Ibrutinib improves survival compared to chemotherapy in mantle cell lymphoma with central nervous system relapse

Abstract

Central nervous system (CNS) relapse of Mantle Cell Lymphoma (MCL) is a rare phenomenon with dismal prognosis, where no standard therapy exists. Since the covalent Bruton tyrosine kinase inhibitor ibrutinib is effective in relapsed/refractory MCL and it penetrates the blood-brain barrier (BBB), on behalf of Fondazione Italiana Linfomi and European Mantle Cell Lymphoma Network we performed a multicenter retrospective international study to investigate the outcomes of patients treated with ibrutinib or chemo-immunotherapy.

In this observational study we recruited MCL patients with CNS involvement at relapse, who received CNS directed therapy between 2000 to 2019. The primary objective was to compare overall survival (OS) of patients treated with ibrutinib or BBB crossing chemotherapy.

A propensity score based on a multivariable binary regression model was applied to balance treatment cohorts. Eighty-eight patients were included. Median age at study entry was 65 years (range: 39-87), 76% were males, and median time from lymphoma diagnosis to CNS relapse was 16 months (range: 1-122).

Patients were treated with ibrutinib (n=29, ibrutinib cohort), BBB crossing chemotherapy, i.e. high-dose methotrexate ± cytarabine (n=29, BBB cohort), or miscellaneous treatments (n=30, other therapy cohort). Both median OS (16.8 versus 4.4 months; p=0.007) and median PFS (13.1 versus 3.0 months; p=0.009) were superior in the ibrutinib cohort as compared to BBB cohort.

Multivariable Cox regression model revealed that ibrutinib therapeutic choice was the strongest independent favorable predictive factor for both OS (HR: 6.8, 95% CI: 2.2-21.3; p <0.001) and PFS (HR 4.6, 95% CI: 1.7-12.5; p=0.002), followed by CNS progression of disease (POD) > 24 months from first MCL diagnosis (HR for death: 2.4, 95% CI: 1.1-5.3; p=0.026; HR for death or progression: 2.3, CI 95%: 1.1-4.6; p=0.023). The addition of intrathecal chemotherapy to systemic CNS directed therapy was not associated with superior OS (p=0.502), as the morphological variant (classical versus others, p=0.118).

Ibrutinib was associated with superior survival compared to BBB penetrating chemotherapy in patients with CNS relapse of MCL, and should be considered as a therapeutic option.