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Leukemia

Overcoming Treatment Resistant CML

Summary & Participants

If one promising drug fails to help against chronic myeloid leukemia, what can be done? Listen to experts explain your options for hard to treat cancers.

Medically Reviewed On: July 08, 2008

Webcast Transcript

ANNOUNCER: Most people with chronic myeloid leukemia, or CML, are benefiting from treatment with a targeted anti-cancer drug called imatinib. But resistance to imatinib sometimes occurs. It can fall into one of two broad categories.

STEPHEN NIMER, MD: Primary resistance is if you give a patient imatinib, or Gleevec, and from the very beginning, they don't have a very good response. And the second type, secondary or acquired resistance, is when a patient initially responds to Gleevec, but then over time they lose the responsiveness.

ANNOUNCER: To understand both types of resistance, we need to understand something of what goes wrong when a person develops CML.

GWEN NICHOLS, MD: What we think is the initial or the most important cause of CML is what we call a translocation, or a criss-crossing, of two pieces of genetic material, one on chromosome 9 and one on chromosome 22, that during the division of the cells, these two chromosomes criss-cross, break, and fuse to each other. And in doing so, they create a gene that wasn't there before.

ANNOUNCER: Made up of the two parts, the new gene is called BCR-ABL. BCR-ABL creates an abnormal protein, or enzyme, a type called a tyrosine kinase. Kinases signal in biochemical pathways, in this case, leading to the uncontrolled production of white blood cells.

ERIC FELDMAN, MD: It's what we call a signal transducer, a signal transduction protein, meaning that it signals to the cell to grow, and if it's constantly in the "on" phase, the cell constantly grows. It's as if a light switch got turned on and there's no turning it off.

ANNOUNCER: Imatinib, also known as Gleevec, works by binding to the aberrant BCR-ABL enzyme, at a particular site on the molecule.

GWEN NICHOLS, MD: Within the kinase, there is an energy center which is called the ATP binding site, and this is critical for the kinase's activity. The molecule, the imatinib, specifically fits into that binding site, and in doing so keeps the kinase, or the enzyme, from being active.

ANNOUNCER: One reason imatinib may be ineffective is a possible proliferation of the faulty BCR-ABL enzyme. This can happen in a process called gene amplification.

STEPHEN NIMER, MD: So, normally, in any given CML cell, there's only one gene of BCR-ABL. Sometimes the cell can, what we call amplify, the number of copies of this BCR-ABLE, and it can make twenty copies. And so, if there's twenty times as much BCR-ABL in the cell, then the imatinib may not be able to inhibit it completely, and so the cell can escape.

ANNOUNCER: This type of resistance may, in some cases, be overcome with an increase in the dose of medication.

STEPHEN NIMER, MD: In many of these circumstances, if you simply go up to a higher dose of imatinib, you can recapture the response.

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