Schiffer Spotlights Potential for TKI Discontinuation in Select Patients With CML

With the integration of TKIs, such as imatinib (Gleevec), into the chronic myeloid leukemia (CML) treatment paradigm, more patients have been able to discontinue treatment and remain in remission, according to Charles Schiffer, MD.

“Multiple studies have shown that approximately 50% of [patients with CML] can stay off of therapy without a molecular relapse for a minimum of over 4 years,” said Schiffer. “We don't understand entirely why some relapse and others do not. We believe that long-term follow-up on patients who have not relapsed [through] periodic pathologic complete response (pCR) tests is advisable. However, this is a very important new change in how we treat patients with CML.”

For example, patients with CML who had received a TKI for at least 3 years without treatment failure and had a confirmed deep molecular response for at least 1 year were enrolled in the prospective, non-randomized phase 3 EURO-SKI trial (NCT01596114). After a median follow-up of 27 months, the molecular relapse-free survival reported was 61% (95% CI, 57-64) at 6 months and 50% (95% CI, 46-54) at 24 months.¹ These findings support TKI discontinuation for select patients who have achieved deep molecular responses, explained Schiffer.

The phase 2 TRAD and LAST studies are also examining the possibility of TKI discontinuation for patients with CML; these trials are currently ongoing in Canada and the US, respectively. The TRAD study aims to help patients achieve operational cure. If the patient progresses, however, dasatinib (Sprycel) will be administered. LAST is a non-randomized, prospective, single-group longitudinal study, the goal of which is to help improve the decision-making process with regard to discontinuing treatment with TKIs in eligible patients with CML.^2,3

In an interview with OncLive® during the 2020 Institutional Perspectives in Cancer webinar on Leukemia and Lymphoma, Schiffer, a professor of Oncology and Medicine at Wayne State University, as well as an oncologist/hematologist at Barbara Ann Karmanos Cancer Institute, further discussed the possibility of TKI discontinuation for certain patients with CML.

OncLive®: Could you expand on how CML treatment has evolved?

Schiffer: Before imatinib came along in 1999/2000, CML was a uniformly fatal disease unless patients underwent an allogeneic stem cell transplant. At that time, the mortality from transplant was higher than it is now; the technique for this procedure has improved appreciably. Back then, it was a very difficult decision for patients who were otherwise feeling quite well, who had no limitations on their activity and no symptoms, to elect to turn to something that had such [high] morbidity and mortality.

That changed dramatically with the availability of TKIs such that, on average, those who respond have an expected lifespan similar to age-matched controls. We had thought that patients would have to stay on therapy indefinitely; however, [we are seeing] that we may be able to stop therapy in select patients.

What are some of the benefits of stopping treatment with TKIs in this patient population?

Some are obvious, right? It's better not to take medicines [if you don’t have to]. The second is cost. Even with generic imatinib, [treatment is] still quite expensive. The second-generation TKIs still [cost] more than $100,000 a year. Once everything becomes generic, [we also need to focus on] the reduction in AEs. Imatinib is extremely well tolerated; it has minimal, if any, organ toxicity, [with regard to the] liver, kidneys, lungs, and heart, among others. However, some of the other [agents] clearly have long-term toxicities. With some of these agents, such as nilotinib, cardiovascular toxicity exceeds 10%; that is a huge number if you consider that patients are going to take this [drug] for the rest of their lives.

How do you approach discontinuation of TKIs in your own practice? What are some of the key factors that you consider when making this decision?

We participated in the LAST trial, which was conducted in the United States and enrolled 20 patients. I have also stopped therapy in at least a couple dozen or three dozen other patients. Essentially, I look to see whether patients have been negative or have very, very low transcript levels for a number of years. In general, you want [those levels] to be consecutively low or negative.

It's our obligation now to explain this opportunity to patients who qualify. I explain [to my patients] that we will monitor them closely—not with bone marrow, just with blood. We monitor their pCR values closely every month to 2 months for the first 6 to 8 months, then every couple of months thereafter, and then every 3 months thereafter. It [can] produce a little anxiety in our patients.

There's also a very unusual syndrome that we have termed the “withdrawal syndrome” where some develop musculoskeletal aches; [this AE is] usually modest and manageable with [agents such as] nonsteroidal anti-inflammatory drugs. This toxicity is also usually transient; however, occasionally, [some become] somewhat worse and more persistent. Essentially, everyone who relapses, as long as they are monitored appropriately, responds again when they are restarted on medication.

Could you expand on the importance of the EURO-SKI trial?

The EURO-SKI study was the largest; another study was done in the United States. The original study and the credit goes to French investigators and, almost simultaneously, to investigators in Australia. The point is that they're all almost identical in that there's a very rapid relapse rate within the first 6 to 8 months, which tails off dramatically thereafter.

What was learned from the Canadian study evaluating discontinuation with dasatinib?

[The TRAD trial] looked at patients who had discontinued therapy, restarted therapy appropriately, and had very low transcript levels, which actually is the rule after you restart therapy. For a while, after a couple of years at least [of treatment], investigators made a second attempt to discontinue treatment. In this particular study, unfortunately, almost everyone relapsed rapidly. Other studies have shown the same thing, but a couple of studies have shown a higher rate of sustained remission; the jury's still out on that. We don’t know how to select patients who are more likely to persistently benefit, but it's worth considering in selected patients. The bottom line is that the relapse rate is very high.

References

1. Saussele S, Richter J, Guilhot J, et al. Discontinuation of tyrosine kinase inhibitor therapy in chronic myeloid leukaemia (EURO-SKI): a prespecified interim analysis of a prospective, multicentre, non-randomised, trial. Lancet. 2018;19(6):P747-757. doi:10.1016/S1470-2045(18)30192X
2. Treatment-free remission accomplished with dasatinib in patients with CML (TRAD). ClinicalTrials.gov. Updated November 29, 2019. Accessed October 01, 2020. https://clinicaltrials.gov/ct2/show/NCT02268370​
3. Atallah E, Schiffer CA, Weinfurst KP, et al. Design and rationale for the life after stopping tyrosine kinase inhibitors (LAST) study, a prospective, single-group longitudinal study in patients with chronic myeloid leukemia. BMC Cancer. 2018;18(1):359. doi:10.1186/s12885-018-4273-1