Acalabrutinib Plus Venetoclax and Obinutuzumab Displays High Level of Activity in First-Line High-Risk CLL

The combination of acalabrutinib (Calquence), venetoclax (Venclexta), and obinutuzumab (Gazyva) was safe and active for the treatment of patients with previously untreated high-risk chronic lymphocytic leukemia (CLL), according to findings from a phase 2 study (NCT03580928) published in the Journal of Clinical Oncology.1 High-risk disease was defined as the presence of a TP53 aberration.

At a median follow-up of 38.5 months, patients with CLL with a TP53 aberration who received the triplet (n = 45) experienced a complete remission (CR) with bone marrow–undetectable minimal residual disease (BM-uMRD) at a rate of 42% (95% CI, 28%-58%) at the start of cycle 16; 49% (95% CI, 34%-64%) achieved a CR. The peripheral blood–undetectable minimal residual disease (PB-uMRD) and BM-uMRD rates among patients with a TP53 aberration who reached cycle 25 were 57% (95% CI, 41%-72%) and 76% (95% CI, 61%-88%), respectively. The median time to BM-uMRD and PB-uMRD was 13.6 months (95% CI, 6.7-14.0) and 6.7 months (95% CI, 6.5-7.0), respectively.

“The [phase 3] AMPLIFY trial [NCT03836261] recently established fixed-duration acalabrutinib, venetoclax, and obinutuzumabas a new standard-of-care option for patients with previously untreated CLLwith wild-type TP53; however, due to the chemoimmunotherapy control arm, AMPLIFY excluded patients with high-risk TP53 aberration, for whom current standards of care are continuous BTK inhibitor therapy or alternatively fixed-duration venetoclax-based doublets. Acalabrutinib, venetoclax, and obinutuzumab has not previously been evaluated in patients with CLL with TP53 aberration,” the study authors wrote.

Study Design and Baseline Patient Characteristics

The single-arm, open-label study enrolled patients with previously untreated CLL or small lymphocytic lymphomarequiring initial therapy per International Workshop on CLL 2018 criteria. Eligible patients also needed to be at least 18 years old, have measurable disease, an ECOG performance status of 2 or less, and adequate organ and marrow function.2

Eligible patients received 1 cycle of acalabrutinib, followed by 2 cycles of acalabrutinib plus obinutuzumab in cycles 2 and 3, then acalabrutinib, venetoclax, and obinutuzumab in cycles 4 through 7, and acalabrutinib and venetoclax over the course of cycles 8 to 15.1 Acalabrutinib was administered at a dose of 100 mg twice daily and obinutuzumab was given at 1000 mg once daily. At cycle 4, venetoclax was administered at 20 mg once daily on day 1, then 50 mg once daily on day 2, with subsequent weekly ramp-up dosing to 100 mg once daily, 200 mg once daily, and 400 mg on day 22, followed by 400 mg once daily for subsequent cycles.

At the beginning of cycle 16, patients were permitted to discontinue acalabrutinib and venetoclax if they achieved a CR with BM-uMRD. If this end point was not reached or they chose to continue acalabrutinib and venetoclax, they remained on treatment until cycle 25 when they could discontinue therapy if they had BM-uMRD and a minimum of a partial remission (PR).

The primary end point was CR with BM-uMRD per flow cytometry at a sensitivity of 10−4 at the start of cycle 16. Secondary end points included overall survival (OS), progression-free survival (PFS), CR rate, PR rate, and PB-uMRD rate.2

At baseline, the median age of patients with a TP53 aberration was 65 years (range, 36-80).1 Most patients were male (62.2%), had an ECOG performance status of 0 (53.3%), and had deletion 17p with a TP53 mutation (68.9%). The median white blood cell count was 94 × 109/L (range, 2-281), the median hemoglobin count was 11.1 g/dL (range, 7.6-15.7), and the median immunoglobulin G count was 747 mg/dL (range, 108-2506).

Additional Safety and Efficacy Data

The 4-year PFS and OS rates in patients with a TP53 aberration were 70% (95% CI, 55%-91%) and 88% (95% CI, 75%-100%), respectively. The best ORR was 98%, the best CR rate was 71%, and the best rate of CR with BM-uMRD was 58%.

In the overall population (n = 72), at the start of cycle 16 the CR with BM-uMRD rate was 42% (95% CI, 30%-54%); the BM-uMRD and PB-uMRD rates were 78% (95% CI, 66%-87%) and 83% (95% CI, 73%-91%), respectively. The median time to BM-uMRD and PB-uMRD was 13.6 months (95% CI, 6.7-14.0) and 6.7 months (95% CI, 6.5-7.0), respectively.

In terms of safety, any-grade adverse effects (AEs) were reported in 99% of the overall population; grade 3 or higher AEs occurred in 56% of patients. Common any-grade AEs included fatigue (82%), headache (75%), and neutropenia (72%). Grade 3 or higher AEs included neutropenia (36%), thrombocytopenia (28%), infection (10%), and hypertension (10%). One patient died due to an AE during active treatment due to grade 5 COVID-19 infection; this was also the only treatment discontinuation due to an AE possibly related to therapy. Twenty-four percent of patients experienced dose reductions, including for acalabrutinib only (4%), venetoclax only (8%), and for both agents (11%).

“In this trial enriched for patients with previously untreated high-risk CLL, acalabrutinib, venetoclax, and obinutuzumab given with MRD-guided treatment duration is a well-tolerated and highly active frontline therapy,” the study authors wrote in their conclusion. “Our data complement those reported in patients without TP53 aberration in AMPLIFY, and support acalabrutinib, venetoclax, and obinutuzumab as a new standard of care option as initial therapy for a broad population of patients with CLL, including those with TP53 aberration.”

References

1. Davids MS, Ryan CE, Lampson BL, et al. Phase II study of acalabrutinib, venetoclax, and obinutuzumab in a treatment-naïve chronic lymphocytic leukemia population enriched for high-risk disease. J Clin Oncol. 2025;43(7):788-799. doi:10.1200/JCO-24-02503
2. Acalabrutinib, venetoclax, and obinutuzumab for initial therapy of CLL (AVO). ClinicalTrials.gov. Updated July 30, 2024. Accessed March 7, 2025. https://www.clinicaltrials.gov/study/NCT03580928