Contents lists available at ScienceDirect Critical Reviews in Oncology / Hematology journal homepage: www.elsevier.com/locate/critrevonc Primary central nervous system lymphoma: Novel precision therapies Patrizia Mondello a,b, ⁎ , Michael Mian c , Francesco Bertoni d a Department of Medicine, Division of Hematology and Medical Oncology, Weill Cornell Medical College, 413 East 69th Street, 10021 New York, NY, USA b Department of Human Pathology, University of Messina,Via Consolare Valeria, 98125 Messina, Italy c Department of Hematology & CBMT, Ospedale di Bolzano, Via Lorenz Böhler, 5, 39100 Bolzano, Italy d Università della Svizzera italiana, Institute of Oncology Research, Via Vela 6, 6500 Bellinzona, Switzerland ARTICLE INFO Keywords: PCNSL Precision therapies Ibrutinib Lenalidomide Nivolumab Rituximab CAR T-cell Temsirolimus ABSTRACT Primary central nervous system lymphoma (PCNSL) is a rare and aggressive form of diffuse large B-cell lym- phoma. The frontline treatment with high-dose methotrexate based immunochemotherapy is not curative for the majority of patients. Gene expression profiling and next-generation sequencing have recently provided plethora of data shedding light on pathogenic mechanisms sustain PCNSL and identifying potential vulnerable me- chanisms to be explored therapeutically. Here, we review established molecular drivers of PCNSL and targeted drugs that may change the current therapeutic paradigm. 1. Introduction Primary central nervous system lymphoma (PCNSL) is a rare but aggressive form of diffuse large B-cell lymphoma (DLBCL), which can involve brain, spinal cord, meninges and eyes.(Han and Batchelor, 2017) The incidence increases with age and median age of presentation is 65 years old. Although it has a more favorable response to che- motherapy compared to other brain tumors, PCNSL has a poor prog- nosis compared with other DLBCL outside the brain with 5- and 10-year survival rates of 29.9% and 22.2%, respectively.(Ostrom et al., 2015) PCNSL is classified as a distinct subtype of DLBCL in the World Health Organization (WHO) Classification (Swerdlow, 2019) and ex- presses pan B-cell antigens (CD19, CD20 and CD79A)(Giannini et al., 2014). Melanoma associated antigen 1 (MUM1)/interferon regulatory factor 4 (IRF4) is virtually always positive; B cell lymphoma 6 (BCL6) is expressed in about 50% of cases; BCL2 is not constantly expressed; and CD10 is present in a minority of cases.(Giannini et al., 2014) Conse- quently, the majority of PCNSL resembles the activated B cell (ABC) immunophenotype.(Camilleri-Broët et al., 2006) Genomic profiling studies have provided insights into the patho- genesis of this disease. Whole-exome sequencing studies confirmed enrichment of proteins coding mutations that induce NF-kB activation, the majority of which are identified in the ABC subtype. Differently from secondary CNS (SCNSL) DLBCL (Kersten et al., 2014), mutations in the adaptor protein myeloid differentiation primary response 88 (MYD88) and in the B-cell antigen receptor-associated protein cluster of differentiation 79B (CD79B) are detected in about 55% and 40% of cases, respectively.(Knittel et al., 2016) Importantly, the two lesions often co-occur in PCNSL (Chapuy et al., 2016; Lionakis et al., 2017), suggesting a possible oncogenic cooperation in activating NF-kB. No- tably, the mutational frequency for these genes is considerably higher in PCNSL compared to ABC DLBCL outside the brain (Braggio et al., 2015), although it is comparable to two highly overlapping ABC DLBCL subgroups, termed Cluster 5 and MCD, recently described in two se- parate studies (Chapuy et al., 2018; Schmitz et al., 2018). In addition, MYD88 L265P mutation has been detected in cerebrospinal fluid (CSF) https://doi.org/10.1016/j.critrevonc.2019.06.009 Received 5 April 2019; Received in revised form 18 June 2019; Accepted 19 June 2019 Abbreviations: PCNSL, primary central nervous system lymphoma; DLBCL, diffuse large B cell lymphoma; WHO, World Health Organization; MUM1, melanoma associated antigen 1; IRF4, interferon regulatory factor 4; BCL6, B cell lymphoma 6; ABC, activated B cell; SCNSL, secondary CNS; MYD88, myeloid differentiation primary response 88; CD79B, cluster of differentiation 79B; CSF, cerebrospinal fluid; IL-4, interleukin-4; HD-MTX, high-dose methotrexate; HD-ara-C, high dose cytarabine; HDC/ASCT, high-dose chemotherapy consolidation followed by autologous stem cell transplantation; R/R, relapsed/refractory; CR, complete responses; PFS, progression free survival; OS, overall survival; TEDDi-R, temozolomide, etoposide, liposomal doxorubicin, dexamethasone, rituximab plus ibrutinib; PD-1, programmed cell death protein 1; PD-L1, programmed death ligand 1; PR, partial response; PTL, primary testicular lymphoma; IMiD, immunomodulatory drug; AE, adverse event; IV, intravenous; WBRT, whole brain radiation therapy; MVBP, HD-MTX, teniposide, carmustine, and prednisone; CAR, chimeric antigen receptor ⁎ Correspondence author at: Department of Medicine, Division of Hematology and Medical Oncology, Weill Cornell Medical College, 413 East 69th Street, 10021 New York, NY, USA. E-mail address: pam2068@med.cornell.edu (P. Mondello). Critical Reviews in Oncology / Hematology 141 (2019) 139–145 1040-8428/ © 2019 Elsevier B.V. All rights reserved. T