Drug Combination Kills Stem Cells and Prevents Leukemia Relapse

Cancer researchers have used a dual-component drug therapy regimen to treat chronic myelogenous leukemia (CML) that kills actively growing tumor cells and triggers apoptosis in quiescent leukemia stem cells.

CML results from transformation of a hematopoietic stem cell by the BCR-ABL gene. The BCR-ABL tyrosine kinase inhibitor imatinib mesylate (IM) is effective in inducing remissions and improving survival in patients with CML but does not eliminate leukemia stem cells (LSCs). Patients need continued treatment to prevent disease relapse.

Investigators at the City of Hope National Medical Center (Duarte, CA, USA) searched for another drug that could augment the action of IM by killing IM-resistant LSCs. They reported in the May 18, 2010, issue of the journal Cancer Cell that a class of drugs known as histone deacetylase inhibitors (HDACi) combined with IM effectively induced apoptosis in quiescent CML progenitors that were resistant to elimination by IM alone. Furthermore, this drug combination eliminated CML stem cells capable of engrafting immunodeficient mice, and in vivo administration of HDACis with IM markedly diminished LSCs in a transgenic mouse model of CML.

"Although most CML patients initially respond well to IM treatment, there is evidence that primitive quiescent leukemia stem cells are retained in patients achieving remission after IM treatment and that these stem cells are responsible for disease recurrence,” said senior author Dr. Ravi Bhatia, director of stem cell and leukemia research at the City of Hope National Medical Center. "Our studies indicate that treatment with HDACi combined with IM is effective against CML leukemia stem cells that resist elimination by IM alone. Several HDACi are in clinical development, and our studies support clinical trials of HDACi in combination with tyrosine kinase inhibitors to eliminate leukemia stem cells in patients with CML.”

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City of Hope National Medical Center