Acalabrutinib Approval Offers Time-Limited Approach in CLL/SLL

In a conversation with CancerNetwork^® at the Columbia University Irving Cancer Research Center, Nicole Lamanna, MD, highlighted the implications of the FDA approving fixed-duration acalabrutinib (Calquence) plus venetoclax (Venclexta) for patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL).¹ She spoke in the context of findings from the phase 3 AMPLIFY trial (NCT03836261) assessing acalabrutinib/venetoclax with or without obinutuzumab (Gazyva; AVO) vs standard chemoimmunotherapy in this patient population.²

Lamanna, an associate clinical professor of medicine in the Hematologic Malignancies Section of the Hematology/Oncology Division at Columbia University Irving Medical Center, began by detailing considerations for determining candidates for AVO triplet therapy or acalabrutinib/venetoclax doublet therapy. She noted that the FDA’s recent decision offers the first approved all-oral regimen for CLL, which may offer less toxicity compared with other therapeutic options. Additionally, she described how findings from the AMPLIFY trial demonstrated some differences in outcomes with acalabrutinib/venetoclax and AVO triplet therapy among patients with and without IGHV mutations, which may raise questions regarding future clinical trials in the space.

Transcript:

When we think about who might be appropriate for a triplet combination, we have to think about the age of our patients, their comorbidities, and which subset of [patients with] CLL might benefit from a triplet to have the additional toxicity that the triplet offers. We still need work on the triplets and future trials, but with the doublet, at least this gives the first FDA-approval [option] of having this oral/oral combination [of acalabrutinib/venetoclax], which will be great for patients. They have yet another choice for a time-limited approach. Instead of oral/intravenous, they can do oral/oral [treatment]. This is with acalabrutinib, which is a second-generation BTK inhibitor. One of the advantages is there’s less toxicity. In Europe, they had already approved oral/oral [therapy] with ibrutinib [Imbruvica] and venetoclax.³ We did not do that here in the US because we were looking to do this with one of the second-generation [agents] because of decreased toxicity compared to ibrutinib. Now, we finally have that. This was already on our NCCN guidelines for [patients with] CLL, but now we fully have an FDA approval.

In the future, the other aspect I would comment on is there was a bit of a difference in patients who [had] unmutated vs mutated [disease]. We also need to think about trials where we can look at these combinations and see what might be better for the unmutated group, because the triplet looked better in terms of the PFS compared with the mutated [population] with the oral/oral [therapy] vs AVO. The AVO, the triplet, was better for unmutated [disease]. Again, this is that caveat of who should we be looking forward to in future clinical trials to look at triplets vs doublets. Should we look at higher-risk patient populations? Our patients [with mutated disease] do well, so their options can be oral/oral continuous therapy, depending on patient preference. In general, this is a nice study, which finally [gave] us the approval that everybody was looking for: an oral/oral doublet.

References

1. CALQUENCE® plus venetoclax approved in the US as first all-oral, fixed-duration combination for patients with chronic lymphocytic leukemia in the 1st-line setting. News release. AstraZeneca. February 20, 2026. Accessed March 12, 2026. https://tinyurl.com/38zbx96s
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
3. European Commission approves IMBRUVICA® (ibrutinib) in a fixed-duration combination regimen for adult patients with previously untreated chronic lymphocytic leukaemia (CLL). News release. The Janssen Pharmaceutical Companies of Johnson & Johnson. August 4, 2022. Accessed March 12, 2026. https://tinyurl.com/yeyny4st