Clinical characteristics and survival outcomes of patients with primary central nervous system lymphoma treated with high-dose methotrexate-based polychemotherapy and consolidation therapies

Fleur A de Groot; Tim J A Dekker; Jeanette K Doorduijn; Stefan Böhringer; Mirian Brink; Ruben A L de Groen; Lorraine M de Haan; F J Sherida H Woei-A-Jin; Troy Noordenbos; Aniko Sijs-Szabo; Mirjam A Oudshoorn; King H Lam; Arjan Diepstra; Liane C J Te Boome; Valeska Terpstra; Lara H Bohmer; Alina Nicolae; Eduardus F M Posthuma; Lianne Koens; Marc F Durian; Jeroen Stavast; Marjolein W M van der Poel; Myrurgia Abdul Hamid; Wendy B C Stevens; Sjo L M van Rooij; Rimke S Oostvogels; Angelika Mühlebner; Karen J Neelis; Michiel van den Brand; Thomas Tousseyn; Daan Dierickx; Okke de Weerdt; Aart Beeker; Patty M Jansen; Marie José Kersten; Josée M Zijlstra; Martine E D Chamuleau; Hendrik Veelken; Jacoline C E Bromberg; Marcel Nijland; Joost S P Vermaat

doi:10.1016/j.ejca.2024.115068

Clinical characteristics and survival outcomes of patients with primary central nervous system lymphoma treated with high-dose methotrexate-based polychemotherapy and consolidation therapies

Eur J Cancer. 2024 Dec:213:115068. doi: 10.1016/j.ejca.2024.115068. Epub 2024 Oct 13.

Authors

Fleur A de Groot¹, Tim J A Dekker², Jeanette K Doorduijn³, Stefan Böhringer⁴, Mirian Brink⁵, Ruben A L de Groen¹, Lorraine M de Haan⁶, F J Sherida H Woei-A-Jin⁷, Troy Noordenbos⁶, Aniko Sijs-Szabo¹, Mirjam A Oudshoorn¹, King H Lam⁸, Arjan Diepstra⁹, Liane C J Te Boome¹⁰, Valeska Terpstra¹¹, Lara H Bohmer¹², Alina Nicolae¹³, Eduardus F M Posthuma¹⁴, Lianne Koens¹⁵, Marc F Durian¹⁶, Jeroen Stavast¹⁷, Marjolein W M van der Poel¹⁸, Myrurgia Abdul Hamid¹⁹, Wendy B C Stevens²⁰, Sjo L M van Rooij²¹, Rimke S Oostvogels²², Angelika Mühlebner²³, Karen J Neelis²⁴, Michiel van den Brand²⁵, Thomas Tousseyn²⁶, Daan Dierickx²⁷, Okke de Weerdt²⁸, Aart Beeker²⁹, Patty M Jansen⁶, Marie José Kersten³⁰, Josée M Zijlstra³⁰, Martine E D Chamuleau³⁰, Hendrik Veelken¹, Jacoline C E Bromberg³¹, Marcel Nijland³², Joost S P Vermaat³³

Affiliations

¹ Department of Hematology, Leiden University Medical Center, Leiden, the Netherlands.
² Department of Internal Medicine, Leiden University Medical Center, Leiden, the Netherlands.
³ Department of Hematology, Erasmus MC Cancer Institute, University Medical Center Rotterdam, Rotterdam, the Netherlands.
⁴ Department of Biomedical Data Sciences, Leiden University Medical Center, Leiden, the Netherlands; Department of Pharmacology and Toxicology, Leiden University Medical Center, Leiden, the Netherlands.
⁵ Department of Research and Development, Netherlands Comprehensive Cancer Organisation (IKNL), Utrecht, the Netherlands.
⁶ Department of Pathology, Leiden University Medical Center, Leiden, the Netherlands.
⁷ Department of General Medical Oncology, University Hospitals Leuven, Leuven, Belgium.
⁸ Department of Pathology, Erasmus Medical Center, Rotterdam, the Netherlands.
⁹ Department of Pathology and Medical Biology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands.
¹⁰ Department of Hematology, Haaglanden Medical Center, Den Haag, the Netherlands.
¹¹ Department of Pathology, Haaglanden Medical Center, Den Haag, the Netherlands.
¹² Department of Hematology, Haga Teaching Hospital, Den Haag, the Netherlands.
¹³ Department of Pathology, Haga Teaching Hospital, Den Haag, the Netherlands.
¹⁴ Department of Internal Medical, Reinier de Graaf Gasthuis, Delft, the Netherlands.
¹⁵ Department of Pathology, Amsterdam University Medical Centers, Amsterdam, the Netherlands.
¹⁶ Department of Hematology, Elisabeth-TweeSteden Ziekenhuis Tilburg, Tilburg, the Netherlands.
¹⁷ Department of Pathology, Elisabeth-TweeSteden Ziekenhuis Tilburg, Tilburg, the Netherlands.
¹⁸ Department of Internal Medicine, Division of Hematology, GROW School for Oncology and Developmental Biology, Maastricht University Medical Center, Maastricht, the Netherlands.
¹⁹ Department of Pathology, Maastricht University Medical Center, Maastricht, the Netherlands.
²⁰ Department of Hematology, Radboud University Medical Center, Nijmegen, the Netherlands.
²¹ Department of Neurology, University Medical Center Utrecht, Utrecht, the Netherlands.
²² Department of Hematology, University Medical Center Utrecht, Utrecht, the Netherlands.
²³ Department of Pathology, University Medical Center Utrecht, Utrecht, the Netherlands.
²⁴ Department of Radiotherapy, Leiden University Medical Center, Leiden, the Netherlands.
²⁵ Department of Pathology, Radboud University Medical Center, Nijmegen, the Netherlands.
²⁶ Department of Pathology, University Hospitals Leuven, Leuven, Belgium.
²⁷ Department of Hematology, University Hospitals Leuven, Leuven, Belgium.
²⁸ Department of Internal Medicine, St. Antonius Hospital, Nieuwegein, the Netherlands.
²⁹ Department of Internal Medicine, Spaarne Gasthuis, Haarlem, the Netherlands.
³⁰ Department of Hematology, Amsterdam University Medical Centers Cancer Center Amsterdam and LYMMCARE, Amsterdam, the Netherlands.
³¹ Department of Neurology, Erasmus Medical Center, Rotterdam, the Netherlands.
³² Department of Hematology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands.
³³ Department of Hematology, Leiden University Medical Center, Leiden, the Netherlands. Electronic address: [email protected].

PMID: 39427440
DOI: 10.1016/j.ejca.2024.115068

Abstract

Given the rarity of primary central nervous system lymphoma (PCNSL), evaluations of different high-dose methotrexate-(HD-MTX)-based treatment regimens is sparse. This retrospective, multicenter study evaluates clinical characteristics and outcomes (progression-free, overall and disease-specific survival) after five HD-MTX-based polychemotherapeutic regimens and two consolidation therapies. 346 patients with histologically confirmed PCNSL, treated with ≥ 1 cycle HD-MTX-based strategies (≥3g/m²/cycle) were included. The regimens included MATRIX (HD-MTX, HD-AraC, thiotepa, and rituximab), (R)MBVP±HD-AraC (HD-MTX, teniposide/etoposide, carmustine, prednisolone, ± HD-AraC, ± rituximab), (R)MP (HD-MTX, procarbazine, ± rituximab), and a combination of HD-MTX and HD-AraC. The overall response rate after induction was 69 %, 28 % complete remission and progressive disease was observed in 100 (29 %) patients. 126 (36 %) patients received consolidation, including high-dose-BCNU-thiotepa with autologous stem cell transplantation (HD-BCNU-TT/ASCT, n = 59 (17 %)) or whole brain radiotherapy (WBRT, n = 67 (19 %)). Clinical characteristics associated with adverse mortality risk by multivariable prognostication contained age > 60 years (HR 1.61, p = 0.011), elevated LDH (HR 1.75, p = 0.004) and WHO status ≥ 2 (HR 1.56, p = 0.010). Independently, induction regimens containing HD-AraC demonstrated survival benefit compared to induction regimens without HD-AraC (HR 0.59, p = 0.002). Without preference for HD-BCNU-TT/ASCT or WBRT, a favorable effect of consolidation (HR 0.44 and HR 0.42, p < 0.001) was confirmed, also with consolidation as time-dependent variable. Competing risk analysis showed similar low incidence of lymphoma-unrelated deaths in consolidated and unconsolidated patients. This study confirms that age, elevated LDH and WHO status increase the mortality risk. HD-AraC containing treatment regimens and consolidation with HD-BCU-TT/ASCT or WBRT were associated with superior survival, including a favorable low incidence of lymphoma-unrelated deaths.

Keywords: Clinical characteristics; Consolidation; High-dose methotrexate; Induction; PCNSL; Polychemotherapy; Survival outcomes.

Publication types

Multicenter Study

MeSH terms

Adult
Aged
Aged, 80 and over
Antineoplastic Combined Chemotherapy Protocols* / therapeutic use
Central Nervous System Neoplasms* / drug therapy
Central Nervous System Neoplasms* / mortality
Central Nervous System Neoplasms* / therapy
Consolidation Chemotherapy
Female
Humans
Lymphoma / drug therapy
Lymphoma / mortality
Lymphoma / therapy
Male
Methotrexate* / administration & dosage
Middle Aged
Retrospective Studies
Treatment Outcome
Young Adult

Substances

Methotrexate