Can Therapy With TKIs for CML Ever Be Stopped?
Published Online: Thursday, March 21, 2013
Can tyrosine kinase inhibitor (TKI) therapy for chronic myelogenous leukemia (CML) ever be stopped—and if so, should it be stopped and what are the risks? Moshe Talpaz, MD, director of Translational Research at the University of Michigan Comprehensive Cancer Center, Alexander J. Trotman Professor, and associate chief of the Division of Hematology/Oncology at the University of Michigan, Ann Arbor, discussed these issues in a presentation at the 17th International Congress on Hematologic Malignancies.
The STIM trial looked at relapse-free survival after discontinuation of imatinib in a nonrandomized study in 100 patients with CML who had maintained complete molecular remission (CMR) for at least 2 years. At 12 months, the probability of persistent CMR in the 69 patients who had follow-up data available was 41% (95% CI, 29-52).
One limitation of STIM was that patients were not prospectively chosen, Talpaz said. In addition, some patients had received prior treatment with interferon, and some had not. Previous studies have demonstrated that some patients have excellent long-term outcomes even after interferon therapy is stopped. "But the take-home message here was that 39% of the patients did not relapse," Talpaz said. Patients who relapsed did so in the first 7 months, except for one patient who relapsed after 18 months. Talpaz stressed that more trials of the impact of stopping TKIs are needed before it can become standard practice.
Patients with a low Sokal risk score and who have had a longer duration of treatment with imatinib (>5 years) are more likely to remain in remission, Talpaz said. Studies are needed to better define the patient population that might do well when TKI therapy is stopped. A deep remission is important, he said, though it's likely not possible to completely eliminate all residual disease.
Talpaz also addressed whether TKI treatment should be stopped, discussing the clinical, adherence, and financial challenges associated with chronic TKI therapy. Studies of TKIs have noted a range of adverse effects, from edema, nausea, muscle cramps, and diarrhea, to symptomatic QT prolongation, and fluid retention. "Side effects can be sustained and can even appear as new while treatment goes on," Talpaz said.
Emerging long-term toxicities include pleural effusion and pulmonary hypertension associated with dasatinib, and impaired glucose tolerance and vascular toxicities associated with nilotinib. For long-term treatment, clinicians will have to remain aware of and monitor for adverse reactions, Talpaz said.
Ten percent to 15% of patients in TKI clinical trials tend to drop out, primarily from side effects, Talpaz said, noting that patient adherence outside the setting of a clinical trial was likely to be even more of a challenge. TKI therapy also presents a financial burden for society, in that CML is a rare disease, but patients live for a long time with it and require expensive treatment—raising the issue of how society will pay for such long-term treatments.
Are there risks associated with stopping TKI therapy? "It's relatively safe if we do frequent testing and we catch the patient with early relapse and resume treatment," Talpaz said. "I don't think there's a risk of resistance. There is no theoretical buildup of resistance in short interruptions. However, treatment with TKIs does not cure CML." Resistant, or quiescent CML stem cells remain after treatment—they are not eliminated by TKIs, and there is a risk of progression.
TKIs may offer an operational cure, but we don't know the mechanisms via which the therapies achieve this, Talpaz said. "There is a stem cell dormancy, but we don't know why. It may be an effect on the stromal niche that supports the stem cell, it may be an immunologic effect."
"But, in conclusion, the risks associated with chronic treatment far outweigh the risks of treatment discontinuation," Talpaz said. "TKI discontinuation may have enormous benefit for quality of life and cost—that's my conclusion. But the takehome message is test it first in a study before we actually do it."