Most patients with progressive chronic lymphocytic leukemia (CLL) receiving ibrutinib therapy harbor BTK and/or PLCG2 mutations, and concurrent mutations of both are common at progression, an integrated analysis presented at the American Academy for Cancer Research (AACR) Annual Meeting 2016 has shown.1

Ibrutinib is indicated for the treatment of patients with CLL, and those with CLL and a 17p deletion; however, progressive disease on ibrutinib has been reported due to histologic transformation or mutations of BTK or PLCG2. Therefore, researchers sought to describe the clinical and molecular characteristics of patients with CLL who progressed on ibrutinib.

A phase 2 trial evaluated the efficacy and safety of ibrutinib 420 mg daily in 84 patients with 17p deletion or TP53 deletion, or those aged 65 years and older. Samples from 13 patients with progressive disease on ibrutinib were tested for mutations of BTK and PLCG2 by a high-sensitivity assay.

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Results showed that 3 of 4 patients who experienced early disease progression were due to histologic transformation, while 8 of 9 cases of late progressive disease were due to CLL. Further, researchers found that progression-free survival was inferior in patients with TP53 aberration, unmutated IGHV, advanced Rai stage, high β-2 microglobulin, and relapsed/refractory disease (P < .05).

Researchers identified 2 types of non-synonymous mutations at BTK exon 15 and 5 types of non-synonymous mutations at PLCG2 exon 19, 20, and 24 in 8 of the 9 patients with progressive disease. No mutation was detected in those with transformation and in 1 patient with progressive CLL.

The investigators also observed concomitant BTK and PLCG2 mutation in 5 of 8 patients, suggesting that concurrent mutations of BTK and PLCG2 are common at CLL progression.  Mutations pre-dating clinical progressive disease were identified in stored samples from 6 patients as early as 13 months before progression, meaning either or both of these mutations can be acquired many months before clinical progression.

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Ultimately, patients who harbor detectable mutation but have not demonstrated clinical progression can benefit from prolonged ibrutinib treatment until clinical progression occurs. Upon clinical progression, patients can still achieve response to alternative targeted agents.


  1. Ahn IE, Albitar A, Underbayev C, et al. Integrated analysis of ibrutinib resistance in chronic lymphocytic leukemia. Poster presentation at: AACR Annual Meeting 2016; April 16-20, 2016; New Orleans, LA.