The FDA has approved oral acalabrutinib (Calquence, AstraZeneca) in combination with venetoclax (Venclexta, AbbVie and Genentech) for the first-line treatment of adults with chronic lymphocytic leukemia (CLL), including small lymphocytic lymphoma.

The acalabrutinib and venetoclax (AV) treatment combination is “the first all-oral, fixed-duration regimen designed to provide patients with the potential to experience time off treatment,” according to a Genentech statement.

CLL is one of the most common forms of leukemia in adults, the company noted, adding that outcomes have improved in recent years, but “patients often face long treatment durations and ongoing disease management challenges,” Genentech noted.

“Fixed-duration regimens are a critical component of today’s chronic lymphocytic leukemia management,” John M. Burke, MD, a hematologist/oncologist specializing in CLL at Rocky Mountain Cancer Centers, Aurora, Colorado, stated in the Genentech press release. “Having an all-oral option with a defined end date can provide patients with a clear and predictable treatment timeline. This approval provides an important new option for eligible patients to achieve durable responses in the first line.”

The FDA approval was based on findings from the global, open-label, phase 3 AMPLIFY study showing improved safety and progression-free survival (PFS) for patients receiving AV with or without obinutuzumab (Gazyva, Genentech) vs investigator’s choice of chemotherapy, the FDA said in a approval announcement. 

In AMPLIFY, previously untreated adults with CLL without del(17p) or TP53 mutation were randomized 1:1:1 to receive AV, AV plus obinutuzumab for a fixed duration, or investigator’s choice of fludarabine plus cyclophosphamide plus rituximab or bendamustine plus rituximab.

Patients in the AV arms were treated for 14 28-day cycles. Chemoimmunotherapy was administered for six cycles.

At median follow-up of 42.6 months, median PFS was not estimable among patients in the AV arms vs 47.6 months in chemotherapy arm (hazard ratio [HR], 0.65). At a median follow-up of 41.0 months, there were 18 (6%) vs 42 (14%) deaths in the arms, respectively.

Acalabrutinib and venetoclax are each approved separately for CLL as monotherapy and in combination with other agents. Acalabrutinib is also approved for mantle cell lymphoma. 

The safety profile of AV was consistent with the known safety profile for each agent alone. Adverse reactions occurring in at least 20% of patients were neutropenia, headache, diarrhea, musculoskeletal pain, and COVID-19. Serious adverse reactions occurring in at least 2% of patients receiving AV were COVID-19, including COVID-19 pneumonia (9%), second primary malignancies (2.7%), and neutropenia (2.1%) 

Acalabrutinib prescribing information includes warnings and precautions for serious and opportunistic infections, hemorrhage, cytopenias, second primary malignancies, cardiac arrythmias, and hepatotoxicity, and venetoclax prescribing information includes warnings and precautions for tumor lysis syndrome, neutropenia, infections, and embryo-fetal toxicity, the FDA noted. 

The recommended regimen for AV consists of up to 14 28-day cycles of acalabrutinib and 12 cycles of venetoclax starting at cycle 3. The recommended acalabrutinib dose is 100 mg approximately every 12 hours until disease progression, unacceptable toxicity, or completion of 14 cycles. Venetoclax should be started at 20 mg according to the 5-week ramp-up dosing schedule in the prescribing information, followed by 400 mg once daily until disease progression, unacceptable toxicity, or until the last day of cycle 14. 

Full prescribing information for acalabrutinib and venetoclax will be posted on Drugs@FDA. 

Sharon Worcester, MA, is an award-winning medical journalist based in Birmingham, Alabama, writing for Medscape, MDedge and other affiliate sites. She currently covers oncology, but she has also written on a variety of other medical specialties and healthcare topics. She can be reached at sworcester@mdedge.com or on X: @SW_MedReporter.