Diamonds Are Forever, but TKIs in CML Don't Have to Be

Alexander M. Castellino, PhD

June 06, 2019

CHICAGO — Tyrosine kinase inhibitors (TKIs) have made such an impact in the treatment of chronic myeloid leukemia (CML) that life expectancy for patients is now similar to that of the general population, provided patients continue on therapy. But do they have to continue receiving TKI therapy forever?

This question has been addressed by several trials, the evidence from which show that TKI therapy can be stopped for some CML patients. Adding to that evidence are now long-term results from a follow-up of ENESTop, which show treatment-free remission (TFR) in approximately 50% of patients 3.7 years after stopping treatment.

In ENESTop, patients were initially treated with imatinib (Gleevec, Novartis) and were then switched to nilotinib (Tasigna, Novartis) with the aim of achieving deep molecular remission, after which treatment was stopped and patients were routinely monitored for relapse.

Dr François-Xavier Mahon

"Treatment-free remission is a new goal for patients with CML," commented study author François-Xavier Mahon, MD, PhD, from the Bergonie Cancer Center of the University of Bordeaux, France.

The data were presented here at the American Society of Clinical Oncology (ASCO) 2019 Annual Meeting (abstract 7005).

Dr Jorge Cortes

Discussing the new data in a Highlights of the Day session, Jorge E. Cortes, MD, chief of the CML and the acute myeloid leukemia sections at the University of Texas MD Anderson Cancer Center in Houston, provided insights into how ENESTop translates into clinical practice. He introduced the topic with a slide showing the James Bond film Diamonds Are Forever, commenting that recent data suggest that TKI therapy does not have to be forever.

Stopping treatment can be done, but it has to be done right. Dr Jorge Cortes

"Stopping treatment can be done, but it has to be done right. Otherwise, we turn a good situation for patients into a bad situation for patients," Cortes said. Although the rate of relapse within the first 6 months after stopping treatment is small, relapse does happen, and that's why it is important to continuously monitor patients, he pointed out.

Continuous monitoring is also important to identify late relapses so that patients can be rechallenged with the TKI. "Most, but not all, regain responses upon restarting treatment," he said. Clinicians need to discuss with the patient the benefits and risks of stopping TKI therapy before they stop treatment, he added.

Cortes noted that "TKI withdrawal symptoms" have been reported. Such symptoms occur as musculoskeletal pain that requires treatment with nonsteroidal anti-inflammatory agents. "But occasionally, some patients will have to resume treatment with the TKI," he said.

"Treatment-free remission is a reality," he said. He indicated that greater success is achieved when remissions are deeper and more durable. A minimum of 2 years of treatment with a TKI may be sufficient, but the chances of achieving deeper molecular remissions are higher with 5 years of treatment, he suggested.

Cortes cautioned that this strategy is not for all patients. It is not recommended for patients who have experienced prior resistance or transformation to the accelerated or blast phases of the disease.

Treatment cessation is successful in approximately 25% of patients, he said. Although 50% of patients may respond to treatment cessation, only 50% of these will maintain the response required to remain treatment free, he explained.

He suggested that one way to decrease relapses is to provide the TKI in combination with drugs such as interferon (multiple brands), pioglitazone (multiple brands), ruxolitinib (Jakafi, Incyte), asciminib (under development by Novartis), and venetoclax (Venclexta, AbbVie).

ENESTop Study Details

ENESTop enrolled patients with CML who were treated first with imatinib for more than 4 weeks and were then switched to nilotinib, which they received for at least 2 years. Patients who achieved deep molecular remission were again treated with nilotinib in the consolidation phase for 1 year.

Patients who retained deep molecular remission entered the TFR phase, during which they were monitored for relapse every 4 weeks during the first year, every 6 weeks during the second year, and every 12 weeks thereafter.

Patients who did not achieve deep remission in the consolidation phase were treated with nilotinib for another year, during which they were again monitored for entry into the TFR phase.

Patients who experienced relapsed in the TFR phase were rechallenged with nilotinib.

Of 163 patients who were enrolled in the study, 126 had deep molecular remission and entered the TFR phase of the study.

Patients were aged 56 years and had received therapy with nilotinib for 32.1 months after achieving deep remission before entering the TFR phase.

Duration of total TKI therapy prior to entry into the TFR phase was 87.7 months. Total duration of therapy with nilotinib prior to entry into the TFR phase was 53 months.

As of data cutoff, 56 patients were still in TFR. Of the 70 patients who came off the TFR phase, 11 discontinued study, owing to lack of efficacy, death, adverse events, or withdrawal of consent; 59 entered the reinitiation phase; and 40 remain in the reinitiation phase.

Median duration of TFR was 3.7 years. The estimated treatment-free survival rate was 50.3%, and the TFR rate was 46% (58 of 126).

Mahon indicated that at the previous follow-up of 2.8 years, 61 patients were in TFR. Response was lost for one patient at 3.7 years, and two patients discontinued, one because of a serious adverse event, and one because of a decision by the patient.

Of 59 patients who were rechallenged with nilotinib, 56 regained molecular remission, and 55 regained deep molecular remission.

"Stopping treatment is safe because it is possible to reinduce molecular remission," Mahon said.

In no patient did disease progress to the acute phase or blast phase. Rates of estimated progression-free survival and overall survival were each 96.8%.

Mahon reported that stopping long-term therapy with a TKI is associated with TKI withdrawal syndrome, which manifests as musculoskeletal pain. Unlike other adverse events during the TFR phase, the rate of musculoskeletal pain peaks at 48 weeks and then resolves over time. Adverse events such as myalgia and arthralgia — both musculoskeletal adverse events — follow the same trend.

"Adverse events reported in the nilotinib reinitiation phase were consistent with the known safety profile of nilotinib," Mahon said.

"Data from the long-term follow-up of 3.7 years in ENESTop support the durability and safety of TFR in patients who achieved MR [ie, deep molecular remission] and TFR eligibility on second-line nilotinib," Mahon concluded.

Mahon has received honoraria from Pfizer, Novartis, and BMS. He also consults with Novartis and receives travel/accommodations/expenses from Celgene and AstraZeneca. Cortes has a consultancy or advisory role with Amphivena Therapeutics, Astellas Pharmaceticals, Bio-Path Holdings, BioIncRx, BMS, Daiichi Sankyo, Jazz Pharmaceuticals, Novartis, Pfizer, and Takeda.

American Society of Clinical Oncology (ASCO) 2019 Annual Meeting: Abstract 7005. Presented June 1, 2019.

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