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Consistent Findings Validate Viability of TKI Discontinuation in CML

Caroline Seymour
Published: Thursday, Feb 14, 2019

Frank T. Slovick, MD

Frank T. Slovick, MD

First- and second-generation TKIs confer a significant survival benefit for patients with chronic-phase chronic myeloid leukemia (CP-CML)—so much so, that treatment discontinuation has become a viable option for select patients.

Although the safety of TKI treatment discontinuation has been questioned in the past, long-term follow-up data indicate that specific patients, in accordance with NCCN guidelines, are able to come off treatment without sacrificing outcomes.

“If you stop the TKI, it’s important that you’re prepared to monitor the patient monthly for the first 12 months, every 6 to 8 weeks for the next 12 months, and pretty much every 3 months indefinitely,” said Frank T. Slovick, MD, a medical oncologist at Sarah Cannon Research Institute, HCA Midwest Health, in a presentation during the 2019 OncLive® State of the Science Summit™ on Hematologic Malignancies.

In the presentation, Slovick discussed the trials that have examined TKI discontinuation in patients with CP-CML that were presented at the 2018 ASH Annual Meeting and 2018 ASCO Annual Meeting.

The criteria for TKI discontinuation are very stringent, explained Slovick. Patients have to be in CP, have received a TKI >3 years, and be in a deep molecular remission for more than 2 years—a benchmark that is commonly defined as MR4.5, and is also quantified by an undetectable BCR/ABL transcript of <.0032.

Patients who lose their major molecular response (MMR) are unlikely to qualify for discontinuation, as they often have a MR3, or BCR/ABL transcript >.1 on consecutive tests, added Slovick.  

The first trials to examine TKI discontinuation were conducted in 2010 and 2013 in the STIM1 and TWISTER2 trials, respectively. Both trials examined discontinuation with the first-generation TKI imatinib (Gleevec), and showed treatment-free remissions (TFR; MR4.5) ranging from 40% to 47% at 24 months. The majority of relapses occurred in the first 4 to 6 months of therapy, said Slovick. Notably, there were no relapses after the first year of discontinuation. If MMR was lost, all patients regained sensitivity to imatinib upon retreatment.

In 2017, a second-generation TKI discontinuation trial was conducted, referred to as STOP 2G-TKI, explained Slovick. Sixty patients in their first-, second-, or third-line of therapy were enrolled and included in the interim analysis. Although 63.3% of patients experienced a 1-year TFR, 26 patients later relapsed.3 The median time to relapse was 4 months (range, 1-38 months), and cumulative incidences of molecular relapse by 12 months was 35%.

Investigators noted that patients who had a suboptimal response or resistance to initial treatment with imatinib had a higher relapse rate upon discontinuation. Although 26% of patients lost MR4.5, they remained in a major molecular response off-therapy, noted Slovick.

Similar findings were reported at the 2018 ASCO Annual Meeting with the updated data from the ENESTop trial,4 in which 126 patients discontinued second-line nilotinib (Tasigna). At 144 weeks, 61 patients (48.8%) remained treatment-free, said Slovick. However, 6 of the initial 67 patients who were treatment free at 96 weeks lost MMR at 144 weeks. Similarly, a trend toward regained sensitivity was noted in the trial, as 97% of patients who restarted nilotinib responded, and 91% regained MR4.5.

“Patients had no progression to accelerated phase or blast crisis, nor was there any death related to CML,” said Slovick.

These findings were echoed in the ENESTfreedom trial,5 in which 190 patients receiving first-line nilotinib were taken off treatment. At 144 weeks, (46.8%) patients remained in TFR; however, 4 patients lost MMR after 96 weeks. Of 91 patients who restarted nilotinib, 90 regained MMR and 84 regained MR4.5. Although 10 patient deaths were reported, none resulted from CML.  

“As long as patients meet the criteria and are followed closely, it’s safe to stop the TKI, realizing that you’re going to have to restart it about 50% of the time” said Slovick.

In the community setting, several trials have reported on the feasibility of TKI discontinuation, including a Korean trial6 with imatinib and a Spanish trial7 that compiled data on patients receiving imatinib, nilotinib, and dasatinib (Sprycel). Both trials reported TFR rates >50% at 2 years, although 1 patient who achieved MMR in the first trial developed blast crisis and went on to receive transplant, reported Slovick. In the second trial, 64% of patients remained treatment-free at 4 years. Seventy-five percent of relapses occurred in the first 6 months off the drug, with the latest reported relapse occurring at 30 months. If patients had been on a TKI >5 years or had a MR4.5 >4 years, they were less likely to relapse, said Slovick.

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