Most people who start taking a TKI for their CML will respond very well to the medication. But as we saw in Part 1, a small number of people will be resistant to Gleevec from the outset (called “primary resistance”), and different therapies are needed to get their disease under control.
A more common situation is “secondary resistance”. About 20-30% of people who start taking a TKI will start to lose their response to the medication at some point (Quintas-Cardama and colleagues. Cancer Control 2009;16:122-131). Their initial response is good, but subsequent blood tests show that their molecular response isn’t as robust as it was, e.g. a 3-log reduction is now 2-log and the molecular response is at risk of being lost altogether. That’s why it’s so important to get regular blood tests – to ensure that the results are continuing in the right direction, and to take immediate action if they aren’t.
But how is it that someone’s disease initially responds to a treatment, and then stops responding?
What drives white blood cells to proliferate in CML is the cancer gene BCR-ABL, which effectively works like a switch. TKIs work by fitting themselves into BCR-ABL much like a key fits into a lock. However, the key will no longer fit if the shape of the lock changes. Many of the mutations that are seen in CML act this way: changing the shape of the lock or altering the binding site just enough to stop Gleevec from working. In some cases, another drug (such as Tasigna, Sprycel or Bosulif) is adaptable enough that it can still shut down BCR-ABL.
The most common mutations affect the region that powers BCR-ABL (called the P loop or ATP binding site) of BCR-ABL. The shape of this region can be either open or closed. For Gleevec to work, it must be in the closed position. So Gleevec will be ineffective if a mutation (e.g. E255K/V or M244V) prevents BCR-ABL from adopting this closed position. However, other TKIs, such as Sprycel and Bosulif, remain active even if the shape is open, so it continues to be effective even if these shape-changing mutations are present. This is why a person who starts to lose a response to Gleevec will be switched to another TKI – the new drug may be active against a range of mutations that confer resistance to Gleevec.
Some mutations cause resistance to all of the first- and second-generation TKIs. An example of this is the T315I mutation. (This notation refers to the sequence of amino acids that make up the protein. In this case, Threonine is replaced by Isoleucine at position 315. A single amino acid substitution may seem trivial, but isoleucine is bulkier than threonine and it is just big enough to block the TKI docking site).
Fortunately, T315I mutations are uncommon. And in recent years, researchers have developed two medications that are effective against it. The newest TKI, Iclusig, was developed to accommodate the bulkier isoleucine and still allow the drug to bind where it should. In addition, the non-TKI drug Synribo is also effective against the T315I mutation. So treatment options are available even in the rare event that a person develops this mutation.
Over 100 BCR-ABL mutations have been identified thus far, but many of these won’t affect a TKI’s ability to work. A recent analysis of TKI studies estimated that the risk of a significant mutation emerging is about 10% with Gleevec, about 2% with Sprycel and about 3% with Tasigna (Ursan and colleagues. J Manag Care Pharm 2015;21:114-122). This risk may increase during the course of treatment, in part because suppressing BCR-ABL may allow less hardy mutations to emerge, much like drug-resistant bacteria can develop once an antibiotic has killed off the dominant, non-drug-resistant strain.
If a mutation does develop, it’s important to recognize this early and switch to a treatment that will be more effective. So current guidelines recommend mutation testing in people who start to lose their response during the course of treatment (Baccarani and colleagues. Blood 2013;122:872-884). Testing involves providing a sample of blood or bone marrow. If a mutation is detected, you can still achieve control of your CML by switching to another one of the many medications now available to treat CML.
Go to www.nccn.org/patients/guidelines/cml/ to read more about mutation testing and CML.