Clinical Outcomes and Treatment Patterns of Primary Central Nervous System Lymphoma: Multicenter Retrospective Analysis
Objectives: Primary central nervous system lymphoma (PCNSL) is a rare malignant disease with poor prognosis. Its low incidence leads to challenges in decision-making for treatment. As a matter of fact, there is still no consensus on the appropriate treatment modalities. In this context, the objective of this study is to investigate and comparatively assess the efficacies of several treatment modalities in the treatment of PCNSL.
Methods: Thirty-four patients diagnosed with PCNSL at 5 different hematology centers between 2007 and 2021 were included in the study. Patients’ data from all five centers were collected retrospectively. Since ibrutinib is not approved for this indication in Turkey, consent for off-label use of ibrutinib is obtained from each patient. Ethics committee approval was obtained on June 9, 2021 with decision number 2021/18-05.
Results: The median age of the patients was 59 (min.: 22, max.: 78) years. The male-to-female ratio was 1.26/1. Nineteen (55.9%) patients had Eastern Cooperative Oncology Group (ECOG) performance score of ≥2. Fifteen (44.1%) patients had normal lactate dehydrogenase (LDH) levels and only 14.7% of the patients had B symptoms at the time of diagnosis. Magnetic resonance imaging (MRI) revealed a single mass lesion in 14 (41.2%) patients. As an induction therapy, methotrexate-based regimen was administered in 29 (85.3%) patients. Only 14 of the 34 patients received 4 or more cycles of high-dose methotrexate (MTX). About 32.4% of the patients received radiation therapy (RT) during follow-up as a part of induction therapy. Five patients received only RT due to poor performance status. Ibrutinib was administered in 5 patients for refractory disease. It was determined that four or more cycles of MTX treatment increased progression-free survival (PFS) (p=0.031) and overall survival (OS) (p=0.012). Moreover, RT improved PFS (p=0.023). Considering that the complete response achieved by induction therapy influences long-term survival, achievement of the best response to the treatment regimens administered in combination with new agents may prolong survival (PFS: p=0.01, OS: p=0.023).
Conclusion: The findings of this study indicate that the initial response to treatment is crucial. Additionally, it was found that high-dose MTX treatment should be administered for 4 cycles or more in order to achieve the best results. Furthermore, it was determined that ibrutinib monotherapy was well-tolerated in our patients with relapsed/refractory disease, with excellent clinical benefits. In conclusion, a combination therapy consisting of high-dose MTX, ibrutinib, and rituximab appears to be a promising initial treatment approach in appropriate patients.
1. Yuan Y, Ding T, Wang S, Chen H, Mao Y, Chen T. Current and emerging therapies for primary central nervous system lymphoma. Biomark Res 2021;9:32.
2. Deckert M, Engert A, Brück W, Ferreri AJ, Finke J, Illerhaus G, et al. Modern concepts in the biology, diagnosis, diferential diagnosis and treatment of primary central nervous system lymphoma. Leukemia 2011;25:1797–807.
3. Villano JL, Koshy M, Shaikh H, Dolecek TA, McCarthy BJ. Age, gender, and racial diferences in incidence and survival in primary CNS lym phoma. Br J Cancer 2011;105:1414–8.
4. Swerdlow SH, Campo E, Harris NL, Jafe ES, Pileri SA, Stein H, et al. WHO classifcation of tumours of haematopoietic and lymphoid tissues. 4th ed. Lyon: IARC Press; 2017.
5. WHO Classifcation of Tumours Editorial Board. WHO classifcation of tumours of the central nervous system. 5th ed. Lyon: International Agency for Research on Cancer; 2021.
6. Schultz C, Scott C, Sherman W, Donahue B, Fields J, Murray K, et al. Preirradiation chemotherapy with cyclophosphamide,
doxorubicin, vincristine, and dexamethasone for primary CNS lymphomas: initial report of radiation therapy oncology group protocol 88-06. J Clin Oncol 1996;14:556–64.
7. Glass J, Won M, Schultz CJ, Brat D, Bartlett NL, Suh JH, et al. Phase I and II study of ınduction chemotherapy with methotrexate, rituximab, and temozolomide, followed by wholebrain radiotherapy and postirradiation temozolomide for primary CNS lymphoma: NRG oncology RTOG 0227. J Clin Oncol 2016;34:1620–5.
8. Van Dijck R, Doorduijn JK, Bromberg JEC. The role of rituximab in the treatment of primary central nervous system lymphoma. Cancers (Basel) 2021;13:1920.
9. Ferreri AJM. Therapy of primary CNS lymphoma: role of intensity, radiation, and novel agents. Hematology Am Soc Hematol Educ Program 2017;2017:565–77.
10. Hoang-Xuan K, Bessell E, Bromberg J, Hottinger AF, Preusser M, Rudà R, et al; European Association for Neuro-Oncology Task Force on Primary CNS Lymphoma. Diagnosis and treatment of primary CNS lymphoma in immunocompetent patients: guidelines from the European Association for NeuroOncology. Lancet Oncol 2015;16:e322–32.
11. Bojarczuk K, Siernicka M, Dwojak M, Bobrowicz M, Pyrzynska B, Gaj P, et al. B-cell receptor pathway inhibitors affect CD20 levels and impair antitumor activity of anti-CD20 monoclonal antibodies. Leukemia 2014;28:1163–7.
12. Houillier C, Ghesquières H, Chabrot C, Soussain C, Ahle G, Choquet S, et al. Rituximab, methotrexate, procarbazine, vincristine and intensified cytarabine consolidation for primary central nervous system lymphoma (PCNSL) in the elderly: a LOC network study. J Neurooncol 2017;133:315–20.
13. Correa DD, DeAngelis LM, Shi W, Thaler H, Glass A, Abrey LE. Cognitive functions in survivors of primary central nervous system lymphoma. Neurology 2004;62:548–55.
14. Thiel E, Korfel A, Martus P, Kanz L, Griesinger F, Rauch M, et al. High-dose methotrexate with or without whole brain radiotherapy for primary CNS lymphoma (G-PCNSL-SG-1): a phase 3, randomised, non-inferiority trial. Lancet Oncol 2010;11:1036–47.
15. Abrey LE, Moskowitz CH, Mason WP, Crump M, Stewart D, Forsyth P, et al. Intensive methotrexate and cytarabine followed by high-dose chemotherapy with autologous stem-cell rescue in patients with newly diagnosed primary CNS lymphoma: an intent-to-treat analysis. J Clin Oncol 2003;21:4151–6.
16. Colombat P, Lemevel A, Bertrand P, Delwail V, Rachieru P, Brion A, et al. High-dose chemotherapy with autologous stem cell transplantation as first-line therapy for primary CNS lymphoma in patients younger than 60 years: a multicenter phase II study of the GOELAMS group. Bone Marrow Transplant 2006;38:417–20.
17. Montemurro M, Kiefer T, Schüler F, Al-Ali HK, Wolf HH, Herbst R, et al. Primary central nervous system lymphoma treated with high-dose methotrexate, high-dose busulfan/thiotepa, autologous stem-cell transplantation and response-adapted whole-brain radiotherapy: results of the multicenter Ostdeutsche Studiengruppe Hamato-Onkologie OSHO-53 phase II study. Ann Oncol 2007;18:665–71.
18. 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;125:1403–10.
19. Mao C, Chen F, Li Y, Jiang X, Liu S, Guo H, et al. Characteristics and outcomes of primary central nervous system lymphoma: a retrospective study of 91 cases in a chinese population. World Neurosurg 2019;123:e15–e24.
20. Soussain C, Choquet S, Blonski M, Leclercq D, Houillier C, Rezai K, et al. Ibrutinib monotherapy for relapse or refractory primary CNS lymphoma and primary vitreoretinal lymphoma: Final analysis of the phase II 'proof-of-concept' iLOC study by the Lymphoma study association (LYSA) and the French oculo-cerebral lymphoma (LOC) network. Eur J Cancer 2019;117:121– 30.