| Summary: | ABSTRACT Introduction Recent advancements in risk stratification have greatly improved outcomes in pediatric B‐cell precursor acute lymphoblastic leukemia (BCP‐ALL). Despite favorable prognostic indicators, including the absence of cytogenetic abnormalities and minimal residual disease (MRD) negativity, relapse remains a major clinical concern. Methods and Results We investigated the clinical significance of immunoglobulin heavy chain (IGH) clonality using RNA sequencing data in BCP‐ALL. We analyzed IGH clonality from 136 patients. IGH abundance followed a power law distribution, which enabled us to identify disease clones as outliers based on read count. In total, 330 disease clones were detected, and patients were categorized into three clonotype groups: undetectable disease clone (UDC), incomplete disease clone (IDC), and complete disease clone (CDC). Clinical outcomes were compared across clonotypes, including in subgroups with high hyperdiploidy (HHD) and MRD negativity. Among patients with HHD, significant prognostic differences were observed across clonotypes (event‐free survival [EFS], p = 0.01; overall survival [OS], p = 0.08), even among those who were MRD‐negative (EFS, p = 0.01; OS, p = 0.03). Furthermore, comparisons of IGH sequences between diagnosis and relapse indicated that while initial disease clones often contributed to relapse, newly expanded clones frequently emerged, particularly in patients with HHD. Conclusions These findings highlight the importance of analyzing the IGH repertoire in refining risk stratification and underscore the need for advanced sequencing‐based MRD monitoring.
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