The addition of the relatively well-tolerated BTK inhibitor acalabrutinib (Calquence) to bendamustine plus rituximab (Rituxan; BR) significantly improved progression-free survival (PFS) and complete response (CR) rates vs BR alone in patients with mantle cell lymphoma (MCL), with the greatest benefit observed in those with high-risk disease, according to Martin Dreyling, MD, PhD.
Updated data from the phase 3 ECHO trial (NCT02972840) presented at the 2025 EHA Congress showed that patients in the high-risk population who received acalabrutinib plus BR (n = 187) achieved an overall response rate of 89.8% (95% CI, 84.9%-93.6%) and a CR rate of 67.9%.1 These respective rates were 84.7% (95% CI, 78.9%-89.4%) and 47.5% in the population of patients who received placebo plus BR (n = 183). Additionally, the median PFS was 49.5 months (95% CI, 35.6-not evaluable) in the acalabrutinib arm vs 36.0 months (95% CI, 26.9-50.1) in the placebo arm (unstratified HR, 0.74; 95% CI, 0.55-0.99; P = .0432).
“For older patients, which are the vast majority of patients [with MCL], now we have the option to treat with an on-label [regimen of a] BTK inhibitor plus chemotherapy,” Dreyling said in an interview with OncLive®.
In January 2025, the FDA approved acalabrutinib plus BR for the treatment of adult patients with previously untreated MCL who are ineligible for autologous hematopoietic stem cell transplantation, based on prior data from ECHO.2
In the interview, Dreyling discussed the rationale for the ECHO trial; how the ECHO efficacy findings fit into the context of the larger MCL research paradigm, which includes the phase 3 TRIANGLE (NCT02858258) and phase 2 ENRICH (NCT01880567) trials; and the role of BTK inhibition in the first-line treatment of younger patients with MCL.
Dreyling is a full professor in the Department of Medicine and head of the Medical Clinic III at University Hospital/Ludwig-Maximilians-University Munich in Germany.
OncLive: What was the rationale for conducting the ECHO trial of BR with or without acalabrutinib in patients with previously untreated, high-risk MCL?
Dreyling: In younger patients, at least in the past, we were pushing for dose intensification. However, the TRIANGLE trial has shown that we can achieve incredible benefit by adding a BTK inhibitor to this still rather intensive chemotherapy. However, that does not help most patients, because [patients with MCL have a] median age of approximately 70 years.
In patients [approximately 70 years of age, there are typically] some age-related comorbidities, and we can’t use such an intensified approach. In these patients, the standard of care [SOC] is BR, mostly based on tolerability. Therefore, the control arm [of ECHO] was BR plus rituximab maintenance. That was compared with the addition of the second-generation BTK inhibitor acalabrutinib. [We wanted to know]: What was the difference concerning efficacy? They’re comparable [regimens], but acalabrutinib is better tolerated, especially regarding the typical adverse effects like atrial fibrillation or bleeding disorders, both of which are especially relevant for older patients.
What key findings from ECHO have been previously presented?
For the overall group, there was a significant PFS benefit [with the addition of acalabrutinib], and that translated to a trend toward an overall survival [OS] benefit. However, this study was performed during the COVID-19 pandemic, so in the protocol, there was a predefined analysis censoring for COVID-19 events. [Under that protocol], the slight difference in OS [between the 2 arms] became borderline significant. We still have to wait for longer follow-up. However, this study has the potential to show a similar [OS] benefit as we saw in the TRIANGLE trial, essentially opening the door to apply chemotherapy plus a BTK inhibitor for most patients [with MCL], which is patients between 65 and 75 years of age.
What updated efficacy data were presented at EHA 2025?
There was also the ENRICH study [investigating] skipping chemotherapy overall and only testing a BTK inhibitor plus rituximab [in older patients with previously treated MCL]. That trial showed that in patients with a low-risk profile, skipping chemotherapy and moving on to, in this case ibrutinib plus rituximab, was superior to using SOC chemotherapy. One pill a day is better than what we used to do during the past decades, which was applying efficient but toxic chemotherapy. That was the starting point [that made us consider]: What about the high-risk patients in the ECHO trial?
For the high-risk patients in the ENRICH trial, [the addition of] chemotherapy was [more effective] than a BTK inhibitor [plus rituximab alone]. Therefore, the logical consequence was to combine both and test BR plus acalabrutinib in high-risk patients. Importantly, high risk [means] biological high risk, either blastoid variant disease, a Ki-67 score above 30%, or a TP53 mutation. If we apply these criteria, 1 of those risk factors is enough to make a patient high risk.
The ECHO regimen of chemotherapy plus a BTK inhibitor has greater benefits in the high-risk patients. Regarding the CR rate, it was [66.6]% in the overall group and [67.9]% in the high-risk group. That also translates into a PFS benefit for the overall group.
For example, if you also consider the single risk factors like blastoid morphology and look at the benefit in PFS…the HR was 0.59—a more pronounced benefit compared with 0.73 in the overall group. The same also holds up for patients with a Ki-67 score of at least 50%, with an HR of 0.69. The PFS curves split further apart. For the high-risk group, chemotherapy [alone] is not enough, which we knew before, but now we have confirmation in a randomized trial. Unfortunately, the data [for patients with TP53 mutations are too small of a sample], so we cannot make a comment on that [subgroup].
Given the totality of data with BTK inhibitors in MCL, what is the current role of these agents in the first-line setting? How do you personalize treatment based on disease factors that patients might have?
BTK inhibitors are a mandatory part of first-line [treatment]. In younger, fit patients, it improved OS by [approximately] 10% after 4 years, which was a major landscape shift. In the middle-aged patients, which is most patients [with MCL], in the ECHO trial, [we showed that] we can combine [a BTK inhibitor with chemotherapy]. That’s specifically for biological high-risk patients or patients with standard-risk disease but huge tumor bulk. On the other edge of the spectrum are the older patients—80 years of age or older, as well as younger patients with significant comorbidities and a low-risk MCL profile. For those patients, we have the new option of ibrutinib plus rituximab.
A new question has arisen, because in most younger patients now, we skip autologous transplant. This means that the TRIANGLE regimen without autologous transplant is feasible for patients up to 70 years of age, or 75 years of age in very fit patients. Therefore, we have an overlap [in the populations eligible for the ECHO and TRIANGLE regimens].
The question is: How do we treat these intermediate-age patients? I don’t have an answer to that because we don’t have comparative studies, but my gut feeling would guide me to [decide that] if the risk factor is a Ki-67 score of approximately 50%—meaning that Ki-67 proliferation is the driver [of the disease]—then, I would lean more toward the TRIANGLE regimen. If patients have a TP53 mutation but not that much Ki-67 proliferation, I would probably tend toward the ECHO regimen. That’s the current scenario.
However, for the future, we already know we’re challenging [the role of] chemotherapy overall. Ibrutinib plus rituximab alone is inferior to chemotherapy plus rituximab. However, you might prefer to use a combination, such as a triplet combination of an anti-CD20 antibody, a BTK inhibitor, and venetoclax [Venclexta]. That triplet combination generated impressive PFS [outcomes] in the phase 1/2 OAsIs trial [NCT02558816]. There were small patient numbers, but the PFS rate was 80% after 5 years, and the OS rate was 90%. This is why we are currently performing several randomized trials comparing chemotherapy vs non-cytostatic combinations.
The classical-risk patients are probably better off skipping chemotherapy. For the higher-risk patients in the first-line treatment setting, one has to be honest. Even with a combination like ibrutinib plus venetoclax, the duration of remission is short, even in phase 2 studies.
Therefore, our hope—and there is some reason for this—is that immunotherapy can overcome some of the prognostic relevance of these risk factors. In the very high–risk patients with very high Ki-67 scores and TP53 alterations, we think immunotherapy plus targeted therapy potentially shows some advantage over our current standard, which is chemotherapy plus a BTK inhibitor. [Overall], BTK inhibitors will remain the cornerstone of first-line treatment in MCL, but the combination partners will potentially switch from chemotherapy to nonchemotherapy partners.
What is your main message about the ECHO trial results?
My recommendation for hands-on medicine if and when I apply this combination in patients is that the first thing I reduce is the chemotherapy backbone, specifically bendamustine because it is immunosuppressive, so it may hamper [the feasibility of] subsequent potential treatments. Therefore, I try to avoid late toxicities and reduce [the number of] bendamustine cycles to 4 and also reduce the dose per cycle according to age.
This tells us how important academic, independent trials are. The TRIANGLE and ENRICH trials are pure academic trials. The ECHO trial was a company-sponsored trial, but with the advice of academics, we recommended the SOC arm be the best potential [therapy] compared with the [investigational] arm. This tells us [how important] the role of clinical research is, and how important this is to improve outcomes and treatments for our patients.
References
- Dreyling M, Zinzani PL, Pavlovsky MA, et al. Efficacy of rituximab-bendamustine with or without acalabrutinib in patients with untreated, high-risk mantle cell lymphoma: an analysis of the phase 3 ECHO trial. Presented at: European Hematology Association 2025 Congress; June 12-15, 2025; Milan, Italy. Abstract S233.
- FDA approves acalabrutinib with bendamustine and rituximab for previously untreated mantle cell lymphoma. FDA. January 16, 2024. Accessed August 7, 2025. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-acalabrutinib-bendamustine-and-rituximab-previously-untreated-mantle-cell-lymphoma