Real-World Covalent BTK Inhibitor Use Confers Limited Efficacy in R/R MCL

Real-world patients with relapsed/refractory mantle cell lymphoma (MCL) in the United States (US) frequently exhibited high-risk disease characteristics at the start of covalent BTK inhibitor therapy and experienced poor outcomes, which progressively worsened as the line of therapy for their first covalent BTK inhibitor advanced from the second line to the fourth or later line, according to findings from a real-world analysis presented at the 2025 ASH Annual Meeting.¹

In the overall study population (n = 745), the median time to treatment discontinuation or death (TTD) was 8.0 months (95% CI, 6.2-10.5), and the median time to next treatment (TTNT) was 10.8 months (95% CI, 8.2%-13%).

From index date to each line of therapy, the median TTD and TTNT were as follows:

• Second line: TTD, 9.1 months (95% CI, 6.6-12.0); TTNT, 12.1 months (95% CI, 9.1-13.7)
• Third line: TTD, 5.7 months (95% CI, 3.5-9.7); TTNT, 7.1 months (95% CI, 4.8-10.8)
• Fourth line or later: TTD, 2.7 months (95% CI, 1.7-16.5); TTNT, 3.9 months (95% CI, 1.9-16.5)

“In aggressive diseases such as MCL, there continues to be a need for more treatments for patients who receive their first covalent BTK inhibitor in the second line or later,” lead study author Kami J. Maddocks, MD, stated in a presentation of the data.

Maddocks is a professor in the Division of Hematology at The Ohio State University (OSU) and a member of the Leukemia and Hematologic Malignancies Program at the OSU Comprehensive Cancer Center—James in Columbus.

What was the rationale for investigating the real-world efficacy of BTK inhibitors in relapsed/refractory MCL?

“First-line treatment for MCL often yields high overall response rates, but we also know that the majority of patients will relapse and will require further therapy,” Maddocks explained. “Covalent BTK inhibitors have been the cornerstone of treatment for relapsed/refractory MCL for more than 10 years and remain the preferred option in the second-line setting. As the treatment landscape for MCL continues to evolve, understanding use and real-world [efficacy] of initial covalent BTK inhibitor therapy in patients with relapsed/refractory MCL is important to improve outcomes for this patient population.”

Ibrutinib (Imbruvica) was the first covalent BTK inhibitor to beFDA approved for patients with relapsed/refractory MCL following at least 1 prior line of therapy.² However, this indication was later voluntarily withdrawn in the US by the Janssen Pharmaceutical Companies of Johnson & Johnson. The most recent covalent BTK inhibitor to gain FDA approval for patients with relapsed/refractory MCL following at least 1 prior line of therapy was zanubrutinib (Brukinsa) in 2019.³

This retrospective study aimed to identify real-world treatment patterns, patient characteristics, and time to event (TTE) outcomes with covalent BTK inhibitor–based therapy in the second line or later among patients with MCL in the US.

What was the design of this real-world study of BTK inhibitors in MCL?

The study included patients who were enrolled in the Flatiron Health MCL Enhanced Data Mart database between January 1, 2011, and January 31, 2025. Patients needed to be at least 18 years of age when they initiated their first line of therapy with systemic anticancer agents; treatment must have been initiated on or after January 1, 2018. Prior receipt of at least 2 lines of systemic therapy, including a covalent BTK inhibitor, was also required; of note, the BTK inhibitor could not have been received in the first-line setting. BTK inhibitors received included ibrutinib, acalabrutinib (Calquence), and zanubrutinib. Key end points included the TTE outcomes TTD, TTNT, and overall survival (OS).

The covalent BTK inhibitor was administered to patients in the second line (n = 600), third line (n = 121), or fourth-line or later (n = 24). In the overall population, the median age of patients was 72 years (Q1-Q3, 64-78) at the index date and 70 years (Q1-Q3, 62-76) at diagnosis. Most patients were male (73.4%), White (74.6%), and treated in the community setting alone (69.9%). Disease subtypes included blastic MCL (9.3%), leukemic MCL (6.2%), pleomorphic MCL (4.3%), and MCL not otherwise specified (80.3%). Ann Arbor stages at diagnosis included stage I (1.3%), II (4.2%), III (15.4%), and IV (57.3%) disease; 21.7% of patients had missing information. Patients received 2 (44.0%), 3 (26.4%), or 4 or more (29.5%) total lines of therapy. Most patients (92.8%) had never received stem cell transplant.

The median follow-up from index to last observation or death was 13.3 months (Q1-Q3, 5.7-28.6), and the median time from initial diagnosis to index date was 12.6 months (Q1-Q3, 5.8-26.3). Most patients had an ECOG performance status of 0 or 1 (53.6%). Ki-67 levels before or on the index date were at least 30% in 47.2% of patients and at least 50% in 31.7% of patients. TP53 mutation statuses included negative (13.3%), positive (9.4%), and missing (77.3%). 17p deletion statuses included absent (39.5%), present (9.4%), and missing (51.2%).

Single-agent ibrutinib, acalabrutinib, or zanubrutinib was administered to 13.0%, 33.8%, and 20.1% of patients, respectively, in the overall population. Regimens including other agents combined with ibrutinib, acalabrutinib, or zanubrutinib were received by 14.2%, 9.7%, and 9.0% of patients, respectively.

What additional efficacy findings were seen in this real-world study of BTK inhibitors in MCL?

Among patients in the overall population who received covalent BTK inhibitor monotherapy (n = 500), the median TTD was 9.4 months (95% CI ,7.2-12.4), and the median TTNT was 11.1 months (95% CI, 8.8-13.9). Among patients in the overall population who received covalent BTK inhibitor–based combination therapy (n = 245), the median TTD was 5.9 months (95% CI, 4.5-8.4), and the median TTNT was 9.0 months (95% CI, 6.1-13.2).

In the overall population, with 54.8% of patients censored, the Kaplan-Meier OS probabilities from index date were as follows:

• 12 months: 68.6% (95% CI, 65.0%-72.0%)
• 24 months: 56.5% (95% CI, 52.4%-60.4%)
• 36 months: 48.0% (95% CI, 43.5%-52.4%)
• 48 months: 40.3% (95% CI, 35.3%-45.2%)

In the second-line population, with 54.5% of patients censored, the OS probabilities from index date were as follows:

• 12 months: 68.9% (95% CI, 64.8%-72.6%)
• 24 months: 55.8% (95% CI, 51.2%-60.2%)
• 36 months: 47.6% (95% CI, 42.6%-52.4%)
• 48 months: 39.9% (95% CI, 34.3%-45.4%)

In the third-line population, with 53.7% of patients censored, the OS probabilities from index date were as follows:

• 12 months: 66.5% (95% CI, 56.7%-74.5%)
• 24 months: 56.7% (95% CI, 46.3%-65.9%)
• 36 months: 47.5% (95% CI, 36.0%-58.1%)
• 48 months: 40.8% (95% CI, 28.9%-52.3%)

In the fourth-line or later population, with 66.7% of patients censored, the OS probabilities from index date were as follows:

• 12 months: 73.2% (95% CI, 49.7%-87.0%)
• 24 months: 73.2% (95% CI, 49.7%-87.0%)
• 36 months: 62.7% (95% CI, 33.8%-81.8%)
• 48 months: 31.4% (95% CI, 1.8%-71.6%)

What were the limitations of this real-world MCL research?

The study authors noted that limitations for this research included the use of electronic health record–derived data that, although nationally distributed and curated, could lack certain data points and have variable documentation and residual confounding that cannot be completely addressed using descriptive methods. Additionally, the authors noted that physicians may employ variable diagnostic documentation practice patterns that may lead to missing data. Furthermore, the study’s requirement for patients to have received at least 2 lines of therapy since January 2018 may have created a cohort that was biased toward the inclusion of patients who advanced to the second-line or later treatment settings more quickly than others.

References

1. Maddocks K, Tracey M, Winfree K, et al. Real-world treatment patterns, patient characteristics, and outcomes of cBTKi-based therapies amongst a contemporary cohort of patients with R/R MCL in the United States. Blood. 2025;146(suppl 1):2725. doi:10.1182/blood-2025-2725
2. Update on Imbruvica (ibrutinib) U.S. accelerated approvals for mantle cell lymphoma and marginal zone lymphoma indications. News release. The Janssen Pharmaceutical Companies of Johnson & Johnson. April 6, 2023. Accessed January 7, 2026. https://www.jnj.com/media-center/press-releases/update-on-imbruvica-ibrutinib-u-s-accelerated-approvals-for-mantle-cell-lymphoma-and-marginal-zone-lymphoma-indications
3. FDA approves therapy to treat patients with relapsed and refractory mantle cell lymphoma supported by clinical trial results showing high response rate of tumor shrinkage. PR Newswire. November 14, 2019. Accessed January 7, 2026. https://www.prnewswire.com/news-releases/fda-approves-therapy-to-treat-patients-with-relapsed-and-refractory-mantle-cell-lymphoma-supported-by-clinical-trial-results-showing-high-response-rate-of-tumor-shrinkage-300958791.html