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Abstract Philadelphia chromosome (Ph)‐like acute lymphoblastic leukemia (ALL) is recognized for its genetic and clinical diversity. In this study, we identified a novel high‐risk subset of Ph‐like ALL, characterized by the activation of oncogenic signaling and the inactivation of the tumor suppressor gene IKZF1 , resulting in a dismal outcome. The association between cytogenetic aberrations and clinical features was assessed on a cohort of 191 patients with Ph‐like ALL. Our findings revealed that patients with inactivation of IKZF1 combined with activation of oncogenic signaling ( CRLF2/EPOR/JAK2 rearrangements or p‐CRKL/p‐STAT5 high expression) had the worst outcome (3‐year overall survival OS of 28.8% vs. 80.1% for others, p < 0.001; 2‐year event‐free survival EFS of 6.5% vs. 57.0% for others, p < 0.001). Multivariable analysis demonstrated that this high‐risk feature was an independent inferior prognostic factor (adjusted hazard ratio for OS = 4.55, 95% confidence interval CI: 2.35–8.81, p < 0.001; adjusted hazard ratio for EFS = 3.27, 95% CI: 1.99–5.39, p < 0.001). Allogeneic hematopoietic stem cell transplantation was associated with improved prognoses in patients within the high‐risk subgroup. In conclusion, this study identified a clinically distinct entity that possesses effective prognostic features and provides potential guidance for refining risk stratification in Ph‐like ALL.
Huang et al. (Wed,) studied this question.