Real-World Characteristics and Survival Outcomes of Patients with Mantle Cell Lymphoma Treated with Covalent Bruton's Tyrosine Kinase Inhibitors in First-Line

Introduction: The advancement of covalent Bruton's tyrosine kinase inhibitors (cBTKi) into the first-line (1L) setting to improve outcomes in patients with Mantle Cell Lymphoma (MCL) is a highly attractive treatment approach, given the rapid disease progression and poor outcomes after treatment failure in the relapsed/refractory setting. A few prospective studies have combined cBTKi with cytotoxic chemotherapy to achieve this aim without demonstrating a survival advantage. This study analyzed the real-world characteristics and survival outcomes of patients with MCL treated with a cBTKi without cytotoxic chemotherapy in the 1L setting.

Methods:This longitudinal, retrospective cohort study used patient-level data from the nationwide Flatiron Health electronic health record-derived de-identified database. We included patients who had a chart-confirmed diagnosis of MCL between November 1, 2013 and November 30, 2023 and evidence of receiving a cBTKi in the 1L setting as monotherapy or in combination with an anti-CD20 monoclonal antibody (mAb), allowing for at least 6 months of potential follow-up before the data cut-off date (May 30, 2024). Outcomes included real-world progression-free survival (rwPFS), real-world event-free survival (rwEFS), and real-world overall survival (rwOS). Descriptive statistics and time-to-event analysis via the Kaplan-Meier method were employed. The log-rank test was used to compare survival outcomes between patients who received cBTKi monotherapy and patients who received cBTKi plus an anti-CD20 mAb.

Results:We selected 4500 patients who started 1L therapy for MCL during the study period, of which 217 initiated cBTKi as monotherapy (66%) or in combination with an anti-CD20 mAb (34%). Among those who initiated any cBTKi therapy, the median age at initiation of 1L treatment was 75 years (interquartile range, 66-82). The majority of patients were male (67%), White (86%), non-Hispanic/Latino (94%), and treated in a community setting (70%), while 50% had an Eastern Cooperative Oncology Group performance status of less than 2. Patients varied by socioeconomic status (SES; from low to high area-level SES index quintile 1 [10%], 2 [12%], 3 [13%], 4 [25%], 5 [29%], Unknown [12%]). Patients treated with cBTKi monotherapy were diagnosed in earlier years (median, 2018) compared with those treated with cBTKi in combination with an anti-CD20 mAb (median, 2021).

Patients with stage IV disease accounted for 42% of the cohort and only 9% had bulky disease. Aggressive morphologic variants were described in a small portion of the population with 8% having a blastoid variant and 5% having the pleomorphic variant. Leukemic disease was described for 9% of the cohort. Detected biomarkers were as follows: 33% had a high Ki67 (≥30%), 13% had a TP53 mutation, and 24% had SOX11 expression. Only 26% of the patients had elevated lactate dehydrogenase, and 9% had impaired renal function (estimated glomerular filtration rate < 45 mL/min).

After a median follow-up of 29 months (mo), the cBTKi monotherapy cohort had a rwPFS of 14.2 mo (95% confidence interval [CI], 12.8-22.8), rwEFS of 14.0 mo (95% CI, 11.5-22.8), and rwOS of 30.7 mo (95% CI, 24.8-37.5). In combination with an anti-CD20 mAb, the median follow-up was 23 mo with a rwPFS of 31.6 mo (13.3-59.5), rwEFS of 27.8 mo (13.3-54.2), and rwOS of 52.3 mo (41.6-not reached). All three endpoints were significantly different between cBTKi monotherapy and cBTKi plus anti-CD20 mAb groups (p<0.05). Among all patients treated with a cBTKi, 51% initiated second-line therapy, and 2% received stem cell transplantation in 1L or later.

Conclusions:In this retrospective analysis, we described the 1L off-label use of cBTKi in a real-world setting for patients with MCL. This population is characterized by advanced age without notable adverse risk factors such as poor performance status or renal dysfunction. Patients who received a cBTKi plus an anti-CD20 mAb had better outcomes compared with patients who received cBTKi monotherapy.

This study highlights the need for guidance in the treatment and development of tolerable and effective therapies for the 1L treatment of patients with MCL, while suggesting that the use of a cBTKi plus an anti-CD20 mAb may improve outcomes, especially for those who are older (aged ≥66).

Sawas:Kite: Honoraria; Lilly: Honoraria; Seagen: Honoraria; Flatiron Health Inc.: Current Employment, Current equity holder in publicly-traded company; Daiichi: Honoraria. Brown Wadé:Flatiron Health Inc.: Current Employment, Current equity holder in publicly-traded company. Roose:Roche Group: Current equity holder in publicly-traded company; Flatiron Health: Current Employment.

Covalent bruton's tyrosine kinase Inhibitors are not FDA approved in the front line treatment for patients with mantle cell lymphoma. This research describes the off label use of these agents in the clinical setting.