When a person first starts treatment for CML, an obvious concern is whether the medication will work. Will CML respond, or is your body somehow resistant to the TKI (tyrosine kinase inhibitor)? But what does “treatment resistance” mean, and what can be done about it?
A response to a TKI medication is assessed at three levels: the blood (a hematologic response in which your blood cell counts normalize); the cell (a cytogenetic response in which abnormal cells are no longer detectable); and the molecule (a molecular response in which the amount of cancer proteins becomes very low or undetectable). Each of these responses represents a treatment milestone that needs to be achieved during the treatment course.
When considering “resistance”, there are actually two types – called “primary” (or innate) and “secondary” (or acquired) resistance. We’ll first consider primary resistance, and address secondary resistance in next week’s issue.
Primary resistance is when a person doesn’t respond to treatment from the outset. Fortunately, this is fairly uncommon. Perhaps 1 in 20 people (5%) with chronic-phase CML fail to achieve a hematologic response after starting Gleevec (Hochhaus and colleagues. Leukemia 2002;16:2190-2196). A higher proportion of people may not achieve later milestones (a cytogenetic or molecular response), but in many of these cases the problem will be secondary resistance.
“Primary resistance” may be a misnomer in many cases since a likely reason is that the person hasn’t been taking their medication as prescribed by their doctor. If you are resistant to the idea of therapy, this doesn’t mean that the medication is resistant to your CML. Daily doses of Gleevec are needed to keep CML in its prison. Skipping even a few doses gives CML the time it needs to plan its escape.
If person does keep to the regimen of daily medication, the risk of resistance is very low – but not zero. This can be due to insufficient levels of drug in the bloodstream which are not enough to control CML (Peng and colleagues. J Clin Oncol 2004;22:935-942). Certain liver enzymes (such as 3A4 for Gleevec) are needed to break down medications, and people are genetically different in how they metabolize drugs (Larson and colleagues. Blood 2008;111:4022-4028). So someone who is a “fast metabolizer” will have lower levels of the drug in their bloodstream compared to someone who is a “slow metabolizer”. (This refers only to liver function, not your body as a whole.)
Slow/fast drug metabolism can also be influenced by other medications that use the same enzymes. Medications that induce (stimulate) key liver enzymes will affect Gleevec levels. Examples are dexamethasone (a steroid), epilepsy medications (e.g. phenytoin [Dilantin] and carbamazepine [Tegretol]), and St. John’s wort (a non-prescription remedy for depression). These should be avoided while taking Gleevec. So it’s important to talk to your doctor or pharmacist about any other medications you’re taking so you can avoid drug-drug interactions.
For Gleevec to work, it needs to be taken up by cells in the body, a job performed by a specialized protein called hOCT1 (for human organic cation transporter). Genetically-determined variations in this protein will result in not enough Gleevec being pumped into the cell (Thomas and colleagues. Blood 2004;104:3739-3745). In such cases, a higher dose of Gleevec (such as 600 mg or 800 mg per day) may be able to counteract this transporter effect.
At the moment there are no tests to determine who will respond to a TKI and who will have primary resistance to a drug. Fortunately, the majority of people have a very good initial response to their first-choice TKI (Gleevec, Tasigna or Sprycel). If primary resistance does occur, there are still many options – either increasing the dose of Gleevec, or switching to another TKI.
For most people with CML, TKIs are highly effective in controlling their disease throughout the course of treatment. However, a minority will find that their medication becomes less effective over time. We’ll look at the reasons for this secondary treatment resistance in Part 2.