Impact of Novel Therapies (NTs) on Real-World (RW) Clinical Outcomes of Patients (pts) with Relapsed/Refractory (RR) Mantle-Cell Lymphoma (MCL) By Race/Ethnicity and TP53 Mutation Status
Authors: Phillips Tycel J. , Danilov Alexey V. , Ruan Jia , Patel Krish , Kumar Anita , Wang Yucai , Maglinte Gregory A. , Seymour Erlene , Kamdar Manali 
Published: December 2024

Introduction: Treatments for R/R MCL have evolved with NTs, including BTK inhibitors (BTKis). Little is known about RW treatment patterns and clinical outcomes of pts with R/R MCL for chemoimmunotherapy (CIT) vs NTs among pts of different race/ethnicity. Data on RW testing and clinical outcomes of pts with R/R MCL harboring a TP53 mutation are limited.
Methods: This retrospective cohort study included adult pts with R/R MCL who initiated second-line (2L) or third-line (3L) treatment on 1/1/2018 or later and were followed up until loss to follow-up, death, or data cut-off using US Flatiron Health electronic health record-derived de-identified databases. Median RW time to next treatment (mrwTTNT) and median RW overall survival (mrwOS) were estimated based on Kaplan-Meier analyses and adjusted for age and sex. CIT included any MCL treatment with chemotherapy + anti-CD20 antibody. NTs included BTKis, BCL2 inhibitors, lenalidomide, bortezomib, and CAR-T, or combinations.
Results:This study included 1,377 pts with R/R MCL who received 2L+ therapy. Of these, 1,028 (75%) were non-Latinx (NL)-White, 53 (4%) were NL-Black, 86 (6%) were Latinx, 108 (8%) were NL-Asian or other race, and 102 (7%) were of unknown/undocumented race. The overall 2L+ population had a median age of 71 y (range 63-78), were mostly male (74%), had a diagnosis of MCL not otherwise specified (NOS; 85%), and had stage IV disease (62%). Sixty-three percent had disease progression within 24 mo from first-line (1L) treatment (POD24) before starting 2L therapy. Relative to all pts, NL-Black and NL-Asian/other race pts had more variants of MCL (blastic, leukemic, pleomorphic) and higher Ki67% and lactose dehydrogenase (LDH) levels at 2L/3L index date. In contrast, Latinx pts had more MCL NOS (92%) and lower Ki67% and LDH levels at 2L index date. More NL-Black and unknown race pts had POD24 than did other races (70% and 76%, respectively).
Overall, the most common NTs used were BTKis. 1L treatments were bendamustine-rituximab (BR; 54%), R-CHOP (18%), and cytarabine-containing CIT (9.7%). The most common 2L treatments were BR (32%), acalabrutinib (31%), ibrutinib (21%), zanubrutinib (11%), and RCHOP (11%). The most common 3L therapies were BR (34%), acalabrutinib (21%), zanubrutinib (12%), ibrutinib (10%), R-CHOP (9.2%), and brexucabtagene autoleucel (7.4%). Transplantation rates before 2L and CAR-T use in 3L was highest among White pts.
When assessing mrwTTNT and mrwOS by therapy in 2L, 766 pts (70%) received NTs and 333 (30%) received CIT. Among all pts, mrwTTNT (mo [95% CI]) was longer with 2L NT (11.9 [10.6, 14.5]) vs CIT (9.9 [8.1, 12.9]). NL-White, NL-Black, and NL-Asian/other race pts had longer mrwTTNT with NT (11.9 [10.5, 14.6], 12.9 [7.6, NR], and 14.6 [8.5, 21.4], respectively) vs CIT (9.9 [7.6, 12.9], 9.7 [3.0, NR], and 6.0 [3.2, 21.2]). Latinx pts had longer mrwTTNT with CIT (14.9 [11.8, NR]) vs NT (9.0 [3.8, 24.2]).
Among all pts, mrwOS (mo [95% CI]) was longer with 2L CIT (43.0 [34.1, 56.5]) vs NT (35.6 [29.9, 41.2]). White and Latinx pts had longer mrwOS with CIT (47.3 [33.9, NR] and NR [33.3, NR], respectively) vs NT (35.0 [28.8, 48.4] and 42.3 [31.0, NR]). Black and Asian/other race pts had longer mrwOS with NT (41.2 [32.8, NR] and 38.8 [23.5, NR], respectively) vs CIT (34.8 [9.7, NR] and 13.5 [8.3, NR]).
Among all 3L pts (n=364 on NTs, n=119 on CIT), mrwTTNT (mo [95% CI]) improved when using NTs (7.9 [6.8, 10.3]) vs CIT (4.4 [3.5, 6.9]). NTs demonstrated better mrwTTNT vs CIT in all race/ethnic groups except Latinx pts. For all race/ethnic groups, mrwOS was improved with NTs (32.5 [24.7, 42.6]) vs CIT (19.5 [13.7, 47.3]).
Overall RW testing for TP53 aberrations was limited, with 72 pts (5%) found to be positive for a TP53 mutation. For pts with TP53 mutations, mrwTTNT and mrwOS were longer for 2L NTs (3.3 [2.2, 6.4] and 18.3 [9.0, NR], respectively; n=42) vs CIT (3.0 [1.9, 7.6] and 15.0 [7.2, NR]; n=16).
Conclusions: High-risk features, treatment patterns, and clinical outcomes for NTs vs CIT in R/R MCL differed by race/ethnicity. Use of 2L+ NTs was associated with a trend towards improved mrwTTNT and mrwOS among NL-Black and NL-Asian/other race pts. NT use in 3L numerically improved mrwTTNT and mrwOS for most pts vs CIT. RW pts with TP53 mutations had a poor prognosis and numerically improved outcomes with the use of 2L NT, although testing remains limited. Future research evaluating reasons for these differences and increased RW TP53 testing is warranted.