Acalabrutinib Gains Landmark EU Approval in First-Line MCL
In an interview, Prof Martin Dreyling discussed the approval of first-line acalabrutinib for the treatment of adult patients with mantle cell lymphoma.
Diffuse large B-cell lymphoma - Generated with Google Gemini AI
On May 6, 2025, acalabrutinib (Calquence) in combination with bendamustine and rituximab (Rituxan; BR) received approval in the European Union (EU) for the treatment of adult patients with previously untreated mantle cell lymphoma (MCL) who are not eligible for an autologous stem cell transplant.1
This approval stems from the positive results of the phase 3 ECHO trial (NCT02972840), which showed that the acalabrutinib combination reduced the risk of disease progression or death by 27% compared with standard chemoimmunotherapy (HR, 0.73; 95% CI, 0.57-0.94; P =.016). 2 The median progression-free survival (PFS) for patients on the acalabrutinib combination was 66.4 months, significantly longer than the 49.6-month PFS for those on chemoimmunotherapy alone.
MCL is a rare and aggressive form of non-Hodgkin lymphoma. This approval provides a new first-line treatment option in the EU for this challenging disease, offering a significant improvement in PFS.
“This is a striking era for mantle cell lymphoma,” said Prof Martin Dreyling, a professor in the Department of Medicine in the University Hospital and head of the lymphoma program at the Department of Medicine III, LMU Hospital Munich, in an interview with Targeted OncologyTM. “I'm very happy witnessing these steps of progression.”
In the interview, Dreyling provided background on MCL, discussed the ECHO trial’s significance, and considered the future of the treatment landscape in MCL.
Targeted OncologyTM: Can you give us some background on the treatment landscape of MCL? What were the key findings from the ECHO trial?
Prof Martin Dreyling
Dreyling: We have [had] optimized chemotherapy for more than 2 decades in mantle cell lymphoma, and we still would like to improve. On one hand, we have the younger patients who very well tolerated or are still tolerating chemotherapy, and even in [those instances] we were able to show that with the addition of [Bruton tyrosine kinase inhibitors (BTKi)], we can improve long-term outcomes—not only progression-free survival, but also overall survival.
In elderly patients, tolerability is, of course, very picky. Therefore, bendamustine, as a well-tolerated chemotherapy, became standard of care. The question was, how to improve on that and in relapsed disease. In fact, we have data that the BTKi are better than chemotherapy, so logically, we would like to add that to first-line treatment to further improve outcomes.
Having said that, this is what we tested in [older] patients. We had a standard arm, BR, and in the experimental arm, we added acalabrutinib. This is a huge trial; it is almost 600 patients. And [it is] an international, multicenter trial, so this is really representing our patients.
Now, after a long time, we had to look at the outcomes, and what we have seen is progression-free survival has been significantly improved. What is even more important [is] in [older] patients, the high-risk patients are the challenge. And why is that? Well, simply said, we cannot intensify a treatment, so we cannot intensify chemotherapy, and outcomes with BR in these biological high-risk patients, which are high Ki67 or blastoid variant or p53 mutation, they are insufficiently treated. Therefore, it is nice to see that specifically, this patient population also benefits from the addition of acalabrutinib, with a hazard ratio of 0.73. And for overall survival, we see a trend.
What is the significance of this approval?
It is important to say that we in Europe, especially in Germany, are lucky that we could also treat younger patients with the BTK-chemotherapy combination [for the last] 2 years. [But] you have to remember the median age of patients with mantle cell lymphoma is between 65 and 70. For the majority of patients, this treatment option was missing, and therefore, this is really filling an important lack of treatment. We are very happy with that. Having said that, acalabrutinib is a second-generation BTKi, so it has a more favorable toxicity profile than ibrutinib [Imbruvica], and that seems to translate also to improved survival data. If we compare these data to the previous trials [assessing] BR plus or minus ibrutinib, we see improvement of long-term outcome, and that is probably due to toxicity.
How do you characterize the safety profile of this regimen?
The takeaway message is you gain some efficacy without buying in a lot of toxicity. Let’s say the [older] patients [that are] still low risk—they may be even well off with the shortened BR regimen. However, the huge intermediate group, and specifically the high-risk group, [is] where you really need some improvement. These are the patients for whom we did not have a standard of care before. Now, we have this combination with acalabrutinib, and that's a huge improvement. When I said it's better tolerated, I was referring to cardiac toxicity, and that almost does not play a role in younger patients, but specifically in elderly patients. We have seen that this is a major advantage. So again, buying in more long-term efficacy without additional toxicity or only very little additional toxicity.
What are the unmet needs that still exist in this patient population?
Let's start with a positive thing. It is extremely important that this is an improvement [in the] first line, because [in the] first line, there is really the most to gain. If with a standard treatment, let's say you have a PFS of 2 or 3 years, and you increase that by 50%, we are talking about a number of years. So, really a major improvement from the perspective of the patient. Once it is relapsed disease, we are talking about only months [of survival]; therefore, the gain is also less meaningful for the patient.
What is the shortcoming, though? This is my personal opinion, but if you do perform a study-to-study comparison, you do get the impression that bendamustine is probably not the optimal combination partner, and that is due to strong immunosuppressive [adverse] effects. Therefore, if you see other studies with other chemotherapy combination partners, the benefit seems to be superior. For the routine application, to be honest, if I start now treating the next patients who step into my outpatient department tomorrow with this ECHO regimen, the first thing I will reconsider [is] reducing or adapting the bendamustine dose, both in number of cycles and cumulative dose.
That is what the future will be. Do we really need the chemotherapy backbone, or may we substitute it [with] a pure, targeted combination? These studies are ongoing; they are recruiting. I am aware of at least 2 randomized studies by the European MCL Consortium, which are testing exactly such a nonchemotherapy combination. Of course, this is specifically important for the [older] patients, where tolerability of such a regimen plays an important role.
This is a striking era for mantle cell lymphoma. To be honest, when we started 20 years ago and started with our first randomized studies, I got the comment by the reviewers, “Well, you cannot perform a randomized study in mantle cell lymphoma because there is no standard of care.” Now we are 20 years later, and we not only have a standard of care, but we are also improving the outcomes of our patients, even in the older patients with potential comorbidities. If you go to the internet for mantle cell lymphoma, it is still saying, “Oh, it is the worst of all B-cell lymphomas,” when it comes to long-term perspective. But this is now totally changing, and I am very happy witnessing these steps of progression.
