Ibrutinib Resistance Common in Patients with MCL, Highlighting Need for Post-Ibrutinib Options

Although previous research has shown that ibrutinib leads to longer progression-free survival (PFS) and overall survival (OS) in patients with mantle cell lymphoma (MCL), resistance to the drug, and the limited therapeutic options in the post-ibrutinib setting, remains a challenge.

Primary resistance to the drug occurs in nearly one-third of all patients with MCL, while acquired resistance “appears to be universal” in this patient population, according to Peter Martin, MD, from Weill Cornell Medical College in New York, and colleagues. Mutations in the Bruton tyrosine kinase (BTK) binding have been identified as a possible mechanism of ibrutinib resistance.

To determine the outcomes of patients who experience ibrutinib failure, Dr. Martin and co-authors conducted a large, international, retrospective, cohort study of all patients with MCL who experienced disease progression while receiving ibrutinib across 15 sites in the United States, United Kingdom, Germany, and Poland.

The authors analyzed medical records for clinical characteristics, pathologic and radiologic data, and therapies used both before and after ibrutinib in 114 patients. Patients were treated with a median of three prior therapies (range = 0-10 therapies). The average time between the last dose of prior therapy and initiation of ibrutinib was two months (range = 0-59 months). At the start of ibrutinib treatment, 23 percent of patients had a low MCL International Prognostic Index (MIPI) score, 31 percent had an intermediate MIPI score, and 46 percent had a high MIPI score.

The median duration of ibrutinib use was 4.7 months (range = 7.4-12.1 months; 95% CI 3.8-5.7). Among those who responded to treatment, the median duration was 8.6 months (95% CI 7.4-12.1). The investigator-assessed best response rate to ibrutinib was 55 percent, with 43 percent of patients achieving a partial response and 12 percent achieving a complete response.

The median OS from diagnosis was 54 months (95% CI 43-70 months). At the time of analysis, only 29 patients were still alive; 85 had died. The causes of death were lymphoma (79), treatment-related toxicity (3), unrelated (2), and not reported (1).

“The group of patients included in the study appeared to be fairly high risk before starting ibrutinib, and not surprisingly, patients that were higher risk tended to do worse,” Dr. Martin told ASH Clinical News. “Many of these patients had also likely already exhausted most standard therapies before receiving ibrutinib.”

The presence of a BTK mutation did not appear to act as a mechanism of ibrutinib resistance, as seen from the results of a BTK status assessment at relapse in 10 patients. “We found a C481S mutation in two patients who received ibrutinib for 12.1 months and 12.6 months,” Dr. Martin and colleagues wrote. The other eight patients with wild-type post-ibrutinib BTK, however, received ibrutinib for a median of 3.3 months, and only one of these patients experienced a durable response of more than one year. “These numbers are small but consistent with the hypothesis that BTK mutation as a mechanism of ibrutinib resistance in MCL is not common and that other mechanisms are likely more relevant.”

After stopping ibrutinib treatment, 73 patients (70%) received subsequent treatment (including rituximab, lenalidomide, cytarabine, bendamustine, bortezomib, anthracycline, and PI3K inhibitors). The median time between the end of ibrutinib treatment and the start of a subsequent treatment was 0.3 months (range = 0-21.7 months; 95% CI 0.2-0.5). Following cessation of ibrutinib, the median OS was 2.9 months (95% CI 1.6-4.9 months), compared with 0.8 months among those not receiving subsequent treatment.

“Although the response rate and side-effect profile of ibrutinib are unprecedented in MCL, long-term remissions remain elusive, and the outcomes of patients who experience ibrutinib appears to be poor,” the researchers wrote. “Poor clinical outcomes were noted in the majority of patients with primary or secondary ibrutinib resistance.”

“Caution should be used when interpreting the average survival of patients in this study,” the authors wrote, adding that, “despite the large sample size, there was limited statistical power to evaluate all possible predictors of survival such as pre-ibrutinib therapies.”

Given the poor outcomes with ibrutinib and post-ibrutinib treatment in these previously treated patients, the question of how to optimally sequence therapy for people with MCL remains. “It could be argued that it is reasonable to ‘save’ ibrutinib for use in patients who are refractory to other standard therapies,” Dr. Martin and colleagues wrote. “Of note, the median OS from diagnosis of the entire cohort was only 54 months, suggesting that even in the ibrutinib and lenalidomide era, there remains considerable room for improvement.”

“Clinicians should be prepared for the eventual, inevitable relapse that happens when a person with MCL is treated with ibrutinib,” Dr. Martin told ASH Clinical News. “Clinicians, scientists, and pharmaceutical companies need to recognize the unique challenges associated with ibrutinib failure and should work together with the goals of preventing ibrutinib failure and developing appropriate therapies for the post-ibrutinib setting.”

Limitations of the study include the retrospective design and the selection bias that occurred in patients receiving subsequent therapy who thus lived longer.


Martin P, Maddocks K, Leonard JP, et al. Post-ibrutinib outcomes in patients with mantle cell lymphoma. Blood. 2016 January 13. [Epub ahead of print]