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.

1st Department of Internal Medicine Hematology General University Hospital Prague and 1st Faculty of Medicine Charles University Prague Czech Republic

3rd Faculty of Medicine University Hospital Kralovske Vinohrady Charles University Prague Czech Republic

APHP Saint Louis Hospital Hemato oncology Department Paris and University of Paris Diderot University Paris France

Centre for Haemato Oncology St Bartholomew's Hospital Barts Health NHS Trust London United Kingdom

Department of Clinical Oncology Maria Sklodowska Curie National Institute of Oncology Cracow Poland

Department of Clinical Sciences and Community Health University of Milan Milan Italy

Department of Haematology Royal Cornwall Hospital NHS Trust Truro United Kingdom

Department of Hematology Peter MacCallum Cancer Centre and Royal Melbourne Hospital Melbourne Australia

Department of Hematology Sir Charles Gairdner Hospital Perth Australia

Department of Medical Oncology and Hematology Humanitas Clinical and Research Center IRCCS Rozzano Milan Italy

Department of Medicine 3 LMU University Hospital Munich Germany

Department of Medicine Section of Hematology University of Verona Verona Italy

Division of Hematology A O Città della Salute e della Scienza di Torino Torino Italy

Division of Hematology and Bone Marrow Transplantation Fondazione IRCCS Istituto Nazionale dei Tumori Milan Italy

Division of Hematology ASST Grande Ospedale Metropolitano Niguarda Milan Italy

Division of Hematology Cardarelli Hospital Napoli Italy

Division of Hematology Fondazione IRCCS Policlinico San Matteo Pavia Italy

Divisione di Ematologia ASST Spedali Civili Brescia Italy

Haematology and Bone Marrow Transplant Unit Guglielmo da Saliceto Hospital Piacenza Italy

Hematology Department Hospital Clínic Barcelona Spain

Hematology Department Vall d'Hebron Institute of Oncology Barcelona Spain

Hematology Oncology Division University of Virginia Cancer Center Charlottesville VA

Lymphoma Unit Department of OncoHematology San Raffaele Scientific Institute Milan Italy

Onco Hematology Unit Istituto Oncologico Veneto IOV IRCSS Castelfranco Veneto Italy

Oxford University Hospitals NHS Foundation Trust Oxford Cancer and Haematology Centre Churchill Hospital Oxford United Kingdom

SCDU Medicina Interna a Indirizzo Ematologico AOU San Luigi Gonzaga Orbassano Italy

U O C di Ematologia Dipartimento di Medicina Specialistica Unità Locale Socio Sanitaria della Marca Trevigiana Treviso Italy

U O C Ematologia Ospedale Policlinico Santa Maria alle Scotte Siena Italy

Unit of Clinical Epidemiology and Trial Organization Department of Applied Research and Technology Development Fondazione IRCCS Istituto Nazionale dei Tumori Milan Italy

University Medical Center Groningen University of Groningen Groningen The Netherlands

UOC di Ematologia Azienda Ospedaliera Papardo Messina Italy

Blood. 2022 Oct 27;140(17):1835-1836. doi: 10.1182/blood.2022017285. PubMed

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