Background

Central nervous system (CNS) involvement is a rare complication (<5% of cases) of mantle cell lymphoma (MCL) and is associated with poor outcomes, highlighting the need for novel treatment approaches. We report the outcomes of a large cohort of patients (pts) with CNS MCL from Mayo Clinic and Memorial Sloan Kettering Cancer Center (MSKCC).

Methods

MCL pts with CNS involvement seen at Mayo Clinic and MSKCC between 1/2000-1/2021 were included. CNS involvement was defined by histologically confirmed CNS MCL, CSF analysis demonstrating lymphoma cells, and/or neuroimaging findings compatible with CNS lymphoma. Medical records were reviewed for baseline characteristics, treatment, and outcomes. First-line MCL chemotherapy was categorized into higher intensity chemotherapy (i.e., anthracycline-based +/- high-dose cytarabine), moderate intensity chemotherapy (i.e., bendamustine-based regimens or single agent chemotherapy), and other. CNS treatment regimens were categorized as intrathecal (IT) therapy alone, systemic therapy (with CNS penetration such as IV cytarabine or IV methotrexate) with/without IT therapy, regimens with Bruton's tyrosine kinase inhibitors (BTKi), chimeric antigen receptor T cell (CAR-T) therapy, or radiation alone. Kaplan-Meier method was used for time to event analysis. Forest plots were developed using univariable Cox proportional hazards models.

Results

Seventy patients were included in the cohort, 34 from MSKCC and 36 from Mayo Clinic. Median age at MCL diagnosis was 65 years (range 56-72) and 52 were male (74%). MIPI score was available in 60 pts: low (n=10, 17%), intermediate (n=20, 33%), and high (n=30, 50%) risk. First line therapy included: higher intensity chemotherapy (n=42, 60%), moderate intensity chemotherapy (n=25, 36%) and other (n=3, 4%). Twenty-five (36%) pts underwent autologous hematopoietic cell transplantation in CR1.

Median time from initial MCL diagnosis to CNS involvement was 24 months (m) (range 0-167). Four (6%) pts had CNS involvement at initial diagnosis. Abnormal CNS imaging was reported in 53 (76%) pts: leptomeningeal (n=37), leptomeningeal and parenchymal (n=4), parenchymal (n=8), orbital (n=4). The most common regimen following CNS diagnosis was systemic therapy with or without IT therapy (n=34, 54%) followed by treatment including BTKi (n=13, 21%), IT alone (n=10, 16%), radiation alone (n=3, 5%), and treatment including CAR-T (n=3, 5%). Three patients elected hospice care and four patients had missing/unknown CNS treatment.

The overall CNS response to therapy was available in 54 patients: CR in 22 (41%) pts, PR in 8 (15%), SD in 11 (20%), and PD in 13 (24%) pts.

Of the 70 patients, 63 died. Median follow up was 6.9 years (range: 1.6-11.2) from initial MCL diagnosis and 2.1 years from CNS diagnosis (range: 0.4-7.9). Median OS from MCL diagnosis was 3.4 years (95% CI: 2.4-4.6). In univariable Cox models, sex, stage, performance status, Ki67, or first line systemic chemotherapy type were not significantly associated with OS from MCL diagnosis. Low risk MIPI score (score < 5.7) was associated with favorable OS (HR 0.31, 94% CI: 0.12-0.77; p value 0.01) compared to high risk. First-line treatment and treatment intensity were not associated with a significant difference in OS. Median PFS for the first CNS-directed therapy was 2.4 m (95% CI: 1.7-4.3). Cause of death was disease-related in a majority (n=49, 78%) of pts and therapy-related in 10% (n=6). The remaining 8 deaths had cause of death reported as missing or other (13%). Median OS from CNS involvement was 5.1 m (95% CI: 3.3-10.0) (Figure 1). When assessing OS from time of CNS diagnosis, treatment regimens incorporating BTK inhibitors were associated with a more favorable OS compared to systemic therapy +/- IT therapy (HR=0.37, 95% CI: 0.16-0.89, p value=0.03) (Figure 2).

Conclusions

Our dual center series confirms patients with CNS involvement by MCL have poor outcomes. When evaluating OS from the time of CNS diagnosis, novel therapies, including BTKi and CAR-T, may be more effective than CNS-penetrant chemotherapy for treatment of CNS relapse suggesting newer therapeutic approaches are required to improve outcomes.

Wang:Kite: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; TG Therapeutics: Membership on an entity's Board of Directors or advisory committees; Genmab: Research Funding; Genentech: Research Funding; Novartis: Research Funding; Morphosys: Research Funding; Eli Lilly: Membership on an entity's Board of Directors or advisory committees, Research Funding; LOXO Oncology: Membership on an entity's Board of Directors or advisory committees, Research Funding; Innocare: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Incyte: Membership on an entity's Board of Directors or advisory committees, Research Funding; BeiGene: Membership on an entity's Board of Directors or advisory committees; Astra Zeneca: Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy. Witzig:ADC: Membership on an entity's Board of Directors or advisory committees; Salarius Pharma: Membership on an entity's Board of Directors or advisory committees; Kura Oncology: Research Funding; Karyopharm: Research Funding. Zelenetz:Janssen Pharmaceuticals: Consultancy, Honoraria; SAB: Membership on an entity's Board of Directors or advisory committees; Abbvie: Research Funding; AstraZeneca: Consultancy, Honoraria; BeiGene: Consultancy, Honoraria, Research Funding; Pharmacyclics: Consultancy, Honoraria; Gilead: Consultancy, Honoraria; F. Hoffmann-La Roche Ltd: Consultancy, Honoraria, Research Funding; MEI Pharma Inc: Consultancy, Honoraria, Research Funding; None other than mutual funds (401K): Current equity holder in publicly-traded company; BMS: Consultancy, Honoraria; Lymphoma Research Foundation: Membership on an entity's Board of Directors or advisory committees. Scordo:Medscape, LLC: Honoraria; Angiocrine Bioscience, Inc.: Research Funding; Omeros Corporation: Consultancy, Research Funding; Amgen, Inc.: Research Funding; CancertNetwork (Intellisphere LLC): Honoraria. Hamlin:ADC Therapeutics: Consultancy. Bennani:Acrotech: Other: Advisory board; No personal compensation; Acrotech: Other: Scientific Advisory Committee, No personal compensation ; Affimed: Other: Advisory board; No personal compensation; Secura Bio: Other: Advisory board; No personal compensation; Kymera: Other: Advisory board; No personal compensation; Astellas Pharma: Other: Advisory board; No personal compensation. Nowakowski:Blueprint Medicines: Consultancy; Bantam Pharmaceutical LLC: Consultancy; Abbvie: Consultancy; Debiopharm: Consultancy; Kite Pharma: Consultancy; Fate Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees; F Hoffmann-La Roche Limited: Consultancy; Celgene Corporation: Consultancy; ADC Therapeutics: Consultancy; MorphoSys: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; TG Therapeutics: Consultancy; Genentech: Consultancy; Incyte: Consultancy; Karyopharm Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees; Ryvu Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Curis: Consultancy; Kymera Therapeutics: Consultancy; MEI Pharma: Consultancy; Seagen: Consultancy; Selvita Inc: Consultancy; Zai Lab Limited: Consultancy. Habermann:sorrento: Research Funding; Genentech: Research Funding; BMS: Research Funding. Ansell:Bristol-Myers Squibb: Other: Contracted Research; Takeda Pharmaceuticals USA Inc: Other: Contracted Research; Seagen Inc: Other: Contracted Research; Pfizer, Inc: Other: Contracted Research; Affirmed: Other: Contracted Research; ADC Therapeutics: Other: Contracted Research; Regeneron Pharmaceuticals Inc: Other: Contracted Research. Kumar:Abbvie Pharmaceuticals: Research Funding; Pharmacyclics: Research Funding; Adaptive Biotechnologies: Research Funding; Loxo/Lily Oncology: Consultancy, Research Funding; Astra Zeneca: Consultancy, Research Funding; Kite Pharma: Consultancy; Beigene: Research Funding; BridgeBio: Current equity holder in publicly-traded company; Janssen: Consultancy; Celgene: Research Funding; Genentech: Consultancy, Research Funding; Seattle Genetics: Research Funding. Paludo:AbbVie: Consultancy; Karyopharm: Research Funding; Biofourmis: Research Funding.

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2023
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