Ostrom QT, Cioffi G, Waite K, Kruchko C, Barnholtz-Sloan JS. CBTRUS statistical report: primary brain and other central nervous system tumors diagnosed in the United States in 2014-2018. Neuro Oncol. 2021;23(12 Suppl 2):iii1-iii105.

Grommes C, Rubenstein JL, DeAngelis LM, Ferreri AJM, Batchelor TT. Comprehensive approach to diagnosis and treatment of newly diagnosed primary CNS lymphoma. Neuro Oncol. 2019;21(3):296–305.

PubMed  Google Scholar 

Rubenstein JL, Gupta NK, Mannis GN, Lamarre AK, Treseler P. How I treat CNS lymphomas. Blood. 2013;122(14):2318–30.

CAS  PubMed  PubMed Central  Google Scholar 

Illerhaus G, Kasenda B, Ihorst G, Egerer G, Lamprecht M, Keller U, Wolf HH, Hirt C, Stilgenbauer S, Binder M, Hau P, Edinger M, Frickhofen N, Bentz M, Möhle R, Röth A, Pfreundschuh M, von Baumgarten L, Deckert M, et al. High-dose chemotherapy with autologous haemopoietic stem cell transplantation for newly diagnosed primary CNS lymphoma: a prospective, single-arm, phase 2 trial. Lancet Haematol. 2016;3(8):e388–97.

PubMed  Google Scholar 

• DeAngelis LM, Yahalom J, Thaler HT, Kher U. Combined modality therapy for primary CNS lymphoma. J Clin Oncol. 1992;10(4):635-43. Note: This reference is of outstanding importance as this paradigm shifting trial demonstrated the significant survival benefit resulting from the addition of HD-MTX to conventional WBRT in PCNSL patients.

• Batchelor T, Carson K, O'Neill A, Grossman SA, Alavi J, New P, et al. Treatment of primary CNS lymphoma with methotrexate and deferred radiotherapy: a report of NABTT 96-07. J Clin Oncol. 2003;21(6):1044-9. Note: This reference is of outstanding importance as this trial suggested that HD-MTX without additional WBRT results in similar outcome and lower toxicity rates.

Ferreri AJM, Cwynarski K, Pulczynski E, Fox CP, Schorb E, La Rosée P, et al. Whole-brain radiotherapy or autologous stem-cell transplantation as consolidation strategies after high-dose methotrexate-based chemoimmunotherapy in patients with primary CNS lymphoma: results of the second randomisation of the International Extranodal Lymphoma Study Group-32 phase 2 trial. Lancet Haematol. 2017;4(11):e510–e23.

PubMed  Google Scholar 

Houillier C, Taillandier L, Dureau S, Lamy T, Laadhari M, Chinot O, Moluçon-Chabrot C, Soubeyran P, Gressin R, Choquet S, Damaj G, Thyss A, Abraham J, Delwail V, Gyan E, Sanhes L, Cornillon J, Garidi R, Delmer A, et al. Radiotherapy or autologous stem-cell transplantation for primary CNS lymphoma in patients 60 years of age and younger: results of the intergroup ANOCEF-GOELAMS randomized phase II PRECIS study. J Clin Oncol. 2019;37(10):823–33.

CAS  PubMed  Google Scholar 

Jahnke K, Thiel E, Martus P, Herrlinger U, Weller M, Fischer L, Korfel A, on behalf of the German Primary Central Nervous System Lymphoma Study Group (G-PCNSL-SG). Relapse of primary central nervous system lymphoma: clinical features, outcome and prognostic factors. J Neurooncol. 2006;80(2):159–65.

PubMed  Google Scholar 

Nayak L, Hedvat C, Rosenblum MK, Abrey LE, DeAngelis LM. Late relapse in primary central nervous system lymphoma: clonal persistence. Neuro Oncol. 2011;13(5):525–9.

PubMed  PubMed Central  Google Scholar 

Langner-Lemercier S, Houillier C, Soussain C, Ghesquières H, Chinot O, Taillandier L, Soubeyran P, Lamy T, Morschhauser F, Benouaich-Amiel A, Ahle G, Moles-Moreau MP, Moluçon-Chabrot C, Bourquard P, Damaj G, Jardin F, Larrieu D, Gyan E, Gressin R, et al. Primary CNS lymphoma at first relapse/progression: characteristics, management, and outcome of 256 patients from the French LOC network. Neuro Oncol. 2016;18(9):1297–303.

PubMed  PubMed Central  Google Scholar 

• Plotkin SR, Betensky RA, Hochberg FH, Grossman SA, Lesser GJ, Nabors LB, et al. Treatment of relapsed central nervous system lymphoma with high-dose methotrexate. Clin Cancer Res. 2004;10(17):5643-6. Note: This reference is of importance as this retrospective clinical study revealed HD-MTX remains an effective treatment in recurrent primary CNS lymphoma cases with initial response to HD-MTX-based first-line therapy.

Pentsova E, Deangelis LM, Omuro A. Methotrexate re-challenge for recurrent primary central nervous system lymphoma. J Neurooncol. 2014;117(1):161–5.

CAS  PubMed  PubMed Central  Google Scholar 

• Kasenda B, Ihorst G, Schroers R, Korfel A, Schmidt-Wolf I, Egerer G, et al. High-dose chemotherapy with autologous haematopoietic stem cell support for relapsed or refractory primary CNS lymphoma: a prospective multicentre trial by the German Cooperative PCNSL study group. Leukemia. 2017;31(12):2623-9. Note: This study is of importance as it showed that high-dose chemotherapy followed by autologous stem cell transplantation appears to be an effective treatment for selected patients with recurrent primary CNS lymphoma resulting in promising outcome and moderate toxicities.

Hottinger AF, DeAngelis LM, Yahalom J, Abrey LE. Salvage whole brain radiotherapy for recurrent or refractory primary CNS lymphoma. Neurology. 2007;69(11):1178–82.

PubMed  Google Scholar 

Nguyen PL, Chakravarti A, Finkelstein DM, Hochberg FH, Batchelor TT, Loeffler JS. Results of whole-brain radiation as salvage of methotrexate failure for immunocompetent patients with primary CNS lymphoma. J Clin Oncol. 2005;23(7):1507–13.

PubMed  Google Scholar 

Grommes C, Nayak L, Tun HW, Batchelor TT. Introduction of novel agents in the treatment of primary CNS lymphoma. Neuro Oncol. 2019;21(3):306–13.

PubMed  Google Scholar 

Kim P, Omuro A. Consolidation therapy in primary central nervous system lymphoma. Curr Treat Options Oncol. 2020;21(9):74.

PubMed  Google Scholar 

Chapuy B, Roemer MG, Stewart C, Tan Y, Abo RP, Zhang L, et al. Targetable genetic features of primary testicular and primary central nervous system lymphomas. Blood. 2016;127(7):869–81.

CAS  PubMed  PubMed Central  Google Scholar 

Kaulen LD, Erson-Omay EZ, Henegariu O, Karschnia P, Huttner A, Günel M, Baehring JM. Exome sequencing identifies SLIT2 variants in primary CNS lymphoma. Br J Haematol. 2021;193(2):375–9.

CAS  PubMed  Google Scholar 

Fukumura K, Kawazu M, Kojima S, Ueno T, Sai E, Soda M, Ueda H, Yasuda T, Yamaguchi H, Lee J, Shishido-Hara Y, Sasaki A, Shirahata M, Mishima K, Ichimura K, Mukasa A, Narita Y, Saito N, Aburatani H, et al. Genomic characterization of primary central nervous system lymphoma. Acta Neuropathol. 2016;131(6):865–75.

CAS  PubMed  Google Scholar 

Braggio E, Van Wier S, Ojha J, McPhail E, Asmann YW, Egan J, et al. Genome-wide analysis uncovers novel recurrent alterations in primary central nervous system lymphomas. Clin Cancer Res. 2015;21(17):3986–94.

CAS  PubMed  PubMed Central  Google Scholar 

• Vater I, Montesinos-Rongen M, Schlesner M, Haake A, Purschke F, Sprute R, et al. The mutational pattern of primary lymphoma of the central nervous system determined by whole-exome sequencing. Leukemia. 2015;29(3):677-85. Note: This reference is of importance as it represents a high quality exome sequencing study of this rare entity, which provided insights into the genetic landscape of primary CNS lymphomas thereby paving the way for novel targeted therapies.

• Frigault MJ, Dietrich J, Gallagher K, Roschewski M, Jordan JT, Forst D, et al. Safety and efficacy of tisagenlecleucel in primary CNS lymphoma: a phase 1/2 clinical trial. Blood. 2022;139(15):2306-15. Note: This reference is of importance as it demonstrated the safety and efficacy of CAR-T cell therapy for primary CNS lymphomas, which were excluded from most early clinical trials due to the concern for immune effector cell-associated neurotoxicity syndrome.

Karschnia P, Rejeski K, Winkelmann M, Schöberl F, Bücklein VL, Blumenberg V, Schmidt C, Blobner J, von Bergwelt-Baildon M, Tonn JC, Kunz WG, Subklewe M, von Baumgarten L. Toxicities and response rates of secondary CNS lymphoma after adoptive immunotherapy with CD19-directed chimeric antigen receptor T cells. Neurology. 2022;98(21):884–9.

CAS  PubMed  PubMed Central  Google Scholar 

Nayak L, Iwamoto FM, LaCasce A, Mukundan S, Roemer MGM, Chapuy B, Armand P, Rodig SJ, Shipp MA. PD-1 blockade with nivolumab in relapsed/refractory primary central nervous system and testicular lymphoma. Blood. 2017;129(23):3071–3.

CAS  PubMed  PubMed Central  Google Scholar 

Kaulen LD, Gumbinger C, Hinz F, Kessler T, Winkler F, Bendszus M, et al. Intraventricular immune checkpoint inhibition with nivolumab in relapsed primary central nervous system lymphoma. Neurooncol Adv. 2022;4(1):vdac051.

• Grommes C, Tang SS, Wolfe J, Kaley TJ, Daras M, Pentsova EI, et al. Phase 1b trial of an ibrutinib-based combination therapy in recurrent/refractory CNS lymphoma. Blood. 2019;133(5):436-45. Note: This reference is of importance as this clinical trial revealed that targeted treatment approaches with bruton tyrosine kinase inhibitor, ibrutinib, may be combined with HD-MTX and rituximab therapy, which resulted in acceptable toxicity profiles and promising overall response rates in recurrent primary CNS lymphoma.

Houillier C, Chabrot CM, Moles-Moreau MP, Willems L, Ahle G, Waultier-Rascalou A, Fornecker LM, Hoang-Xuan K, Soussain C. Rituximab-lenalidomide-ibrutinib combination for relapsed/refractory primary CNS lymphoma: a case series of the LOC network. Neurology. 2021;97(13):628–31.

CAS  PubMed  Google Scholar 

Ghesquieres H, Chevrier M, Laadhari M, Chinot O, Choquet S, Moluçon-Chabrot C, Beauchesne P, Gressin R, Morschhauser F, Schmitt A, Gyan E, Hoang-Xuan K, Nicolas-Virelizier E, Cassoux N, Touitou V, le Garff-Tavernier M, Savignoni A, Turbiez I, Soumelis V, et al. Lenalidomide in combination with intravenous rituximab (REVRI) in relapsed/refractory primary CNS lymphoma or primary intraocular lymphoma: a multicenter prospective ‘proof of concept’ phase II study of the French Oculo-Cerebral lymphoma (LOC) Network and the Lymphoma Study Association (LYSA)†. Ann Oncol. 2019;30(4):621–8.

CAS  PubMed  Google Scholar 

Rubenstein JL, Geng H, Fraser EJ, Formaker P, Chen L, Sharma J, Killea P, Choi K, Ventura J, Kurhanewicz J, Lowell C, Hwang J, Treseler P, Sneed PK, Li J, Wang X, Chen N, Gangoiti J, Munster PN, Damato B. Phase 1 investigation of lenalidomide/rituximab plus outcomes of lenalidomide maintenance in relapsed CNS lymphoma. Blood Adv. 2018;2(13):1595–607.

CAS  PubMed  PubMed Central  Google Scholar 

Schaff LR, Grommes C. Update on novel therapeutics for primary CNS lymphoma. Cancers (Basel). 2021;13(21).

Ferreri AJ, Cwynarski K, Pulczynski E, Ponzoni M, Deckert M, Politi LS, Torri V, Fox CP, Rosée PL, Schorb E, Ambrosetti A, Roth A, Hemmaway C, Ferrari A, Linton KM, Rudà R, Binder M, Pukrop T, Balzarotti M, et al. Chemoimmunotherapy with methotrexate, cytarabine, thiotepa, and rituximab (MATRix regimen) in patients with primary CNS lymphoma: results of the first randomisation of the International Extranodal Lymphoma Study Group-32 (IELSG32) phase 2 trial. Lancet Haematol. 2016;3(5):e217–27.

PubMed  Google Scholar 

Rubenstein JL, Hsi ED, Johnson JL, Jung SH, Nakashima MO, Grant B, Cheson BD, Kaplan LD. Intensive chemotherapy and immunotherapy in patients with newly diagnosed primary CNS lymphoma: CALGB 50202 (Alliance 50202). J Clin Oncol. 2013;31(25):3061–8.

CAS  PubMed  PubMed Central  Google Scholar 

Omuro A, Chinot O, Taillandier L, Ghesquieres H, Soussain C, Delwail V, Lamy T, Gressin R, Choquet S, Soubeyran P, Huchet A, Benouaich-Amiel A, Lebouvier-Sadot S, Gyan E, Touitou V, Barrié M, del Rio MS, Gonzalez-Aguilar A, Houillier C, et al. Methotrexate and temozolomide versus methotrexate, procarbazine, vincristine, and cytarabine for primary CNS lymphoma in an elderly population: an intergroup ANOCEF-GOELAMS randomised phase 2 trial. Lancet Haematol. 2015;2(6):e251–9.

PubMed  Google Scholar 

Omuro A, Correa DD, DeAngelis LM, Moskowitz CH, Matasar MJ, Kaley TJ, et al. R-MPV followed by high-dose chemotherapy with TBC and autologous stem-cell transplant for newly diagnosed primary CNS lymphoma. Blood. 2015;125(9):1403–10.

CAS  PubMed  PubMed Central  Google Scholar 

Ferreri AJM, Cwynarski K, Pulczynski E, Fox CP, Schorb E, Celico C, Falautano M, Nonis A, la Rosée P, Binder M, Fabbri A, Ilariucci F, Krampera M, Roth A, Hemmaway C, Johnson PW, Linton KM, Pukrop T, Gørløv JS, et al. Long-term efficacy, safety and neurotolerability of MATRix regimen followed by autologous transplant in primary CNS lymphoma: 7-year results of the IELSG32 randomized trial. Leukemia. 2022;36:1870–8.

CAS  PubMed  Google Scholar 

Morris PG, Correa DD, Yahalom J, Raizer JJ, Schiff D, Grant B, Grimm S, Lai RK, Reiner AS, Panageas K, Karimi S, Curry R, Shah G, Abrey LE, DeAngelis LM, Omuro A. Rituximab, methotrexate, procarbazine, and vincristine followed by consolidation reduced-dose whole-brain radiotherapy and cytarabine in newly diagnosed primary CNS lymphoma: final results and long-term outcome. J Clin Oncol. 2013;31(31):3971–9.

CAS  PubMed  PubMed Central  Google Scholar 

Glass J, Won M, Schultz CJ, Brat D, Bartlett NL, Suh JH, Werner-Wasik M, Fisher BJ, Liepman MK, Augspurger M, Bokstein F, Bovi JA, Solhjem MC, Mehta MP. Phase I and II study of induction chemotherapy with methotrexate, rituximab, and temozolomide, followed by whole-brain radiotherapy and postirradiation temozolomide for primary CNS lymphoma: NRG oncology RTOG 0227. J Clin Oncol. 2016;34(14):1620–5.

CAS  PubMed  PubMed Central  Google Scholar 

Fritsch K, Kasenda B, Schorb E, Hau P, Bloehdorn J, Möhle R, Löw S, Binder M, Atta J, Keller U, Wolf HH, Krause SW, Heß G, Naumann R, Sasse S, Hirt C, Lamprecht M, Martens U, Morgner A, et al. High-dose methotrexate-based immuno-chemotherapy for elderly primary CNS lymphoma patients (PRIMAIN study). Leukemia. 2017;31(4):846–52.

CAS  PubMed  Google Scholar 

• Soussain C, Hoang-Xuan K, Taillandier L, Fourme E, Choquet S, Witz F, et al. Intensive chemotherapy followed by hematopoietic stem-cell rescue for refractory and recurrent primary CNS and intraocular lymphoma: Société Française de Greffe de Moëlle Osseuse-Thérapie Cellulaire. J Clin Oncol. 2008;26(15):2512-8. Note: This reference is of oustanding importance as this prospective trial revealed that intensive polychemotherapy followed by autologous stem cell transplantation is an effective and safe treatment option for selected patients with recurrent primary CNS lymphoma.

Mappa S, Marturano E, Licata G, Frezzato M, Frungillo N, Ilariucci F, Stelitano C, Ferrari A, Sorarù M, Vianello F, Baldini L, Proserpio I, Foppoli M, Assanelli A, Reni M, Caligaris-Cappio F, Ferreri AJM. Salvage chemoimmunotherapy with rituximab, ifosfamide and etoposide (R-IE regimen) in patients with primary CNS lymphoma relapsed or refractory to high-dose methotrexate-based chemotherapy. Hematol Oncol. 2013;31(3):143–50.