Clinical Challenges > ASH: Leukemia
Clinical Challenges: Discontinuing TKIs in Chronic Myeloid Leukemia
— Discontinuing TKI therapy has become a major focus for patients with long-term CML
by Mike Bassett, Contributing Writer, MedPage Today December 11, 2020
Treatment-free remission is now regarded as a primary aim of patients with long-term chronic myeloid leukemia (CML).
Starting with the approval of imatinib in 2001, the effectiveness of tyrosine kinase inhibitors (TKIs) has resulted in significant improvements in outcomes for CML patients, and with that success has come a focus on discontinuing treatment in patients when appropriate.
Results from trials such as the DADI (Dasatinib Discontinuation) and the STIM (Stop Imatinib) trials suggest this approach is feasible, and the National Comprehensive Cancer Network has modified its guidelines by incorporating TKI discontinuation in appropriately selected patients.
There are a number of factors that go into the decision to stop TKI treatments. They do come with side effects, as well as an accompanying impact on a patient's quality of life. These can include fatigue, nausea, sleep disturbance, and depression. Other issues include concerns about drug-drug interactions, financial toxicity related to treatment, as well as cardiovascular safety issues associated with second- and third-generation TKIs.
Cognitive issues have also been associated with TKI treatment. In a study presented at this year's American Society Hematology annual meeting, Kelly Schoenbeck, MD, of the University of California San Francisco, and colleagues reported that CML chronic phase patients showed cognitive dysfunction after taking first- and second-generation TKIs.
Who are appropriate candidates for TKI discontinuation? According to Ehab Atallah, MD, of the Medical College of Wisconsin, the first consideration is disease course.
"Patients have to be in the chronic phase," Atallah told MedPage Today. "They have to have been on a TKI for at 3 least years, and in deep remission for at least 2 years."
Patients also need to be compliant with more frequent checkups, Atallah added. "Normally, a patient with CML needs to come in to be checked every 3 to 6 months, especially a patient who is doing well on deep remission. If they stop treatment. they need to come monthly for 6 months, then every 2 months for 18 months, and then every 3 months after that. So it's more intense monitoring."
Finally, Atallah noted that physicians have to follow and correctly interpret patients' lab results, and be ready to restart a patient on treatment if the patient loses major molecular response. "The patient and the physician, together, need to make that decision to stop," he said.
Why do patients choose to discontinue treatment? That topic was addressed in a recent study led by Kathryn Flynn, PhD, also of the Medical College of Wisconsin, appearing in The Oncologist.
"This was a small interview study where we talked to patients who wanted to stop treatment, as well as patients who were clinically eligible to stop but didn't want to stop. And we tried to understand the reasoning that goes into that," Flynn told MedPage Today. "And that was interesting because some people would say they have a busy life and don't want to think about more testing, or think about their disease coming back, and that the side effects aren't so bad and they'll stay on treatment. Others would also say they have busy life and want to get off the drug. So patients would give the same reason to justify two different preferences."
Flynn and her colleagues found that the most commonly given reason for wanting to discontinue TKI therapy was to reduce side effects, while concern about relapse was most common reason for preferring continued treatment.
As for outcomes after stopping TKI treatment, in a recent study (the Life After Stopping TKIs or LAST study) published in JAMA Oncology, researchers including Atallah and Flynn identified certain characteristics associated with successfully discontinuing TKIs, and found that outcomes tended to improve with discontinuation.
Flynn said the biggest improvements were in fatigue and diarrhea. Of the 112 patients in the study who were in treatment-free remission (TFR) at 12 months, 80.4% had clinically meaningful improvement in fatigue, while 87.5% had clinically meaningful improvement in diarrhea. Clinically meaningful improvements were less frequent in depression (34.8%), sleep disturbance (21.4%), and pain interference (4.5%).
"These were measurable changes, and patients improved over time," Flynn said. "And when people restarted treatment we noticed that the scores got worse again for all of these domains."
This study showed 60.8% of percent of who fit the clinical criteria for discontinuation were able to stay off TKIs, while the remainder needed to restart therapy. "We found that the droplet digital PCR test, which is not commonly available, but is one of four PCR [tests] that is FDA-approved, is a much better predictor of who will have a successful TFR, and who won't," said Atallah. "And we found that a combination of the PCR at the time a patient stopped, and at three months, is very predictive of successful or unsuccessful TFR."
"So if someone has detectable PCR when they stop and three months later has another detectable PCR, the chances of the disease coming back were very high," Atallah explained. "And if both were negative, the chances of it coming back were very low. So, this really gives us a better prognostic marker for who can and can't stay off the drug."
But there are also potential drawbacks to discontinuing TKIs.
In addition to more intensive monitoring, as well as anxiety experienced by patients who may be concerned that their disease will return, musculoskeletal pain has – for reasons that are unclear -- been associated with discontinuation of TKI therapy.
"In our study we had three patients who needed to restart their drug because the pain was unbearable," said Atallah. "So, we always warn patients about the possibility of musculoskeletal pain."
Ehab Atallah: Research funding, Bristol‐Myers Squibb, Novartis, Takeda, Pfizer (C/A), Novartis, Bristol‐Myers Squibb, Pfizer