Measurable Residual Disease in Adult Acute B-Lymphoblastic Leukemia: Methods, Guidelines, and Emerging Actionability at Ultra-Low-Level

Measurable residual disease (MRD) is the most powerful predictor of relapse and long-term survival in adult acute lymphoblastic leukemia (ALL), consistently outperforming traditional clinical and cytogenetic risk factors. The advent of high-sensitivity next-generation sequencing (NGS) capable of detecting MRD at 10−6 has transformed monitoring, reclassifying a substantial proportion of patients previously deemed negative by multiparameter flow cytometry (MFC) or quantitative PCR (qPCR), and revealing clinically relevant disease persistence at ultra-low levels. This review synthesizes current MRD detection platforms and their clinical applications across frontline therapy, allogeneic hematopoietic cell transplantation, and relapsed/refractory disease with specific focus on B-ALL. We integrate the 2024 European LeukemiaNet (ELN) and the 2025 US expert panel recommendations, highlighting important differences in preferred methodologies and decision thresholds. Particular attention is given to the emerging role of early deep NGS negativity in guiding transplant deferral among selected standard-risk patients, including some with Ph+ ALL treated with chemotherapy-free regimens, and to the challenges of interpreting persistent low-level positivity (10−4–10−6). Despite technological advances, key questions remain: when should deeper detection trigger therapeutic escalation, and how should discordance between modalities, peripheral blood monitoring, and subtype-specific variability be interpreted? Addressing these issues through prospective validation, platform harmonization, and broader global access will be essential to ensure that increasing sensitivity translates into evidence-based, equitable clinical benefit.