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

Author(s): Chiara Rusconi1; Chan Y. Cheah2,3; Toby A. Eyre3; David Tucker4; Pavel Klener5; Eva Giné6; Lara Crucitti7; Cristina Muzi7; Sara Iadecola8; Gabriele Infante9; Sophie Bernard10; Rebecca L. Auer11; Chiara Pagani12; Monika Duglosz-Danecka13; Heidi Mocikova14; Tom van Meerten15; Emanuele Cencini16; Ana Marin-Niebla17; Michael E. Williams18; Piera Angelillo19; Paolo Nicoli20; Annalisa Arcari21; Lucia Morello22; Donato Mannina23; Orsola Vitagliano24; Roberto Sartori25; Annalisa Chiappella26; Roberta Sciarra27; Piero M. Stefani28; Martin Dreyling29; John F. Seymour30; Carlo Visco31
Source: Blood (2022) 140 (17): 1907–1916
Maem Hussein MD

Dr. Maen Hussein's Thoughts

This is not a randomized study, results though can not be ignored since ibrutinib is less toxic than many of the treatments used.


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.

Author Affiliations

1Division of Hematology and Bone Marrow Transplantation, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy; 2Department of Hematology, Sir Charles Gairdner Hospital, Perth, Australia; 3Oxford University Hospitals, NHS Foundation Trust, Oxford Cancer and Haematology Centre, Churchill Hospital, Oxford, United Kingdom; 9Department of Clinical Sciences and Community Health, University of Milan, Milan, Italy; 8Unit of Clinical Epidemiology and Trial Organization, Department of Applied Research and Technology Development, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy; 7Division of Hematology, ASST Grande Ospedale Metropolitano Niguarda, Milan, Italy; 6Hematology Department, Hospital Clínic, Barcelona, Spain; 5First Department of Internal Medicine-Hematology, General University Hospital in Prague and First Faculty of Medicine, Charles University, Prague, Czech Republic; 4Department of Haematology, Royal Cornwall Hospital NHS Trust, Truro, United Kingdom; 26Division of Hematology, A.O. Città della Salute e della Scienza di Torino, Torino, Italy; 25Onco Hematology Unit, Istituto Oncologico Veneto IOV-IRCSS, Castelfranco Veneto, Italy; 24Division of Hematology, Cardarelli Hospital, Napoli, Italy; 23UOC di Ematologia, Azienda Ospedaliera Papardo, Messina, Italy; 22Department of Medical Oncology and Hematology, Humanitas Clinical and Research Center-IRCCS, Rozzano, Milan, Italy; 21Haematology and Bone Marrow Transplant Unit, “Guglielmo da Saliceto” Hospital, Piacenza, Italy; 20SCDU Medicina Interna a Indirizzo Ematologico, AOU San Luigi Gonzaga, Orbassano, Italy; 19Lymphoma Unit Department of OncoHematology San Raffaele Scientific Institute, Milan, Italy; 18Hematology/Oncology Division, University of Virginia Cancer Center, Charlottesville, VA; 17Hematology Department, Vall d’Hebron Institute of Oncology, Barcelona, Spain; 16U.O.C. Ematologia, Ospedale Policlinico Santa Maria alle Scotte, Siena, Italy; 15University Medical Center Groningen, University of Groningen, Groningen, The Netherlands; 14Third Faculty of Medicine, University Hospital Kralovske Vinohrady, Charles University in Prague, Czech Republic; 13Department of Clinical Oncology, Maria Sklodowska-Curie National Institute of Oncology, Cracow, Poland; 12Divisione di Ematologia, ASST Spedali Civili, Brescia, Italy; 11Centre for Haemato-Oncology, St.Bartholomew’s Hospital Barts Health NHS Trust, London, United Kingdom; 10APHP, Saint-Louis Hospital, Hemato-oncology Department, Paris & University of Paris, Diderot University, Paris, France; 31Department of Medicine, Section of Hematology, University of Verona, Verona, Italy; 30Department of Hematology, Peter MacCallum Cancer Centre & Royal Melbourne Hospital, Melbourne, Australia; 29Department of Medicine III, LMU University Hospital, Munich, Germany; 28U.O.C. di Ematologia, Dipartimento di Medicina Specialistica, Unità Locale Socio-Sanitaria della Marca Trevigiana, Treviso, Italy; 27Division of Hematology, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy

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