AbbVie Submits sNDA to FDA for Venclexta-Acalabrutinib Combo in Frontline CLL

AbbVie has submitted a supplemental New Drug Application (sNDA) to the FDA for the approval of Venclexta (venetoclax) in combination with acalabrutinib in previously untreated patients with chronic lymphocytic leukemia (CLL).¹

AMPLIFY study supports time-limited oral combination

The submission is supported by positive data from the Phase III AMPLIFY clinical trial (NCT03836261). In the study, the combination regimen of Venclexta and acalabrutinib improved progression-free survival (PFS) compared to standard chemoimmunotherapy in previously untreated patients with CLL.

In a press release, Svetlana Kobina, vice president, global medical affairs, oncology, AbbVie, said: "This FDA submission marks a milestone for CLL treatment with the potential approval for the first oral combination regimen of Venclexta 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.”

Efficacy and safety profile of the new combination

Detailed data from the AMPLIFY study were shared at the 2024 American Society of Hematology Annual Meeting.

• Results from AMPLIFY demonstrated that a fixed-duration combination of Venclexta and acalabrutinib reduced the risk of disease progression or death by 35% compared to chemoimmunotherapy (HR 0.65; 95% CI: 0.49–0.87; p=0.004).
• The safety profile of the combination was consistent with the known profiles of each agent when used individually.
• Common adverse events of any grade included neutropenia, bleeding, and COVID-19 infection.
• Grade 3 or higher neutropenia was reported in 26.8% of patients receiving the combination treatment.
• Tumor lysis syndrome occurred infrequently, with any-grade events seen in just 0.3% of patients on the Venclexta–acalabrutinib regimen versus 3.1% in the chemoimmunotherapy group.
• No new safety concerns emerged in the AMPLIFY study.

Interim AMPLIFY findings

An interim analysis of AMPLIFY was published in The New England Journal of Medicine (NEJM) earlier in February. The multicenter, open-label trial randomized a total of 867 patients 1:1:1 across three arms: 291 were assigned to receive acalabrutinib plus venetoclax, 286 acalabrutinib-venetoclax–obinutuzumab, and 290 chemoimmunotherapy.²

“In this interim analysis of the AMPLIFY trial in fit patients with previously untreated CLL, fixed-duration acalabrutinib–venetoclax (with or without obinutuzumab) significantly prolonged progression-free survival as compared with chemoimmunotherapy,” the study authors wrote. “Results for progression-free survival suggest that the benefit of adding obinutuzumab to acalabrutinib–venetoclax was most apparent in the subgroup with unmutated IGHV (immunoglobulin heavy-chain variable region), which had results that were similar to those in the subgroup with mutated IGHV.”

CLL14 trial underpinned previous Venclexta approval

Venclexta’s latest FDA approval in the CLL space came in May 2019 when it was cleared as part of a combination regimen alongside Gazyva (obinutuzumab). This approval was based on data from the prospective, multicenter, open-label, randomized Phase III CLL14 trial (NCT02242942), which showed that patients who received the regimen of Venclexta and Gazyva achieved superior PFS compared to those who received chlorambucil plus obinutuzumab.³

• After a median follow-up of 28 months, treatment with Venclexta plus obinutuzumab reduced the risk of disease progression or death by 67% compared to the combination of chlorambucil and obinutuzumab (HR 0.33; 95% CI: 0.22–0.51; p<0.0001).
• The combination of Venclexta and obinutuzumab also led to significantly higher rates of minimal residual disease (MRD) negativity, a secondary endpoint indicating deep remission.
• Three months post-treatment, MRD negativity in bone marrow was achieved in 57% of patients receiving Venclexta plus obinutuzumab versus 17% in the chlorambucil group (p<0.0001).
• In peripheral blood, MRD negativity was seen in 76% of patients in the Venclexta arm, compared to 35% with chlorambucil plus obinutuzumab (p<0.0001).

References

1. AbbVie Submits for U.S. FDA Approval of Combination Treatment of VENCLEXTA® (venetoclax) and Acalabrutinib for Previously Untreated Patients with Chronic Lymphocytic Leukemia (CLL). News release. AbbVie. July 29, 2025. Accessed July 29, 2025. https://news.abbvie.com/2025-07-29-AbbVie-Submits-for-U-S-FDA-Approval-of-Combination-Treatment-of-VENCLEXTA-R-venetoclax-and-Acalabrutinib-for-Previously-Untreated-Patients-with-Chronic-Lymphocytic-Leukemia-CLL

2. Jennifer R. Brown, MD, et al., Fixed-Duration Acalabrutinib Combinations in Untreated Chronic Lymphocytic Leukemia. New England Journal of Medicine. https://www.nejm.org/doi/full/10.1056/NEJMoa2409804. (2025)

3. AbbVie Announces US FDA Approval of VENCLEXTA® (venetoclax) as a Chemotherapy-Free Combination Regimen for Previously Untreated Chronic Lymphocytic Leukemia Patients. News release. AbbVie. May 15, 2019. Accessed July 29, 2025. https://news.abbvie.com/2019-05-15-AbbVie-Announces-US-FDA-Approval-of-VENCLEXTA-R-venetoclax-as-a-Chemotherapy-Free-Combination-Regimen-for-Previously-Untreated-Chronic-Lymphocytic-Leukemia-Patients