FDA Approval of Acalabrutinib Plus Venetoclax as Initial Therapy for CLL: A New Option but Questions Remain

By Dr. John Burke
CLL Society Medical Advisory Board Member and Hematologist/ Medical Oncologist
Rocky Mountain Cancer Centers
Aurora, CO 

As anyone who has followed trends in chronic lymphocytic leukemia (CLL) knows, the treatment options for patients with this disease have evolved greatly over the past two decades. When I started my career in the early 2000s, we had learned that adding immunotherapy in the form of the anti-CD20 antibody rituximab was providing value beyond that of chemotherapy alone. In the most recent decade, we have learned that use of drugs inhibiting Bruton tyrosine kinase (BTK) – specifically ibrutinib, acalabrutinib, and zanubrutinib – and one inhibiting BCL2 – venetoclax – lead to better outcomes than conventional chemotherapy.

For the past five years or so, when I have educated patients with CLL as they approach a need to start their first therapy, I have told them that there are two main options to treat their CLL: 1) continuous therapy with a BTK inhibitor (occasionally, but not usually, given with an anti-CD20 antibody) and 2) fixed-duration therapy for one year with the BCL2 inhibitor venetoclax plus the anti-CD20 antibody obinutuzumab. Both treatments lead to excellent outcomes, so the factors impacting patients’ decisions include, not so much efficacy, but the different durations of therapy, the need for intravenously administered infusions, and the different toxicity profiles of the regimens. Indeed, the results of the CLL17 trial, which were presented at the 2025 annual meeting of the American Society of Hematology (ASH), confirmed that, at least with the relatively short follow-up of about 3 years, outcomes with the two options are similar.

A third option has been tested in several different trials but, until now, had never achieved approval by the U.S. Food and Drug Administration (FDA). That option is the all-oral combination of a BTK inhibitor and venetoclax. Trials called CAPTIVATE, GLOW, an MD Anderson study, and most recently CLL17 have investigated the combination of ibrutinib plus venetoclax. In fact, the regulatory agency in Europe – called the European Commission – approved this combination in 2022. However, around that same time, safety concerns with ibrutinib were emerging – in particular concerns about cardiovascular risks. In the U.S., there was a shift toward increasing usage of the “second-generation” BTK inhibitors acalabrutinib and zanubrutinib, largely because of their lower cardiovascular risks, so the ibrutinib-venetoclax combination was never FDA approved and never got nearly as much usage in the U.S. as it did in other countries.

The AMPLIFY trial, first presented at the 2024 ASH annual meeting and published simultaneously in the New England Journal of Medicine, was the first to compare the combination of the BTK inhibitor acalabrutinib and venetoclax with other regimens.¹ In AMPLIFY, 867 patients with previously untreated CLL were randomly assigned to receive one of 3 treatments: acalabrutinib-venetoclax (AV), acalabrutinib-venetoclax-obinutuzumab (AVO), or chemoimmunotherapy. Compared with chemoimmunotherapy, AV improved both progression-free and overall survival. While AVO had the highest rate of progression-free survival, more deaths from infectious complications occurred in the AVO arm, so the best overall survival results occurred in the AV group. Of note, the trial was conducted during the COVID-19 pandemic, which clearly influenced the results. Based on AMPLIFY, on February 19, 2026, the FDA approved the AV combination. FDA approval for the triplet AVO was not sought, although some experts argue that AVO is reasonable to use in some patients. The duration of AV treatment is 14 months because the schedule requires 2 months of lead-in therapy with acalabrutinib followed by 12 months of the AV combination.

How has the FDA approval of AV changed the treatment landscape? For one, it has added a third option for patients who need to start therapy for CLL. In some ways, the option appears attractive: all-oral (no intravenous infusions required), less chair time in the physician office or hospital, and only 14 months of therapy as opposed to indefinite therapy with single-agent BTK inhibitors. In addition, in the CLL17 trial, the combination of ibrutinib-venetoclax had a lower rate of fatal infections than did venetoclax-obinutuzumab, so perhaps the same would be true of AV. However, there are some potential downsides to AV that patients should consider. First, all covalent BTK inhibitors – in this case acalabrutinib – pose at least some risk of cardiovascular events like atrial fibrillation and bleeding; that risk could be minimized by use of the venetoclax-obinutuzumab. Second, it appears that the depth of remission as determined by measurements of “minimal residual disease” (MRD) may be less with AV than with venetoclax-obinutuzumab; in AMPLIFY, the rate of undetectable MRD with AV measured 3 months after the end of treatment was 29.9%; with IV in CLL17 it was 47.2%, and with venetoclax-obinutuzumab in CLL17 it was 73.3%. Whether those differences in rates of undetectable MRD translate to meaningful differences in lifespan is unknown, and more may be learned from ongoing comparative trials like one called MAJIC, in which venetoclax-obinutuzumab is being compared directly with AV.

Other important questions remain. Is 14 months the best duration of AV therapy, or should treatment be extended, as was done with ibrutinib-venetoclax in the FLAIR trial, which led to the best results we have ever seen in CLL? If one year is not the best duration, should we treat patients for 2-3 years, or should we use MRD assessments to determine treatment duration? Is acalabrutinib the “best” BTK inhibitor to combine with venetoclax? Or are there drug interactions or other effects that lead to ibrutinib or zanubrutinib or pirtobrutinib being a better partner for venetoclax? Will the novel BCL2 inhibitor sonrotoclax prove to be a better partner for BTK inhibitors than venetoclax? Should the AVO triplet be used, and was the adverse effect of COVID-19 on the outcomes in the AMPLIFY trial a fluke that will not be repeated if there is not another pandemic?

Thus, there are still many unanswered questions in CLL for which we need well designed clinical trials and patients with the courage and opportunity to enroll on them. Progress is being made, and outcomes continue to get better. The choices are good ones to have.

References

1. Brown JR, Seymour JF, Jurczak W, et al. Fixed-duration acalabrutinib combinations in untreated chronic lymphocytic leukemia. N Engl J Med 2025;392:748-762.