Trial Results Show Potential of Combination Therapy for Chronic Lymphocytic Leukemia

Acalabrutinib (Calquence; AstraZeneca) plus venetoclax (Vemclexta; AbbVie Inc), with or without obinutuzumab (Gazyva; Genentech), showed optimal safety and efficacy in first line chronic lymphocytic leukemia (CLL) treatment in the phase 3 AMPLIFY trial (NCT03836261). The data revealed a meaningful improvement in progression-free survival (PFS) and overall survival (OS) compared with standard of care chemoimmunotherapy.¹

The data indicated that acalabrutinib plus venetoclax, with or without Obinutuzumab, showed statistically significant improvements on PFS. Image Credit: © Matan - stock.adobe.com

CLL is the most common low-grade B-cell leukemia in the US and Europe, affecting about 4.9 per 100,000 patients annually. It is a slow-growing malignancy characterized by the proliferation of mature but immunologically dysfunctional B lymphocytes in the blood, bone marrow, and lymph nodes. This results in swelling of the lymph nodes, weakness or fatigue, anemia, infection, and bleeding. Bruton tyrosine kinase (BTK) inhibitors are a crucial treatment pathway for patients with CLL and demonstrate improved efficacy, safety, and tolerability. They work by disrupting B-cell receptor signaling pathways to interfere with the abnormal growth of malignant cells. Acalabrutinib is a second-generation, orally administered BTK inhibitor that has been approved in the US since 2019.^2-4

AMPLIFY, a randomized, global, multi-center, open-label phase 3 trial, investigated acalabrutinib plus venetoclax, with or without obinutuzumab, for the treatment of patients with previously untreated CLL without del(17p) or TP53 mutation. To evaluate the safety and efficacy, patients were randomized to receive either acalabrutinib in combination with venetoclax or acalabrutinib in combination with venetoclax and obinutuzumab for a fixed duration or standard of care chemoimmunotherapy.^5,6

PFS, assessed by an Independent Review Committee, served as the trial’s primary end point for the acalabrutinib plus venetoclax arm. Secondary end points included OS, overall response rate, duration of response, and time to next treatment.^5,6

The data indicated that acalabrutinib plus venetoclax, with or without Obinutuzumab, showed statistically significant improvements on PFS. The researchers also observed a favorable trend in OS; however, the OS data were not mature, and AMPLIFY will continue to evaluate this as a key secondary end point. Additionally, the safety and tolerability profile was consistent with the known safety profiles of each agent, with low rates of cardiac toxicity observed.^5,6

“The AMPLIFY results demonstrate the potential of acalabrutinib and venetoclax with or without obinutuzumab to be effective and well-tolerated, fixed-duration treatment options for patients with chronic lymphocytic leukemia,” said Jennifer R. Brown, MD, PhD, director of the CLL Center of the Division of Hematologic Malignancies, Dana-Farber Cancer Institute, the Worthington and Margaret Collette Professor of Medicine at Harvard Medical School, and principal investigator of the trial, in a press release. “This is an important advance in this setting as fixed-duration regimens allow those living with this chronic disease to take breaks from their treatment, thereby decreasing the possibility of long-term adverse events and drug resistance and improving quality of life.”⁵

References

1. ClinicalTrials.gov. study of acalabrutinib (acp-196) in combination with venetoclax (abt-199), with and without obinutuzumab (ga101) versus chemoimmunotherapy for previously untreated cll (amplify). May 29, 2024. Accessed August 5, 2024. https://clinicaltrials.gov/study/NCT03836261 

2. Long-term follow-up of ibrutinib in cll/sll: insights and outcomes. Pharmacy Times. July 1, 2024. Accessed August 5, 2024. https://www.pharmacytimes.com/view/long-term-follow-up-of-ibrutinib-in-cll-sll-insights-and-outcomes

3. Chronic lymphocytic leukemia treatment (pdq®)–patient version. National Cancer Institute. January 19, 2024. Accessed August 5, 2024. https://www.cancer.gov/types/leukemia/patient/cll-treatment-pdq#:~:text=and%20treatment%20options.-,Chronic%20lymphocytic%20leukemia%20(CLL)%20is%20a%20type%20of%20cancer%20in,that%20usually%20gets%20worse%20slowly. 

4. Calquence approved in the US for adult patients with chronic lymphocytic leukaemia. AstraZeneca. November 21, 2019. Accessed August 5, 2024. https://www.astrazeneca.com/media-centre/press-releases/2019/calquence-approved-in-the-us-for-adult-patients-with-chronic-lymphocytic-leukaemia-21112019.html#!

5. Fixed-duration calquence® (acalabrutinib) plus venetoclax, with or without obinutuzumab, significantly improved progression-free survival in 1st-line chronic lymphocytic leukemia in amplify phase III trial. AstraZeneca. July 29, 2024. Accessed August 5, 2024. https://www.astrazeneca-us.com/media/press-releases/2024/fixed-duration-calquence-acalabrutinib-plus-venetoclax-with-or-without-obinutuzumab-significantly-improved-progression-free-survival-in-first-line-chronic-lymphocytic-leukemia-in-amplify-phase-iii-trial.html

6. Fixed-duration acalabrutinib/venetoclax yields pfs benefit vs soc in frontline cll. OncLive. July 29, 2024. Accessed August 5, 2024. https://www.onclive.com/view/fixed-duration-acalabrutinib-venetoclax-yields-pfs-benefit-vs-soc-in-frontline-cll