Factors in Ibrutinib Discontinuation in Patients With Chronic Lymphocytic Leukemia


Key Points

  • In total, 18 of 31 cases of discontinuation due to progression were due to Richter’s transformation, with a 12-month cumulative incidence of progression of 4.5%.
  • BTK or PLCG2 mutation was found in 2 of 8 patients with progression due to Richter’s transformation and in each of 11 with CLL progression.

In a single-center study reported in JAMA Oncology, Maddocks et al found that Richter’s transformation accounted for early progression-related discontinuation of ibrutinib (Imbruvica) in patients with chronic lymphocytic leukemia (CLL) and that CLL progression but not Richter’s transformation was associated with BTK or PLCG2 mutation.

The study involved 308 patients participating in four sequential trials of ibrutinib at The Ohio State University Comprehensive Cancer Center between May 2010 and April 2014, with data locked in June 2014.

Progression-Related Discontinuation

Over a median follow-up of 20 months, 232 patients remained on ibrutinib, with 31 (10%) discontinuing treatment due to disease progression and 45 (15%) discontinuing for other reasons. Of the 31 discontinuing treatment due to disease progression, 13 progressed with CLL and 18 with Richter’s transformation, with most of the latter (78%) developing diffuse large B-cell lymphoma. One-year cumulative incidence was 4.5% for Richter’s transformation and 0.3% for progressive disease due to CLL. Median survival was 3.5 months following Richter’s transformation and 17.6 months following CLL progression.

Sequencing of peripheral blood from eight patients with Richter’s transformation showed two with BTK mutation, with a lymph node sample showing no BTK or PLCG2 mutations. Deep sequencing showed BTK or PLCG2 mutations in each of 11 evaluated patients with CLL progression, with the mutations not being identified prior to treatment in any patient.

Discontinuation for Other Reasons

Among the 45 patients discontinuing therapy for reasons other than disease progression, 28 did so due to infection, 8 due to other adverse events, and 9 due to other conditions. Only one nonprogression discontinuation occurred after 24 months. Discontinuation related to infection occurred at a median of 102 days, with discontinuation occurring in 16 of 28 cases within the first 6 months. On multivariate analysis, age was the only significant predictor of nonprogression discontinuation (hazard ratio [HR] = 1.87, P < .001, for each 10-year increase).

Overall, patients discontinuing treatment due to nonprogression reasons had median survival of 8 days after discontinuation, reflecting death on the same day as discontinuation in 16 of 28 patients with infection. Median survival was 238 days in patients discontinuing for nonprogression reasons other than infection.

The investigators concluded: “[These] outcomes data show poor prognosis after [ibrutinib] discontinuation, especially for those patients with [Richter’s transformation]…. [S]equencing data confirm initial reports associating mutations in BTK and PLCG2 with progression and clearly show that CLL progressions are associated with these mutations, while [Richter’s transformation] is likely not.”

Jennifer A. Woyach, MD, of The Ohio State University, Columbus, Ohio, is the corresponding author for the JAMA Oncology article.

The study was supported by the Leukemia and Lymphoma Society, National Cancer Institute, and others. For full disclosures of the study authors, visit

The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.