Central nervous system relapse of diffuse large B-cell lymphoma in the rituximab era: results of the UK NCRI R-CHOP-14 versus 21 trial

M Gleeson; N Counsell; D Cunningham; N Chadwick; A Lawrie; E A Hawkes; A McMillan; K M Ardeshna; A Jack; P Smith; P Mouncey; C Pocock; J A Radford; J Davies; D Turner; A Kruger; P Johnson; J Gambell; D Linch

doi:10.1093/annonc/mdx353

Central nervous system relapse of diffuse large B-cell lymphoma in the rituximab era: results of the UK NCRI R-CHOP-14 versus 21 trial

Ann Oncol. 2017 Oct 1;28(10):2511-2516. doi: 10.1093/annonc/mdx353.

Authors

M Gleeson¹, N Counsell², D Cunningham³, N Chadwick², A Lawrie², E A Hawkes⁴, A McMillan⁵, K M Ardeshna⁶, A Jack⁷, P Smith², P Mouncey², C Pocock⁸, J A Radford⁹, J Davies¹⁰, D Turner¹¹, A Kruger¹², P Johnson¹³, J Gambell², D Linch¹⁴

Affiliations

¹ Department of Medicine, The Royal Marsden Hospital, London and Surrey, UK.
² Cancer Research UK and UCL Cancer Trials Centre, UCL Cancer Institute, London, UK.
³ Department of Medicine, The Royal Marsden Hospital, London and Surrey, UK;. Electronic address: david.cunningham@rmh.nhs.uk.
⁴ Department of Oncology and Clinical Haematology, Austin Health, Heidelberg, Melbourne, Australia;; Department of Medical Oncology, Eastern Health, Melbourne, Australia.
⁵ Department of Haematology, Nottingham City Hospital, Nottingham, UK.
⁶ Department of Haematology, University College London, London, UK;; Department of Haematology, Mount Vernon Cancer Centre, Northwood, UK.
⁷ HMDS, Leeds Teaching Hospitals NHS Trust, Leeds, UK.
⁸ Department of Haematology, East Kent Hospitals, Canterbury, UK.
⁹ The University of Manchester and The Christie NHS Foundation Trust, Manchester Academic Health Science Centre, Manchester, UK.
¹⁰ Department of Haematology, Western General Hospital, Edinburgh, UK.
¹¹ Department of Haematology, Torbay Hospital, Torquay, UK.
¹² Department of Haematology, Royal Cornwall Hospital, Truro, UK.
¹³ Cancer Research UK Centre, Southampton, UK.
¹⁴ Department of Haematology, University College London, London, UK.

Abstract

Background: Central nervous system (CNS) relapse of diffuse large B-cell lymphoma (DLBCL) is associated with a dismal prognosis. Here, we report an analysis of CNS relapse for patients treated within the UK NCRI phase III R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine and prednisolone) 14 versus 21 randomised trial.

Patients and methods: The R-CHOP 14 versus 21 trial compared R-CHOP administered two- versus three weekly in previously untreated patients aged ≥18 years with bulky stage I-IV DLBCL (n = 1080). Details of CNS prophylaxis were retrospectively collected from participating sites. The incidence and risk factors for CNS relapse including application of the CNS-IPI were evaluated.

Results: 177/984 patients (18.0%) received prophylaxis (intrathecal (IT) methotrexate (MTX) n = 163, intravenous (IV) MTX n = 2, prophylaxis type unknown n = 11 and IT MTX and cytarabine n = 1). At a median follow-up of 6.5 years, 21 cases of CNS relapse (isolated n = 11, with systemic relapse n = 10) were observed, with a cumulative incidence of 1.9%. For patients selected to receive prophylaxis, the incidence was 2.8%. Relapses predominantly involved the brain parenchyma (81.0%) and isolated leptomeningeal involvement was rare (14.3%). Univariable analysis demonstrated the following risk factors for CNS relapse: performance status 2, elevated lactate dehydrogenase, IPI, >1 extranodal site of disease and presence of a 'high-risk' extranodal site. Due to the low number of events no factor remained significant in multivariate analysis. Application of the CNS-IPI revealed a high-risk group (4-6 risk factors) with a 2- and 5-year incidence of CNS relapse of 5.2% and 6.8%, respectively.

Conclusion: Despite very limited use of IV MTX as prophylaxis, the incidence of CNS relapse following R-CHOP was very low (1.9%) confirming the reduced incidence in the rituximab era. The CNS-IPI identified patients at highest risk for CNS recurrence.

Clinicaltrials.gov: ISCRTN number 16017947 (R-CHOP14v21); EudraCT number 2004-002197-34.

Keywords: central nervous system; diffuse large B-cell lymphoma; relapse; rituximab.

Publication types

Clinical Trial, Phase III
Randomized Controlled Trial

MeSH terms

Antibodies, Monoclonal, Murine-Derived / administration & dosage
Antineoplastic Combined Chemotherapy Protocols / administration & dosage*
Central Nervous System Neoplasms / pathology*
Cyclophosphamide / administration & dosage
Doxorubicin / administration & dosage
Drug Administration Schedule
Female
Humans
Lymphoma, Large B-Cell, Diffuse / drug therapy*
Lymphoma, Large B-Cell, Diffuse / pathology
Male
Middle Aged
Neoplasm Recurrence, Local / pathology
Prednisone / administration & dosage
Prospective Studies
Rituximab / administration & dosage
Vincristine / administration & dosage

Substances

Antibodies, Monoclonal, Murine-Derived
R-CHOP protocol
Rituximab
Vincristine
Doxorubicin
Cyclophosphamide
Prednisone