Isolated central nervous system (CNS) relapse of diffuse large B-cell lymphoma (DLBCL) is a serious and potentially fatal complication of the disease. Delivery of chemotherapy with adequate CNS penetration as part of primary therapy provides an opportunity to prevent this complication. However, there is no universally agreed approach to CNS prophylaxis and there are open questions with respect to patient selection and prophylaxis choice. Nevertheless, appropriate CNS prophylaxis during primary therapy for DLBCL should be considered in patients with recognised risk factors for CNS relapse.
The eviQ Haematology Reference Committee issues this guidance document to summarise risk factors for CNS relapse and provide a possible approach to patient selection and prophylactic treatment. Individual units may have equally valid approaches to this matter.
Until recently, much of the data used to define groups at high risk of CNS relapse antedated modern immuno-histochemical diagnostic algorithms, PET-staging techniques, and the advent of routine chemo-immunotherapy with rituximab. Across all series, several or all factors in the International Prognostic Index (IPI) and revised International Prognostic Index (R-IPI) have conferred increased risk of CNS relapse.rrrrrr The German High-Grade Lymphoma Study Group performed a retrospective analysis of prospectively collected data from clinical trials performed by their network. All patients had received chemo-immunotherapy.r The following factors were identified as predictive of isolated CNS relapse:
Each risk factor in the IPI:
- age > 60
- stage III/IV disease
- raised LDH
- multiple extranodal sites
- performance status >1
- renal and/or adrenal involvement.
These findings were validated in an independent cohort analysed by the BCCA.rr
The following risks of CNS relapse were reported:
||Number of factors
||Risk of CNS relapse
(German cohort n=2164)
|Risk of CNS relapse
(BCCA cohort n=1597)
Some caution is required when incorporating these data into patient counselling and treatment decisions as it is yet (January 2016) to appear in the peer-reviewed literature. However two reputable research groups have reported the initial and confirmatory data in international conference forums.
Specific sites of disease involvement lead to increasing risk of relapse. The BCCA and German cohorts did not identify specific sites of disease as high risk apart from renal or adrenal involvement.
Based on the published cohorts, enriched with extranodal disease at specific locations, the following additional extranodal sites should be considered as high risk for CNS relapse:rr
- base of skull
Isolated large cell involvement of the bone marrow is not considered independently high risk for CNS disease, but typically marrow involvement is associated with other risk factors.r
Biological subtypes warranting consideration of CNS prophylaxis
Double hit lymphoma:
DLBCL that co-expresses MYC and BCL2 (or BCL6) by immunohistochemistry confers a risk of CNS relapse of between 9 and 17%.r "Double/triple-hit" lymphoma demonstrating rearrangements of MYC and BCL2 by FISH have a similar risk of CNS relapse with a large series reporting a 13% of CNS relapse.r
CNS involvement is common at baseline in this disease (up to 39%) and CNS prophylaxis is recommended.r
Choice of prophylaxis regimen
There is no agreed standard approach to CNS prophylaxis. Intrathecal chemotherapy with methotrexate has long been a component of CNS prophylaxis and is beneficial in patients with testicular lymphoma.r However in other forms of DLBCL efficacy of IT MTX appears to provide little benefit. Use of CNS-penetrating intravenous antimetabolite or purine analogue therapy (methotrexate or cytarabine) has become increasingly popular globally in patients thought to be at high risk of CNS disease. Based on evidence predominantly from the pre-rituximab era, systemic methotrexate is thought to be more effective than IT MTX at preventing parenchymal relapse, as opposed to leptomeningeal relapse.
However prospective, controlled data are rare. Observations from a pre rituximab, French, randomised study of intensive combination chemotherapy (ACVBP) incorporating 2 cycles of 3 g/m2 methotrexate versus CHOP with no CNS directed therapy showed a significantly lower risk of CNS relapse.r A local, multicentre, retrospective study of 269 patients explored three approaches to CNS prophylaxis (IT MTX alone with R-CHOP-like chemotherapy; IT MTX + IV MTX 3 g/m2 x 2 doses with R-CHOP-like chemotherapy; regimens containing high doses of ara-C and MTX (CODOX-M/IVAC or HyperCVAD) and found CNS relapse rates of 18.4%, 6.9% and 2.3% (p=0.006).r