1. Gemtuzumab Ozogamicin (GO) Inclusion to Induction Chemotherapy Eliminates Leukemic Initiating Cells and Significantly Improves Survival in Mouse Models of Acute Myeloid Leukemia.
- Author
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Zhang CC, Yan Z, Pascual B, Jackson-Fisher A, Huang DS, Zong Q, Elliott M, Fan C, Huser N, Lee J, Sung M, and Sapra P
- Subjects
- Aminoglycosides therapeutic use, Animals, Antibodies, Monoclonal, Humanized therapeutic use, Antineoplastic Agents, Immunological therapeutic use, Cell Line, Tumor, Cell Survival drug effects, Disease Models, Animal, Female, Gemtuzumab, Humans, Induction Chemotherapy, Leukemia, Myeloid, Acute drug therapy, Leukemia, Myeloid, Acute mortality, Mice, Mice, Knockout, Molecular Targeted Therapy, Neoplasm, Residual pathology, Phenotype, Xenograft Model Antitumor Assays, fms-Like Tyrosine Kinase 3 antagonists & inhibitors, fms-Like Tyrosine Kinase 3 metabolism, Aminoglycosides pharmacology, Antibodies, Monoclonal, Humanized pharmacology, Antineoplastic Agents, Immunological pharmacology, Leukemia, Myeloid, Acute metabolism, Leukemia, Myeloid, Acute pathology, Neoplastic Stem Cells drug effects, Neoplastic Stem Cells metabolism
- Abstract
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., (Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.)
- Published
- 2018
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