CML Remissions Continue Even After TKI Drugs Are Stopped

Nancy A. Melville

June 13, 2016

COPENHAGEN, Denmark — Chronic myeloid leukemia (CML) has been transformed by the advent of tyrosine kinase inhibitor (TKI) drugs, such as imatinib and similar agents, but in clinical practice, this therapy is usually regarded as lifelong. Not so, suggest results from a large European cohort study.

"Stopping TKI therapy in a very large cohort of CML patients appears feasible and safe," said lead author Johan Richter, MD, from Lund University in Sweden. There is also no evidence of escape, he added; patients who stop therapy and do relapse are still sensitive to the TKI therapy.

Dr Richter presented results from the European Stop TKI Study (EURO-SKI), a multicenter trial conducted at 61 sites in 11 countries, here at the European Hematology Association 2016 Congress.

"Hopefully, data from EURO-SKI and other TKI-cessation trials made available now can form the basis for guidelines when moving the stop-TKI concept in CML to the clinic," he told Medscape Medical News.

Francois-Xavier Mahon, MD, PhD, from the University of Bordeaux in France, who is a fellow investigator on the EURO-SKI trial, noted at the meeting that preliminary European studies of TKI cessation have shown that the efforts have led, so far, to a savings of approximately €20 million annually.

The study demonstrates the importance of a large population in looking at the effect of discontinuing TKIs in CML, said Richard Clark, MD, professor of hematology molecular and clinical cancer medicine at the University of Liverpool in the United Kingdom.

"The rates of continued remission are similar to what have been shown in the smaller French studies. In that sense, [the EURO-SKI] findings are not a great surprise, but it's great to see the results reproduced in a much broader setting in more countries," he told Medscape Medical News.

Stopping TKI After Deep Molecular Response

Previous smaller studies had suggested that among CML patients who have achieved a deep molecular response, TKI therapy can be successfully stopped, with 40% to 60% of patients maintaining the response.

EURO-SKI was launched to determine the various factors that predict the best chances for sustained molecular relapse-free remission after TKI cessation in a larger number of patients.

The 868 study participants were in the chronic phase of CML, had received TKI treatment for at least 3 years, and had achieved a deep molecular response for at least 1 year. The median time from the diagnosis of CML to the first day of stopping TKI therapy was 7.7 years (range, 3.1 - 22.6 years), and the median duration of molecular remission prior to stopping TKIs was 4.7 years (range, 1.0 - 13.3 years).

Patients had a median age at diagnosis of 51.9 years, and median age at the discontinuation of TKIs was 60.3 years.

The most common TKIs were imatinib (in 94% of the patients), nilotinib (in 4%), and dasatinib (in 2%), and 115 patients had been switched to second-line TKIs because of intolerance.

In the study cohort, 390 patients had been pretreated with hydroxyurea prior to TKI therapy, and 87 patients received interferon before TKI.

At study enrollment, these patients stopped taking their TKI therapy. They were followed every 4 weeks for 6 months, every 6 weeks for 18 months, and then every 3 months in years 2 and 3.

During the follow-up period, if patients relapsed (defined as a loss of major molecular remission), they were restarted on TKI therapy.

At a median follow-up of 10 months, 62% of patients continued to have deep molecular remission 6 months after discontinuing TKI therapy. At 12 months, 56% still had deep remission, as did 52% at 24 months and 49% at 36 months.

Of the 348 patients who did have molecular relapse, 37% relapsed 6 months after TKI discontinuation, 43% relapsed at 12 months, 47% relapsed at 24 months, and 50% relapsed at 36 months. Five patients died in remission.

Dr Richter noted that in other research, patients followed for as long as 8 years have shown a plateau effect in terms of the risk for relapse.

"Most of these recurrences appear quite early after stopping," he said.

Of patients who resumed TKI treatment, the median time for restarting was 4.1 months, and the therapy appears to be effective in those patients, despite the interruption.

All patients who do relapse are sensitive when you put them back on the TKI therapy, so there is no evidence of an escape.

"Regarding emergence of any resistant disease, so far it has been shown that all patients who do relapse are sensitive when you put them back on the TKI therapy, so there is no evidence of an escape when you put them back on the therapy," he said.

Although a univariate analysis showed that factors such as age, sex, and CML risk score were not associated sustained remission, factors that were significantly associated with remission at 6 months included the duration of TKI treatment (imatinib) and the duration of a deeper molecular response (MR4) status (odds ratio [OR], 1.16; P < .001).

In terms of duration of treatment, the rate of molecular relapse-free survival at 6 months was 65.5% in patients treated with imatinib for at least 5.8 years and 42.6% for those treated with the drug for 5.8 years or less.

"One additional year of imatinib treatment and one additional year in MR4 status prior to stopping a TKI increases the odds of staying in molecular remission at 6 months by 16%," Dr Richter said.

In looking at safety issues associated with stopping TKIs, the researchers found that 72 patients had BCR/ABL1 genetic status greater than 1%, whereas 11 patients had a loss of complete cytogenetic response.

In terms of adverse events, approximately 30% of patients experienced musculoskeletal symptoms, which have been previously reported in TKI discontinuation studies. Dr Richter and his colleagues describe the adverse events as grade 1 or 2, although 1.2% had symptoms that were grade 3.

Additional follow-up of patients in the ongoing 3-year study is planned.

The findings underscore the message that, regardless of whether patients are in the clinic or a clinical trial, their BCR/ABL status should be checked when attempting to discontinue TKIs, Dr Richter noted.

"Regardless of setting, for a cessation attempt, it is essential to know that the patient has a typical BCR/ABL transcript, and [clinicians should] have access to a lab where this can be monitored in a reliable way on the international scale."

Tapering Off Instead of Stopping?

Commenting on the new findings for Medscape Medical News, Dr Clark from Liverpool University suggested that the relation between the duration of previous treatment and the risk of losing a response likely needs more examination.

"We see that people who have been on treatment for many years have a lower probability of losing the molecular remission when they stop the treatment, which intuitively makes sense," he said.

Although the research shows an increased risk when patients are discontinued after less than 6 years, the scenario becomes more challenging in the real world, Dr Clark noted.

"If I have a female patient, for instance, who has only been treated for 3 years but wants to discontinue the drugs in order to start a family, or a patient who does not respond well to a first drug but does to a second, can I safely stop them? I don't think this trial answers those questions," he said.

"The reason none of these scenarios is answered is because of the exclusion or inclusion criteria for the trial. And while it's not a criticism — I think it's a very good trial — it raises more questions than answers," he added.

Dr Clark reported that his team in the United Kingdom is looking at the effects of TKI cessation from another angle — a tapering down approach.

"We are looking at [reducing TKI dosing] by half, at first, to see if perhaps a softer landing may allow more patients to at least decrease their dose. Most studies just involve stopping the drug altogether," he said.

Results from that research will likely begin to be reported sometime in 2017, he added.

Dr Richter reports receiving honoraria and/or research support not related to EURO-SKI from BMS, Novartis, Pfizer, and Ariad. Dr Clark reports relationships with Novartis, Bristol-Myers Squibb, and Pfizer.

European Hematology Association (EHA) 2016 Congress: Abstract S145 . Presented June 11, 2016.


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