Real-World Survival Outcomes in MCL Before Modern BTKis, CAR T-Cell Therapy

Real-world evidence can be useful in evaluating how key therapies perform outside of a clinical trial. There’s always a balance of waiting for a data set to mature versus the knowledge gained from clinical trials that advance treatment by extending survival or limiting toxicity or both.

Such is the case with a retrospective observational study recently published in Annals of Hematology, which represents the first comprehensive population-level analysis of mantle cell lymphoma (MCL) in Germany.¹ Based on claims data from 4.5 million publicly insured individuals enrolled in the Betriebskrankenkassen statutory health insurance fund, the study evaluates the MCL population, use of treatments, and survival statistics from 2015 to 2020; limits on some data meant the bulk of the analysis ended at 2019.

The study leader was Heiko Friedel, PhD, of the Health Out­come Research and Health Economics Department, Team Gesundheit in Essen, Germany. Eli Lilly funded the study.

The study period precedes approval of the chimeric antigen receptor (CAR) T-cell therapy brexucabtagene autoleucel, or brexu-cel (Tecartus; Kite Pharma), or the third-generation noncovalent Bruton tyrosine kinase (BTK) inhibitor pirtobrutinib (Jaypirca; Eli Lilly), among other advances. Authors noted that ibrutinib (Imbruvica; Janssen), the first BTK inhibitor, was largely used in the relapsed/refractory (R/R) setting through most of the study period.¹

The authors note that MCL could rapidly progress and exhaust the limited options that existed during the study period, despite the emergence of covalent BTK inhibitors. “Although some patients have indolent MCL at diagnosis, the majority experience an aggressive disease course and require multiple lines of therapy, usually associated with a poor prognosis,” they write.¹

MCL prevalence and incidence showed a clear upward trend over the study period. Extrapolated to the broader German statutory health insurance population, annual prevalence rose from 6.64 to 10.25 per 100,000 individuals between 2015 and 2019, while incidence ranged from 1.28 to 2.06 per 100,000 individuals at risk.¹ Across all study years, both prevalence and incidence were more than double in men compared to women. The rise in incidence was driven primarily by patients aged 80 years and older, underscoring a growing clinical burden among elderly patients that demands therapeutic strategies sensitive to age-related comorbidities and frailty.

A Fragile Real-World Population: High Comorbidity and Advanced Age

Among the 369 patients in Cohort A—those receiving at least 1 line of anti-cancer treatment—the median age at diagnosis was 71 years, over 75% were male, and the average Charlson Comorbidity Index (CCI) was 2.9. Comorbidity burden increased in later cohorts, with a mean CCI of 3.7 at the start of covalent BTK inhibitor treatment and 4.2 at discontinuation.¹ Essential hypertension affected more than 60% of patients across all cohorts, and metabolic disorders were highly prevalent, indicating a cardiovascular risk profile that may complicate covalent BTK inhibitor use.

Of note, ibrutinib has been shown to cause cardiovascular adverse effects, which are less common with second-generation therapies, zanubrutinib (Brukinsa; BeOne Medicines) and acalabrutinib (Calquence; AstraZeneca).²

Low Transplant Rates and the Dominance of Early Chemoimmunotherapy

In first-line treatment, 77.2% of patients received chemoimmunotherapy, consistent with German guideline recommendations at the time. Only 13.8% proceeded to autologous stem cell transplantation (auto-SCT), a notably low rate likely reflecting the advanced age and comorbidity burden of the real-world population. Rituximab maintenance was used in 30.9% of first-line patients.

In the second line, chemoimmunotherapy remained the most common approach (45.6%), while 22.3% received a covalent BTK inhibitor. Among the 82 patients who received a covalent BTK inhibitor (Cohort B), 52.4% received this in the second line, 22.0% in the third line, and 15.9% in the fourth line. The vast majority (89.5%) received a covalent BTK inhibitor as monotherapy.

Following discontinuation of a covalent BTK inhibitor, only 44.4% of Cohort C patients received further anticancer therapy, while 55.5% received no subsequent systemic treatment. Median treatment duration declined with each successive line, falling to just 18 days following discontinuation of a covalent BTK inhibitor.

Survival Gaps Following Covalent BTKi Discontinuation

Median overall survival (OS) from initial MCL diagnosis was 75.3 months, aligning closely with a comparable Finnish/Spanish cohort study. Survival outcomes were substantially worse for patients treated with a covalent BTK inhibitor: median OS following initiation was just 11.2 months, similar to the 14.6 months reported in the SCHOLAR-2 European real-world study, which evaluated data from 240 patients with R/R MCL in Europe who were treated with BTK inhibitor-based therapy between July 2012 and July 2018 and experienced disease progression and stopped therapy due to intolerance. It is important to note that the BTK inhibitors were used in the R/R setting during the study period.³

Median OS following covalent BTK inhibitor discontinuation was only 3.0 months, demonstrating the unmet need for patients who progressed or could no longer tolerate BTK inhibitors in that era. Although the authors caution that the small sample size (n=45) limits the precision of this estimate, the findings signaled the gap that would be addressed for MCL patients in the years ahead, as brexu-cel was approved in 2020.⁴ Zanubrutinib moved into frontline care in chronic lymphocytic leukemia in January 2023 on the strength of the SEQUOIA (NCT03336333) and ALPINE (NCT03734016) trials,⁵ and has shown efficacy in first-line combinations in MCL in studies such as the BOVen trial.⁶

The authors establish a valuable baseline characterization of MCL management in Germany prior to the emergence of novel therapies such as brexu-cel, pirtobrutinib, and ibrutinib-inclusive first-line regimens demonstrated in the TRIANGLE trial.⁷ “By offering a comprehensive overview of the epidemiology, treatment patterns, and survival outcomes of MCL in routine care in Germany before the introduction of these therapeutic advancements, this study establishes a foundation for future research on the German MCL treatment landscape,” they conclude.¹

References

1. Friedel H, Hennies N, Zschocke J, et al. Epidemiology, treatment patterns, and survival outcomes of patients with mantle cell lymphoma in Germany: a retrospective analysis of administrative claims data. Ann Hematol. Published online March 13, 2026. doi:10.1007/s00277-026-06915-3
2. Doherty K. Acalabrutinib and zanubrutinib both best ibrutinib in real-world safety and efficacy CLL/SLL outcomes. OncLive^®. June 17, 2024. Accessed March 26, 2026. https://www.onclive.com/view/acalabrutinib-and-zanubrutinib-both-best-ibrutinib-in-real-world-safety-and-efficacy-cll-sll-outcomes
3. Hess G, Dreyling M, Oberic L, et al. Real-world experience among patients with relapsed/refractory mantle cell lymphoma after Bruton tyrosine kinase inhibitor failure in Europe: The SCHOLAR-2 retrospective chart review study. Br J Haematol. 2023;202(4):749-759. doi:10.1111/bjh.18519
4. Caffrey M. FDA approves CAR T-cell therapy for adults with R/R mantle cell lymphoma. AJMC^®. July 24, 2020. Accessed March 26, 2026. https://www.ajmc.com/view/fda-approves-car-tcell-therapy-for-adults-with-rr-mantle-cell-lymphoma
5. Caffrey M. FDA gives zanubrutinib approval for first line, R/R CLL, SLL. AJMC. January 19, 2023. March 26, 2026. https://www.ajmc.com/view/fda-gives-zanubrutinib-approval-for-first-line-r-r-cll-sll
6. Kumar A, Soumerai J, Abramson JS, et al. Zanubrutinib, obinutuzumab, and venetoclax for first-line treatment of mantle cell lymphoma with a TP53 mutation. Blood. 2025;145(5):497-507. doi:10.1182/blood.2024025563.
7. Dreyling M, Doorduijn J, Giné E, et al. Ibrutinib combined with immunochemotherapy with or without autologous stem-cell transplantation versus immunochemotherapy and autologous stem-cell transplantation in previously untreated patients with mantle cell lymphoma (TRIANGLE): a three-arm, randomised, open-label, phase 3 superiority trial of the European Mantle Cell Lymphoma Network. Lancet. 2024;403:2293-2306. doi:10.1016/S0140-6736(24)00184-3