A Phase 2 Study of Zanubrutinib and Venetoclax (ZV) in Relapsed or Refractory (R/R) Chronic Lymphocytic Leukemia (CLL)
Authors: Ahn Inhye E. , Ren Yue , Fisher David C. , Kim Austin I. , Kaddis Nancy E. , Arnason Jon E. , Winters John P. , Balasubramanian Sobana , Walker Heather A. , Patterson Victoria , Fernandes Stacey M. , Tyekucheva Svitlana , Davids Matthew S. , Brown Jennifer R. 
Published: December 2024

Background
The combination of the Bruton tyrosine kinase inhibitor (BTKi) zanubrutinib and the B-cell lymphoma 2 inhibitor (BCL2i) venetoclax (ZV) is effective in treatment-naïve CLL patients (pts) with deletion 17p (del(17p)) and/or mutations (mut) of TP53 (Ma et al, 2024 EHA Meeting). The efficacy of ZV in R/R CLL, particularly for pts who had been exposed to or progressed on targeted agents, remains unknown.
Methods
In this investigator-sponsored, multicenter trial, pts with R/R CLL were enrolled at 4 sites in the United States into 3 non-randomized cohorts defined by prior treatment history (NCT05168930). Eligible pts were BTKi- and BCL2i-naïve (Cohort A), exposed to BTKis and/or BCL2is and stopped the therapy due to reasons other than disease progression (Cohort B), or progressed on a covalent BTKi without BTK C481 mut (Cohort C). The study therapy comprised a fixed-duration of 15 cycles (C) of ZV. Each cycle was 28 days. Zanubrutinib 160 mg BID began on C1 Day (D) 1, followed by the initiation of a standard 5-week ramp-up of venetoclax on C4D1 for Cohorts A and B and on C2D1 for Cohort C. All pts stopped ZV after C15 regardless of clinical response or minimal residual disease (MRD) status at end of therapy (EoT). For pts with detectable MRD at EoT, retreatment with 12C of ZV was allowed at time of clinical progression. For pts with undetectable MRD at EoT, retreatment was allowed at time of MRD recurrence. The primary endpoint was the rate of undetectable MRD in bone marrow (BM-uMRD) at EoT using central multicolor flow cytometry at 10-4 (Mayo labs). Adverse events (AEs) were assessed based on CTCAE v5. Clinical response based on the 2018 iwCLL guidelines and MRD assessments were performed after C3, C9, and C15. 90-gene targeted NGS was applied to available pre-treatment samples.
Results
As of June 20, 2024, 26 pts were enrolled including 13 in Cohort A, 12 in Cohort B and 1 in Cohort C. The median age at enrollment was 68 years (range 37-83). 65% of pts were male, and 54% had unmutated IGHV. Seven (27%) pts had TP53 aberration including 3 with concurrent TP53 mut and del(17p), 3 with TP53 mut alone, and 1 with del(17p) alone. SF3B1, RAS/RAF, and NOTCH1 mut were detected in 7 (27%), 6 (23%), and 4 (15%) pts, respectively. Seven (27%) pts had complex karyotype (≥3 abnormalities). The median number of prior lines of therapy was 1 for Cohort A and 2 for Cohorts B and C. In Cohorts B and C, 11 (85%) had prior covalent BTKis, most commonly ibrutinib. One pt had prior therapy with ibrutinib and venetoclax (double-exposed), another pt had prior ibrutinib and acalabrutinib which were stopped due to intolerance, and two had prior idelalisib.
In the overall study population, the most common treatment-emergent AE was bruising (57%, all Grade [G] 1), followed by diarrhea (42%, all G1-2) and thrombocytopenia (38%, all G1-2). Neutropenia occurred in 35% (including 19% G3-4). Febrile neutropenia and sepsis were uncommon (4% each). Two (8%) pts developed atrial fibrillation (Afib); one with G3 Afib went off study during C1 and the other with G2 Afib continued study therapy. No tumor lysis syndrome event occurred.
After a median follow-up of 8 months, 9 pts completed planned 15C of ZV, and 17 pts were still on active therapy. A pt with TP53 mut progressed 10 months after the initial therapy, began retreatment with ZV, and was in response to the ongoing retreatment. The remaining 8 pts who completed 15C of ZV remained in remission and off therapy. The overall response rate (ORR) at best response in 22 evaluable pts who had at least 3C of study therapy was 95% including 18% in complete response (CR). There was no difference in clinical response across the cohorts (ORR: 91% for Cohort A and 100% for Cohorts B and C, CR rate: 18% for both Cohort A and Cohorts B and C). Partial response (PR) was achieved in 1 pt with double-exposed disease, 1 pt with two prior covalent BTKis, and another patient who had previously progressed on acalabrutinib. All 6 pts who completed response assessments at EoT achieved PR including 1 pt with BM-uMRD.
Conclusions
Fixed-duration combination therapy with ZV is active and well-tolerated in R/R CLL, including in pts with previous exposure to targeted agents. This study is actively accruing, and larger numbers of pts with longer follow-up will help further improve our understanding of the potential benefits of this regimen in R/R CLL.