Controversies and current practices in CNS relapse of diffuse large B-cell lymphoma (2023)

Authors

  • Robert Puckrin, MD, FRCPC
  • Douglas A. Stewart, MD, FRCPC

Abstract

Central nervous system (CNS) relapse is an uncommon complication of diffuse large B-cell lymphoma (DLBCL), occurring in approximately 3–5% of patients and at a median timepoint of 6–9 months from diagnosis. Approximately half of these cases present as isolated CNS relapse caused by occult seeding of the CNS early in the disease course, while the remaining cases occur in the context of concurrent systemic relapse. The median survival after CNS relapse is only 4–6 months, highlighting the unmet need to identify effective prophylaxis and management strategies. This article provides an overview of current controversies and optimal strategies for prognosticating, preventing, and treating CNS relapse in patients with DLBCL.

Author Biographies

Robert Puckrin, MD, FRCPC

Dr. Robert Puckrin is a hematopoietic cell transplant and cellular therapy fellow at the University of Calgary with interests in lymphoma, transplantation, CAR-T cell therapy, and clinical research.

Douglas A. Stewart, MD, FRCPC

Dr. Douglas Stewart obtained his medical degree from the University of Alberta in 1987, completed Internal Medicine and Medical Oncology residencies at the University of Ottawa, and then completed a fellowship in Bone Marrow Transplantation and Lymphoma Management at the University of Nebraska Medical Center in Omaha. Since July 1994, Dr. Stewart has been practicing Medical Oncology at the Tom Baker Cancer Centre in Calgary, where he is a member of the Blood and Marrow Transplant Program, Hematology, and Breast Tumour groups. His clinical research activities involving lymphoma and hematopoietic stem cell transplantation have resulted in over 180 published peer-reviewed manuscripts, and in 2019 he attained the academic rank of Professor Emeritus in the Department of Oncology at the University of Calgary for services in teaching, research, and engagement. Since 2017, Dr. Stewart has held the position of Senior Medical Director of the Cancer Strategic Clinical Network for Alberta Health Services.

References

Savage KJ. Secondary CNS relapse in diffuse large B-cell lymphoma: defining high-risk patients and optimization of prophylaxis strategies. Hematology Am Soc Hematol Educ Program. 2017;2017(1):578-86.

Kansara R, Villa D, Gerrie AS, Klasa R, Shenkier T, Scott DW, et al. Site of central nervous system (CNS) relapse in patients with diffuse large B-cell lymphoma (DLBCL) by the CNS-IPI risk model. Br J Haematol. 2017;179(3):508-10.

El-Galaly TC, Cheah CY, Bendtsen MD, Nowakowski GS, Kansara R, Savage KJ, et al. Treatment strategies, outcomes and prognostic factors in 291 patients with secondary CNS involvement by diffuse large B-cell lymphoma. Eur J Cancer. 2018;93:57-68.

Schmitz N, Zeynalova S, Nickelsen M, Kansara R, Villa D, Sehn LH, et al. CNS International Prognostic Index: A Risk Model for CNS Relapse in Patients With Diffuse Large B-Cell Lymphoma Treated With R-CHOP. J Clin Oncol. 2016;34(26):3150-6.

Klanova M, Sehn LH, Bence-Bruckler I, Cavallo F, Jin J, Martelli M, et al. Integration of cell of origin into the clinical CNS International Prognostic Index improves CNS relapse prediction in DLBCL. Blood. 2019;133(9):919-26.

Alduaij W, Jiang A, Villa D, Collinge B, Ben-Neriah S, Boyle M, et al. Risk of Central Nervous System Involvement in High-Grade B-Cell Lymphoma with MYC and BCL2 Rearrangements: Analysis of a Population-Based Cohort with Routine Fluorescence in Situ Hybridization Testing in British Columbia. Blood. 2022;140(Suppl 1):1332-3.

Boehme V, Schmitz N, Zeynalova S, Loeffler M, Pfreundschuh M. CNS events in elderly patients with aggressive lymphoma treated with modern chemotherapy (CHOP-14) with or without rituximab: an analysis of patients treated in the RICOVER-60 trial of the German High-Grade Non-Hodgkin Lymphoma Study Group (DSHNHL). Blood. 2009;113(17):3896-902.

Harrysson S, Eloranta S, Ekberg S, Enblad G, Jerkeman M, Wahlin BE, et al. Incidence of relapsed/refractory diffuse large B-cell lymphoma (DLBCL) including CNS relapse in a population-based cohort of 4243 patients in Sweden. Blood Cancer J. 2021;11(1):9.

Eyre TA, Djebbari F, Kirkwood AA, Collins GP. Efficacy of central nervous system prophylaxis with stand-alone intrathecal chemotherapy in diffuse large B-cell lymphoma patients treated with anthracycline-based chemotherapy in the rituximab era: a systematic review. Haematologica. 2020;105(7):1914-24.

Abramson JS, Hellmann M, Barnes JA, Hammerman P, Toomey C, Takvorian T, et al. Intravenous methotrexate as central nervous system (CNS) prophylaxis is associated with a low risk of CNS recurrence in high-risk patients with diffuse large B-cell lymphoma. Cancer. 2010;116(18):4283-90.

Ferreri AJ, Bruno-Ventre M, Donadoni G, Ponzoni M, Citterio G, Foppoli M, et al. Risk-tailored CNS prophylaxis in a mono-institutional series of 200 patients with diffuse large B-cell lymphoma treated in the rituximab era. Br J Haematol. 2015;168(5):654-62.

Cheah CY, Herbert KE, O’Rourke K, Kennedy GA, George A, Fedele PL, et al. A multicentre retrospective comparison of central nervous system prophylaxis strategies among patients with high-risk diffuse large B-cell lymphoma. Br J Cancer. 2014;111(6):1072-9.

McKay P, Wilson MR, Chaganti S, Smith J, Fox CP, Cwynarski K, et al. The prevention of central nervous system relapse in diffuse large B-cell lymphoma: a British Society for Haematology good practice paper. Br J Haematol. 2020;190(5):708-14.

Tilly H, Gomes da Silva M, Vitolo U, Jack A, Meignan M, Lopez-Guillermo A, et al. Diffuse large B-cell lymphoma (DLBCL): ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2015;26(Suppl 5):v116-25.

Orellana-Noia VM, Reed D, McCook AA, Sen JM, Barlow CM, Malecek MK, et al. Single-route CNS prophylaxis for aggressive non-Hodgkin lymphomas: real-world outcomes from 21 US academic institutions. Blood. 2022 Jan 20;139(3):413-423. doi:10.1182/blood.2021012888

Jeong H, Cho H, Kim H, Chae H, Lee JB, Lee K, et al. Efficacy and safety of prophylactic high-dose MTX in high-risk DLBCL: a treatment intent-based analysis. Blood Adv. 2021;5(8):2142-52.

Puckrin R, El Darsa H, Ghosh S, Peters A, Owen C, Stewart D. Ineffectiveness of high-dose methotrexate for prevention of CNS relapse in diffuse large B-cell lymphoma. Am J Hematol. 2021;96(7):764-71.

Lewis KL, Jakobsen LH, Villa D, Bobillo S, Ekstroem Smedby K, Savage KJ, et al. High-Dose Methotrexate Is Not Associated with Reduction in CNS Relapse in Patients with Aggressive B-Cell Lymphoma: An International Retrospective Study of 2300 High-Risk Patients. Blood. 2021;138(Suppl 1):181.

Wilson MR, Eyre TA, Kirkwood AA, Wong Doo N, Soussain C, Choquet S, et al. Timing of high-dose methotrexate CNS prophylaxis in DLBCL: a multicenter international analysis of 1384 patients. Blood. 2022;139(16):2499-511.

Shimada K, Yamaguchi M, Atsuta Y, Matsue K, Sato K, Kusumoto S, et al. Rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone combined with high-dose methotrexate plus intrathecal chemotherapy for newly diagnosed intravascular large B-cell lymphoma (PRIMEUR-IVL): a multicentre, single-arm, phase 2 trial. Lancet Oncol. 2020;21(4):593-602.

Conconi A, Chiappella A, Orsucci L, Gaidano G, Ferreri AGM, et al. Intensified (intravenous and intrathecal) CNS prophylaxis in primary testicular diffuse large B-cell lymphoma: 5-year results of the IELSG30 trial. Hematol Oncol. 2021 Jun 17;39(S2). doi:10.1002/hon.48_2879

Doolittle ND, Abrey LE, Shenkier TN, Tali S, Bromberg JE, Neuwelt EA, et al. Brain parenchyma involvement as isolated central nervous system relapse of systemic non-Hodgkin lymphoma: an International Primary CNS Lymphoma Collaborative Group report. Blood. 2008;111(3):1085-93.

Korfel A, Elter T, Thiel E, Hänel M, Möhle R, Schroers R, et al. Phase II study of central nervous system (CNS)-directed chemotherapy including high-dose chemotherapy with autologous stem cell transplantation for CNS relapse of aggressive lymphomas. Haematologica. 2013;98(3):364-70.

Ferreri AJ, Donadoni G, Cabras MG, Patti C, Mian M, Zambello R, et al. High Doses of Antimetabolites Followed by High-Dose Sequential Chemoimmunotherapy and Autologous Stem-Cell Transplantation in Patients With Systemic B-Cell Lymphoma and Secondary CNS Involvement: Final Results of a Multicenter Phase II Trial. J Clin Oncol. 2015;33(33):3903-10.

Ferreri AJM, Doorduijn JK, Re A, Cabras MG, Smith J, Ilariucci F, et al. MATRix-RICE therapy and autologous haematopoietic stem-cell transplantation in diffuse large B-cell lymphoma with secondary CNS involvement (MARIETTA): an international, single-arm, phase 2 trial. Lancet Haematol. 2021;8(2):e110-e21.

Puckrin R, Chua N, Shafey M, Stewart DA. Improving the outcomes of secondary CNS lymphoma with high-dose thiotepa, busulfan, melphalan, rituximab conditioning and autotransplant. Leuk Lymphoma. 2022;63(10):2444-52.

Khwaja J, Kirkwood AA, Isbell LK, Steffanoni S, Goradia H, Pospiech L, et al. International multicentre retrospective analysis of thiotepa-based autologous stem cell transplantation for secondary central nervous system lymphoma. Haematologica. 2022.

Cook MR, Dorris CS, Makambi KH, Luo Y, Munshi P, Donato M, et al. Toxicity and Efficacy of CAR T-cell Therapy in PCNSL and SCNSL: A Meta-Analysis of 128 Patients. Blood Adv. 2022.

Lewis KL, Chin CK, Manos K, Casey J, Hamad N, Crawford J, et al. Ibrutinib for central nervous system lymphoma: the Australasian Lymphoma Alliance/MD Anderson Cancer Center experience. Br J Haematol. 2021;192(6):1049-53.

Ghesquieres H, Chevrier M, Laadhari M, Chinot O, Choquet S, Moluçon-Chabrot C, 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.

Walburn T, Grover NS, Shen CJ, Ranganathan R, Dittus C, Beaven AW, et al. Consolidative or palliative whole brain radiation for secondary CNS diffuse large B-Cell lymphoma. Leuk Lymphoma. 2021;62(1):68-75.

Younes A, Sehn LH, Johnson P, Zinzani PL, Hong X, Zhu J, et al. Randomized Phase III Trial of Ibrutinib and Rituximab Plus Cyclophosphamide, Doxorubicin, Vincristine, and Prednisone in Non-Germinal Center B-Cell Diffuse Large B-Cell Lymphoma. J Clin Oncol. 2019;37(15):1285-95.

Nowakowski GS, Chiappella A, Gascoyne RD, Scott DW, Zhang Q, Jurczak W, et al. ROBUST: A Phase III Study of Lenalidomide Plus R-CHOP Versus Placebo Plus R-CHOP in Previously Untreated Patients With ABC-Type Diffuse Large B-Cell Lymphoma. J Clin Oncol. 2021;39(12):1317-28.

Bernard S, Ghesquieres H, Casasnovas RO, Griolet S, Gomes da Silva M, Feugier P, et al. Incidence of central nervous system relapses in patients with DLBCL treated with lenalidomide as maintenance after R-CHOP. Blood Adv. 2021;5(15):2965-8.

Ollila TA, Kurt H, Waroich J, Vatkevich J, Sturtevant A, Patel NR, et al. Genomic subtypes may predict the risk of central nervous system recurrence in diffuse large B-cell lymphoma. Blood. 2021;137(8):1120-4.

Twa DDW, Lee DG, Tan KL, Slack GW, Ben-Neriah S, Villa D, et al. Genomic predictors of central nervous system relapse in primary testicular diffuse large B-cell lymphoma. Blood. 2021;137(9):1256-9.

Olszewski AJ, Chorzalska AD, Petersen M, Ollila TA, Zayac AS, Kurt H, et al. Detection of clonotypic DNA in the cerebrospinal fluid as a marker of central nervous system invasion in lymphoma. Blood Adv. 2021.

Tilly H, Morschhauser F, Sehn LH, Friedberg JW, Trněný M, Sharman JP, et al. Polatuzumab Vedotin in Previously Untreated Diffuse Large B-Cell Lymphoma. N Engl J Med. 2022;386(4):351-63.

Locke FL, Miklos DB, Jacobson CA, Perales MA, Kersten MJ, Oluwole OO, et al. Axicabtagene Ciloleucel as Second-Line Therapy for Large B-Cell Lymphoma. N Engl J Med. 2021.

Kamdar M, Solomon SR, Arnason J, Johnston PB, Glass B, Bachanova V, et al. Lisocabtagene maraleucel versus standard of care with salvage chemotherapy followed by autologous stem cell transplantation as second-line treatment in patients with relapsed or refractory large B-cell lymphoma (TRANSFORM): results from an interim analysis of an open-label, randomised, phase 3 trial. Lancet. 2022;399(10343):2294-308.

Top Articles
Latest Posts
Article information

Author: Nicola Considine CPA

Last Updated: 08/05/2023

Views: 6130

Rating: 4.9 / 5 (69 voted)

Reviews: 84% of readers found this page helpful

Author information

Name: Nicola Considine CPA

Birthday: 1993-02-26

Address: 3809 Clinton Inlet, East Aleisha, UT 46318-2392

Phone: +2681424145499

Job: Government Technician

Hobby: Calligraphy, Lego building, Worldbuilding, Shooting, Bird watching, Shopping, Cooking

Introduction: My name is Nicola Considine CPA, I am a determined, witty, powerful, brainy, open, smiling, proud person who loves writing and wants to share my knowledge and understanding with you.