Outcomes of Ibrutinib Therapy Given after Prior Venetoclax Therapy in Ibrutinib-Naïve Patients with Relapsed/Refractory (R/R) Chronic Lymphocytic Leukemia (CLL)

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), with