Ibrutinib improves survival compared with 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 (BTK) inhibitor ibrutinib is effective in relapsed/refractory MCL and 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 chemoimmunotherapy. In this observational study, we recruited patients with MCL with CNS involvement at relapse who received CNS-directed therapy between 2000 and 2019. The primary objective was to compare the 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. The median age at study entry was 65 years (range, 39-87), 76% were males, and the 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 (ie, high-dose methotrexate ± cytarabine; n = 29, BBB cohort), or miscellaneous treatments (n = 30, other therapy cohort). Both median OS (16.8 vs 4.4 months; P = .007) and median progression-free survival (PFS) (13.1 vs 3.0 months; P = .009) were superior in the ibrutinib cohort compared with the BBB cohort. Multivariable Cox regression model revealed that ibrutinib therapeutic choice was the strongest independent favorable predictive factor for both OS (hazard ratio [HR], 6.8; 95% confidence interval [CI], 2.2-21.3; P < .001) and PFS (HR, 4.6; 95% CI, 1.7-12.5; P = .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 = .026; HR for death or progression, 2.3; 95% CI, 1.1-4.6; P = .023). The addition of intrathecal (IT) chemotherapy to systemic CNS-directed therapy was not associated with superior OS (P = .502) as the morphological variant (classical vs others, P = .118). Ibrutinib was associated with superior survival compared with BBB-penetrating chemotherapy in patients with CNS relapse of MCL and should be considered as a therapeutic option.

Gene-edited and -engineered stem cell platform drives immunotherapy for brain metastatic melanomas

“…IT injection for patients with LM is feasible because the IT technique is common and clinically used for pain control after surgery (65). This is supported by the previous studies in which IT-delivered chemotherapy was tested in patients with LM and CNS lymphoma (66,67). Our results support that allogeneic SC-based OV immunotherapy is widely applicable to varying forms of clinical metastases, including LM.…”

How I manage mantle cell lymphoma: indolent versus aggressive disease

“…7 The presence of blastoid morphology and a high-risk MIPI score increase the risk of central nervous system involvement in MCL, which has been associated with a poor prognosis, although more recently promising results have been reported with ibrutinib. 27,28 Biological factors…”

“…GI involvement is relatively common but its prognostic significance is unclear – one previous retrospective analysis compared patients with primary (isolated) GI MCL with non‐isolated GI cases and found that although primary GI MCL was often managed more conservatively, long‐term survival rates were very similar 7 . The presence of blastoid morphology and a high‐risk MIPI score increase the risk of central nervous system involvement in MCL, which has been associated with a poor prognosis, although more recently promising results have been reported with ibrutinib 27,28 …”

Claiming the mantle of the brain

“…In this issue of Blood, Rusconi et al provide evidence that ibrutinib improves survival compared with chemotherapy that crosses the blood-brain barrier (BBB) in patients with central nervous system (CNS) relapse of mantle cell lymphoma (MCL). 1 The development of CNS involvement or CNS relapse poses a significant clinical challenge in the management of MCL. In a retrospective series, the overall incidence of CNS relapse in MCL is uncommon, reportedly in the range of 4% to 5% in unselected cohorts.…”