Preferential Genetic Pathways Lead to Relapses in Adult B-Cell Acute Lymphoblastic Leukemia.

Area of Science:

• Hematology
• Oncology
• Genetics

Background:

• Adult B-cell acute lymphoblastic leukemia (B-ALL) presents significant genetic diversity and a high relapse rate.
• Understanding the underlying mechanisms of relapse in adult B-ALL is crucial for improving patient outcomes.

Purpose of the Study:

• To investigate the genetic landscape of adult B-ALL at diagnosis and relapse.
• To identify key genetic pathways and clonal evolution patterns contributing to B-ALL relapse in adults.

Main Methods:

• Next-generation sequencing (NGS) was employed to analyze genetic profiles of 44 adult B-ALL patients at diagnosis and relapse.
• Comparative genomic analysis was performed to identify genetic alterations and clonal dynamics associated with relapse.

Main Results:

• Four primary genetic pathways to relapse were identified: IKZF1plus profile, RAS/TP53 alterations in Ph-negative B-ALL, and ABL1 mutations in Ph-positive B-ALL.
• IKZF1 deletion was frequent at diagnosis, with the IKZF1plus profile largely retained at relapse.
• Relapse in Ph-negative B-ALL was associated with acquired RAS mutations, TP53 alterations, or subclone expansion; Ph-positive B-ALL relapses frequently involved acquired ABL1 mutations.
• Three distinct clonal evolution patterns were observed: persistent, expanding, and therapy-boosted trajectories.

Conclusions:

• Specific biological pathways preferentially drive relapse in adult B-ALL.
• These findings highlight the necessity for tailored therapeutic strategies to enhance clinical outcomes in adult B-ALL patients.