Outcomes of Ibrutinib Therapy Given after Prior Venetoclax Therapy in Ibrutinib-Naïve Patients with Relapsed/Refractory (R/R) Chronic Lymphocytic Leukemia (CLL)
Authors: Brown Jennifer R. , Davids Matthew S , Chang Julie , Ma Shuo , Biondo Juliana , Mobasher Mehrdad , Mun Yong , Mato Anthony R 
Published: October 2019

Abstract
Introduction
While the initial approval of venetoclax (VEN), a BCL2 inhibitor, was limited to relapsed patients with del17p, the data from the phase 3 MURANO trial demonstrated significant progression-free survival (PFS) benefit with venetoclax in combination with rituximab (R) versus bendamustine + rituximab (BR) and has recently led to the expansion of this approval to any relapsed CLL patient in the USA. Furthermore, several studies have demonstrated efficacy of venetoclax in treatment-naïve patients and a prospective, open-label, multicenter, randomised phase III trial with registration purpose is ongoing to explore venetoclax in the front-line CLL setting. While ibrutinib has demonstrated efficacy in CLL when patients are treated until disease progression, venetoclax trials have a finite duration of treatment in both relapsed and first-line settings. Although we have data demonstrating the efficacy of venetoclax after B-cell receptor inhibitors, including the Bruton's tyrosine kinase inhibitor, ibrutinib (Jones et al. Lancet Oncol, 2018), limited data are available on the efficacy of ibrutinib after venetoclax (Mato AR. Haematol 2018; Anderson M. Blood 2017).
Methods
We undertook this US multicenter retrospective chart-review data analysis to explore the outcomes of ibrutinib treatment given after venetoclax, in previously ibrutinib-naïve patients treated for R/R CLL.
Results
Data are available on eleven patients from four centers. Their median time from diagnosis to first therapy was 33.9 (range 4.0-53.0) months and median number of therapies prior to venetoclax was two (range 1-10). One patient had previously received both idelalisib and lenalidomide, but for all other patients venetoclax was their first targeted inhibitor for R/R CLL. The median time from diagnosis to venetoclax therapy was 77.8 (range 14.9-159.6) months. Prior to venetoclax initiation, four of eleven patients had del(17p), six of eleven had del(11q) and three had complex karyotype. Five of six evaluable patients had unmutated IGHV. Seven of eleven had a lymph node ≥ 5 cm. Ten of eleven patients achieved a partial response (PR) to venetoclax and the univariate median time to clinical progression on venetoclax was 19.0 (range 6.0-58.0) months, with a median time on venetoclax of 19.0 (range 1.2-57.5) months. One of eleven patients achieved stable disease on venetoclax, and remained on drug for 19 months. Reasons for discontinuation of venetoclax were: disease progression (n=8), withdrawal of consent (n=1), and allogeneic stem cell transplant after PR (n=2). The median time to ibrutinib treatment initiation, after discontinuing venetoclax, was 1.0 (range 0.1-30.8) month. For all eleven patients, ibrutinib was their next therapy after venetoclax. Ten of eleven patients achieved a PR to ibrutinib. The eleventh patient, who has only been on ibrutinib treatment for 1 month and continues on ibrutinib, has so far achieved stable disease. The time on ibrutinib therapy ranged from 0.5 to 30 months, with only three patients having discontinued. Of the responders, one patient progressed with Richter's transformation at 13 months on therapy and subsequently died. Two other patients stopped ibrutinib, one for an adverse event (AE) [atrial fibrillation and brain abscess] after 11.6 months, and a second for pneumonia that was ultimately fatal after 30 months on ibrutinib. Other notable AEs included one with major bleeding and five of eleven with joint pain. Two patients had ibrutinib dose reductions for fatigue and general malaise.
Conclusions
With the limitations of a very small dataset, we conclude that the efficacy and toxicity profile of ibrutinib appears similar in the relapsed setting after venetoclax as in patients not yet exposed to venetoclax. A larger dataset is being explored and will be presented at the meeting.

Disclosures
Brown: Beigene: Membership on an entity's Board of Directors or advisory committees; Genentech: Consultancy; Loxo: Consultancy; Celgene: Consultancy; Janssen: Consultancy; TG Therapeutics: Consultancy; Sunesis: Consultancy; Gilead: Consultancy, Research Funding; Acerta / Astra-Zeneca: Membership on an entity's Board of Directors or advisory committees; Morphosys: Membership on an entity's Board of Directors or advisory committees; Boehringer: Consultancy; Invectys: Membership on an entity's Board of Directors or advisory committees; Sun Pharmaceutical Industries: Research Funding; Roche/Genentech: Consultancy; Abbvie: Consultancy; Pharmacyclics: Consultancy; Verastem: Consultancy, Research Funding. Davids:Sunesis: Membership on an entity's Board of Directors or advisory committees; Roche: Consultancy; Surface Oncology: Research Funding; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pharmacyclics: 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; Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; MEI Pharma: Consultancy, Research Funding; Merck: Consultancy; Pharmacyclics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Surface Oncology: Research Funding; Pharmacyclics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; TG Therapeutics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Consultancy; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees; Verastem: Consultancy, Research Funding; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Roche: Consultancy; Sunesis: Membership on an entity's Board of Directors or advisory committees; Sunesis: Membership on an entity's Board of Directors or advisory committees; Verastem: Consultancy, Research Funding; Celgene: Consultancy; Gilead: Membership on an entity's Board of Directors or advisory committees; MEI Pharma: Consultancy, Research Funding; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees; TG Therapeutics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Astra-Zeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; TG Therapeutics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Astra-Zeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Astra-Zeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Merck: Consultancy; Merck: Consultancy; Celgene: Consultancy; Celgene: Consultancy; Gilead: Membership on an entity's Board of Directors or advisory committees; BMS: Research Funding; BMS: Research Funding; MEI Pharma: Consultancy, Research Funding; BMS: Research Funding; Surface Oncology: Research Funding; Verastem: Consultancy, Research Funding. Chang:Celgene: Research Funding; Genentech: Research Funding. Ma:Pharmacyclics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Incyte: Research Funding; Gilead: Membership on an entity's Board of Directors or advisory committees, Research Funding; Abbvie: Membership on an entity's Board of Directors or advisory committees, Research Funding; Acerta: Research Funding; Genentech: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Membership on an entity's Board of Directors or advisory committees. Biondo:Roche: Equity Ownership; Genentech, Inc.: Employment, Other: May own stocks/stock options at Roche. Mobasher:Genentech Inc: Employment; F. Hoffmann-La Roche Ltd: Other: Ownership interests non-PLC. Mun:Genentech: Employment, Equity Ownership. Mato:AstraZeneca: Consultancy; Janssen: Consultancy, Honoraria; Sunesis: Honoraria, Research Funding; Abbvie: Consultancy; Prime Oncology: Speakers Bureau; Acerta: Research Funding; Pharmacyclics: Consultancy, Honoraria, Research Funding; TG Therapeutics: Research Funding; Celgene: Consultancy; Regeneron: Research Funding.