FDA Approves First-Line Acalabrutinib Plus Venetoclax for CLL/SLL

The FDA has approved the combination of acalabrutinib (Calquence) and venetoclax (Venclexta) for the treatment of adult patients with chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL).¹

This regulatory decision was supported by findings from the phase 3 AMPLIFY trial (NCT03836261), which showed that at a median follow-up of 40.8 months (range, 0-59), acalabrutinib plus venetoclax (n = 291) elicited an estimated 3-year progression-free survival (PFS) rate of 76.5% (95% CI, 71.0%-81.1%) vs 66.5% (95% CI, 59.8%-72.3%) with standard-of-care (SOC) chemoimmunotherapy (n = 290), which was investigator’s choice of fludarabine plus cyclophosphamide and rituximab (Rituxan), or bendamustine plus rituximab (HR, 0.65; 95% CI, 0.49-0.87; P = .004).² The median PFS was not reached with acalabrutinib plus venetoclax compared with 47.6 months with SOC.^1,2

“The continuous regimens frequently used to [manage] CLL often come with [adverse] effects [AEs] that may become burdensome to patients over time,” Jennifer Brown, MD, PhD, director of the CLL Center of the Division of Hematologic Malignancies at Dana-Farber Cancer Institute in Boston, Massachusetts, the Worthington and Margaret Collette Professor of Medicine at Harvard Medical School, and principal investigator of the AMPLIFY trial, stated in a news release.¹ “The US approval of the [acalabrutinib] combination offers patients an all-oral, 14-month, fixed-duration treatment option that is highly effective and well tolerated, and gives physicians greater flexibility to tailor treatment plans for individual patient needs and goals.”

The safety and tolerability of acalabrutinib in AMPLIFY were deemed consistent with the known safety profile of the agent, and trial investigators saw no new safety signals, according to the news release.

“Managing an incurable blood cancer that progresses slowly can often feel indefinite and overwhelming,” Gwen Nichols, MD, chief medical officer of Blood Cancer United, added in the news release. “We welcome new treatment options that may ease the burden, restore a sense of control, and offer renewed hope for those navigating life with CLL.”

What was the design of the AMPLIFY study?

This global, multicenter, open-label trial enrolled adult patients with previously untreated CLL that did not harbor 17p deletions or TP53 mutations. Patients were randomly assigned 1:1:1 to receive acalabrutinib plus venetoclax, acalabrutinib plus venetoclax and fixed-duration obinutuzumab (Gazyva; n = 286), or SOC chemoimmunotherapy. Acalabrutinib was administered for a fixed duration of 14 28-day cycles. Patients in the SOC arm received treatment for 6 cycles.

The primary end point was PFS in the acalabrutinib/venetoclax arm. PFS in the acalabrutinib/venetoclax/obinutuzumab arm was a key secondary end point. Other secondary end points were overall survival (OS) and undetectable minimal residual disease (MRD) status.

What additional findings were seen in AMPLIFY?

The estimated 36-month OS rate was 94.1% (95% CI, 90.7%-96.3%) with acalabrutinib plus venetoclax vs 85.9% (95% CI, 81.0%-89.6%) with SOC.²

The rates of undetectable MRD levels in peripheral blood by flow cytometry at a sensitivity of 10^–4 in the intention-to-treat population favored the SOC arm, at 51.0% with acalabrutinib plus venetoclax vs 26.8% with SOC (HR, 0.5; 95% CI, 0.4-0.7; P < .001). However, among evaluable patients, the rates of undetectable MRD levels at end of treatment (EOT) and 3 months after EOT were 45.0% and 38.0%, respectively, in the acalabrutinib/venetoclax arm vs 72.9% and 77.9%, respectively, in the SOC arm.

The most common grade 3 or higher AEs of clinical interest in the acalabrutinib/venetoclax arm were cardiac events (1.7%), atrial fibrillation or flutter (0.3%), hypertension (2.7%), hemorrhage (1.0%), neutropenia (32.3%), infection (12.4%), second primary cancer (1.7%), and tumor lysis syndrome (0.3%).

Today’s approval delivers the first all-oral, fixed-duration BTK inhibitor-based regimen in the US for the [management] of CLL,” Dave Fredrickson, executive vice president of the Oncology Haematology Business Unit at AstraZeneca, added in the news release.¹ “This [acalabrutinib] combination has the potential to meaningfully change first-line CLL treatment decisions and underscores our commitment to improving on the current SOC for people living with blood cancers.”

References

1. Calquence plus venetoclax approved in the US as first all-oral, fixed-duration combination for patients with chronic lymphocytic leukaemia in the 1st-line setting. News release. AstraZeneca. February 20, 2026. Accessed February 20, 2026. https://www.astrazeneca.com/media-centre/press-releases/2026/fixed-duration-calquence-combo-approved-in-us.html
2. Brown JR, Seymour JF, Jurczak W, et al. Fixed-duration acalabrutinib combinations in untreated chronic lymphocytic leukemia. N Engl J Med. 2025;392(8):748-762. doi:10.1056/NEJMoa2409804