AMPLIFY Redefines CLL Care: Adam Kittai, MD

On February 20, the FDA approved the first all-oral combination regimen for chronic lymphocytic leukemia (CLL): acalabrutinib (Calquence; AstraZeneca) and venetoclax (Venclexta; AbbVie). Adam Kittai, MD, NYU Langone Health; director, CLL Program, Perlmutter Cancer Center; and director, Lymphoma Program, Perlmutter Cancer Center - Long Island, here discusses results from the phase 3 AMPLIFY trial (NCT03836261) that led to this approval.

The study compared acalabrutinib plus venetoclax (AV), acalabrutinib plus venetoclax plus obinutuzumab (AVO), and investigator’s choice chemoimmunotherapy, either fludarabine/cyclophosphamide/rituximab (FCR) or bendamustine/rituximab (BR). Patients in the AV arm received 2 cycles of acalabrutinib lead-in followed by 12 cycles of combination therapy. The AVO arm added obinutuzumab beginning in cycle 2 for 6 cycles. Importantly, patients with del(17p) or TP53 mutations were excluded because these high‑risk groups are known to respond poorly to chemoimmunotherapy. The median age was 61, younger than typical CLL trials, due to the inclusion of chemoimmunotherapy.

AMPLIFY findings demonstrated that time-limited AV improved progression-free survival and overall survival compared with chemoimmunotherapy. However, the study did not compare AV or AVO with continuous BTK inhibitor therapy or with venetoclax plus obinutuzumab, leaving unanswered questions about relative positioning among modern frontline options. Kittai emphasizes that this marks the first FDA‑approved all-oral, time-limited regimen for CLL in the US. Although the GLOW study (NCT03462719) also evaluated ibrutinib plus venetoclax, it did not receive FDA approval.

Regarding patient selection, Kittai would consider AV for individuals with favorable‑risk disease. Because TP53-aberrant patients were excluded, continuous BTK inhibition remains preferred for that group. He also notes that patients with CLL and IGHV-unmutated status had worse-than-expected outcomes with AV, prompting caution. Still, for patients who strongly prefer time‑limited therapy and want to avoid infusions, he would consider AV even in higher‑risk cases after discussing potential limitations.

Overall, AMPLIFY expands the treatment landscape by offering a new, convenient, fixed‑duration oral option for appropriate patients.