A combination of the oral drugs acalabrutinib and venetoclax may be more effective at improving progression-free survival and minimizing serious adverse events in patients with previously untreated chronic lymphocytic leukemia (CLL) compared with one of two standard multidrug treatment regimens, according to recet findings presented by Brown et al at the 2024 American Society of Hematology (ASH) Annual Meeting & Exposition (Abstract 1009).
Background
CLL is the most common type of leukemia in U.S. adults, with around 19,000 new diagnoses per year in mostly patients aged 65 and older. The disease is more prevalent among male patients compared with female patients. Roughly 50% of those with CLL carry mutations in a gene from the IgHV gene family. In these patients, cancer cells tend to grow more slowly, and with treatment, tend to go into remission for many years. However, patients with unmutated IgHV, the malignancy is typically more aggressive and can relapse more quickly after treatment.
Treatment regimens for CLL have included acalabrutinib and ibrutinib, which are Bruton's tyrosine kinase (BTK) inhibitors, and venetoclax, a BCL2 inhibitor. Nonetheless, BTK inhibitors need to be taken indefinitely, leading to an accumulation of adverse effects. Venetoclax is often combined with obinutuzumab, a drug often administered as an infusion. The combination regimen can be burdensome in many patients, since it involves more visits to the clinic.
Study Methods and Results
In the phase III AMPLIFY trial, researchers randomly assigned 867 patients with previously untreated CLL across 27 countries to receive either acalabrutinib plus venetoclax (arm A), acalabrutinib plus venetoclax with obinutuzumab (arm B), or one of two combination regimens selected by their physicians: fludarabine, cyclophosphamide, and rituximab or bendamustine and rituximab (arm C). The patients had a median age of 61 years, and 64.5% of them identified as male.
About 60% of the patients who participated in the trial had unmutated IgHV. The patients with the highest risk CLL, who had TP53-mutated or -deleted disease, were not enrolled in the trial, because this type of the disease is known not to respond to the chemotherapy used in the control arm of the trial. The primary endpoint, progression-free survival, was defined as the elapsed time from random assignment to worsening of the cancer among patients who received acalabrutinib plus venetoclax compared with those who received the combination regimens. Disease progression was assessed by an independent review committee using internationally accepted criteria. Secondary endpoints included progression-free survival in arm B vs arm C. All patients were treated for 14 months or until their cancer showed signs of worsening.
After a median follow-up of 41 months, both patients who received acalabrutinib plus venetoclax and acalabrutinib plus venetoclax with obinutuzumab showed a statistically significant improvement in progression-free survival compared with those who received either fludarabine, cyclophosphamide, and rituximab or bendamustine and rituximab. The researchers determined that 76.8% of the patients in arm A and 83.1% of those in arm B experienced progression-free survival after 3 years compared with 66.5% of the patients in arm C. The researchers found that patients who received obinutuzumab experienced better progression-free survival but reported a higher rate of serious adverse events.
“The study met its primary endpoint, demonstrating superior progression-free survival for the acalabrutinib/venetoclax combination regimen compared with standard therapy,” detailed lead study author Jennifer R. Brown, MD, PhD, the Worthington and Margaret Collette Professor of Medicine in the Department of Hematologic Oncology at Harvard Medical School and Director of the CLL Center at Dana-Farber Cancer Institute. “Findings were similar when obinutuzumab was added to the two oral agents, and both regimens had manageable safety profiles,” she continued.
Serious adverse events occurred in 24.7% of patients in arm A, 38.4% of those in arm B, and 27.4% of those in arm C. A low white blood cell count was found to be the most common serious adverse event across all three treatment arms. The trial was performed during the COVID-19 pandemic, and a total of 56 patients (10 in arm A, 25 in arm B, and 21 in arm C) died of COVID-19–related complications.
Conclusions
The researchers explained that the acalabrutinib/venetoclax combination may offer a fixed-duration regimen consisting of all oral agents in patients with previously untreated CLL. The treatment is expected to be approved in the United States.
“It’s a simple regimen that will be easier for patients to take,” Dr. Brown highlighted. “The addition of obinutuzumab to acalabrutinib and venetoclax improved efficacy but also led to more adverse effects and more COVID-[19–related] deaths. 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,” she underscored.
A study limitation included that fludarabine, cyclophosphamide, and rituximab as well as bendamustine and rituximab—regimens that were considered to be the standard of care for the initial treatment of CLL when the AMPLIFY trial began in 2019—are no longer considered the standard of care in the United States. The researchers noted that this is a common challenge for clinical trials, since the standards of care can evolve quickly, whereas results from a large clinical trial may take several years to obtain. She noted that although the fludarabine, cyclophosphamide, and rituximab regimen has higher rates of adverse effects compared with some other therapies, it remains a highly effective treatment option that is used globally and can be curative in a subset of patients.
“It’s very encouraging to see advances being made across the continuum of care for [hematologic malignancies],” underlined Surbhi Sidana, MD, Associate Professor of Medicine at Stanford University. “In this [study], investigators are focused on … identifying promising new treatment approaches for patients for whom existing options fall short,” she concluded.
Disclosure: The research in this study was funded by AstraZeneca. For full disclosures of the study authors, visit ash.confex.com.
