Journal
BLOOD
Volume 119, Issue 26, Pages 6198-6208Publisher
AMER SOC HEMATOLOGY
DOI: 10.1182/blood-2011-11-325050
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Funding
- National Cancer Institute/National Institutes of Health [P30-CA015704-35S6, U10-CA098543]
- Leukemia & Lymphoma Society (Specialized Center of Research) [7008-08]
- St Baldrick's Foundation
- Seattle Genetics Inc.
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Although the identification of cancer stem cells as therapeutic targets is now actively being pursued in many human malignancies, the leukemic stem cells in acute myeloid leukemia (AML) are a paradigm of such a strategy. Heterogeneity of these cells was suggested by clonal analyses indicating the existence of both leukemias resulting from transformed multi-potent CD33(-) stem cells as well others arising from, or predominantly involving, committed CD33(+) myeloid precursors. The latter leukemias, which may be associated with an intrinsically better prognosis, offer a particularly attractive target for stem cell-directed therapies. Targeting the CD33 differentiation antigen with gemtuzumab ozogamicin was the first attempt of such an approach. Emerging clinical data indicate that gemtuzumab ozogamicin is efficacious not only for acute promyelocytic leukemia but, in combination with conventional chemotherapy, also for other favorable- and intermediate-risk AMLs, providing the first proof-of-principle evidence for the validity of this strategy. Herein, we review studies on the nature of stem cells in AML, discuss clinical data on the effectiveness of CD33-directed therapy, and consider the mechanistic basis for success and failure in various AML subsets. (Blood. 2012; 119(26):6198-6208)
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