(Update) Acalabrutinib in CLL and MCL

Editor’s Note: This Spotlight article was originally posted about a year after acalabrutinib (Calquence) was approved by the U.S. Food and Drug Administration (FDA). Since that time, several key clinical trials have been reported (eg, AMPLIFY, ECHO) that have resulted in expanded indications and recommendations. This update summarizes those data and reviews the newer indications. For observations about clinical use, adverse effects, and management of patients being considered for or receiving acalabrutinib, please click on this link to the original Spotlight.

Commentary by Jeremy S. Abramson, MD, MMSc, CLL/MCL Site Editor for JNCCN 360

Director, Jon and Jo Ann Hagler Center for Lymphoma, Massachusetts General Hospital; Associate Professor of Medicine, Harvard Medical School, Boston

Acalabrutinib is a second-generation covalent Bruton tyrosine kinase (BTK) inhibitor that now plays a prominent role in the treatment of patients with chronic lymphocytic lymphoma (CLL) and mantle cell lymphoma (MCL). Emerging data across indications have led to acalabrutinib being preferred over the first-generation BTK inhibitor ibrutinib due to a more favorable safety profile, particularly in terms of reducing cardiac adverse events. Today, acalabrutinib should be considered as monotherapy or in combination with venetoclax and/or obinutuzumab in CLL. In MCL, acalabrutinib may be combined with rituximab or bendamustine/rituximab as initial treatment (induction therapy) for transplant-ineligible patients or as monotherapy in the relapsed or refractory setting. Ongoing trials will expand and refine future indications for acalabrutinib in CLL and MCL.

Acalabrutinib (Calquence) was approved by the FDA in 2017 for the treatment of adults with MCL who had received at least one prior therapy.¹ Its approval was extended in 2019 to include adults with treatment-naive or relapsed/refractory CLL or small lymphocytic lymphoma (SLL).² Acalabrutinib, a second-generation BTK inhibitor, targets the B-cell receptor signaling pathway.

Despite its efficacy, treatment with continuous acalabrutinib monotherapy presents several challenges, including persistent treatment-related toxicities, development of treatment resistance, necessity for long-term adherence, and elevated costs associated with continuous therapy.³ These challenges have prompted ongoing research efforts focused on the development of novel treatment strategies that aim to mitigate these issues while sustaining or enhancing clinical efficacy. Of note, several clinical trials are exploring combination therapies as an alternative approach to enhance therapeutic outcomes.

The AMPLIFY trial assessed the clinical utility of a fixed-duration treatment with venetoclax and acalabrutinib alone (AV) or AV in combination with obinutuzumab (AVO) in comparison to the investigator’s choice of chemoimmunotherapy in patients with treatment-naive with CLL.⁴ The trial demonstrated that fixed-duration treatment with both regimens (AV and AVO) significantly improved progression-free survival, with deep and durable clinical responses. Moreover, these regimens exhibited manageable safety profiles, highlighting their potential as first-line therapeutic options for patients with treatment-naive CLL. Furthermore, the AVO regimen also has demonstrated clinical efficacy in a separate trial for patients with treatment-naive, high-risk CLL with TP53 aberrations.³ These findings reinforce its potential in addressing high-risk disease subgroups.

A significant improvement in progression-free survival was similarly observed in patients with treatment-naive MCL treated with a combination regimen of acalabrutinib, bendamustine, and rituximab, as demonstrated in the ECHO trial.⁵ This combination resulted in clinical responses without the emergence of additional treatment-related toxicities, thereby highlighting its clinical efficacy and favorable safety profile. These findings underscore the therapeutic benefit of acalabrutinib in the management of patients with high-risk MCL, particularly when combined with bendamustine and rituximab or as continuous monotherapy.

On January 16, 2025, based on the results of the ECHO trial, the FDA granted approval for the use of acalabrutinib in combination with bendamustine and rituximab for the treatment of adults with previously untreated MCL.⁶ This approval is specifically intended for patients who are deemed ineligible for autologous hematopoietic cell transplantation. The recommended dosing schedule for this combination regimen is 100 mg of acalabrutinib administered every 12 hours, continuing until evidence of disease progression or the occurrence of unacceptable treatment-related toxicity.

Evaluating Potential Resistance Mechanisms to Acalabrutinib

Given the critical role of acalabrutinib therapy for managing MCL, CLL, and SLL, the identification of predictive biomarkers capable of determining which patients are at risk of developing treatment resistance is of paramount importance. Mutations in BTK and in PLCG2 are known mechanisms for resistance to covalent BTK inhibitors. Recent studies have identified CD49d and CD79b as additional biomarkers, with increased surface expression correlating with disease progression in patients receiving acalabrutinib.⁷ Furthermore, emerging evidence suggests a potential association between acalabrutinib resistance and the upregulation of key oncogenes, including MYC, LAG3, and MCL1, as well as integrin alpha-4 expression. Additional investigative efforts evaluating these potential biomarkers are warranted.

References

1. U.S. Food and Drug Administration. FDA grants accelerated approval to acalabrutinib for mantle cell lymphoma. January 16, 2025. Available at https://fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-acalabrutinib-mantle-cell-lymphoma. Accessed February 15, 2025.
2. U.S. Food and Drug Administration. Project Orbis: FDA approves acalabrutinib for CLL and SLL. November 21, 2019. Available at https://fda.gov/drugs/resources-information-approved-drugs/project-orbis-fda-approves-acalabrutinib-cll-and-sll. Accessed February 15, 2025.
3. Davids MS, Ryan CE, Lampson BL, et al. Phase II study of acalabrutinib, venetoclax, and obinutuzumab in a treatment-naive chronic lymphocytic leukemia population enriched for high-risk disease. J Clin Oncol 2025;43:788–799.
4. Brown JR, Seymour JF, Jurczak W, et al. 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. 2024 ASH Annual Meeting & Exposition. Abstract 1009.
5. Dreyling M, Mayer J, Belada D, et al. High-risk subgroups and MRD: An updated analysis of the phase 3 ECHO trial of acalabrutinib with bendamustine/rituximab in previously untreated mantle cell lymphoma. 2024 ASH Annual Meeting & Exposition. Abstract 1626.
6. U.S. Food and Drug Administration. FDA approves acalabrutinib with bendamustine and rituximab for previously untreated mantle cell lymphoma. January 16, 2025. Available at https://fda.gov/drugs/resources-information-approved-drugs/fda-approves-acalabrutinib-bendamustine-and-rituximab-previously-untreated-mantle-cell-lymphoma. Accessed February 27, 2025.
7. Bibikova E, Parsa S, Floren M, et al. Molecular profiling identifies CD49d and CD79b as predictive markers for acquired acalabrutinib resistance in patients with chronic lymphocytic leukemia. Hematol Oncol 2025;43:e70008.