Venetoclax Elicits Responses in B-Cell Receptor–Pretreated CLL Regardless of Mutation Status

Jennifer A. Woyach, MD

Treatment with single-agent venetoclax (Venclexta) led to prolonged disease response in patients with chronic lymphocytic leukemia (CLL) who had relapsed or become refractory to prior B-cell receptor inhibitors including ibrutinib (Imbruvica) and idelalisib (Zydelig), according to findings from a phase 2 study (NCT02141282) that were presented at the 2023 International Workshop on CLL.¹ 

“Venetoclax monotherapy demonstrated durable responses in patients with CLL who progressed on BCR inhibitors, irrespective of BTK mutation status,” lead study author Jennifer A. Woyach, MD, professor, Division of Hematology, The Ohio State University, and coleader of the Leukemia Research Program at The Ohio State Comprehensive Cancer Center–James in Columbus, said in a presentation of the data.

Limited treatment options are available to patients with CLL who are refractory to B-cell receptor pathway inhibitors. In this analysis, investigators evaluated the outcomes of patients with relapsed/refractory CLL following long-term treatment with venetoclax (n = 127). Of these patients, 91 had received ibrutinib (arm A) prior to venetoclax and 36 received idelalisib (arm B) before venetoclax. Results from the primary analysis were previously presented and published in Lancet Oncology in 2018.²

Pretreatment mutational data were available for 72 samples, resulting in 68 matched pre and post venetoclax treatment samples.

Baseline demographics were similar between prior treatment arms. Overall, most patients were female (70%), 65 years of age or older (58%), and had an ECOG performance status of 0 or 1 (91%), and deletion 17p and/or a TP53 mutation (46%). The median number of prior lines of therapy was 4 (range, 1-14), and 22% of patients had received at least 2 prior BCR inhibitors. Notably, half of all patients who received a prior BCR inhibitor (n = 127) discontinued treatment due to disease progression.

In terms of response, the objective response rates (ORRs) in the prior ibrutinib and idelalisib groups were 65% and 69%, respectively. Stable disease occurred in 23% and 25% of patients, respectively. The rates of undetectable minimal residual disease were 31% and 25%, respectively.

Median progression-free survival (PFS) was 24.7 months (95% CI, 19.2-40.9) in patients who received prior ibrutinib (n = 91) and 43.4 months (95% CI, 20.1-not evaluable) in patients who received prior idelalisib (n = 36). Median overall survival (OS) was 69.6 months (95% CI, 51.3-NE) and not reached with prior ibrutinib and prior idelalisib, respectively.

Notably, pre-existing BTK mutations did not affect PFS with venetoclax, with medians of 19.2 months (95% CI, 15.0-48.9) and 21.9 months (95% CI, 13.6-36.9) in patients without pre-existing BTK mutations (n = 38) and those with pre-existing BTK mutations (n = 34), respectively. Patients without a pre-existing BTK mutation (n = 38) experienced improved OS compared with those with a pre-existing BTK mutation (n = 34; HR, 2.03; 95% CI, 1.03-4.03). The ORRs among patients with and without pre-existing BTK mutations were 79% (95% CI, 62%-91%) and 87% (95% CI, 71%-95%), respectively. Regarding pre-existing mutation type, 47% of patients overall (ibrutinib, n = 34; idelalisib, n = 3) had BTK C481 and 60% had a TP53 mutation (ibrutinib, n = 35; idelalisib, n = 8).

Median duration of response to ibrutinib and idelalisib was 35.1 months (95% CI, 19.4-50.5) and 55.4 months (95% CI, 32.0-not evaluable), respectively. Median duration of therapy was 19.5 months (95% CI, 0.1-83.1) and 35.5 months (95% CI, 1.3-82.3), respectively.

A total of 32% of patients discontinued the study because of disease progression (24%), Richter’s transformation (6%), and an AE related to disease progression (2%).

At study’s end, 72 patients remained alive. Most patients had experienced a grade 3 or higher adverse effect (89%; AE) and serious AE (66%). Treatment-related discontinuation, interruption, and reduction occurred in 18%, 51%, and 18% of patients, respectively. Ten deaths occurred.

Regarding genomic changes, 5 of 33 patients with available data experienced loss of BTK mutations during treatment with venetoclax. Acquired BCL-2 mutations were identified in 19% (n = 13) of patients, 30% of which occurred in patients with progressive disease and 11% in those without disease progression. Median time on venetoclax was 32 months (range, 12-48) in patients with acquired BCL-2 mutations.

Notably, the variant-allele fractions (range, 0.7%-34.0%) of BCL-2 mutations were largely sub-clonal, regardless of CLL progression status. The most identified mutations were G101V (n = 8), D103E/V/Y (n = 3/1/3), R107-R110dup (n = 5), A113G (n = 2), and V156D (n = 2). Mutations in other BCL-2 family members such as BAX, BAD, and NOXA were not seen.

“Acquired mutations were detectable in patients with prolonged venetoclax exposure, supporting further exploration of strategies focused on time-limited venetoclax,” Woyach concluded.

Disclosures: Dr Woyach reported serving as a consultant for AbbVie, AstraZeneca, Beigene, Genentech, Janssen, Loxo, Newave Pharmacyclics, Schrodinger, and received funding from AbbVie, Janssen, Morphosys, and Schrodinger.

References

1. Woyach J, Popovic R, Rossi E, et al. Recurrent genomic alterations in the apoptotic machinery in patients with CLL treated with venetoclax monotherapy following treatment with BCRi. Presented at: 2023 iwCLL Annual Meeting; October 6-9, 2023; Boston, MA. Abstract 1553189.
2. Jones JA, Mato AR, Wierda WG, et al. Venetoclax for chronic lymphocytic leukaemia progressing after ibrutinib: an interim analysis of a multicentre, open-label, phase 2 trial. Lancet Oncol. 2018;19(1):65-75. doi:10.1016/S1470-2045(17)30909-9