Sequential Bruton Tyrosine Kinase Inhibitor Therapy in Relapsed or Refractory Mantle Cell Lymphoma Following Chemotherapy: Real-World Outcomes and Attrition Rates - an Updated Report from the Asia-Pacific Multinational Retrospective Registry
Authors: Cho Hyungwoo , Yoon Dok Hyun , Chan Jason Yongsheng , Kim Dajung , Huang Haiwen , Cai Qingqing , Lin Tongyu , Kato Koji , Bunworasate Udomsak , Tan Sen Mui , Kang Ka-Won , Kwak Jae-Yong , Chen Tsai-Yun , Lee Jeong-Ok , Jeong Seong Hyun , Do Young Rok , Chan Esther , Kang Hye Jin , Uhm Hyun-Seok , Oh Sung Yong , Koh Youngil , Kim Hyo Jung , Kim Se Hyung , Won Jong Ho , Park Young Hoon , Yang Deok-Hwan , Ng Soo Chin , Jo Jae-Cheol , Kim Won Seog 
Published: December 2024

I ntroduction
We conducted a multinational, multicenter retrospective registry study to evaluate the efficacy of sequential 2L or 3L Bruton Tyrosine Kinase inhibitor (BTKi) therapy following chemotherapy in patients with MCL in the Asia-Pacific region. In addition, we evaluated the prognostic significance of the time to disease progression (POD) following 1L therapy and the attrition rate across each subsequent line of therapy to gain a deeper insight into the real-world outcomes of sequential therapy.
Methods
Data were collected from newly diagnosed MCL patients between January 2008 and November 2020 from 27 hospitals in Asian countries, including China, Malaysia, Japan, Singapore, South Korea, Taiwan, and Thailand. Interim analysis with 289 patients was previously reported. An updated analysis of 632 patients was performed at the data cutoff date of December 15, 2023. Progression-free survival (PFS) was defined as the time from index line treatment start to the first event (progression, relapse, or death). Overall survival (OS) was defined as the time from index line treatment start to death. PFS2 or PFS3 was defined as the time from 1L start to progression, relapse, or death following 2L or 3L treatment, respectively. Attrition was defined as failure to receive a subsequent line of therapy due to death or despite the progression of MCL in patients alive at the time of the last follow-up.
Results
The median age was 62 years (range, 26-90), and 475 patients were male (75.2%). Most of the patients had stage 3 or 4 diseases (n = 552, 87.3%). According to the MIPI score, risk was low in 297 (47.3%), intermediate in 142 (22.5%), and high in 134 (21.2%) patients (unknown in 59 [9.3%] patients). The most frequently administered 1L regimen was R-CHOP or R-CHOP-like regimens (n = 266, 42.1%), followed by cytarabine-containing regimens (n = 200, 31.6%; including R-Hyper-CVAD [n = 91], NORDIC regimen [n = 42], and R-CHOP/R-DHAP [n = 36], and bendamustine-rituximab (BR) (n = 57, 9.0%). With a median follow-up duration of 84.5 months, the median PFS was 35.2 months (95% CI 32.3-41.1), and the median OS was 87.8 months (95% CI 75.4-102.0).
A total of 316 patients were treated with 2L treatment. The most frequently administered 2L regimen was BTKi (n = 73, 23.1%; ibrutinib [n = 70]), followed by BR (n = 61, 19.3%) and cytarabine-containing regimens (n = 61, 19.3%; ESHAP or DHAP with or without rituximab [n = 37]). The median PFS was 16.8 months (95% CI 14.0-20.5). Patients who experienced disease progression to 1L treatment within 24 months (POD ≤ 24, n = 154) were significantly associated with worse PFS and OS compared with patients with POD &gt; 24 (n = 161), with a median PFS of 7.3 (95% CI 5.8-10.8) vs. 27.4 months (95%CI 23.3-42.8) (P &lt; 0.01) and OS of 23.9 (95%CI 15.7-36.3) vs. 77.9 months (95%CI 52.9-105.4) (P &lt; 0.01), respectively. For those who were treated with 2L BTKi, the median PFS2 was 52.5 months (95% CI 42.5-76.1) compared with 41.3 months (95%CI 34.1-49.4) in those who were treated with non-BTKi (P = 0.130).
A total of 169 patients were treated with 3L treatment. The most frequently administered 3L regimen was BTKi (n = 44, 26.0%; ibrutinib [n = 39]), followed by BR (n = 27, 16.0%) and cytarabine-containing regimens (n = 21, 12.4%; ESHAP or DHAP with or without rituximab [n = 11]). The median PFS was 11.6 months (95% CI 9.7-15.8). For those who were treated with BTKi in the 2L (n = 21) or 3L (n = 44) treatment (total 65 patients), the median PFS3 was 68.9 months (95% CI 49.1-77.1) compared with 40.9 months (95%CI 34.6-51.5) in those who were treated with non-BTKi in the 2L and 3L treatment (n = 104) (P = 0.005).
The attrition rates were 21.3% (135/632 patients, 126 due to death), 25.3% (80/316 patients, 78 due to death), and 26.8% (45/169 patients, 42 due to death) for 1L, 2L, and 3L treatment, respectively.
Conclusion
Our study showed that R/R MCL patients in the Asia-Pacific region were mostly treated with BTKis, and the sequential treatment with BTKi in the 2L or 3L demonstrated favorable survival outcomes. Nevertheless, patients with POD &lt; 24 were associated with worse PFS and OS. In addition, the attrition rate increased with each line of therapy, and death was the dominant contributor to attrition across all lines of therapy. These results may indicate that although sequential treatment with a BTKi may provide favorable survival outcomes, the use of more effective treatments in the front-line setting is important for achieving better outcomes for more patients.