The development of Gleevec in 2001 revolutionized the treatment of CML. But the medication – although highly effective – won’t work in everyone, and some people may develop resistance to the drug. One reason for resistance is mutations, and over 80 different mutations have now been described that can make Gleevec ineffective.
Fortunately, in the intervening 15 years since Gleevec became available, second- and third-generation TKIs (tyrosine kinase inhibitors) that now provide an important safety net. These medications are Tasigna (nilotinib), Sprycel (dasatinib) and Bosulif (bosutinib).
Tasigna was developed by the same company that makes Gleevec and was designed to be a more potent version. One study showed that Tasigna was effective against 32 of the 33 mutations that can occur in people not responding to Gleevec (Weisberg and colleagues. Cancer Cell 2005;7:129-141). In phase II testing, 59% of people who weren’t doing well on Gleevec were able to achieve a major cytogenetic response within two years of starting Tasigna (Kantarjian and colleagues. Blood 2011;117:1141-1145). Tasigna can affect cholesterol and blood sugar levels, so people with diabetes and cardiovascular disease need to be closely monitored.
The other second-generation TKI is Sprycel, which has a somewhat broader effect on disease pathways and is effective against most mutations conferring resistance to Gleevec. In the phase II START-R trial, 53% of people with resistance to Gleevec achieved a major cytogenetic response with Sprycel compared to only 33% who responded to a high dose of Gleevec (Kantarjian and colleagues. Cancer 2009;115:4136-4147). About 1 in 4 people develop fluid around the lungs (called pleural effusion) (Shah and colleagues. Haematologica 2010;95:232-240). This is treatable, but some caution is needed in people at higher risk, such as those with lung disease, smokers/ex-smokers, and people with frequent lung infections (e.g. bronchitis, pneumonia).
It’s important to note that in recent years, both Tasigna and Sprycel are often used as the first medication since they can produce a faster, deeper effect on leukemia compared to Gleevec.
A third option for people resistant to Gleevec is Bosulif, which is similar to Sprycel in how it works. A phase I/II study found that 53% of people not doing well on Gleevec had a major cytogenetic response at two years (Cortes and colleagues. Blood 2011;118:4567-4576). Bosulif was effective against all mutations – except for one.
This sole exception – a mutation called T315I – confers resistance to Gleevec, Tasigna and Sprycel as well.
As an explanatory note: mutations are named after the changes that occur. In the case of T315I, an amino acid called threonine (T) is replaced by another amino acid called isoleucine (I) at position 315. TKIs interact with the leukemia gene much like a key turns a lock. A change in one amino acid may appear small, but isoleucine is a bulkier amino acid than threonine and this size difference is enough to block TKIs from fitting into the lock (Nagar and colleagues. Cancer Res 2002;62:4236-4243).
Fortunately, for the small number of people for whom all else fails, there are still three very good options. In a phase I trial of a TKI called Iclusig (ponatinib), 11 of 12 people with the T315I mutation were able to achieve a major cytogenetic response (Cortes and colleagues. N Engl J Med 2012;367:2075-2088). Alternatively, there is the non-TKI medication Synribo (omacetaxine). A phase II study showed that 23% of people with the T315I mutation were able to achieve a major cytogenetic response (Cortes and colleagues. Blood 2012;120:2573-2580).
There is also the option of a bone marrow transplant, which can potentially cure CML even in people with the T315I mutation (Xu and colleagues. Biol Blood Marrow Transplant 2016; epublished March 16, 2016). Iclusig, Synribo and bone marrow transplantation can be associated with severe side effects so they are generally kept in reserve for people who haven’t responded to anything else.
Most people with CML will do very well on their first medication – either Gleevec, Tasigna or Sprycel – and won’t need anything more. But for that minority who run into trouble, there are still many options to control the CML disease process.