Gemtuzumab ozogamicin (GO) is an anti-CD33 antibody-drug conjugate for the 
treatment of acute myeloid leukemia (AML). Although GO shows a narrow 
therapeutic window in early clinical studies, recent reports detailing a 
modified dosing regimen of GO can be safely combined with induction 
chemotherapy, and the combination provides significant survival benefits in AML 
patients. Here we tested whether the survival benefits seen with the combination 
arise from the enhanced reduction of chemoresidual disease and leukemic 
initiating cells (LICs). Herein, we use cell line and patient-derived xenograft 
(PDX) AML models to evaluate the combination of GO with daunorubicin and 
cytarabine (DA) induction chemotherapy on AML blast growth and animal survival. 
DA chemotherapy and GO as separate treatments reduced AML burden but left 
significant chemoresidual disease in multiple AML models. The combination of GO 
and DA chemotherapy eliminated nearly all AML burden and extended overall 
survival. In two small subsets of AML models, chemoresidual disease following DA 
chemotherapy displayed hallmark markers of leukemic LICs (CLL1 and CD34). In 
vivo, the two chemoresistant subpopulations (CLL1+/CD117- and CD34+/CD38+) 
showed higher ability to self-renewal than their counterpart subpopulations, 
respectively. CD33 was coexpressed in these functional LIC subpopulations. We 
demonstrate that the GO and DA induction chemotherapy combination more 
effectively eliminates LICs in AML PDX models than either single agent alone. 
These data suggest that the survival benefit seen by the combination of GO and 
induction chemotherapy, nonclinically and clinically, may be attributed to the 
enhanced reduction of LICs.