Outcome of Ibrutinib Treatment by Baseline Genetic Features in Patients with Relapsed or Refractory CLL/SLL with del17p in the Resonate-17 Study
Authors: Stilgenbauer Stephan , Jones Jeffrey A. , Coutre Steven , Mato Anthony R. , Hillmen Peter , Tam Constantine , Osterborg Anders , Siddiqi Tanya , Thirman Michael J. , Furman Richard R. , Ilhan Osman , Keating Michael , Call Timothy G. , Brown Jennifer R. , Li Yunfeng , Eckert Karl , Chang Betty Y. , James Danelle F. , Chu Alvina D. , Hallek Michael , O'Brien Susan 
Published: October 2019

Abstract
Background: Patients (pts) with deletion 17p (del17p) CLL follow an aggressive clinical course and experience poor outcomes with chemoimmunotherapy. Ibrutinib, an oral inhibitor of Bruton's tyrosine kinase (BTK), is approved for pts with CLL with ≥1 prior therapy and for pts with del17p CLL (including first-line). In the phase 2 RESONATE-17 study (PCYC-1117), ibrutinib demonstrated high efficacy with a favorable risk-benefit profile in del17p CLL/SLL (O'Brien, ASH 2014). We evaluate the baseline genetic features and prognostic factors of these pts to determine their impact on outcome.
Methods: Pts with del17p CLL or SLL defined by peripheral blood FISH who failed ≥1 therapy received 420 mg oral ibrutinib once daily until progression or unacceptable toxicity. Using the primary analysis data cut, the overall response rate (ORR; iwCLL 2008 criteria by investigators), progression-free survival (PFS), and overall survival (OS) were assessed by subgroup.
Results: Among 144 treated pts (137 CLL, 7 SLL), the median age was 64 (range 36-89). At baseline, 63% of pts had Rai stage III or IV disease, and 39% had received ≥3 prior therapies. Baseline cytogenetics included del11q (16%), del13q (74%), and trisomy 12 (17%), in addition to del17p in all pts. Of 116 pts with valid baseline genomic samples, IGHV status was unmutated in 84%; genomic variants that included mutations, rearrangements, insertions, deletions, and copy number variants affecting coding regions were identified as follows: ATM (14%), BIRC3 (3%), BTK (1%), MYC (2%), MYD88 (2%), NOTCH1 (16%), PLCG2 (3%), SF3B1 (27%), and TP53 (92%), which were consistent with previously identified mutations in pts with CLL (Wang, NEJM 2011; Winkelmann, Haematologica 2015). At a median follow-up of 11.5 months, the investigator-assessed ORR including partial response with lymphocytosis (PR-L) for all treated pts was 83% (17% PR-L). Median PFS and OS were not reached, with 12-month PFS and OS rates of 79% and 84%. Any-grade adverse events (≥15%) included diarrhea (36%), fatigue (31%), cough (24%), arthralgia (22%), nausea (19%), hypertension (19%), anemia (19%), pyrexia (17%), decreased appetite (17%), muscle spasms (17%), neutropenia (17%), and peripheral edema (15%). Serious AEs occurred in 40% of pts (38% ≥ grade 3). ORR, 12-month PFS, and 12-month OS are presented by subgroup for baseline characteristics, cytogenetics, and genomic variants (Table). There were no substantial differences in response rates and survival outcomes in the subgroups with and without baseline cytogenetic aberrations or genomic variants (Table). Response rates were similar for pts with and without NOTCH1 or SF3B1 variants. Of 11 pts with del17p CLL who developed Richter transformation, baseline aberrations included ATM (n=2), SF3B1 (n=3), and/or NOTCH1 (n=3); none had BIRC3 variants. Overall at baseline, there were 3 pts with a PLCG2 mutation (L163F, H193Q, P236L), and 1 with a BTK mutation (R236Q); all achieved a best overall response of PR-L or better. None had received prior therapy with a BTK or PI3K inhibitor. Two pts had a baseline MYD88 mutation (L265P, L142F) with a best overall response of PR in 1 pt. Two pts had baseline MYC amplifications with 5 of 5 exons amplified to 6 and 7 copies, respectively; 1 pt achieved a best overall response of PR.
Conclusions: These results provide further evidence of ibrutinib's robust clinical activity and encouraging survival outcomes in this high-risk population regardless of baseline cytogenetic aberrations or genomic variants. The prognostic role of these clinical characteristics and genetic anomalies will continue to be elucidated with longer term follow-up of this population.
Figure 1. Investigator-assessed efficacy outcomes by subgroups Figure 1. Investigator-assessed efficacy outcomes by subgroups

Disclosures
Stilgenbauer: AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Pharmacyclics LLC, an AbbVie Company: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Jones:Pharmacyclics LLC, an AbbVie Company: Consultancy, Research Funding; AbbVie: Research Funding. Coutre:AbbVie: Research Funding; Pharmacyclics LLC, an AbbVie Company: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees. Mato:Celgene: Consultancy, Other: Travel, Accommodations, Expenses, Research Funding; TA Therapeutics: Research Funding; Gilead: Consultancy, Other: Travel, Accommodations, Expenses; Pharmacyclics LLC, an AbbVie Company: Consultancy, Other: Travel, Accommodations, Expenses. Hillmen:AbbVie: Honoraria, Research Funding; Roche Pharmaceuticals: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Celgene: Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Pharmacyclics LLC, an AbbVie Company: Honoraria, Research Funding; Gilead: Honoraria, Research Funding. Tam:Janssen: Consultancy, Honoraria, Research Funding. Osterborg:Gilead: Honoraria; Janssen: Honoraria, Research Funding; GSK: Research Funding; Pharmacyclics LLC, an AbbVie Company: Research Funding; Amgen: Research Funding. Siddiqi:Pharmacyclics: Research Funding, Speakers Bureau; Janssen: Speakers Bureau. Thirman:Gilead: Research Funding; Merck: Research Funding; AbbVie: Research Funding; Pharmacyclics LLC, an AbbVie Company: Research Funding. Furman:Gilead: Consultancy; Acerta Pharma BV: Research Funding; Pharmacyclics LLC, an AbbVie Company: Consultancy, Honoraria, Speakers Bureau. Li:Pharmacyclics LLC, an AbbVie Company: Employment. Eckert:Pharmacyclics LLC, an AbbVie Company: Employment. Chang:Pharmacyclics LLC, an AbbVie Company: Employment. James:Pharmacyclics LLC, an AbbVie Company: Employment. Chu:Pharmacyclics LLC, an AbbVie Company: Employment. Hallek:Pharmacyclics LLC, an AbbVie Company: Consultancy, Speakers Bureau; Janssen: Speakers Bureau. O'Brien:Pharmacyclics LLC, an AbbVie Company: Consultancy, Research Funding.