Prognostic value of low-level MRD in adult acute lymphoblastic leukemia detected by low- and high-throughput methods

Abstract

Persistence of minimal residual disease (MRD) after induction/consolidation therapy in acute lymphoblastic leukemia is the leading cause of relapse. The GMALL 07/2003 study used MRD detection by real-time quantitative polymerase chain reaction of clonal immune gene rearrangements with 1 3 1024 as discriminating cutoff: levels $1 3 1024 define molecular failure and MRD-negativity with an assay sensitivity of at least 1 3 1024 defining complete molecular response. The clinical relevance of MRD results not fitting into these categories is unclear and termed “molecular not evaluable” (MolNE) toward MRD-based treatment decisions. Within the GMALL 07/03 study, 1019 consecutive bone marrow samples after first consolidation were evaluated for MRD. Patients with complete molecular response had significantly better outcome (5-year overall survival [OS] 5 85% 6 2%, n 5 603; 5-year disease-free survival [DFS] 5 73% 6 2%, n 5 599) compared with patients with molecular failure (5-year OS 5 40% 6 3%, n 5 238; 5-year DFS 5 29% 6 3%, n 5 208), with patients with MolNE in between (5-year OS 5 66% 6 4%; 5-year DFS 5 52% 6 4%, n 5 178). Of MolNE samples reanalyzed using next-generation sequencing (NGS), patients with undetectable NGS-MRD (n 5 44; 5-year OS 5 88% 6 5%, 5-year DFS 5 70% 6 7%) had significantly better outcome than those with positive NGS-MRD (n 5 42; 5-year OS 5 37% 6 8%; 5-year DFS 5 33% 6 8%). MolNE MRD results not just are borderline values with questionable relevance but also form an intermediate-risk group, assignment of which can be further improved by NGS.