Amid SOHO Data, Reviewers of BTK Inhibitors in MCL Call for Trials

Most comparative reviews or meta-analyses of drugs within a given class are funded by a sponsor of one of the competitors, which can make it challenging for providers to interpret conflicting results.

That’s what adds interest to a review appearing in Journal of Cellular and Molecular Medicine, conducted by authors from Tongji Hospital in Wuhan, China.¹ The team evaluates data for first- and second-generation Bruton tyrosine kinase (BTK) inhibitors in management of mantle cell lymphoma (MCL), an area that lacks direct, head-to-head comparisons among the 3 approved therapies: first-generation ibrutinib (Imbruvica; Janssen), and second-generation therapies acalabrutinib (Calquence; AstraZeneca), and zanubrutinib (BeOne Medicines).

According to the authors, who report no conflicts of interests or financial support from any of the sponsors, data gaps persist across both treatment-naïve (TN) and relapsed/refractory (R/R) patient populations. Both were evaluated in their study.¹

MCL is is diagnosed in between 4000 and 6000 patients per year in the United States, according to the National Cancer Institute.² The disease remains a rare subtype of non-Hodgkin lymphoma, although it is becoming a more common area of study.

Throughout their analysis, the Tongji Hospital authors framed their findings as useful in informing updated treatment guidelines, though they explicitly call for larger randomized controlled trials to confirm these indirect comparisons, since no true head-to-head trial among the 3 BTK inhibitors in MCL exists.

“Notably, acalabrutinib re­cently became a preferred first-line treatment option (combined with bendamustine/rituximab) for MCL in the [National Comprehensive Cancer Network] 2025 guideline, based on the ECHO trial,” the authors wrote, citing data that were updated this past week at the 2026 Society of Hematologic Oncology meeting in Houston, Texas.³

“Zanubrutinib, while approved for frontline use,” the authors continued, “became a first-line treatment option only for TP53-mutant MCL owing to unprecedented CR rates (88% in treatment-naïve TP53-mutant cohorts) in phase 2 trials.”

New results from the ECHO trial (NCT02972840) a phase 3 randomized study assessing the addition of acalabrutinib to frontline bendamustine-rituximab (BR) in older patients, found that the acalabrutinib-BR combination led to a 32% reduction in the risk of disease prevention or death, compared with placebo-BR in patients at least 65 years of age with treatment-naïve MCL after a median time on study of 51.86 months. With a median follow-up of 60.8 months (range, 0–88.5 months; median PFS was 72.5 for the acalabrutinib group vs 47.8 months for the placebo group.³

How the Study Was Conducted

The authors searched PubMed, Embase, and Cochrane through January 2025, ultimately including 70 studies, including 4 randomized controlled trials, 3 retrospective observational studies, and 63 single-arm cohort studies. The evaluation involved mpassing 1641 TN and 1791 R/R patients.¹ Outcomes extracted included complete response (CR) rate, objective response rate (ORR), progression-free (PFS) and overall survival (OS), and adverse events (AEs). Statistical analysis used R with random-effects models applied where heterogeneity (I²) exceeded 50%, and publication bias was assessed via funnel plots, Egger's, and Begg's tests.

Results for Treatment-Naïve Patients Favor Second-Generation Drugs

Pooled CR rates were substantially higher in TN patients (76.5%) than R/R patients (43.2%), with corresponding ORRs of 94.5% and 81.2%. Subgroup analysis by BTK inhibitor type showed that in the TN setting, zanubrutinib achieved a CR rate of 95.2%, statistically superior to acalabrutinib (89.3%) and ibrutinib (61.3%), with a similar pattern in ORR favoring the second-generation agents.

Among patients with R/R disease, CR results for the 3 BTK inhibitors were more of a continuum. When examining monotherapy specifically within the R/R group, acalabrutinib showed the highest CR rate at 43.2%, compared with 37.8% for zanubrutinib and 27.3% for ibrutinib.

Combination strategies also mattered. In the R/R setting, BTK inhibition plus chimeric antigen receptor (CAR) T-cell therapy produced the highest CR rate (80.0%), followed by the combination of a BTK inhibitor, an anti-CD20 antibody, and small-molecule agents such as venetoclax (Venclexta; Genetech/AbbVie), lenalidomide, or proteasome inhibitors (68.3%). Combinations significantly outperforming BTK inhibitor monotherapy.

In the TN setting, adding small-molecule therapy to a BTK inhibitor/anti-CD20 backbone nudged CR and ORR modestly higher than adding traditional chemotherapy, though this difference didn't reach statistical significance.

Safety Profile and Limitations

Zanubrutinib-based regimens showed a lower rate of neutropenia in TN patients and lower thrombocytopenia in R/R patients relative to the other 2 agents. Ibrutinib was associated with a distinctly higher rate of cardiac events (7.7% vs. 2.0% for acalabrutinib and 0.2% for zanubrutinib), consistent with its known cardiotoxicity signal. Interestingly, zanubrutinib carried a higher infection rate in the R/R group (66.1%) compared with ibrutinib (33.8%) and acalabrutinib (53.7%), while acalabrutinib showed the lowest hemorrhage rate.

The authors noted that most included studies were single-arm rather than randomized, “leading to patient selection bias or other uncontrolled confounding factors that may reduce the generalizability and strength of the evidence.” Heterogeneity across studies was moderate-to-high, likely driven by differences in patient demographics, TP53 mutation status, treatment line, and follow-up duration. A meta-analysis of PFS and OS proved infeasible because, the authors wrote, “numerous studies omitted reports on the details of survival outcomes.” The authors also caution that conclusions about BTK inhibitor-plus-CAR-T efficacy rest on a single trial with only 20 patients, meaning that finding should be interpreted with extreme caution.

In conclusion, the authors wrote, “This meta-analysis resolved critical uncertainties in BTK [inhibitor] selection for MCL, demonstrating that acalabrutinib and zanubrutinib may be more promising than ibrutinib as first-line treatment options for MCL, owing to their superior efficacy and more favorable safety profile.

“Chemotherapy-free combi­nation regimens can partially overcome the traditionally unfavorable prognosis associated with R/R MCL,” they continued. “The observed heterogeneity and the absence of survival analysis results under­score the need for further studies to confirm these results. These results provide a roadmap for optimizing MCL therapy.”

Reference

1. Xu F, Zou X, Yang Y, Zhou K, Huang W. Comparative efficacy of BTK inhibitors in treatment-naïve and relapsed/refractory mantle cell lymphoma: a systematic review and meta-analysis. J Cell Mol Med. 2026;30(17):e71340. doi:10.1111/jcmm.71340.
2. National Cancer Institute. Mantle Cell Lymphoma Treatment (PDQ®)–Health Professional Version. Accessed September 12, 2026. https://www.cancer.gov/types/lymphoma/hp/mantle-cell-lymphoma-treatment
3. Wang ML, Paludo J, de Holanda Farias JS, et al. Updated results from the phase 3 ECHO trial of bendamustine-rituximab with or without acalabrutinib in patients with previously untreated mantle cell lymphoma: 50 months of follow-up. Clin Lymphoma Myeloma Leuk. 2026;26(supp 1):S1016-S1017. doi:10.1016/S2152/2650(26)02760-6