Real-World Outcomes for Patients Treated with Ibrutinib for Relapsed/Refractory Mantle Cell Lymphoma in Denmark
Authors: Trab Trine , Chanchiri Iman , Al-Mashhadi Ahmed , Berggreen Dall Emma , Rasch Stine , Johansen Mette , Husby Simon , Clausen Michael Roost , Larsen Thomas Stauffer , Desseau-Arp Andriette C , Christensen Jacob Haaber , Pedersen Robert Schou , Frederiksen Mikael , Brown Peter de Nully , El-Galaly Tarec Christoffer , Gronbaek Kirsten 
Published: December 2024

Introduction
In 2013 promising response rates led to accelerated approval of ibrutinib for relapsed/refractory (R/R) mantle cell lymphoma (MCL) by the FDA. The approval was withdrawn in 2023 due to lack of overall survival (OS) benefit in confirmatory trials where ibrutinib was used in first line combination therapies. Ibrutinib still has a marketing authorization in Europe and is frequently used for R/R MCL in some countries. However, data are limited on tolerability and outcomes in unselected real-world populations that are typically older with more frailty than patients enrolled in clinical trials.
Aim
To estimate tolerability, response rates, and survival in a population-based study of patients treated with ibrutinib for R/R MCL.
Methods
Patients diagnosed with MCL in Denmark in 2010-2022 were identified in the Danish Lymphoma Registry and screened for eligibility. Patients were included if they received ibrutinib in second or later lines. Follow-up was from the start of ibrutinib until death or censoring on the last date known to be alive. Data were collected in 2023-2024 from health records and imaging reports. Best overall response rate (ORR) was the proportion with partial (PR) or complete remission (CR) at any time. Progression-free survival (PFS) was estimated as time until first progression (PD), relapse, or death, and OS as time until death (Kaplan Meier method). Adverse events (AE) were identified and graded according to the CTCAE, and reasons for discontinuations and dose reductions were collected.
Results
Out of 835 screened patients with MCL, 137 were included (69% male, 31% female) with a median age of 72 years (interquartile range (IQR) 68-79). Of the 137 patients, 35 (26%) patients had blastoid or pleomorphic MCL at the time of ibrutinib initiation, 65 (48%) had Ki67 ≥30%, 36 (26%) had high MCL prognostic index, 16 (12%) had central nervous system (CNS) involvement, and 38 (28%) were refractory to the treatment line before ibrutinib. Patients received ibrutinib in second (63%) or later lines (37%), the majority (87%) initiated 560 mg ibrutinib daily, 13% initiated reduced dose. Monotherapy ibrutinib was used in 83%, and combination therapy was most commonly with lenalidomide or chemotherapy regimens. Median follow-up was 48 months, and median time on ibrutinib was 5 months (IQR 2-15).
Response on ibrutinib was available for 113 (82%) patients (57% PET-CT +/- bone marrow (BM), 29% CT, 1% BM, 13% clinical). Among the 113 patients, ORR was 59% (26% CR, 25% PR, 8% clinical remission). Median PFS and OS after start of ibrutinib were 6 months (95% confidence interval (CI) 4-10) and 12 months (95% CI 8-20), respectively. The 3-year PFS and OS were 17% (95% CI 11-25) and 26% (95% CI 19-35), respectively. There were no differences in PFS or OS between patients receiving ibrutinib in second line (median PFS 5 months (95% CI 3-10), OS 14 months (95% CI 8-24)) versus later lines (median PFS 7 months (95% CI 4-13), OS 11 months (95% CI 7-21)). A total of 101 (74%) patients had at least one relapse/PD after start of ibrutinib. Median OS was 1.2 months (95% CI 0.7-2.5) after discontinuation due to PD/no response and 8.8 months (95% CI 1.2-20.3) after discontinuation due to other reasons.
There were 38 bleeding AEs in 26 patients (19%) including 16 skin, 9 gastrointestinal, 3 CNS, and 10 others, 16 bleedings were serious AEs (SAEs) or grade ≥3, five led to dose reduction. Three (2%) patients developed heart failure and 15 atrial fibrillation (11%). In total, 21 patients (15% of 137) discontinued ibrutinib due to AEs, 34 AEs led to dose reduction in 22 (16%) patients, and 11 deaths were assessed as directly related to AEs (nine infections, two others).
Conclusions
Patients with R/R MCL receiving ibrutinib in the real-world setting in Denmark have inferior PFS and OS compared to clinical trials (median PFS 13 months in a meta-analysis of trials) and a higher discontinuation rate from AEs. Despite the short PFS, ibrutinib induced high response rates, which were durable in a minority of patients. The findings highlight a need for improved treatment for R/R MCL and the importance of managing AEs during ibrutinib treatment. Identification of which patients are most likely to benefit from ibrutinib is warranted, especially now that ibrutinib may be implemented in first line for younger patients based on results from the TRIANGLE trial.