Understanding and clinical approach to early T-cell precursor acute lymphoblastic leukemia

Early T-cell precursor acute lymphoblastic leukemia (ETP-ALL) is a distinct biological subtype of T-cell acute lymphoblastic leukemia (T-ALL) that was first described in 2009 based on a gene expression profile resembling that of early T-cell precursors in the thymus. ETP-ALL is characterized by an immature immunophenotype featuring positivity for CD7 and cytoplasmic CD3, with co-expression of myeloid/stem cell markers, and absence of CD1a, CD8, with weak or absent CD5 expression. ETP-ALL accounts for 5.5%-17.1% of pediatric and 15.8%-47.3% of adult T-ALL cases. Early studies identified ETP-ALL as a high-risk entity associated with induction failure and poor outcomes. However, subsequent prospective clinical trials demonstrated that outcomes with contemporary intensive chemotherapy were not significantly inferior to those of non-ETP T-ALL, challenging its designation as a uniformly high-risk disease. Recent large-scale genomic studies have identified molecularly defined subtypes that supersede immunophenotypic classifications, including ETP-like, BCL11B-rearranged, and SPI1-rearranged subtypes, with markedly different prognostic implications. Minimal residual disease (MRD) response remains the most robust prognostic indicator for guiding treatment intensification. Allogeneic hematopoietic stem cell transplantation (HSCT) is recommended for patients with persistent MRD positivity after consolidation. For relapsed/refractory disease, novel agents, including daratumumab, venetoclax, and bortezomib, have demonstrated promising activity, with allogeneic HSCT in the second complete remission remaining the treatment goal. This review provides an overview of the definitions, genomic classifications, clinical outcomes, and evolving treatment approaches for ETP-ALL.