Combining Bruton’s tyrosine kinase (BTK) inhibition with chemoimmunotherapy induction significantly extended progression-free survival for older patients with mantle cell lymphoma, and there was also a trend toward improvement on the overall survival benefit, according to data presented during the European Hematology Association 2024 Congress.¹

With a median follow-up of 45 months, results from the phase III ECHO trial showed a median progression-free survival of 66.4 months for patients randomly assigned to the BTK inhibitor acalabrutinib plus bendamustine and rituximab compared with 49.6 months for those who received placebo plus bendamustine and rituximab (hazard ratio [HR] = 0.73; P = .0160).

Authors of the study suggested that these findings represent an advancement in front-line treatment options for this patient population, who may not be suitable candidates for more aggressive therapies. However, some experts questioned the role of bendamustine in this setting (see Expert Point of View).

Michael Wang, MD

“The addition of acalabrutinib to bendamustine and rituximab in older patients with mantle cell lymphoma reduced the risk of disease progression or death by 27%,” said lead study author Michael Wang, MD, of The University of Texas MD Anderson Cancer Center, Houston. “ECHO also provided the first evidence of a positive trend in overall survival when adding a BTK inhibitor to front-line-standard chemoimmunotherapy for older patients with mantle cell lymphoma.”

As Dr. Wang explained, mantle cell lymphoma is an aggressive type of non-Hodgkin lymphoma that predominantly affects older adults. Although intensive chemoimmunotherapy regimens may provide durable responses in younger, fit patients, he explained, these approaches are often too toxic for elderly or less fit individuals. The ECHO trial sought to evaluate whether adding the second-generation BTK inhibitor acalabrutinib to standard chemoimmunotherapy could improve outcomes without significantly increasing toxicity.

Trial Design

ECHO is a multicenter, double-blind, placebo-controlled phase III trial evaluating acalabrutinib in combination with bendamustine and rituximab. The study enrolled 598 patients (aged 65 or older) with previously untreated mantle cell lymphoma and an Eastern Cooperative Oncology Group performance status of 0 to 2.

Patients were randomly assigned to receive either acalabrutinib plus bendamustine and rituximab or placebo plus bendamustine and rituximab. Acalabrutinib or placebo was given until disease progression or unacceptable toxicity. Bendamustine and rituximab were administered for six cycles, followed by 2 years of rituximab maintenance for patients who achieved at least a partial response.

Key Outcomes and Toxicity

In addition to improved progression-free survival in the intervention arm, findings from the study showed a higher overall response rate with acalabrutinib vs placebo (91.0% vs 88.0%). Complete response rates were also higher in the intervention group (66.6% vs 53.5%, respectively), although these differences did not reach statistical significance.

The safety profile was generally similar between the two groups, with serious adverse events reported in 69% of those given acalabrutinib vs 62% of those given placebo. Treatment discontinuation because of adverse events was more common with acalabrutinib (42.8% vs 31.0%). Atrial fibrillation (6.1% vs 4.4%) and infections (78.1% vs 71.0%) occurred more frequently in the acalabrutinib group.

Of note, the COVID-19 pandemic had a significant impact on the study outcomes. COVID-19–related deaths occurred in 9.4% of patients receiving acalabrutinib compared with 6.7% of the placebo group. When the authors censored for COVID-19–related deaths, the progression-free survival benefit with acalabrutinib became more pronounced (HR = 0.64; P = .0017).

What About Overall Survival?

Although overall survival data showed a positive trend favoring the acalabrutinib combination (HR = 0.86; P = .27), the difference was not statistically significant. According to Dr. Wang, this may be partly explained by the fact that 69% of patients in the placebo group received subsequent BTK inhibitor treatment after disease progression.

Dr. Wang also noted that the overall survival curves separated in favor of acalabrutinib after accounting for COVID-19 deaths, unlike in the previous SHINE trial of ibrutinib plus bendamustine and rituximab.

“Many would ask, ‘should we give concurrent therapy in first line with bendamustine and rituximab plus acalabrutinib or give bendamustine and rituximab and then sequential therapy with acalabrutinib in the second line?’” said Dr. Wang. “The overall survival curves indicate concurrent therapy is better than subsequent therapy.”

Longer follow-up will be needed to determine whether this approach can deliver meaningful improvements in overall survival and quality of life for this patient population, the study authors concluded.

Expert Point of View

Bijal D. Shah, MD, MS, a hematologist/oncologist at H. Lee Moffitt Cancer Center and Research Institute in Tampa, Florida, highlighted the complexities of interpreting the ECHO trial results and underscored the need for continued research to optimize treatment strategies for patients with mantle cell lymphoma. Dr. Shah’s primary concern was the lack of overall survival benefit.

Bijal D. Shah, MD, MS

“We can talk about trends all we want, but the reality is this is a randomized phase III study that failed to show a survival benefit,” Dr. Shah told The ASCO Post.

Comparing ECHO with the earlier SHINE trial, which tested ibrutinib plus bendamustine and rituximab against placebo plus bendamustine and rituximab, Dr. Shah noted striking similarities in progression-free survival, overall survival, and adverse-event profiles.²

In addition, Dr. Shah questioned whether bendamustine was an appropriate combination partner for Bruton’s tyrosine kinase (BTK) inhibitors. “Unfortunately, bendamustine is a bad drug to combine with a BTK inhibitor, especially in the front-line setting, where you might need backup options like CAR T-cell therapy,” he said. Dr. Shah noted that bendamustine’s “profound lymphodepletion” may compromise future immunotherapy options and increase the risk of infections.

Regarding the impact of COVID-19 on the trial results, Dr. Shah suggested the pandemic likely exacerbated an existing issue with infections. “If it weren’t COVID, it would have been a different infection,” Dr. Shah explained. “There is no reason to think the infectious mortality in either trial is being driven by the BTK inhibitor,” he added. “This really seems to be a bendamustine problem.”

While acknowledging that bendamustine may achieve deeper remissions more quickly, Dr. Shah questioned its utility in mantle cell lymphoma. He suggested ongoing trials should explore BTK inhibitor combinations without bendamustine, which might yield more promising results.

“[Providers] are dropping bendamustine like a bad habit,” Dr. Shah concluded. “This is going to be better in the long run, because it will help preserve our ability to capitalize with immunotherapies for those patients who are not responding.”

DISCLOSURE: The ECHO trial was funded by AstraZeneca. Dr. Wang has received research funding from AstraZeneca, Acerta Pharma, BeiGene, BioInvent, Celgene, Genentech, Innocare, Janssen, Juno Therapeutics, Kite Pharma, Lilly, Loxo Oncology, Molecular Templates, Oncternal, Pharmacyclics, and VelosBio. Dr. Shah has reported consulting and education relationships with Amgen, Pfizer, Novartis, BMS, Kite/Gilead, Precision Biosciences, Jazz, BeiGene, Adaptive, Century Therapeutics, Autolus, Deciphera, Lilly, Takeda, and AstraZeneca; has served on the steering committee for PeproMene Bio; and has received grants from Kite/Gilead, Jazz, and Servier.

REFERENCES

1. Wang M, Mayer J, Belada D, et al: Acalabrutinib plus bendamustine and rituximab in untreated mantle cell lymphoma: Results from the phase 3, double-blind, placebo-controlled ECHO trial. EHA 2024 Congress. Abstract LB3439. Presented June 16, 2024.

2. Wang ML, Jurczak W, Jerkeman M, et al: Ibrutinib plus bendamustine and rituximab in untreated mantle-cell lymphoma. N Engl J Med 386:2482-2494, 2022.