Outcomes of Ibrutinib (Ibr) Therapy in Ibr-Naïve Patients (pts) with Chronic Lymphocytic Leukemia (CLL) Progressing after Venetoclax (Ven)
Authors: Brown Jennifer R. , Davids Matthew S. , Chang Julie E , Ma Shuo , Biondo Juliana M L , Mun Yong , Breuleux Madlaina , Wierda William G. 
Published: November 2019

Introduction: The approval of several new, targeted agents has been transformative in the treatment of CLL. Prospective clinical trial data support the use of Ven after Ibr in CLL (Jones JA et al. Lancet Oncol 2018); however, limited data are available on the inverse sequencing of these agents (Mato AR et al. Br J Haematol 2018; Anderson M et al. Blood 2017). Given the recent FDA approval of Ven + obinutuzumab in first-line (1L) CLL, an upsurge in Ibr-naïve pts needing therapy post-Ven is likely; characterizing this sequencing is of the upmost importance. Here we present a US multicentre, retrospective, chart-review analysis to explore outcomes of Ibr post-Ven, in Ibr-naïve pts with CLL.
Methods: Efficacy and safety outcomes were investigated for pts with Ibr-naïve CLL, treated with Ven +/- CD20 monoclonal antibody (mAb), who developed progressive disease ([PD] or discontinued Ven) and received Ibr salvage therapy (+/- CD20 mAb). Analyses included pts in 1L or relapsed/refractory setting. Pts were treated between Feb 14, 2012 and Jun 6, 2019, across four institutions (US); data cutoff was Jul 18, 2019.
Results: Data were available for 27 pts with CLL who received Ibr post-Ven - the largest cohort to date. Median age was 64 (41-79) years, median time from diagnosis to first therapy was 9.0 (0-117.7) months (mo), and the median number of therapies prior to Ven was 2 (0-9). Prior therapies were varied and included: 1 Bruton's tyrosine kinase inhibitor (BTKi; not Ibr), 3 lenalidomide, 1 pt received 9 lines of therapy (including: idelalisib, lenalidomide, anti-CD22 and temsirolimus), others received chemo- or chemoimmunotherapy, or CD20 mAb only.
Median time from diagnosis to initiation of Ven was 56.3 (0-157.7) mo. At baseline, the median lymphocyte count was 2.2 (0.2-220.0) K/µL; 8/24 (33.3%) pts had a lymph node ≥ 5cm. All evaluable pts (26/26) had ≥1 unfavourable prognostic risk factor; 12/20 (60.0%) pts had del17p, 10/16 (62.5%) had del11q, 12/24 (50.0%) had complex karyotype (CK) and 13/15 (86.7%) pts had unmutated IGHV. A complete or partial response (CR or PR) to Ven was achieved in 4/26 (15.4%) and 18/26 (69.2%) evaluable pts, respectively. The median time to PD on Ven was 29.0 (1.0-118.0) mo, with a median treatment duration of 18.0 (0.1-64.3) mo. Pts discontinued Ven due to PD (n=18), consent withdrawal (n=2), non-compliance (n=1), and other (n=6; allogeneic stem cell transplantation n=2, physician decision n=3, not evaluable n=1).
Prior to initiation of Ibr, the median lymphocyte count was 1.9 (0.01-179.0) K/µL; 15/26 (57.7%) pts had adenopathy, and 5/13 (38.5%) had a lymph node ≥ 5cm. Risk factors included: del17p (4/10; 40.0%), del11q (4/9; 44.4%), CK (8/17; 47.1%) and unmutated IGHV (11/14; 78.6%). Median time from Ven initiation to Ibr initiation was 31.9 (1.8-60.3) mo; median time to Ibr initiation post-Ven was 0.7 (0-39.7) mo. The overall response rate to Ibr was 56.0% (CR: 1/25, PR: 13/25). The time to progression on Ibr, post-Ven, varied from 3.0 to 53.0 mo (n=10). The median duration of Ibr therapy was 18.3 (3.7-53.2) mo and 20.0 (4.9-44.3) mo for those remaining on Ibr (8/27); the median follow-up time matched the median therapy duration. Nineteen pts discontinued Ibr due to: PD (n=9), physician decision (n=4), adverse events (AEs; n=2), transplant (n=2), symptomatic deterioration and unknown reason (n=1 each). The median number of therapies prior to Ven for the 9 pts who discontinued Ibr due to PD was 2 (1-9); 4/9 pts received novel targeted therapies. Richter's transformation occurred in 1 pt (1/9). The 2 pts who discontinued Ibr due to AEs experienced either atrial fibrillation (AF)/brain abscess or pneumonia after 11.6 and 18.2 mo of Ibr, respectively. Other notable AEs were: major bleeding (n=1), AF (n=2), infection (n=1), neutropenia (n=1), myalgia/arthralgia (n=2), and other cardiac event (n=1). Ibr dose reductions due to fatigue and general malaise occurred in 1 pt.
Conclusions: With the limitations of a retrospective series using real-world data, these data suggest that Ibr had substantial clinical activity post-Ven in heavily pre-treated, high-risk CLL pts; no new safety signals arose. Larger, prospective studies are required to fully characterize the efficacy of Ibr after Ven. Meanwhile, salvage therapy with Ibr remains a good option for pts with CLL who relapse after Ven.

Disclosures
Brown: Sunesis: Consultancy; Pharmacyclics: Consultancy; Pfizer: Consultancy; Novartis: Consultancy; Kite, a Gilead Company: Consultancy, Research Funding; Loxo: Consultancy, Research Funding; Invectys: Other: Data safety monitoring board; Octapharma: Consultancy; Morphosys: Other: Data safety monitoring board; Janssen: Honoraria; Dynamo Therapeutics: Consultancy; Teva: Honoraria; Sun Pharmaceuticals: Research Funding; Genentech/Roche: Consultancy; Gilead: Consultancy, Research Funding; BeiGene: Consultancy; Catapult Therapeutics: Consultancy; AstraZeneca: Consultancy; Acerta Pharma: Consultancy; AbbVie: Consultancy; Juno/Celgene: Consultancy; TG Therapeutics: Consultancy; Verastem: Consultancy, Research Funding. Davids:Research to Practice: Honoraria; AbbVie, Acerta Pharma, Adaptive, Biotechnologies, Astra-Zeneca, Genentech, Gilead Sciences, Janssen, Pharmacyclics, TG therapeutics: Membership on an entity's Board of Directors or advisory committees; AbbVie, Astra-Zeneca, Genentech, Janssen, MEI, Pharmacyclics, Syros Pharmaceuticals, Verastem: Consultancy; Acerta Pharma, Ascentage Pharma, Genentech, MEI pharma, Pharmacyclics, Surface Oncology, TG Therapeutics, Verastem: Research Funding. Chang:Genentech: Research Funding; Celgene: Research Funding; Adaptive Biotechnologies: Research Funding. Ma:Kite: Consultancy; Xeme: Research Funding; Abbvie: Research Funding; Beigene: Research Funding; Bioverativ: Consultancy; Incyte: Research Funding; Genentech: Consultancy; Astra Zeneca: Consultancy, Research Funding, Speakers Bureau; Gilead: Research Funding; Janssen: Consultancy, Speakers Bureau; Novartis: Research Funding; Juno: Research Funding; Acerta: Research Funding; Pharmacyclics: Consultancy, Research Funding, Speakers Bureau. Biondo:Genentech, Inc.: Employment; F. Hoffmann-La Roche Ltd: Equity Ownership. Mun:Genentech: Employment, Equity Ownership. Breuleux:F. Hoffmann - La Roche Ltd: Employment, Equity Ownership; Gilead: Equity Ownership; Basilea Ltd: Equity Ownership. Wierda:Janssen: Research Funding; Xencor: Research Funding; Gilead Sciences: Research Funding; Pharmacyclics LLC: Research Funding; Cyclcel: Research Funding; Sunesis: Research Funding; AbbVie: Research Funding; KITE pharma: Research Funding; Miragen: Research Funding; Juno Therapeutics: Research Funding; GSK/Novartis: Research Funding; Oncternal Therapeutics Inc.: Research Funding; Loxo Oncology Inc.: Research Funding; Genentech: Research Funding; Acerta Pharma Inc: Research Funding.