Etiology of Ibrutinib Therapy Discontinuation and Outcomes in Patients With Chronic Lymphocytic Leukemia

Abstract

Importance: The Bruton tyrosine kinase (BTK) inhibitor ibrutinib is effective in patients with chronic lymphocytic leukemia (CLL). Reasons for discontinuing therapy with this drug and outcomes following discontinuation have not been evaluated outside of clinical trials with relatively short follow-up.

Objective: To determine features associated with discontinuation of ibrutinib therapy and outcomes.

Design, setting, and participants: A total of 308 patients participating in 4 sequential trials of ibrutinib at The Ohio State University Comprehensive Cancer Center were included. These clinical trials accrued patients included in this analysis from May 2010 until April 2014, and data were locked in June 2014.

Main outcomes and measures: Patients were evaluated for time to therapy discontinuation, reasons for discontinuation, and survival following discontinuation. For patients who discontinued therapy because of disease progression, targeted deep sequencing was performed in samples at baseline and time of relapse.

Results: With a median follow-up of 20 months, 232 patients remained on therapy, 31 had discontinued because of disease progression, and 45 had discontinued for other reasons. Disease progression includes Richter's transformation (RT) or progressive CLL. Richter's transformation appeared to occur early and CLL progressions later (cumulative incidence at 12 months, 4.5% [95% CI, 2.0%-7.0%] and 0.3% [95% CI, 0%-1.0%], respectively). Median survival following RT was 3.5 months (95% CI, 0.3-6.0 months) and 17.6 months (95% CI, 4.7 months-"not reached") following CLL progression. Sequencing on peripheral blood from 8 patients with RT revealed 2 with mutations in BTK, and a lymph node sample showed no mutations in BTK or PLCG2. Deep sequencing on 11 patients with CLL progression revealed BTK or PLCG2 mutations in all. These mutations were not identified before treatment in any patient.

Conclusions and relevance: This single-institution experience with ibrutinib confirms it to be an effective therapy and identifies, for the first time, baseline factors associated with ibrutinib therapy discontinuation. Outcomes data show poor prognosis after discontinuation, especially for those patients with RT. Finally, sequencing data confirm initial reports associating mutations in BTK and PLCG2 with progression and clearly show that CLL progressions are associated with these mutations, while RT is likely not.

Trial registrations: clinicaltrials.gov Identifiers:NCT01105247, NCT01217749, NCT01589302, and NCT01578707.

Conflict of interest statement

Conflicts of Interest: KJM has received research support and has served as a consultant for Pharmacyclics. KAB has received research funding from Pharmacyclics and Janssen. SMJ has received research funding from Pharmacyclics. JAJ has served as a consultant for Pharmacyclics and Janssen. The remaining authors declare no relevant conflict of interest.

Figures

Figure 1. Cumulative Incidence of Discontinuation of Ibrutinib Therapy

Rate of discontinuation is low overall, with relapse-related discontinuations less frequent than non-relapse. Richter’s transformation tends to occur earlier than progression with typical CLL (A). (B) shows close-up curves to highlight differences in discontinuation patterns between CLL progression, Richter’s transformation, and other events.

Figure 1. Cumulative Incidence of Discontinuation of Ibrutinib Therapy

Rate of discontinuation is low overall, with relapse-related discontinuations less frequent than non-relapse. Richter’s transformation tends to occur earlier than progression with typical CLL (A). (B) shows close-up curves to highlight differences in discontinuation patterns between CLL progression, Richter’s transformation, and other events.