Drug Update · Hematology

FDA Approves Acalabrutinib + Venetoclax for CLL/SLL: PFS HR 0.65 in AMPLIFY

August 17, 2026

Approval date

02/19/2026

Indication

Adults with CLL or SLL previously untreated without del(17p) or TP53 mutation

Trial

AMPLIFY (NCT03836261)

Primary result

Hazard ratio 0.65; 95% CI: 0.49-0.87

Median PFS (AV arm)

Not estimable (NE) (95% CI: 51.1, NE)

Median PFS (FCR/BR arm)

47.6 months (95% CI: 43.3, NE)

Clinical Perspective

This approval affects hematologists, oncologists, and advanced practice providers managing adults with previously untreated CLL or SLL without del(17p) or TP53 mutation. The AMPLIFY data support use of acalabrutinib plus venetoclax over investigator’s choice chemotherapy (FCR or BR) for progression-free survival benefit in that defined population (HR 0.65; 95% CI: 0.49-0.87) ^[1]. How acalabrutinib plus venetoclax will compare with other targeted combinations in front-line care for long-term overall survival and comparative toxicity profiles remains an open question?

Dr. Shruti Pandey, MBBS, MD (General Medicine), DM (Clinical Haematology) · Hematology

The FDA approved acalabrutinib (Calquence) tablets and capsules in combination with venetoclax (Venclexta) for adults with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) on February 19, 2026 based on the AMPLIFY randomized trial. AMPLIFY showed a progression-free survival benefit for acalabrutinib plus venetoclax versus investigator’s choice chemotherapy (fludarabine plus cyclophosphamide plus rituximab [FCR] or bendamustine plus rituximab [BR]) (Hazard ratio 0.65; 95% CI: 0.49-0.87) ^[1].

Clinical Context

The FDA approval covers adults with CLL or SLL previously untreated for CLL without del(17p) or TP53 mutation and is based on the multicenter AMPLIFY trial ^[1]. The approval registers a fixed-duration combination regimen in which patients received 4 cycles of acalabrutinib and 12 cycles of venetoclax starting at cycle 3; each cycle was 28 days in the trial program described by the FDA ^[1]. The recommended acalabrutinib dose is 100 mg orally approximately every 12 hours until disease progression, unacceptable toxicity, or completion of 14 cycles of treatment, and venetoclax is initiated with a 5-week ramp-up to a recommended dose of 400 mg orally once daily until disease progression, unacceptable toxicity, or until the last day of Cycle 14, per the FDA announcement ^[1]. Clinicians should consult current prescribing information for full dosing guidance. The approval was granted with orphan drug designation noted in the FDA review summary ^[1].

Key Findings

The AMPLIFY randomized, multicenter trial in adult patients previously untreated for CLL without del(17p) or TP53 mutation showed that acalabrutinib plus venetoclax reduced the risk of progression or death versus investigator’s choice chemotherapy (FCR or BR) with a Hazard ratio 0.65; 95% CI: 0.49-0.87 (p=0.0038) ^[1].
Median duration of PFS follow-up was 42.6 months; median PFS was not estimable (NE) (95% CI: 51.1, NE) in the acalabrutinib plus venetoclax arm and 47.6 months (95% CI: 43.3, NE) in the FCR/BR arm ^[1].
With a median follow-up of 41.0 months, there were 18 (6%) deaths in the acalabrutinib plus venetoclax arm and 42 (14%) deaths in the FCR/BR arm as reported in the FDA summary ^[1].

Safety & Tolerability

The FDA summary cites the acalabrutinib prescribing information and lists warnings and precautions for: serious and opportunistic infections; hemorrhage; cytopenias; second primary malignancies; cardiac arrhythmias; and hepatotoxicity ^[1]. Safety details specifically for venetoclax were referenced as included in the venetoclax prescribing information in the FDA announcement but were not enumerated in the provided excerpt ^[1].

Study Design

AMPLIFY (NCT03836261) was a randomized, multicenter trial in adult patients previously untreated for CLL without del(17p) or TP53 mutation; patients were randomized to receive acalabrutinib plus venetoclax or investigator’s choice of chemotherapy (FCR or BR) with PFS assessed by independent review committee as the major efficacy outcome measure ^[1]. The median duration of PFS follow-up was 42.6 months and the median follow-up for deaths reported was 41.0 months ^[1]. Recommended dosing per the FDA announcement is acalabrutinib 100 mg orally approximately every 12 hours and venetoclax ramped to 400 mg orally once daily for the specified treatment duration in the approval document ^[1]. Clinicians should consult current prescribing information for complete dosing guidance.

FAQ

Q1 What is acalabrutinib (Calquence) approved for?

A1 The FDA approved acalabrutinib (Calquence) tablets and capsules in combination with venetoclax (Venclexta) for adults with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) on February 19, 2026. The approval applies to adults previously untreated for CLL without del(17p) or TP53 mutation and is based on results from the AMPLIFY randomized multicenter trial comparing acalabrutinib plus venetoclax with investigator’s choice chemotherapy (FCR or BR).

Q2 How does acalabrutinib (Calquence) work?

A2 Information was not available in the provided source excerpts.

Q3 What is the recommended dose of acalabrutinib (Calquence) in the approved combination?

A3 The FDA announcement states the recommended acalabrutinib dose is 100 mg taken orally approximately every 12 hours until disease progression, unacceptable toxicity, or completion of 14 cycles of treatment when used in combination with venetoclax. Venetoclax should be started at 20 mg following the 5-week ramp-up dosing schedule in its prescribing information, with a recommended venetoclax dose of 400 mg orally once daily after ramp-up until disease progression, unacceptable toxicity, or until the last day of Cycle 14.

Q4 What are the most common side effects of acalabrutinib (Calquence) plus venetoclax?

A4 The acalabrutinib prescribing information cited in the FDA announcement includes warnings and precautions for serious and opportunistic infections, hemorrhage, cytopenias, second primary malignancies, cardiac arrhythmias, and hepatotoxicity. The FDA summary references the venetoclax prescribing information as well but the provided excerpt did not enumerate venetoclax-specific adverse events. Clinicians should consult current prescribing information for complete dosing guidance.

Clinicians should consult current prescribing information for complete dosing guidance.

References

FDA — FDA approves acalabrutinib with venetoclax for chronic lymphocytic...

FDA Approves Acalabrutinib + Venetoclax for CLL/SLL: PFS HR 0.65 in AMPLIFY

Direct Clinical Takeaway & Evidence Summary

FDA Approves Acalabrutinib + Venetoclax for CLL/SLL: PFS HR 0.65 in AMPLIFY

Clinical Perspective

Clinical Context

Key Findings

Safety & Tolerability

Study Design

FAQ

References

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