CNS prophylaxis in diffuse large B cell lymphoma

Definition

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.

Patient selection

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:

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

• testicular^r
• intra-ocular
• base of skull
• breast
• epidural
• naso-pharyngeal.

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

Intravascular lymphoma:

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

Patient selection recommendations:

• Consider staging for CNS involvement at baseline with investigations such as diagnostic lumbar puncture and/or MRI in patients with DLBCL 4-6 risk factors when clinically appropriate.
• Strongly consider use of systemic CNS prophylaxis, where patient factors allow, for patients with 4 or more of the above IPI risk factors, or, more than 2 extranodal sites of disease, and/or high risk sites for CNS relapse of disease involvement such as testes.
• Consider systemic CNS prophylaxis in patients where 2-3 IPI risk factors are present, based on physician preference and relative toxicities of the prophylaxis in individual patients.

Prophylaxis recommendations:

In the absence of high quality evidence, the eviQ Haematology Reference Committee does not recommend one approach to CNS prophylaxis over another.

The following approaches to systemic prophylaxis should be considered:

• 2-4 cycles of methotrexate 1.5 to 3 g/m² during or post completion of induction chemotherapy (typically R-CHOP)^rr
• intercalation of methotrexate within R-CHOP at approximately day 10 of the first 2 cycles
• a specific approach to CNS prophylaxis may not be required in patients receiving regimens containing CNS-penetrating agents such as hyperCVAD or CODOX-M/IVAC
• among patients with testicular DLBCL, studies have shown the benefit of CNS prophylaxis with both IT MTX and IV MTX together with irradiation of the contralateral testicle as part of the overall chemotherapy plan.^r

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Bibliography

El-Galaly, T. C., C. Y. Sheah, D. Villa, et al. 2015. "Validation of the German High-Grade Non-Hodgkin Lymphoma Study Group (DSHNHL) prognostic model for CNS relapse in a large cohort of PET/CT staged patients." International Conference on Malignant Lymphoma 2015 Conference Abstract

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Introduction: Central nervous system (CNS) relapse in patients with diffuse large B-cell lymphoma (DLBCL) is an infrequent but usually fatal complication. Our goal was to investigate the external validity of the German High-Grade Non-Hodgkin Lymphoma Study Group (DSHNHL) prognostic model based on the 5 IPI factors (age >60 years, elevated LDH, stage III/IV, >1 extranodal site, and ECOG performance status >1) in addition to kidney/adrenal involvement (Savage 394a, ASH 2014) in an independent large cohort of R-CHOP treated DLBCL patients staged with PET/CT

Methods: This is a retrospective study of patients with newly diagnosed DLBCL presenting to hospitals in Denmark and the Peter MacCallum Cancer Centre (Australia). All patients underwent staging with PET/CT and were treated with R-CHOP or similar first-line chemotherapy, with or without CNS prophylaxis and/or radiotherapy. Patients with CNS involvement at diagnosis were excluded. Consecutive patients were identified through searches in national/local lymphoma registries and screened for eligibility. Medical records were reviewed for clinical information and outcome. The Kaplan–Meier method was used to estimate time to CNS relapse and cumulative incidences.

Results: A total of 1290 PET/CT-staged DLBCL patients with data for all DSHNHL risk factors available were included, with the following characteristics: 65% age >60y, 49% elevated LDH, 63% stages III–IV, 23% >1 extranodal site, 13% performance status >1, and 4% kidney/adrenal involvement. Patients with 0–1 (34%), 2–3 (48%), or >3 (18%) risk factors were categorized as low-risk, intermediate risk, and high-risk for CNS relapse, respectively. With a median follow-up of 43 months (P = 0.19 for difference between the 3 risk groups), 51 (4%) developed CNS relapse. The median time to CNS relapse was 9 months (range 4–78 months). The cumulative incidences of CNS relapse at 2 years were 0.5% (95% CI 0.1–1.9%) for low risk, 2.5% (95% CI 1.5–4.2%) for intermediate risk, and 12.3% (95% CI 8.3–18.0%) for high risk. Within the high-risk group, 85/235 patients received CNS prophylaxis (IT alone 22%, systemic 31%, both 47%). The number of CNS events was similar for high-risk patients treated with and without CNS prophylaxis (12% for both, P = 1.0).

Conclusions: The prognostic model for CNS relapse proposed by the DSHNHL predicts CNS relapse in PET/CT-staged DLBCL patients treated with immunochemotherapy despite frequent use of CNS prophylaxis. The use of CNS prophylaxis did not reduce the risk of CNS events in high-risk patients, but prospective studies are warranted to define optimal strategies to effectively reduce this complication.

Murawski, N., G. Held, M. Ziepert, et al. 2014. "The role of radiotherapy and intrathecal CNS prophylaxis in extralymphatic craniofacial aggressive B-cell lymphomas." Blood 124(5):720-728.

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To define the role of radiotherapy and intrathecal prophylaxis in extralymphatic craniofacial involvement (ECFI) ofaggressive B-cell lymphoma, we analyzed 11 consecutive German High-Grade Non-Hodgkin Lymphoma Study Group trials. ECFI occurred in 290/4155 (7.0%) patients (orbita, 31; paranasal sinuses, 93; main nasal cavity, 38; tongue, 27; remaining oral cavity, 99; salivary glands, 54). In a multivariable analysis adjusted for International Prognostic Index rituximab improved event-free and overall survival both in patients with and without ECFI. Three-year event-free (79% vs 79%; P = .842) and overall survival (86% vs 88%; P = .351) rates were similar in 145 patients receiving and 57 not receiving radiotherapy. Without rituximab, the 2-year cumulative rate of central nervous system (CNS) disease was increased in 205 ECFI patients compared with 2586 non-ECFI patients (4.2% vs 2.8%; P = .038), whereas this was not observed with rituximab (1.6% in 83 ECFI vs 3.4% in 1252 non-ECFI patients; P = .682). In 88 ECFI patients who received intrathecal prophylaxis with methotrexate, the 2-year rate of CNS disease was 4.2% compared with 2.3% in 191 patients who did not (P = .981). In conclusion, rituximab eliminates the increased risk for CNS disease in patients with ECFI. This retrospective analysis does not support intrathecal prophylaxis or radiotherapy to ECFI patients in complete remission/unconfirmed complete remission. These findings should be confirmed in a prospective study.

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