Unveiling Cryptic BCR-ABL1 Rearrangements: Diagnostic Challenges and Clinical Impact in Myeloid Malignancies

Area of Science:

• Hematology
• Molecular Diagnostics
• Oncology

Background:

• BCR-ABL1 fusions define chronic myeloid leukemia (CML) and Philadelphia-positive acute lymphoblastic leukemia.
• Standard cytogenetics can miss cryptic BCR-ABL1 rearrangements, impacting treatment decisions.
• High-depth RNA sequencing enhances fusion transcript detection.

Purpose of the Study:

• To highlight diagnostic challenges posed by cryptic BCR-ABL1 rearrangements in myeloid malignancies.
• To illustrate the impact of detecting these rearrangements on patient classification and therapy.
• To recommend integrated molecular strategies for improved diagnostic accuracy.

Main Methods:

• Case study analysis of two myeloid malignancy patients.
• Utilized an integrated molecular approach combining cytogenetics and targeted sequencing.
• Reviewed diagnostic pitfalls and therapeutic implications.

Main Results:

• Identified cryptic BCR-ABL1 rearrangements in two myeloid cases initially misdiagnosed or with undetected fusions.
• Reclassified a myelodysplastic/myeloproliferative neoplasm as CML after detecting a cryptic e13a2 BCR-ABL1 rearrangement, enabling TKI treatment.
• Detected an undetected BCR-ABL1 fusion in a relapsed acute myeloid leukemia (AML) case, indicating aggressive disease.

Conclusions:

• Integrated molecular approaches are essential for detecting cryptic BCR-ABL1 rearrangements.
• Timely detection of BCR-ABL1 fusions is critical for appropriate CML and AML patient management.
• Multimodal screening strategies should be implemented for atypical myeloid leukemia presentations.