The complexity of genomic mutation dictates the prognosis of acute leukemia with ambiguous lineage

Abstract Acute leukemia with ambiguous lineage (ALAL) is a rare and highly aggressive malignancy with limited molecular characterization and therapeutic recommendations. In this study, we retrospectively analyzed 1635 acute leukemia cases in our center from January 2012 to June 2018.The diagnose of ALAL was based on either EGIL or 2016 WHO criteria, a total of 39 patients were included. Four patients diagnosed as acute undifferentiated leukemia (AUL) by both classification systems. The mutations detected in bi-phenotypic acute leukemia enriched in genes related to genomic stability and transcriptional regulation; while AUL cases frequently mutated in genes involved in signaling pathway. Survival analysis of all patients suggested that the prognosis of ALAL was independent of immunophenotype, chromosome karyotype, treatment, but significantly associated with the mutation complexity, also termed numbers of the mutations carried by each patient (Log rank p = 0.009 for progression-free survival [PFS] and Log rank p = 0.047 for overall survival [OS], respectively). Similar results were obtained when the WHO diagnostic system were applied (Log rank p < 0.001 for both PFS and OS). Among these patients, those excluded by WHO criteria had even worse clinical outcome than the patients included (Log rank p = 0.023 for PFS and Log rank p = 0.031 for OS). Collectively, the complexity of genomic mutation of ALAL patients is significantly associated with the clinical outcomes. The rationality and clinical applicability of the diagnostic criteria of WHO system need to be evaluated by more large-scale clinical studies.