AbstractBackgroundCross‐lineage expression of the myeloid‐associated antigens CD13/CD33 is common in adult B‐lymphoblastic leukemia (B‐ALL) patients, yet its prognostic value is still controversial.MethodsWe conducted a retrospective study of 1005 de novo adult B‐ALL patients from January 2009 to December 2019 in our hospital. Logistic and Cox regression were used to analyze the prognostic value of CD13/CD33 expression in B‐ALL. A Cox regression model was established to predict overall survival (OS) for B‐ALL patients.ResultsOf the 1005 B‐ALL patients, 53.7% (n = 540) aberrantly expressed CD13/CD33 (CD13/CD33+). Patients in the CD13/CD33+ group showed a higher incidence of BCR::ABL1 rearrangement and minimal/measurable residual disease (MRD) positivity but similar complete remission rate, relapse‐free survival, mortality, and OS with CD13/CD33‐. CD13/CD33+ patients had a higher risk of MRD positivity than CD13/CD33‐ patients. Notably, CD13/CD33+ patients who underwent tyrosine kinase inhibitor (TKI) therapy had a better long‐term prognosis than those without TKI experience. Sex, group based on CD13/CD33 expression and TKI experience and white blood cell count were variables independently associated with OS. The Cox regression model integrating these three variables showed a moderate performance for OS prediction (C‐index: 0.724).ConclusionsIn real‐world practice, CD13/CD33 expression can predict the risk of MRD in patients without TKI experience, but has no adverse effect on the prognosis of adult B‐ALL patients. Incorporating CD13/CD33 into the standard antibody panels of B‐ALL diagnosis and MRD measurements can help predict relapse risk and decisions on therapy options.