TKI Discontinuation Still an Unclear Picture in CML

Lindsay A.M. Rein, MD

Despite highly effective TKIs in chronic myeloid leukemia (CML), treatment discontinuation is still an area of ongoing research and should currently be exclusive to specialized centers, said Lindsay A.M. Rein, MD.

According to the current NCCN guidelines, it is considered safe and feasible for adult patients with CML in chronic phase who achieve and maintain a major molecular response to come off TKI therapy.

As an example, 192-week results of the ENESTop trial assessed treatment-free mission in patients with CML in chronic phase following discontinuation with second-line nilotinib (Tasigna). In these updated results presented at the 2019 ASCO Annual Meeting, the treatment-free survival rate was 50.3%, and almost all patients who resumed nilotinib therapy regained MR⁴ or MR^4.5 at 95% and 93%, respectively.

Rein, a cell therapy and hematologic malignancies specialist at Duke Cancer Center, said that major trials in this space have been somewhat mixed. Until a clearer picture is painted of which patients benefit the most from TKI discontinuation, she said that depth and duration of response to TKI therapy could be utilized. Still, a seemingly eligible patient should be referred to an academic center for a second opinion.

In an interview at the 2019 OncLive^® State of the Science Summit™ on Hematologic Malignancies, Rein discussed the current state of TKI discontinuation in patients with CML.

OncLive: What should the audience take home from your State of the Science Summit™ presentation on CML?

Rein: I focused on this idea of TKI cessation or discontinuation of the therapy we typically use, and whether or not we can achieve what we call a treatment-free remission in certain patient populations. I spoke about how well we have done, especially in the last 20 years with treating patients so effectively with TKIs.

We discussed reasons why we would stop these drugs, such as financial toxicity or quality-of-life issues. I also highlighted some of the recent trials that have been done to determine if it's feasible to discontinue TKIs. There were 2 trials looking at nilotinib (Tasigna)—one trial with this agent was in the frontline setting—and the other, ENESTop, looked at nilotinib in the second-line setting and stopped patients on that therapy.

What factors are utilized to determine whether TKI discontinuation is the right strategy?

There are major guidelines out there—the NCCN guidelines have some nice criteria that people should consider when thinking about stopping TKIs in patients with CML. I don't know if we're quite at the point where we should do this outside of a specialized center, so there needs to be access to reliable laboratory testing to measure their BCR-ABL transcript levels. Therefore, we need to determine whether or not the patient is compliant, responsible, and reliable in their follow-up. When people are considering TKI cessation—at this point, where we are in the process—it is very reasonable and advantageous to send a patient to a specialized center where the testing has perhaps faster turnaround.

There is still an element of trying to decide which patients are most appropriate to consider TKI discontinuation. In my talk, I showed a little bit of data that looked at predictive factors of who will maintain a treatment-free remission. There are somewhat mixed data in that area. If there is a patient who you think will be a good candidate for stopping a drug, I would probably still refer to a larger center to have that conversation.

Could you discuss the potential predictive factors of treatment-free remission?

There have been a lot of studies done with stopping different TKIs, such as imatinib (Gleevec), nilotinib, and dasatinib (Sprycel). Some studies have noted that the deeper response the patients have from their TKI, the more likely they are to remain in treatment-free response once they stop drug. This is important, although it hasn't been shown in all studies.

So-called risk score [is also important]. The studies we discussed tonight show that a low risk score has an increased probability of maintaining that response. There are different things that have been sporadic in how they appear in major studies, but the major trends are depth of response as well as duration of response.

What are the key challenges that still exist in this field?

We do have excellent therapies, and they work very well. I am very thankful to have the opportunity to care for these patients. In oncology, we don't always have these kinds of “home run” therapies that are so effective. The challenges are that there are certainly patients who are compliant and take their drugs, and then there are patients who don't. There are also patients who don't tolerate [therapy] for one reason or another. A huge implication for a lot of patients is that they can't afford the drugs. Although we have access to these therapies, there are a lot of challenges from a patient perspective.

We have wonderful patient-assistance programs, so we are very successful at helping patients gain access to these drugs. Access, with the advent of patient-assistance programs, has actually been better. Patients who don't tolerate therapy become a different story.

Hughes TP, Boquimpani C, Takahashi N, et al. ENESTop 192-week results: Treatment-free remission (TFR) in patients (pts) with chronic myeloid leukemia in chronic phase (CML-CP) after stopping second-line (2L) nilotinib (NIL). J Clin Oncol. 2019;37 (suppl; abstr 7005).