A Fixed-Duration Regimen for CLL: Acalabrutinib + Venetoclax Results from the AMPLIFY Trial

For patients newly diagnosed with chronic lymphocytic leukemia (CLL), current therapies, including BTK inhibitors and combinations with venetoclax, are highly effective and have significantly improved outcomes. However, some regimens have limitations in either efficacy or safety. The AMPLIFY study evaluates venetoclax in combination with a BTK inhibitor versus chemoimmunotherapy. At ASH 2024, Dr. Jennifer Brown presented the press briefing for the results. 

Understanding the AMPLIFY Trial

AMPLIFY is a phase 3 ongoing clinical trial that investigates a fixed-duration regimen using acalabrutinib and venetoclax (AV), with or without obinutuzumab (AVO), (all oral therapies), in patients with CLL who have never received prior treatments. This trial compared these combinations to the current chemoimmunotherapy options; fludarabine-cyclophosphamide-rituximab or bendamustine-rituximab. 

The study aimed to assess whether these innovative combinations could improve progression-free survival, response rates, and other critical outcomes in patients who were otherwise healthy enough to tolerate intense therapies.

What is a Fixed-Duration Regimen? 

It is a term designated to treatments that are administered for a limited amount of time to reduce the side effects or prevent that treatment from working. Recent studies have shown that this type of administration is effective for CLL patients. 

How Was the Regimen Administered? 

The participants were randomized into three groups: 

1. Acalabrutinib and venetoclax (AV) received the therapy for 14 cycles
2. Acalabrutinib and venetoclax with obinutuzumab (AVO) for 14 cycles 
3. Chemoimmunotherapy: fludarabine-cyclophosphamide-rituximab or bendamustine-rituximab for 6 cycles

For the experimental arms sing AV and AVO, acalabrutinib was given 100mg (cycles 1-14), venetoclax 400mg (cycles 3-14) and obinutuzumab 1000 mg (cycles 2-7). Each cycle was 28 days. 

What Are the AMPLIFY Study Results? 

At the time of analysis, the AMPLIFY trial enrolled 867 patients, and the results were highly promising:

• Superior Progression-Free Survival (PFS): Both combinations of acalabrutinib with venetoclax, with or without obinutuzumab, showed significant improvement in delaying disease progression compared to chemoimmunotherapy. Median progression-free survival was not yet reached for the experimental arms, compared to 47.6 months in the control group.

  • The estimated progression-free survival (PFS) was 36-month:
    • 76.5% of the group who took acalabrutinib and venetoclax
    • 83.1% for acalabrutinib, venetoclax, and obinutuzumab
    • And 66.5% for the group with chemoimmunotherapy
  • Additionally, the progression free survival improved regardless of mutational status for acalabrutinib+venetoclax (AV), and AV+obinutuzumab (AVO) 

• Higher Response Rates: The overall response rates were 92.8% for AV and 92.7% for AVO, significantly higher than the 75.2% achieved with chemoimmunotherapy.

• Survival Trends: Compared to the control group, acalabrutinib and venetoclax showed a trend toward improved overall survival.

Neutropenia (low counts of neutrophils in blood) was the most common side effect, seen in about 27% of patients on acalabrutinib and venetoclax, 35% when obinutuzumab was added, and 32% in the chemoimmunotherapy group. Importantly, this new approach has proven to be safe as rates of complications like tumor lysis syndrome were very low in the experimental arms.

What This Means for Patients

The AMPLIFY phase III trial introduces a groundbreaking all-oral, fixed-duration combination of acalabrutinib and venetoclax, representing a new standard for patients newly diagnosed with CLL. This regimen offers key benefits such as:

• Convenience: Oral therapy reduces the need for frequent hospital visits.
• Efficacy: Prolonged progression-free survival means more time without disease progression.
• Safety: Manageable side effects and lower risks of severe complications.

For patients, this means a potentially transformative treatment option, allowing for a shorter duration of therapy with lasting benefits.

The Road Ahead

The AMPLIFY study highlights the effectiveness of combining second-generation therapies and sets the stage for further innovations. Future research will refine these regimens and explore their application in broader patient groups, including those with high-risk genetics.

These findings bring hope for improved care for people diagnosed with CLL, empowering patients and their care teams with advanced tools to manage their condition effectively and safely.

If you want to remain updated with more CLL news on conferences and more, don't miss HealthTree University, where we'll feature interviews with CLL specialists, asking them about the latest on treatments, patient-centered care, and more! 

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Sources: 

• Fixed-duration Calquence plus venetoclax, with or without obinutuzumab, significantly improved progression-free survival in 1st-line chronic lymphocytic leukaemia in AMPLIFY Phase III trial
• Fixed-Duration Acalabrutinib Plus Venetoclax with or without Obinutuzumab Versus Chemoimmunotherapy for First-Line Treatment of Chronic Lymphocytic Leukemia: Interim Analysis of the Multicenter, Open-Label, Randomized, Phase 3 Amplify Trial