR-ABL/ABL <0.1% at 3, 6, 9 and 12 months. 11 Our previous multicenter trial in t (8; 21) acute myeloid leukemia (AML) patients found that <3-log reduction of RUNX1-RUNX1T1 fusion transcript levels after 2-course consolidation was associated with high risk of relapse, and such patients benefited from allogeneic hematopoietic stem cell transplantation (allo-HSCT).…”

Have we been qualifying measurable residual disease correctly?

“…There is consensus a flow cytometry-based MRD-test should be reproducible at a limit of detection (LoD) of ≤0.01% leukaemia cells in a blood or bone marrow sample [26]. Based on this reasoning it is proposed a multi-parameter flow cytometry (MPFC)-based MRD-test should only be declared positive if ≥ 5 10E+5 cells are analysed and if ≥20 or ≥50 cells are positive [27][28][29][30].…”

Pediatric Hematopathology in the Era of Advanced Molecular Diagnostics: What We Know and How We Can Apply the Updated Classifications

“…In this era of advanced molecular diagnostics, existing and emerging molecular technologies have revolutionized the diagnostic workup as well as follow-up testing in many disease entities such as BMF syndrome, myeloid neoplasms, and B-ALL [1,[18][19][20][21]. Using molecular methods to evaluate for potential germline predisposition has also gained popularity with rapidly increasing discoveries of causative mutations in these predisposition syndromes.…”