About 3–6% of cases of non-Hodgkin lymphoma (NHL) are mantle cell lymphoma (MCL), an uncommon and usually aggressive type that is frequently detected at a late stage. Globally, the estimated number of individuals living with MCL is around 27,500. The current focus in MCL treatment is on the increasing role of BTK inhibitors and the potential of immunotherapy. Chimeric antigen receptor (CAR) T cells are registered for relapsed MCL, particularly for patients who have failed BTK inhibitor therapy, but the field continues to evolve. Aggressive first-line therapies for MCL can yield durable responses and prolonged progression-free survival (PFS), but are often unsuitable for elderly or unfit patients due to poor tolerability. The SHINE study demonstrated that adding the Bruton tyrosine kinase (BTK) inhibitor ibrutinib to chemoimmunotherapy (bendamustine + rituximab) for first-line MCL treatment prolongs Progression-free survival (PFS), but it negatively impacts overall survival due to excess toxicity.

CALQUENCE (acalabrutinib) is another next-generation, selective inhibitor of BTK that binds covalently to BTK, thereby inhibiting its activity. The drug initially received accelerated approval based on overall response rate in the US in October 2017 for the treatment of adult patients with MCL who have received at least one prior therapy, and later in August 2022 received full approval for the same. Although, now AstraZeneca has been investigating CALQUENCE for earlier use in treatment. However, it is important to note that CALQUENCE is not yet approved for MCL treatment in Japan or the EU.

Results from the Phase III ECHO trial, evaluating the combination of acalabrutinib with bendamustine and rituximab in elderly patients with previously untreated MCL were unrevealed during the EHA 2024 Congress. 

Findings revealed that the CALQUENCE combination regimen reduced the risk of disease progression or death by 27% compared to standard chemoimmunotherapy. Median Progression-free survival (PFS) was 66.4 months for patients treated with the CALQUENCE combination, versus 49.6 months with standard chemoimmunotherapy. The secondary endpoint of overall survival showed a favorable trend for the CALQUENCE combination, further supporting its clinical benefit. However, the overall survival (OS) data were not mature at the time of analysis, and the trial will continue to assess OS as a key secondary endpoint.

The ECHO trial, which enrolled patients during the pandemic, conducted a pre-specified analysis censoring COVID-19-related deaths to assess impact. PFS was further improved in both arms, with the CALQUENCE combination reducing the risk of disease progression or death by 36%. Median PFS was not reached among patients treated with the CALQUENCE combination, compared to 61.6 months for standard chemoimmunotherapy. A favorable OS trend was also observed for the CALQUENCE combination in this analysis.

The safety and tolerability of CALQUENCE were consistent with its known safety profile, with no new safety signals identified. Grade 3 or higher adverse events (AEs) from any cause occurred in 88.9% of patients treated with the CALQUENCE combination, including Grade 3 or higher atrial fibrillation in 3.7% of patients, Grade 3 or higher hypertension in 5.4%, Grade 3 or higher major bleeding in 2.0%, and Grade 3 or higher infections in 41.1%. Serious AEs and Grade 5 events were balanced across arms (69% vs. 62% and 12.1% vs. 10.1%, respectively). AEs leading to discontinuation were observed in 10.4% of patients for the CALQUENCE combination. The trial also reported AEs related to COVID-19, including Grade 5 events.

KOL insights

“For people living with mantle cell lymphoma, a typically aggressive form of non-Hodgkin's lymphoma, the ECHO results offer promise of a new, effective treatment option for adults older than 65, who represent the majority of MCL patients. The improved progression-free survival seen in patients treated with the CALQUENCE combination compared to chemoimmunotherapy demonstrate its potential to change the standard of care as the only BTK inhibitor in this first-line setting.” – MD, United States

Conclusion 

BTK inhibitors are approved in diseases such as MCL, chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL), marginal zone lymphoma (MZL), Waldenström's macroglobulinemia (WM), chronic graft versus host disease (GvHD), and follicular lymphoma (FL). Four BTK inhibitors that have been authorized in the US so far are ibrutinib (IMBRUVICA) by Abbvie/J&J, acalabrutinib (CALQUENCE) by AstraZeneca, zanubritinib (BRUKINSA) by BeiGene, and pirtobrutinib (JAYPIRCA) by Eli Lilly. In terms of treatment strategies, there is some variation in registration status, particularly with BTK inhibitors. In Europe, ibrutinib is the only approved BTK inhibitor for MCL. However, in the US, ibrutinib was voluntarily withdrawn from the market for relapsed MCL in 2023 by AbbVie. In the US, the second-generation BTK inhibitors acalabrutinib and zanubrutinib are available.

Prior approval for CALQUENCE in MCL was granted in second-line and above settings. Rituximab plus bendamustine (BR) therapy is the first-line standard of care for MCL. Roughly 43% of trial participants in the ECHO study discontinued CALQUENCE as a result of treatment emergent adverse events (TEAEs).  Due to AEs, roughly 40% of patients in the ibrutinib + BR group in the SHINE study discontinued treatment. This shows that adding CALQUENCE did not provide a toxicity profile that was preferable to adding ibrutinib.

At present, CALQUENCE stands out as the first and only BTK inhibitor to demonstrate a favorable OS trend compared in previously untreated patients with MCL. The trial data indicate significant progress in improving outcomes for MCL patients, with statistically significant and clinically meaningful improvements in PFS and a favorable overall survival trend. Therefore, CALQUENCE combined with chemoimmunotherapy is expected to become an important new treatment option for patients with this disease.