Abstract 292: Integrated analysis of ibrutinib resistance in chronic lymphocytic leukemia
Authors: Ahn Inhye E. , Albitar Adam , Underbayev Chingiz , Herman Sarah , Tian Xin , Soto Susan , Stetler-Stevenson Maryalice , Maric Irina , Farooqui Mohammed Z. , Albitar Maher , Wiestner Adrian 
Published: July 2016

Abstract
BACKGROUND: Ibrutinib covalently binds to Bruton's tyrosine kinase, inhibits B-cell receptor signaling, and is active in chronic lymphocytic leukemia (CLL). Progressive disease (PD) on ibrutinib has been reported due to histologic transformation or mutations of BTK or PLCG2. Here we report integrated analysis of the clinical and molecular characteristics of CLL pts who progressed on ibrutinib (PD group).
METHODS: Under a phase II investigator-initiated trial (ClinicalTrials.gov, NCT01500733) 84 CLL pts with TP53 aberration (deletion 17p or TP53 mutation) or age ≥65 were treated with ibrutinib 420mg daily. Samples from the PD group were tested for mutations of BTK and PLCG2 by a high-sensitivity assay using branched and locked nucleic acids. In pts with mutations at PD, stored samples from earlier time-points were also sequenced.
RESULTS: 13 (15.5%) of 84 pts progressed at a median follow up of 24 months. 3 of 4 early PDs (≤12 months) were due to histologic transformation, while 8 of 9 late PDs (median 34.9 months) were due to CLL. PFS was inferior in subgroups with TP53 aberration, unmutated IGHV, advanced Rai stage, high β-2 microglobulin and relapsed/refractory disease (log-rank p&lt;0.05 for all tests). 8 pts with progressive CLL were subsequently treated with small molecules targeting PI3K or Bcl-2, and 6 were alive to date (longest follow-up 15 months). Two types of non-synonymous mutations at BTK exon 15 (C481S, C481R) and five types of non-synonymous mutations at PLCG2 exon 19, 20 and 24 (R665W, P664S, P664L, S707Y, L845F) were identified in 8 out of 9 pts having progressive CLL. No mutation was found in pts with transformation and in one pt with progressive CLL. Concomitant BTK and PLCG2 mutations were found in 5 out of 8 pts (62.5%). Mutations pre-dating clinical PD were identified in stored samples from 6 pts as early as 13 months before progression (range 1.8-13.0). The median time to the first detected mutation was 23.1 months (range 5.4-34.7). Mutational complexity increased over time as reflected by increasing types of mutations (n = 3) and allele frequencies (n = 3) at later time-points. Both PD with progressive CLL and non-PD groups showed equivalent depth of best response in peripheral blood (PB) and bone marrow during treatment (p&gt;0.05). At PD, tumor burden increased by 2 to 32-fold from nadir based on PB flow cytometry.
CONCLUSION: Most pts with progressive CLL on ibrutinib carry BTK and/or PLCG2 mutations. Concurrent mutations of BTK and PLCG2 are common at progression, and either or both of these mutations can be acquired many months before clinical progression. In cases with detectable mutations but without clinical progression, pts can benefit from prolonged treatment with ibrutinib until clinical progression occurs. Upon clinical progression with CLL, pts can still show responses to alternative targeted agents.
Citation Format: Inhye E. Ahn, Adam Albitar, Chingiz Underbayev, Sarah Herman, Xin Tian, Susan Soto, Maryalice Stetler-Stevenson, Irina Maric, Mohammed Z. Farooqui, Maher Albitar, Adrian Wiestner. Integrated analysis of ibrutinib resistance in chronic lymphocytic leukemia. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 292.