Starting treatment for CML (or any other chronic illness) introduces something new to your daily routine: taking your medication. How well people are able to stick with the program was examined in a large survey conducted by the CML Advocates Network and involving over 2,500 people in 79 countries (Geissler and colleagues. ASH 2013; abstract 4023). The median age of the survey respondents was 51 years, and they’d been living with CML for about four years. All were taking a TKI, such as Gleevec Tasigna or Sprycel.
Most people admitted to missing a dose of their medication at least once in the past year. About 1 in 5 said they intentionally skipped a dose. The people who intentionally skipped a dose were more likely to be younger, thought that treatment was a burden on their social life, or had financial issues regarding their co-payment. Some took a break from treatment because they wanted to avoid side effects, notably fatigue, diarrhea, nausea and muscle pain.
A further factor contributing to intentional non-adherence to the treatment regimen was dissatisfaction with the information provided by the doctor. In particular, people said they weren’t adequately informed about how important it was to take every dose.
Why is every dose so important?
Most people with CML have acquired the cancer gene BCR-ABL, which produces signalling molecules (called transcripts) that drive white blood cells to proliferate. All of the TKI medications suppress these BCR-ABL transcripts. Your progress is measured by tests that determine the log reduction in transcript levels. A 1-log reduction means the transcript number is one-tenth what it was. A 2-log reduction means the level is 1/100th (i.e. only 1% are left but these are still enough to drive leukemia). The goal is to suppress the transcripts as completely as possible – at least a 3-log reduction – to suppress the leukemia. Otherwise, leukemia can start to run wild and medications may not be able to regain control of the process.
One study looked at how long it takes for the BCR-ABL transcript number to double (Branford and colleagues. Blood2012;119:4264-4271). This indicates that CML is getting out of control, which can happen if a mutation develops that makes the medication less effective. On average, the doubling time was 9 days. However, this short doubling time was also seen in people who had taken a drug holiday. Within 9 days, their transcript level was twice as high.
To prevent this from happening, it’s important to maintain an adequate amount of medication in the body. For example, a study of people with CML taking Tasigna compared those with higher versus lower concentrations of drug in the blood stream (Giles and colleagues. Eur J Clin Pharmacol 2013;69:813-823). As you might expect, those with lower drug concentrations took longer to achieve a complete cytogenetic response (3-log reduction) or a complete molecular response (4-log reduction), and were more at risk of disease progression. So for TKIs to be effective, there has to be an adequate amount of the drug in the body – which is achieved by taking the prescribed dose of the medication every day.
A U.S. study recently looked at how non-adherence to the treatment regimen impacts response (DiBella and colleagues. ASH 2013; abstract 2733). Records from the U.S. Oncology Network database were analysed to compare medication use and outcomes. The study involved 300 people newly-diagnosed with CML who had started treatment with Gleevec, Sprycel or Tasigna. According to the interim analysis, 56% of people who took their medication achieved the key benchmark of a complete cytogenetic response at one year. In comparison, only 39% reached that same milestone if they skipped doses or took short breaks from their treatment regimen. At 18 months, 45% of people who were adherent achieved a major molecular response, compared to 24% who were non-adherent to the regimen. So this tells us that regularly taking a medication can double a person’s chances of having a good response.