Alexander M. Castellino, PhD

December 05, 2016

SAN DIEGO — Once patients with chronic myeloid leukemia (CML) are in remission from their disease, can treatment with tyrosine kinase inhibitors (TKIs) such as imatinib be discontinued? Several smaller studies have suggested it is feasible, and now results from the largest cohort investigated to date, in the European Stop TKI Study (EURO-SKI), show that stopping TKI therapy is feasible and that about half of patients remain free from relapse after 2 years of follow-up.

A further analysis of patients who were taking imatinib suggests that stopping imatinib after 5.8 years is associated with a higher likelihood of molecular relapse-free survival.

The results were presented here at the American Society of Hematology (ASH) 2016 Annual Meeting (abstract 787).

Current guidelines recommend that most patients who achieve remission with TKI therapy continue taking the drugs indefinitely, yet it is unclear whether continued therapy is necessary for all patients, according to an ASH news release.

"Many patients struggle with the decision to stop TKI use because of its side effects and the fear of remission," said lead study author François-Xavier Mahon, MD, PhD, from the Bergonie Cancer Center of the University of Bordeaux, France.

"Now, in the largest cohort of patients, EURO-SKI has provided evidence that may be implemented in guidelines in the near future," Dr Mahon told Medscape Medical News. He also indicated that the criteria for stopping treating in EURO-SKI were less stringent compared with in previous studies, which have required patients to be in deep molecular remission for 2 years. In EURO-SKI, patients were required to be in deep molecular remission for 12 months, he said.

Details of the EURO-SKI Study

In the EURO-SKI study, stopping treatment was proposed for patients with chronic phase CML treated with TKIs (imatinib, dasatinib, or nilotinib) for at least 3 years who were in deep molecular remission (MR4) for at least a year.

The trial enrolled 821 patients with CML from 11 European countries and belonging to the European LeukemiaNet (ELN). At the meeting, an intention-to-stop-treatment analysis was reported for 755 patients.

Median age at diagnosis was 52 years; median age at TKI stoppage was 60 years. The median time from diagnosis to stopping TKI therapy was 7.7 years, median duration of TKI therapy was 7.4 years, and median duration of MR4 before stopping TKI therapy was 4.7 years.

The results show that about half of patients (378/755) did not relapse after stopping TKI therapy. Molecular recurrence-free survival was seen in 61% of patients after 6 months, and in 53% of patients after 18 months.

However, loss of molecular response was reported to occur in 373 patients. Most recurrences occurred within the first 6 months after TKI stoppage.

Median follow-up was 14.9 months for the total population and 26.0 months for patients who did not relapse.

In a prognostic modeling study, which included 448 patients who were receiving imatinib therapy before stopping treatment, Dr Mahon said, "Longer duration of imatinib therapy prior to TKI stopping correlates to a higher probability of relapse-free survival at 6 months." According to this analysis, 5.8 years was the optimal time for imatinib therapy.

In a subset analysis of 405 patients who were not receiving prior interferon therapy, prognostic modeling indicated that patients in MR4 for at least 3.1 years had the best probability of relapse-free survival at 6 months.

Another Strategy

Another management approach for patients with CML is suggested from the British DESTINY (De-Escalation and Stopping Treatment of Imatinib, Nilotinib or sprYcel) study, which determined the feasibility of halving the dose of TKI in patients with stable MR3–BCR-ABL <0.1% or major molecular response (abstract 938). Of 174 study participants, only 12 showed signs of leukemia recurrence, with the rest retaining a level of remission equivalent to MR3 or better, as reported by Medscape Medical News.

"These findings might indicate that some patients are being unnecessarily overtreated," said study author Mhairi Copland, MD, PhD, from the Institute of Cancer Sciences, University of Glasgow, United Kingdom. "The other important implication is that patients do not have to have extremely low levels of leukemia on very sensitive tests in order to safely try reducing their TKI dose."

Both Dr Mahon and Dr Copland indicated that EURO-SKI and DESTINY are complementary studies trying to answer the question of best optimal management option for patients receiving long-term TKI therapy.

Also reported at the ASH meeting were results from patients who relapsed after first stopping TKI therapy, restarted TKI therapy, and then discontinued TKI therapy for the second time. In this report, at second TKI stoppage, 85% of patients were reported to be in undetectable molecular remission, and after 24 months, 40% remained treatment free (abstract 788). The study indicates that a second TKI stoppage is also possible under conditions of close monitoring.

Candidates Eligible for TKI Treatment Cessation

Questions have been raised as to when guidelines may be available for stopping TKI therapy. At this time, the National Comprehensive Cancer Network recommends treatment stoppage only in the context of a clinical study.

Dr Mahon indicated that the ELN guidelines will be reviewed in the next 6 months, and he is hopeful that on the basis of results from the large cohort of patients in EURO-SKI, the ELN will consider providing recommendations on whether TKI treatment stoppage can move into the clinic for appropriate patients.

However, he told Medscape Medical News, the results of EURO-SKI may only be applied to patients receiving long-term imatinib therapy. "Stopping TKI treatment for patients on dasatinib or nilotinib should still be undertaken in the context of clinical trials," he said.

Dr Mahon commented that stopping therapy with imatinib can equate to a saving of €22 million, but he also noted that this was not a pharmacoeconomic study.

Approached for comment, Richard Silver, MD, professor of medicine at Weill-Cornell Medicine, New York City, and an investigator in the International Randomized Study of Interferon and STI571 (IRIS) study that led to the approval of imatinib (Gleevec, Novartis) told Medscape Medical News that these are striking advances in a disease that until 17 years ago was fatal for patients.

"The longer a patient is in remission, the better is the chance to remain in off-treatment remission," he said. He echoed the sentiments of Dr Mahon when he pointed out that many patients with CML do not want to discontinue treatment because they are doing well and fear relapse. Many have a busy life, and frequent monitoring poses a problem, he noted. "The ones who do want to discontinue are younger patients who may want to have children," he said.

Dr Silver told Medscape Medical News that he has been treating CML for 45 years and does not discontinue treatment in his patients outside the context of a clinical trial. Some of his patients are on The LAST (The Life After Stopping Tyrosine Kinase Inhibitors) study, which is a National Cancer Institute study evaluating the role of systematically discontinuing TKI therapy.

For a general hematologist, CML is a rare leukemia, and it is important to have experience with close monitoring, Dr Silver explained.

Two Recent Reviews on Stopping TKIs

Two reviews published in 2016 discuss the question of TKI stoppage in the context of published data.

A review published in Leukemia (2016;30:1638-1647) by Susanne Saussele, MD, from the University of Heidelberg, Germany, and coauthors suggests that "the future in CML treatment will be to define criteria for the safe and most promising discontinuation of TKI on one hand, and, on the other, to increase the number of patients available for such an attempt."

They add, "Since the identification of patients who would benefit most from discontinuation of imatinib remains a key issue, the question of the duration of molecular response before discontinuation is crucial."

Dr Saussele and colleagues also strongly recommend inclusion of patients in clinical trials whenever possible. "Only patients in chronic phase with no history of failure according to ELN criteria should be considered for stopping," they write. Achieving and maintaining an MR4 for "some time" before stopping is mandatory. Finally, "patients must receive follow-up in a center where standardized molecular biology is performed using IS [International Scale,] according to what has been agreed upon and published," they write.

The other review, published in Blood (2016;128:17-23) and authored by Timothy P. Hughes, MD, and David Ross, MD, from the University of Adelaide, Australia, provides pointers to factors that can be considered outside the scope of a clinical trial.

TKI stoppage is not for all patients, they write. For example, TKI therapy should not be stopped in patients with rare BCR-ABL transcripts, which cannot be monitored on the BCR-ABL IS. Also, patients with TKI resistance are likely to have higher risk for relapse, and in these patients, treatment-free remission (TFR) may not be possible, they suggest.

"In our opinion, the safety data from the TFR studies reported to date are sufficiently reassuring that we feel comfortable in offering all eligible patients a supervised test of TKI withdrawal," they write.

Admitting that the optimum eligibility criteria are up for debate, they note that the data so far suggest that a deep molecular response (MR4 or better) lasting for 12 months is necessary before considering TKI stoppage.

"There is some evidence that a longer duration of treatment/deep molecular response is associated with a higher probability of TFR, but there must be a practical balance between the additional burden of prolonged treatment and the potential to improve the TFR rate," they write.

"The absence of a suitable trial should not preclude a patient from stopping TKI treatment, but outside the structure of a clinical trial, it would be useful to have consensus recommendations to guide those clinicians for whom TFR represents a new area of practice," they add.

In their article, Dr Hughes and Dr Ross propose several criteria that need be taken into consideration to initiate TKI therapy stoppage, which include whether institutional criteria have been met, Sokal score at diagnosis, BCR-ABL transcript at diagnosis, CML past history, response to first-line TKI therapy, duration of all TKI therapy, and depth and duration of deep molecular response monitored in a standardized laboratory.

"If all of these criteria can be met, then we believe that TFR should become a routine part of clinical practice," they propose. However, they are aware that quality real-time quantitative reverse transcriptase-polymerase chain reaction is still not widely available to all.

"This poses a dilemma for many clinicians who recognize that some of their patients could otherwise be appropriately offered an attempt at TFR. This represents a new challenge for the global CML community," they conclude.

Dr Mahon consults for and receives honoraria and research funding from Novartis and receives honoraria from Pfizer, Bristol-Myers Squibb, and ARIAD.

American Society of Hematology (ASH) 2016 Annual Meeting. Abstract 787. Presented December 5, 2016.

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