Mutations in Half of Patients With CLL Who Relapse on Ibrutinib

Nancy A. Melville

June 27, 2018

STOCKHOLM — Approximately half of patients with chronic lymphocytic leukemia (CLL) who relapse after treatment with ibrutinib (Imbruvica, Pharmacyclics) show acquired mutations in the Bruton's tyrosine kinase (BTK) gene that are associated with a shorter time to disease progression, according to new research.

"These results indicate the outgrowth of several resistant clones and suggest multiple resistance mechanisms that need to be studied [with a view] towards eventually designing innovative treatment to improve the outcome of these patients," said coauthor Lydia Scarfò, MD. She is from the Department of Oncohematology at the Università Vita-Salute San Raffaele, Milan, Italy.

She was speaking here at the European Hematology Association (EHA) 2018 Congress.

Approximately a third of patients with CLL have had at least one prior treatment relapse when treated with ibrutinib over more than 3 years of follow-up.

Previous reports have described acquired BTK mutations before relapse on ibrutinib, which is a BTK inhibitor, with such mutations believed to render the drug's effects reversible by decreasing BTK binding.

However, these previous reports on BTK mutations, as well as mutations of PLCG2, have come from single-center cohorts.

The new data come from a multicenter study involving 14 institutions worldwide in the European Research Initiative on CLL (ERIC) trial, for which Scarfò and her colleagues analyzed samples from patients with CLL who received ibrutinib outside of clinical trials and in a "real world" setting.

The study included patients who had received ibrutinib treatment at full dose without more than 14 days' interruption, including 22 who relapsed within a median duration of ibrutinib treatment of 19 months (range, 3 - 57 months), and 32 who responded over a median of 35.5 months (range, 16 - 58 months).

Genetic analysis showed that 10 of the 22 relapsed cases had BTK mutations, compared with only two mutations among the 32 responders.

Interestingly, PLCG2 mutations, reported in previous studies, were less common, occurring in 3 of the 22 relapsed cases and 3 of the 32 responders.

"A key observation of this study is that in relapsed cases PLCG2 mutations were never detected alone but were always associated with BTK mutations," Scarfò told Medscape Medical News.

"The size of the clones carrying PLCG2 mutations was generally smaller than that of BTK-mutated clones," she said.

She added that the BTK mutations were not detected at baseline in the cohort.

"At present, both from the published literature and our results, there is no indication that mutations were already present before starting treatment," she said.

"A plausible explanation is that mutations within BTK and/or PLCG2 were acquired following the initiation of treatment and then expanded over time under ibrutinib selective pressure."

The patients who had relapsed were younger than responders (median age, 62 vs 72 years). Serial sampling was not performed to determine how soon after ibrutinib treatment patients acquired mutations.

In addition, no significant differences have been noted, so far, in the time to relapse between those who did and did not have BTK mutations.

Scarfò noted that, to date, clinical and biological features at the time of initiation that might predict the occurrence of BTK mutation have not been identified.

None of the relapsed patients and five responders had ibrutinib as a first-line therapy, and 19 and 20 patients in the groups, respectively, had received two or more prior therapies.

Following treatment failure with ibrutinib, three patients with BTK mutations were treated with a combination of idelalisib and rituximab, five were treated with venetoclax, and one with another therapy.  

Three patients with BTK mutations had a partial response to the next line of treatment compared with four without mutations, two had complete remission compared with one, and three had treatment failures in both groups.

At the most recent follow-up of 5 months (range 0 - 18 months), 13 patients survived, including seven with BTK/PLCG2 mutations, and nine patients had died, including three with the mutations.

Scarfò noted that there currently is no indication to test patients in clinical practice, and despite the new findings, clearly not all those who relapse have the mutation, whereas some who do have the mutation do not relapse. Thus, the situation is not clear cut.

"In our cohort, BTK mutations were only present in 50% of relapsing cases, indicating that additional resistance mechanisms must exist," Scarfò said.

"In addition, two responsive cases were found to carry BTK mutations and did not relapse according to current guidelines," she noted.

"These results should be validated in a prospective study to fully understand whether BTK mutations could be used as a predictive marker for relapse, and potential therapeutic measures, including treatment modification and/or combination, should be tested in clinical trials."

Approached for comment, Arnon P. Kater, PhD, a professor of hematology at the University of Amsterdam, the Netherlands, and a researcher with the ERIC trial, agreed that new study's key value is in demonstrating the link between the mutations and ibrutinib in a real-world setting.

"In the past, there have been many diagnostics with predictive measurement for CLL, but the problem has been that even though a diagnostic marker can hold very high promise, if you can't reproduce it in real life, it loses validity," he told Medscape Medical News.

"Sometimes, for instance, an effect may be found in one lab because of a particularly good technique or a specific technician, but as soon as it's tried in another lab, there may be different results."

"But the main power of this study is in proving indeed that outside of clinical studies, we do still see these same mutations in real life, and it's reliable and you can reproduce it." 

In terms of clinical implementation, Kater added that an important issue will be in determining thresholds.

"These days, when you can get these much more sensitive, next-generation sequencing tests and go very deep to find mutation, it's important to determine what is a valid cutoff level in terms of the presence of a mutation," he explained.

"What if a very low percentage is identified — is that a reason to give more intensive ibrutinib? Or should there be a higher threshold? Before this would be implemented, we would need to know what the threshold is that would place someone at risk of relapse."

"But importantly, the first step has been made," he said.

Scarfò has disclosed no relevant financial relationships. Kater has received research funding from Janssen.

European Hematology Association (EHA) 2018 Congress. Abstract LB2601. Presented June 17, 2018.

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