Abstract Background: Patients (pts) with mantle cell lymphoma (MCL) frequently require initiation of treatment (tx) at diagnosis. While first-line tx often yield high response rates, the vast majority of pts relapse. Covalent Bruton tyrosine kinase inhibitors (cBTKi) have been a cornerstone for tx for relapsed/refractory (R/R) MCL for over 10 years. However, in the current era, there are multiple tx options, and pts are often treated in a variety of settings. This observational study describes real-world tx patterns, pt characteristics, and time-to-event (TTE) outcomes of cBTKi-based tx amongst a contemporary cohort of pts with R/R MCL in the US. Methods: The nationwide Flatiron Health electronic health record-derived de-identified database was used to identify adult pts diagnosed with MCL who initiated first-line (1L) systemic therapy on or after 01 Jan 2018, had received at least two lines of therapy (2L+), and were treated with a cBTKi-based therapy in 2L+. Data cutoff was 31 Jan 2025. Pts were grouped based on the line of therapy where the cBTKi was first received (2L, 3L, 4L+). Index date was defined as the start date of the first cBTKi. Descriptive statistics were used to summarize pt characteristics and tx patterns. Time-to-tx-discontinuation or death (TTD), time-to-next-tx or death (TTNT), and overall survival (OS) were analyzed from index date using the Kaplan-Meier method. Pts who received a cBTKi in more than one line of therapy were analyzed only from the start of the first cBTKi. Results: Out of 3,111 pts with MCL initiating 1L therapy on or after 01 Jan 2018,745 received their first cBTKi-based therapy in 2L+.Of 745 eligible pts, the majority were male (n=547; 73.4%) and treated in a community practice setting (n=521; 69.9%). In total, pts received a median of 3 lines of therapy (Quartile Q 1, Q3; 2,4). Most pts were treated with the first cBTKi in 2L (2L n=600; 80.5%, 3L n=121; 16.2%, 4L+ n=24; 3.2%). Median time from diagnosis to index date was 12.6 months (mo) (Q1, Q3; 5.8, 26.3); median age at index was 72 years (Q1, Q3; 64, 78). Among pts with available data, 19.2% (70/364) had del(17p); 41.4% (70/169) had TP53 mutation; 64.7% (352/544) had a Ki-67 index ≥30%; 16.4% (81/495) had an ECOG performance status of 2+; 13.6% (101/745) had blastoid or pleomorphic disease; and 73.2% (427/583) were stage IV at index date. The prevalence of stem cell transplantation was 7.2% (54/745). Immediately prior to the first cBTKi, the most common tx included anti-CD20ab + chemotherapy regimens (74.6%, n=556), followed by anti-CD20ab monotherapy (10.1%, n=75), and immunomodulatory drugs +/- anti-CD20ab (4.6%, n=34). As the first cBTKi tx, 67.1% of pts (500/745) received cBTKi monotherapy (33.8% n=252 acalabrutinib; 20.1% n=150 zanubrutinib; 13.0% n=97 ibrutinib) while the remainder (n=245) received a cBTKi combination regimen (9.8% n=72 acalabrutinib + other agents; 8.9% n=67 zanubrutinib + other agents; 14.2% n=106 ibrutinib + other agents). Among 344 pts who received at least one subsequent line of therapy immediately following the first cBTKi, 45.9% (n=158) received another cBTKi (cBTKi monotherapy n=41; cBTKi combination regimens n=117). Median follow-up time (Q1, Q3) from index date to last observation or death in 2L+ was 13.3 mo (5.7, 28.6) (2L; 13.5 6.2, 28.5, 3L; 10.6 4.9, 29.1, 4L+; 15.0 4.2, 29.1). Overall median TTD (95% confidence interval CI) was 8.0 mo (6.2-10.5) (2L; 9.1 6.6-12.0, 3L; 5.7 3.5-9.7, 4L+; 2.7 1.7-16.5). Overall median TTNT (95% CI) was 10.8 mo (8.2-13) (2L; 12.1 9.1-13.7, 3L; 7.1 4.8-10.8, 4L+; 3.9 1.9-16.5). In pts who received the first cBTKi as monotherapy in 2L+ (n=500), median TTD (95% CI) was 9.4 mo (7.2-12.4) and median TTNT was 11.1 mo (8.8-13.9). Among those who received the first cBTKi as a combination regimen in 2L+ (n=245), median TTD (95% CI) was 5.9 mo (4.5-8.4) and median TTNT was 9.0 mo (6.1-13.2). The 24-mo OS (95% CI) for the overall cohort was 56.5% (52%-60%). Conclusion: In this real-world study, pts with R/R MCL had high-risk disease characteristics at the start of cBTKi tx. Median time from diagnosis to initiation of cBTKi-based tx in 2L or later was only about 1 year, with median time to TTD and TTNT less than one year. These TTE analyses indicated poor real-world outcomes for patients, particularly as the line of therapy for the first cBTKi advanced. In aggressive diseases such as MCL, there continues to be a need for more effective tx.
Maddocks et al. (Mon,) studied this question.