Integrated clinical genotype‐phenotype characteristics of early T‐cell precursor acute lymphoblastic leukemia

Background Early T‐cell precursor acute lymphoblastic leukemia (ETP‐ALL) is a distinct subtype of T‐ALL with a unique immunophenotype and high treatment failure rate. The molecular genetic abnormalities and their prognostic impact in ETP‐ALL patients are poorly understood. Methods The authors performed systematic analyses of the clinicopathologic features with an emphasis on molecular genetic aspects of 32 patients with ETP‐ALL. Results The median age was 43 years (range, 16–71). The blasts were positive for cytoplasmic CD3 and CD7 and negative for CD1a and CD8. Other markers expressed included CD34 (88%), CD33 (72%), CD117 (68%), CD13 (58%), CD5 (partial, 56%), CD2 (38%), CD10 (25%), CD56 (partial, 19%), and CD4 (6%). Cytogenetic analyses revealed a diploid karyotype in 10 patients, simple (1–2) abnormalities in 10 patients, and complex karyotype in 10 patients. Next‐generation sequencing for 21 patients demonstrated that all had gene mutations (median, four mutations per patient). The most frequently mutated genes were WT1 (38%), NOTCH1 (29%), NRAS (29%), PHF6 (25%), TP53 (24%), ASXL1 (19%), FLT3 (19%), and IKZF1 (19%). All patients except one received multi‐agent chemotherapy, and 22 patients underwent allogeneic stem cell transplantation. Thrombocytopenia, an abnormal karyotype, and TP53 mutation were associated with markedly shortened overall survival. Stem cell transplantation significantly improved overall survival. Conclusions Patients with ETP‐ALL often have high mutation burden with increased genomic instability. TP53 mutation was the only molecular prognostic marker and was associated with complex karyotype and greater than or equal to five mutations. These patients may benefit from stem cell transplantation, and recurrent gene mutations may be novel therapeutic markers. Early T‐cell precursor acute lymphoblastic leukemia cases had high mutation burden and increased genomic instability, enriched in WT1, NOTCH1, NRAS, PHF6, and TP53 mutations. TP53 mutation was the only molecular prognostic marker, and patients benefited from stem cell transplantation.