Among patients with previously untreated chronic lymphocytic leukaemia (CLL), those who received a combination regimen of the oral medications acalabrutinib and venetoclax had significantly better survival without their cancer getting worse and experienced fewer serious adverse events than patients who received one of two standard multidrug treatment regimens for CLL. Patients who also received a third agent, obinutuzumab, had even better survival free of disease progression, but also experienced a higher rate of serious adverse events.

“The study met its primary endpoint, demonstrating superior progression-free survival (PFS) for the acalabrutinib-venetoclax combination regimen compared with standard therapy, said principal investigator Jennifer R. Brown, MD, PhD, director of the CLL Center at Dana-Farber Cancer Institute and the Worthington and Margaret Collette Professor of Medicine in the field of Hematologic Oncology at Harvard Medical School in Boston. “Findings were similar when obinutuzumab was added to the two oral agents, and both regimens had manageable safety profiles.”

The acalabrutinib-venetoclax combination offers the first fixed-duration regimen consisting of all oral agents for patients with previously untreated CLL that is expected to be approved in the U.S., Dr. Brown explained. “It’s a simple regimen that will be easier for patients to take,” she said.

CLL is a cancer that starts in the blood-forming cells of the bone marrow. It is the most common form of leukaemia in adults in the United States, with around 19,000 new cases diagnosed annually, mostly in people aged 65 or older. It is more common in men than in women. Roughly half of patients with CLL carry mutations in a gene from a family of genes known as IgHV; in these patients, the cancer tends to grow more slowly and, with treatment, can go into remission for many years. In patients with unmutated IgHV, the cancer is more aggressive and tends to relapse more quickly after treatment.

Treatment regimens for CLL have included acalabrutinib and a slightly older drug, ibrutinib, which are in a class known as BTK inhibitors, and venetoclax, which is in a class known as BCL2 inhibitors, said Dr. Brown. However, the BTK inhibitors usually need to be taken indefinitely, which can lead to an accumulation of adverse effects, she said. Venetoclax is often combined with obinutuzumab, which is given as an infusion, a regimen that can be burdensome for patients, as it involves more clinic visits, Dr. Brown said.

This study, known as AMPLIFY, tested the effectiveness of combining the BTK inhibitor acalabrutinib with the BCL2 inhibitor venetoclax, and adding obinutuzumab to the two oral medications, in patients with previously untreated CLL. The randomised phase III clinical trial was conducted in 27 countries.

A total of 867 patients (median age 61, 64.5% male) were randomly assigned to one of three study arms. Patients in Arm A received acalabrutinib and venetoclax (AV); in Arm B, acalabrutinib, venetoclax, and obinutuzumab (AVO); and in Arm C, the control arm, one of two combination regimens chosen by their doctor: fludarabine, cyclophosphamide, and rituximab (FCR) or bendamustine and rituximab (BR).

Around 60% of patients enrolled in the trial had unmutated IgHV. Patients with the highest risk CLL, in which a gene called TP53 is mutated or deleted, were not enrolled in the AMPLIFY trial because this form of the disease usually does not respond to the chemotherapy used in the control arm of the trial, Dr. Brown said.

PFS, the primary endpoint, was defined as the elapsed time from random assignment to worsening of the cancer among patients in Arm A (AV) compared with those in Arm C. Disease progression was assessed by an independent review committee using internationally accepted criteria. Secondary endpoints included PFS in Arm B (AVO) versus Arm C. All patients were treated for 14 months or until their cancer showed signs of worsening.

After a median follow-up period of 41 months, both the AV and AVO regimens showed a statistically significant improvement in PFS compared with the control regimen of FCR or BR. Dr. Brown and her colleagues estimated that 76.8% of patients who received AV and 83.1% of those who received AVO were free of disease progression at three years, compared with 66.5% of patients who received FCR or BR.

Serious adverse events occurred in 24.7% of patients who received AV, 38.4% of those who received AVO, and 27.4% of those who received FCR or BR. A low white blood cell count was the most common serious adverse event across all three treatment arms. The trial was carried out during the COVID-19 pandemic and a total of 56 patients (10 in the AV group, 25 in the AVO group, and 21 in the control group) died of COVID complications.

“The addition of obinutuzumab to acalabrutinib and venetoclax improved efficacy but also led to more adverse effects and more COVID deaths,” Dr. Brown said. “Our next steps will include trying to better understand which patients get the most benefit from adding obinutuzumab and what factors lead to some patients relapsing sooner.”

A limitation of the study is that FCR and BR, the combination regimens used to treat patients assigned to the control group, which were considered to be the standard of care for initial treatment of CLL when the AMPLIFY trial began in 2019, are no longer considered standard of care in the U.S. This is a common challenge for clinical trials, Dr. Brown said, as standards of care can evolve quickly whereas it usually takes several years to obtain results from a large clinical trial. She noted that although FCR has higher rates of adverse effects than some other therapies, it remains a highly effective treatment option that is widely used around the world and can be curative in a subset of patients.

Source: ASH