Abstract: S147

Type: Oral Presentation

Session title: Clinical trials with targeted therapies in CLL

Background
Ibrutinib (Ibr) + venetoclax (Ven) have synergistic and complementary antitumor activity that mobilizes and clears chronic lymphocytic leukemia (CLL) cells from multiple disease compartments, providing a rationale to evaluate time-limited treatment. We previously reported results from the Minimal Residual Disease (MRD) cohort of the multicenter phase 2 CAPTIVATE study of first-line Ibr + Ven in patients with CLL/small lymphocytic lymphoma (SLL). In that cohort, undetectable MRD (uMRD) was achieved in over two-thirds of patients (pts) with 12 cycles of Ibr + Ven; 30-month progression-free survival (PFS) rates were ≥95% irrespective of subsequent randomized treatment (Wierda, ASH 2020).

Aims
Here we present results from the fixed-duration (FD) cohort, evaluating fixed-duration treatment with Ibr + Ven.

Methods
Eligible patients were aged ≤70 y with previously untreated CLL/SLL. Patients received 3 cycles of Ibr lead-in followed by 12 cycles of Ibr + Ven (Ibr 420 mg/d orally; Ven ramp-up to 400 mg/d orally). The primary endpoint was complete response (CR) rate, including CR with incomplete recovery (CRi); secondary endpoints were overall response rate (ORR), duration of response, uMRD rate (<10^–4 by 8-color flow cytometry), PFS, overall survival (OS), tumor lysis syndrome (TLS) risk reduction, and adverse events (AEs).

Results
Overall,159 patients were enrolled; median age was 60 y. High-risk features included del(17p)/TP53 mutation (17%), del(11q) (18%), complex karyotype (19%), and unmutated IGHV (56%). 147/159 (92%) patients completed planned treatment with Ibr, and 149/159 (94%) patients completed planned treatment with Ven. Median time on study was 27.9 months (range 0.8–33.2). With fixed-duration Ibr + Ven, 55% of patients in the overall population achieved a CR; the CR rate was consistent across high-risk subgroups. Of 88 patients who achieved CR, durable CR (duration ≥1 y from initial documentation of response) was confirmed in 78 patients (89%); an additional 9 patients (10%) were not yet evaluable with <1 y of post-CR follow-up and 1 pt died 7 months after achieving a CR. ORR was 96%. Best MRD response of uMRD was achieved in peripheral blood (PB) of 77% of patients and in bone marrow (BM) of 60% of patients. 24-month PFS and OS rates were 95% and 98%, respectively. Similar results were achieved in patients without del(17p) (n=136) (Table). In patients with del(17p)/TP53 mutation (n=27), the CR rate was 56%, uMRD rates were 81% (PB) and 41% (BM), and the 24-month PFS rate was 84% (95% CI 63%–94%). Of 34 patients with high baseline TLS risk based on tumor burden, 32 (94%) shifted to medium or low risk after Ibr lead-in; no TLS occurred. AEs were primarily grade 1/2. The most common grade 3/4 AEs were neutropenia (33%), hypertension (6%), and decreased neutrophil count (5%). AEs led to discontinuation of Ibr in 4% of patients and to discontinuation of Ven in 2% of patients.

Conclusion
First-line Ibr + Ven is an all-oral, once-daily, chemotherapy-free fixed-duration regimen that provides deep, durable responses in patients with CLL/SLL. Overall, CR, uMRD rates, PFS, and OS appear favorable, and benefit was observed regardless of genomic high-risk features. No new safety signals were identified, and the safety profile of Ibr + Ven was consistent with known safety profiles of each agent.

Keyword(s): BCL2, Chronic lymphocytic leukemia, Ibrutinib, Phase II