Fixed-Duration Acalabrutinib and Venetoclax Regimens Redefine First-Line Treatment Options for Patients With CLL

An interim analysis of the AMPLIFY trial (NCT03836261) offers new insights into fixed-duration therapies for patients who are treatment-naive with chronic lymphocytic leukemia (CLL). In this randomized, open-label, phase 3 study, investigators evaluated the efficacy and safety of acalabrutinib (Calquence; AstraZeneca) plus venetoclax (Venclexta; AbbVie Inc) (AV); acalabrutinib, venetoclax, and obinutuzumab (Gazyva; Genentech) (AVO); and investigator’s choice of standard chemoimmunotherapy, including fludarabine, cyclophosphamide, and rituximab (Rituxan; Genentech) (FCR) or bendamustine plus rituximab (BR).^1,2

An AI depiction of chronic lymphocytic leukemia cells. Image Credit: © sovova - stock.adobe.com

Jennifer R. Brown, MD, PhD, director of the CLL Center of the Division of Hematologic Malignancies at Dana-Farber Cancer Institute and the Worthington and Margaret Collette professor of medicine in the field of hematologic oncology at Harvard Medical School in Boston, Massachusetts, presented the results of the interim analysis at the 66th American Society of Hematology (ASH) Annual Meeting and Exposition in San Diego, California. A total of 867 patients were enrolled, all of whom were treatment-naive, met the International Workshop on CLL 2018 criteria for requiring therapy, and did not exhibit high-risk genetic mutations such as chromosome 17p deletion or TP53 aberrations. The trial aimed to address the limitations of existing therapies, particularly concerns regarding the safety and tolerability of first-generation Bruton tyrosine kinase inhibitors (BTKis) such as ibrutinib (Imbruvica; Janssen Biotech, Inc. and Pharmacyclics LLC).^1,2

Patients were randomly assigned to 3 treatment arms: AV, AVO, or chemoimmunotherapy. The AV regimen consisted of 14 cycles of oral acalabrutinib and venetoclax, while AVO included the same combination plus intravenous obinutuzumab. In both AV and AVO, treatment began with acalabrutinib monotherapy for 1 cycle, followed by the addition of venetoclax starting in cycle 3 after a gradual dose ramp-up to minimize the risk of tumor lysis syndrome. For patients in the AVO group, obinutuzumab was administered starting in cycle 2 and continued through cycle 7. Chemoimmunotherapy involved 6 cycles of either FCR or BR, determined by the investigator based on patient fitness. Notably, crossover between treatment arms was not permitted.^1,2

The study's primary end point was progression-free survival (PFS) assessed by blinded independent central review, comparing AV to chemoimmunotherapy. Secondary end points included PFS for AVO vs chemoimmunotherapy, rates of undetectable minimal residual disease (uMRD) at a sensitivity of 10^-4 in peripheral blood, and overall survival (OS). These end points were evaluated in a fixed sequential hierarchy, with no direct comparison planned between AV and AVO, according to Brown.^1,2

The results of the interim analysis demonstrated that both AV and AVO provided significant improvements in PFS compared to chemoimmunotherapy. At a median follow-up of 40.8 months, the hazard ratio (HR) for PFS with AV vs chemoimmunotherapy was 0.65, corresponding to an estimated 3-year PFS rate of 76.5%, compared to 66.5% for chemoimmunotherapy. Similarly, AVO achieved an even greater benefit, with a HR of 0.42 and a 3-year PFS rate of 83.1%. Importantly, PFS improvements were observed across all patient subgroups, including those with unmutated immunoglobulin heavy chain variable region gene (IGHV), a group typically associated with poorer outcomes. The addition of obinutuzumab in the AVO arm appeared to overcome the adverse impact of unmutated IGHV, allowing these patients to achieve outcomes comparable to those with mutated IGHV, Brown explained.^1,2

In addition to PFS, rates of uMRD further highlighted the efficacy of the regimens. At the end of treatment, 45% of patients in the AV arm and 95% in the AVO arm achieved uMRD, compared to 72.9% in the chemoimmunotherapy group. These findings suggest that AVO may offer deeper responses, potentially attributable to the synergistic effects of obinutuzumab with acalabrutinib and venetoclax. However, the AV regimen also provided clinically meaningful responses, establishing it as a viable all-oral treatment option for treatment-naive CLL.^1,2

Overall survival, while not the primary focus of this interim analysis, showed promising trends in favor of AV and AVO, according to Brown. In the primary analysis, OS was significantly improved with AV compared to chemoimmunotherapy. When adjusted to censor deaths related to COVID-19, OS benefits were observed for both AV and AVO. Notably, Brown explained that the study was conducted during the height of the COVID-19 pandemic, and pandemic-related complications accounted for a notable proportion of deaths across all treatment arms, with 10 COVID-related deaths in the AV arm, 25 in AVO, and 21 in chemoimmunotherapy.^1,2

Safety was another critical focus of the AMPLIFY trial, particularly given concerns about cardiac toxicity associated with first-generation BTKis, such as ibrutinib, according to Brown. Acalabrutinib, a second-generation BTKi, was selected in the trial for its improved safety and tolerability. The most common grade 3 or higher adverse event (AE) across all arms was neutropenia, reported in 26.8% of patients in the AV arm, 35.2% in AVO, and 32.4% in chemoimmunotherapy. Serious AEs occurred in 24.7% of AV patients, 38.4% in AVO, and 27.4% in the chemoimmunotherapy group. While the overall incidence of cardiac events was higher in the AV and AVO arms (9.3% in AV and 12% in AVO) compared to chemoimmunotherapy (3.5%), the rates of atrial fibrillation were very low at 0.7% for AV, 2.1% for AVO, and 0.8% for chemoimmunotherapy. Hypertension, another known AE of BTKis, was similarly infrequent, occurring in 4% of patients in the acalabrutinib-containing arms and 2.7% in the chemoimmunotherapy arm.^1,2

The findings from AMPLIFY show the potential of fixed-duration regimens in combination with venetoclax with second-generation BTKis to redefine the standard of care for treatment-naive CLL, according to Brown. AV offers the first all-oral, fixed-duration regimen, making it a convenient and effective option, particularly for patients seeking alternatives to long-term therapy. Meanwhile, the addition of obinutuzumab in AVO provides deeper responses and may be especially beneficial for high-risk subgroups such as those with unmutated IGHV. These findings have important implications for clinical practice, particularly as the oncology community continues to move toward more patient-centered approaches that balance efficacy with quality of life.¹

“AMPLIFY provides the first phase 3 evidence of fixed-duration therapy with a combination of venetoclax and a second-generation BTKi in patients with treatment-naive CLL,” Brown said during the ASH presentation. “This interim analysis of AMPLIFY with a median follow up of 40.8 months in fit patients with treatment-naive CLL demonstrated a significantly improved PFS with fixed-duration AV and AVO compared to chemoimmunotherapy, including in the unmutated IGHV subgroup. Rates of uMRD were highest in the AVO arm, and OS was prolonged with AV compared to chemoimmunotherapy. In the primary analysis, with both AV and AVO compared to chemoimmunotherapy, after censoring COVID-19 deaths, both AV and AVO had tolerable safety profiles with a low incidence of cardiac AEs typically associated with BTKis, including atrial fibrillation or hypertension.”¹

REFERENCES

1. Brown JR. Diagnosing and Treating Blood Cancers and “Almost Cancers.” Presented at: 66th ASH Annual Meeting and Exposition; San Diego, California; December 7-10, 2024.

2. Brown JR, Seymour JF, Jurczak W, et al. 1009 Fixed-Duration Acalabrutinib Plus Venetoclax with or without Obinutuzumab Versus Chemoimmunotherapy for First-Line Treatment of Chronic Lymphocytic Leukemia: Interim Analysis of the Multicenter, Open-Label, Randomized, Phase 3 AMPLIFY Trial. 2024. Accessed December 7, 2024. https://ash.confex.com/ash/2024/webprogram/Paper200701.html