Lineage Conversion in Pediatric B-Cell Precursor Acute Leukemia under Blinatumomab Therapy

Area of Science:

• Pediatric Hematology Oncology
• Molecular Leukemia Biology
• Cancer Genomics

Background:

• B-cell precursor acute lymphoblastic leukemia (BCP-ALL) is a common childhood cancer.
• Blinatumomab is an effective immunotherapy for BCP-ALL, but resistance can occur.
• Lineage switch, a transformation to a different leukemia subtype, is a rare but significant challenge.

Purpose of the Study:

• To investigate the incidence and molecular features of lineage switch in pediatric BCP-ALL patients treated with blinatumomab.
• To characterize the genetic landscape and clonal dynamics associated with lineage conversion.
• To identify potential mechanisms and diagnostic markers for lineage switch.

Main Methods:

• Retrospective analysis of 182 pediatric BCP-ALL patients treated with blinatumomab.
• Comprehensive molecular profiling including gene rearrangements and mutation analysis.
• Immunophenotyping and minimal residual disease (MRD) assessment.

Main Results:

• Six cases of lineage switch were documented during or after blinatumomab therapy (3.2% of relapses, 17.4% of resistant cases).
• Switches included transformation to CD19-negative acute myeloid leukemia or mixed phenotypes.
• Consistent gene rearrangements (KMT2A, TCF3::ZNF384) were observed, with variable clonal evolution and mutation acquisition.

Conclusions:

• Lineage switch is an infrequent but notable event in blinatumomab-treated pediatric BCP-ALL.
• Molecular characterization reveals conserved genetic drivers alongside diverse clonal and mutational landscapes.
• Thorough molecular and immunophenotypic evaluation is crucial for accurate lineage switch detection.