TKI Discontinuation Possible for Some CML Patients


Ahead of the 2017 ASCO Annual Meeting, we discuss the discontinuation of TKIs in some chronic myeloid leukemia patients.

Ehab Atallah, MD

The 2017 American Society of Clinical Oncology (ASCO) Annual Meeting is taking place June 2–6 in Chicago. As part of this year’s coverage, we are speaking with Ehab Atallah, MD, associate professor of medicine in the division of hematology and oncology at the Medical College of Wisconsin. At this year’s meeting, he will be speaking during an Education Session about discontinuation of tyrosine kinase inhibitors in chronic myeloid leukemia (CML).

-Interviewed by Leah Lawrence 

Cancer Network: What is the role of tyrosine kinase inhibitors-or TKIs-in the treatment of CML? How long do patients treated with TKIs remain on the drug?

Dr. Atallah: TKIs have completely changed how we treat patients with CML. Currently, with this treatment, patients’ survival is almost very similar to patients who don’t have CML, which is pretty amazing. The only downside is that currently patients need to stay on treatment forever, as long as they are responding to it and tolerating it well.

Cancer Network: What are some of the negative effects of the long duration of treatment with TKIs, physical or otherwise?

Dr. Atallah: There are two major negative effects to patients. First, is the effect on their quality of life. Overall, these treatments are pretty well tolerated, but they do significantly affect patients’ quality of life, especially if they have side effects forever while they are on this medication. For example, if someone has mild fatigue, that is something you could tolerate for a period of time, but when it is for the rest of your life, that mild fatigue or mild diarrhea is not mild anymore. It affects your quality of life. Several studies have clearly demonstrated that patients with CML, compared with normal counterparts, do have reduced quality of life.

The other major negative effect is economical, of course. Some patients have a significant copay; others may be worried about changing jobs or changing insurance because they are afraid to lose their insurance when they are on this expensive medicine. The cost to society is also significant. These medications remain very expensive. As patients live longer and the prevalence increases, the cost to society is becoming very significant.

Cancer Network: How is discontinuation of TKIs for CML being explored? What are some of the strongest studies supporting this possibility?

Dr. Atallah: The first study that published data on this was in 2010, on patients with CML who had a sustained deep response who had been on treatment for at least 3 years and then stopped treatment. About half of these patients did not need to restart the drug. All patients who did restart the drug did well and went back into remission.

Since then, there have been multiple studies across the world looking at this. Currently, the largest in the United States is the LAST study, which is a study funded by the National Institutes of Health. That just completed enrollment in December 2016 and, hopefully, we will be seeing results next year. The other large study was a European study, called the EURO-SKI study, which enrolled 800 patients. Some of the data were presented at last year’s American Society of Hematology Annual Meeting and showed very similar results to the original French STIM1 study.

All in all, when we look across the world, more than 2,000 patients have been enrolled on different stopping studies and the results are surprisingly similar, with approximately 50% of patients having to restart the drug and another 50% not having to restart the drug.

Cancer Network: In what patients should clinicians consider the possibility of discontinuing TKI treatment?

Dr. Atallah: Based on these studies, stopping treatment can be considered in patients with chronic-phase CML and patients who have been on treatment with a TKI for at least 3 years and have had a sustained deep molecular response for at least 2 years.

A couple of studies showed that the longer duration of treatment on a TKI, the more likely that patients would stay in remission. Also, in most studies, if patients have achieved a sustained deep molecular response, which is by definition MR4 or a polymerase chain reaction (PCR) level of less than 0.01% for at least 2 years, these are the patients who would most likely be able to stop and stay off the drug.

Cancer Network: What research is ongoing or needs to be done on this topic?

Dr. Atallah: A lot of research still needs to be done. First of all, if we think about 100 patients who were just diagnosed with CML, only half of them will reach sustained deep molecular response. Of the 50 who are eligible to stop, only half of them will be able to stop. All in all, 20 patients or 20% of patients with CML will be able to stop treatment and 80% will not be able to stop and will need to stay on it forever. The first goal is to get more patients to a sustained deep molecular response, so they can stop treatment.

The second area of research is to understand why some patients are able to stop treatment and others are not. We do have some criteria, such as longer duration of TKI treatment or depth of response, but it still remains unclear why some patients are able to stop treatment and others are not.

The third area of research concerns the many patients who do not restart the drug-meaning that they have not relapsed-who still have low PCR levels detected in their blood. In other words, we currently recommend that patients restart treatment when they lose molecular response or their PCR level is more than 0.1%. You have some patients who do not reach that level-that 0.1% level-but still have very low detectable disease. They don’t need to restart treatment. Their disease stays dormant at these very low levels for many years-up to 10 to 15 years in these earlier studies. This is another group that we need to understand. These are the main areas of research that need to be clarified.

Cancer Network: You have provided us with a lot of good information today. Thank you for speaking with us.

Dr. Atallah: Thank you very much.

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