Both approaches (discontinuing treatment or discontinuing after dose de-escalation) counter the current standard of care calling for patients to adhere religiously to a regimen of daily TKI dosage for life.
With an estimated 100,000 people living with CML in United States alone, and the average cost of TKI treatment close to or above $146,000 per year per patient, reducing or ending treatment would yield billions of dollars in savings.4
TKIs are also associated with cardiovascular adverse events (AEs), including hypertension, heart failure and arterial thrombotic events, as well as lethargy, diarrhea, nausea and skin rashes.
Stopping treatment, Dr Clark said, also would allow most female patients who wanted to start families to “go through perfectly normal pregnancy and labor, and even to lactate.”
Yet to end treatment safely, patients need to meet specific criteria.
A 2016 analysis at the University of Texas MD Anderson Cancer Center in Houston, Texas, found that the “relapse rate for patients with MR4.5 sustained >2 years was 32%, whereas those with <2 years it was 82%; a similar analysis with cutoff of 5 years yielded a relapse rate of 15% and 77%, respectively.”
Furthermore, the authors wrote, “this analysis shows that patients with less than MR4.5 at time of discontinuation have higher risk of relapse.”
“Fortunately,” said Jorge E. Cortes, MD, deputy chair of the MD Anderson’s leukemia department and one of the study’s authors, “if you do it under the right circumstances, with the right patients, then “relapse” means you detected it with a test but nothing else happened….You resume therapy, the patients respond again, and you pick up where you left off. So the risks are minimal.”
Still, Dr Clark said, some patients don’t want to quit taking TKIs.
“I’ve been surprised by the number of patients who say, “no thanks, I take my tablets and that’s my insurance policy for the day and I don’t worry about my disease anymore. But if I had to stop treatment or wind it down, I would just worry all the time.”
One reason, Dr Cortes said, may be that patients have been taught that missing doses has dire consequences. Suddenly telling them they can stop seems confusingly, and frighteningly, contradictory.
“Now when I start a patient on therapy I tell them this is a treatment for the rest of your life…though we are starting to look at the possibility of treatment discontinuation.
“I also explain to them that their chances of getting to that point are much better if they’re very strict with treatment. That way, when they come to that scenario, they’ve heard that that was an option from the beginning.”
The majority of relapses occur within the first 6 months after stopping treatment. But patients who choose to stop treatment need strict molecular monitoring for signs of relapse — indefinitely. Dr Cortes said his initial monitoring schedule consists of tests every month for the first 6 months, then every other month for the another 6.
That’s followed by quarterly tests for another year. Eventually, he said, patients who have shown no signs of recurrence continue with semi-annual tests, for life.
If they don’t, Dr Cortes said, they run the risk of not discovering a recurrence until the disease is advanced and may not be as responsive to retreatment. For the same reason, he said, patients should never stop treatment without consulting their doctor.
“What I tell my patients is, you’re getting rid of the disease, you’re not getting rid of me,” Dr Cortes said. “You’re going to be monitored no matter what.”
- Clark RE, Polydoros F, Apperley JF, et al. De-escalation of tyrosine kinase inhibitor dose in patients with chronic myeloid leukaemia with stable major molecular response (DESTINY): an interim analysis of a non-randomised, phase 2 trial. Lancet Haematol. 2017 May 26. doi: 10.1016/S2352-3026(17)30066-2 [Epub ahead of print]
- Clark RE, Polydoros F, Apperley JF, et al. Initial reduction of therapy before complete withdrawal improves the chance of successful treatment discontinuation in chronic myeloid leukaemia (CML): year 2 results in the British DESTINY study. Paper presented at: European Hematology Association (EHA) Learning Center; June 2017; Madrid, Spain.
- Mahon FX, Richter J, Guilhot J, et al. Cessation of tyrosine kinase inhibitors treatment in chronic myeloid leukemia patients with deep molecular response: results of the EURO-SKI trial. Paper presented at: American Society of Hematology (ASH) 58th Annual Meeting and Exposition; December 3-6, 2016; San Diego, CA.
- Kantarjian H. The arrival of generic imatinib into the U.S. market: an educational event. The ASCO Post website. Published May 25, 2016. Accessed June 2017.
- Chamoun K, Kantarjian HM, Rios MB, et al. CML patients outcome after TKI discontinuation: a single institution experience in the US. Blood. 2016;128:1923.