AbbVie has submitted a supplemental new drug application to the US FDA for a fixed-duration, all-oral combination regimen of venetoclax (Venclexta) and acalabrutinib (Calquence) for patients with previously untreated chronic lymphocytic leukemia (CLL).1 This submission represents a significant step toward providing a new chemotherapy-free, time-limited treatment option for a patient population in need of effective and tolerable regimens. The application is supported by compelling positive results from the phase 3 AMPLIFY trial (NCT03836261).
“This FDA submission marks a milestone for CLL treatment with the potential approval for the first oral combination regimen of [venetoclax] and acalabrutinib for previously untreated patients with chronic blood cancer. This new fixed-treatment duration approach could allow patients the opportunity for time off treatment, if approved, and be potentially practice-changing in frontline CLL care,” said Svetlana Kobina, vice president, global medical affairs, oncology, AbbVie, in a press release.
The AMPLIFY study is a pivotal, global, multi-center phase 3 trial that rigorously evaluated the efficacy and safety of venetoclax plus acalabrutinib, alone or combined with obinutuzumab (Gazyva), against standard chemoimmunotherapy in patients with previously untreated CLL.2 Notably, the trial focused on patients without a 17p deletion or TP53 mutation, aiming to assess the combination’s utility in a broader, common CLL subset.
Data presented at the 2024 American Society of Hematology (ASH) Annual Meeting highlighted the superiority of the fixed-duration venetoclax and acalabrutinib regimen.1 This combination significantly reduced the risk of disease progression or death by 35% when compared with traditional chemoimmunotherapy approaches. These findings underscore the potential for this all-oral, finite-duration therapy to redefine first-line treatment paradigms for CLL.
Histologic image of chronic lymphoblastic leukemia (CLL) cells
The safety profile observed with the venetoclax and acalabrutinib combination regimen was largely consistent with the known safety profiles of each individual therapy. Common adverse events reported in the trial included neutropenia, hemorrhage, and COVID-19 infection. Among these, neutropenia was the most frequently observed grade 3 or higher adverse event. Importantly, the combination therapy demonstrated low rates of tumor lysis syndrome, a critical safety consideration for BCL-2 inhibitors like venetoclax, further affirming its manageable safety profile within a structured treatment protocol.
Venetoclax, developed by AbbVie and Roche and jointly commercialized by AbbVie and Genentech in the US, is a first-in-class agent that selectively binds and inhibits the BCL-2 protein and helps restore the process of apoptosis in cancer cells, thereby directly addressing the underlying pathology of CLL. It is currently approved in over 80 countries for treating adults with CLL or small lymphocytic lymphoma and in combination with other drugs for newly diagnosed acute myeloid leukemia in certain adult patients.
Acalabrutinib (Calquence), a BTK inhibitor, works through a different mechanism, inhibiting the BTK protein crucial for B-cell development and survival. The synergistic action of BCL-2 inhibition and BTK inhibition offers a comprehensive approach to targeting CLL cells and is hypothesized to contribute to the observed efficacy in the AMPLIFY trial.
The potential FDA approval of this venetoclax and acalabrutinib combination could offer a new, highly effective, and finite-duration oral treatment alternative, reducing the reliance on continuous therapy or traditional chemotherapy. This aligns with the evolving treatment landscape in CLL, which increasingly favors targeted, time-limited regimens that aim to minimize long-term toxicity and improve quality of life for patients.