A Potential Game-Changer in CLL
- A fixed-duration combination of Calquence (acalabrutinib), a next-generation Bruton’s tyrosine kinase (BTK) inhibitor, plus Venetoclax, a potent BCL-2 inhibitor has the potential to reshape the frontline management of CLL, offering healthcare providers critical insights into an emerging therapeutic paradigm.
- Promising results showed 77% of patients on fixed-duration Calquence plus Venetoclax remained progression-free.
- This data can alleviate psychological, financial, and logistical burdens associated with prolonged therapies in patients diagnosed with CLL.
Thanks to the novel targeted therapies, patients with chronic lymphocytic leukemia (CLL) have had the opportunity to thrive with better treatment outcomes. The optimal first-line regimens—particularly fixed-duration approaches that deliver deep remissions with limited therapy exposure—remain an area of ongoing investigation. The AMPLIFY phase III trial was designed to determine whether a fixed-duration combination of Calquence (acalabrutinib), a next-generation Bruton’s tyrosine kinase (BTK) inhibitor, plus Venetoclax, a potent BCL-2 inhibitor, could outperform standard-of-care (SOC) therapies in previously untreated CLL.
It is a randomized, multi-center, open-label, controlled trial, sponsored by AstraZeneca, in collaboration with global investigators. The phase III designation signifies that the regimen had shown promise in earlier-phase trials (Phase I/II) and that the study’s aim was to confirm its efficacy and safety on a larger scale, potentially moving toward regulatory approval and standard-of-care status if successful.
Dr. Ann LaCasce, Director of Hematology/Oncology at Dana-Farber Cancer Institute, tells SurvivorNet Connect that data coming out of the trial marks exciting progress for patients.
“This data is both exciting and practice changing,” Dr. LaCasce says. “Time-limited therapy is appealing for patient quality of life and to prevent the emergence of resistant disease. In addition, the efficacy of acalabrutinib plus venetoclax is excellent with high rates of undetectable minimal residual disease (MRD).”
Patients were randomized in a 1:1:1 fashion among three parallel study arms: Calquence plus venetoclax, Calquence plus venetoclax with obinutuzumab for a fixed duration or standard-of-care chemoimmunotherapy.
Enrollment and Duration:
–Patient Population: Adults with previously untreated CLL in need of therapy, without del(17p) or TP53 mutations (based on the trial’s inclusion criteria). These genetic factors were excluded to focus on a population that typically receives standard frontline regimens.
–Enrollment Period: The recruitment began in early 2019 and involved multiple international sites. A broad enrollment window allowed for a diverse patient population reflective of global clinical practice.
–Sample Size: Approximately 780 patients, a substantial cohort to detect clinically meaningful differences in primary and secondary endpoints.
The primary endpoint was to demonstrate whether fixed-duration Calquence plus Venetoclax could extend the time patients remained free from disease progression or death compared to standard therapies.
Detailed Results and Clinical Findings
The initial data release, announced in a 2024 AstraZeneca press release, showed:
Primary Endpoint (PFS)
At 36 months, 77% of patients on fixed-duration Calquence plus Venetoclax remained progression-free. This contrasted favorably against:
1. 63.7% PFS in the Calquence-based SOC arm
2. 58.4% PFS in the chemoimunotherapy arm
These results highlight the superiority of the fixed-duration strategy in controlling disease for at least three years.
Risk Reduction
The combination therapy reduced the risk of disease progression or death by approximately 42% when compared to chemoimmunotherapy and by around 31% when compared to the Calquence-based standard therapy.
Minimal Residual Disease – Negativity
Achieving undetectable MRD is indicative of a deep and durable remission. By the end of treatment (EOT):
1. 55.5% of patients on the fixed-duration combination achieved MRD negativity, suggesting a strong depth of response.
2. The MRD negativity rate with chemoimunotherapy was significantly lower at 16.3%.
3. The Calquence-based SOC arm also demonstrated a high MRD negativity rate (53.8%), but still slightly lower than the combination arm.
Safety Profile
While detailed adverse event data are awaited for full publication, the available information suggests a manageable toxicity profile consistent with the known tolerability of Calquence and Venetoclax. Interestingly, the fixed-duration approach limits long-term exposure, potentially reducing cumulative toxicities over time.
Clinical Implications and Potential Practice Changes
If these results are sustained and validated in longer follow-up and peer-reviewed publications, the Amplify Phase III trial could prompt a shift in first-line CLL therapy, including:
Redefining Standard of Care
The demonstrated superiority in PFS, combined with high MRD negativity and a fixed treatment duration, may position Calquence plus Venetoclax as a new first-line standard for patients with previously untreated CLL.
Reduced Treatment Burden
Unlike continuous therapy paradigms, a fixed-duration approach enables patients to achieve meaningful remissions without indefinite treatment. This can alleviate psychological, financial, and logistical burdens associated with prolonged therapies.
Improved Patient Selection
Patients fitting the trial’s inclusion profile—i.e., those without high-risk del(17p)/TP53 aberrations and suitable for targeted therapy—could especially benefit. Clinicians may use this data to support treatment decisions, balancing short-term intensity against the prospect of time-limited yet highly effective therapy.
Potential for Deeper Remissions and Long-Term Survival Gains
Elevated MRD negativity rates may translate into more durable disease control and possibly enhance overall survival outcomes. A cleaner remission (low MRD) often correlates with longer periods free from progression, potentially deferring the need for subsequent lines of therapy.
Who Stands to Benefit the Most?
- Newly Diagnosed CLL Patients Needing Therapy: Those who are treatment-naive and meet standard eligibility criteria for targeted agents.
- Patients Wishing to Avoid Continuous Therapy: Individuals preferring a set course of treatment rather than prolonged indefinite therapy.
- Intermediate-Risk Groups: Patients who do not carry the highest-risk genetic features but still require effective therapy could achieve long-term disease control and improved quality of life.