High-sensitivity next-generation sequencing MRD assessment in ALL identifies patients at very low risk of relapse

Abstract

Measurable residual disease (MRD) is highly prognostic for relapse and overall survival (OS) in acute lymphoblastic leukemia (ALL), although many patients with apparent "MRD negativity" by standard assays still relapse. We evaluated the clinical impact of a highly sensitive next-generation sequencing (NGS) MRD assay in 74 adults with ALL undergoing frontline therapy. Among remission samples that were MRD negative by multiparameter flow cytometry (MFC), 46% were MRD positive by the NGS assay. After one cycle of induction chemotherapy, MRD negativity by MFC at a sensitivity of 1x10-4 and NGS at a sensitivity of 1x10-6 was achieved in 66% and 23% of patients, respectively. The 5-year cumulative incidence of relapse (CIR) among patients who achieved MRD negativity by MFC at CR was 29%; in contrast, no patients who achieved early MRD negativity by NGS relapsed, and their 5-year OS was 90%. NGS MRD negativity at CR was associated with significantly decreased risk of relapse compared with MRD positivity (5-year CIR: 0% versus 45%, respectively, P=0.04). Among patients who were MRD negative by MFC, detection of low levels of MRD by NGS identified patients who still had a significant risk of relapse (5-year CIR: 39%). Early assessment of MRD using a highly sensitive NGS assay adds clinically relevant prognostic information to standard MFC-based approaches and can identify patients with ALL undergoing frontline therapy who have a very low risk of relapse and excellent long-term survival.

Frontline combination of ponatinib and hyper‐CVAD in Philadelphia chromosome‐positive acute lymphoblastic leukemia: 80‐months follow‐up results

“…The combination of ponatinib and hyper‐CVAD resulted in the highest CMR rate reported so far (exclusive of the blinatumomab and TKI experiences) explaining why, for the first time in the history of Ph‐positive ALL therapy, allogeneic SCT may not be necessary in most patients, particularly in those who achieve a CMR 31 . Using more sensitive techniques to detect MRD, like next‐generation sequencing (NGS) that assesses clonal immunoglobulin heavy chain or T‐cell receptor rearrangements with a sensitivity of 10 −6 , may define better subsets of patients who may or may not benefit from allogeneic SCT in first CR 32 …”

“…31 Using more sensitive techniques to detect MRD, like next-generation sequencing (NGS) that assesses clonal immunoglobulin heavy chain or T-cell receptor rearrangements with a sensitivity of 10 À6 , may define better subsets of patients who may or may not benefit from allogeneic SCT in first CR. 32 Several investigators reported underlying genomic lesions in Ph-positive ALL that significantly influence outcomes, such as deletions of IKZF1 and CDKN2A/B. [33][34][35][36] However, these studies were performed in patients receiving earlier generation TKIs (e.g., imatinib or dasatinib).…”

Treatment de-escalation in Philadelphia chromosome–positive B-cell acute lymphoblastic leukemia: the emerging role of chemotherapy-free regimens

“…within the first cycle of therapy) and more sensitive next-generation sequencing-based MRD assays (sensitivity of) may help to select those who could potentially safely discontinue TKI. 43 , 44 Identification of patients who may safely discontinue TKI therapy is important because of the potential for long-term toxicity with all BCR::ABL1 TKIs.…”

SOHO State of the Art Updates and Next Questions: Measurable Residual Disease in Acute Lymphoblastic Leukemia - Optimization and Innovation in 2022 and Beyond

“…Patients with low levels of MRD by NGS, but negative MRD by MFC, still had a significant risk of relapse (5-year CIR: 39%). 20 Another study examined the association between MRD levels and influence hematopoietic cell transplantation (HCT) outcomes in children. Using an International Pediatric ALL MRD database, the authors examined peri-HCT MRD by either MFC or allele-specific oligonucleotide (ASO)-PCR in over 600 children.…”