The number of extranodal sites assessed by PET/CT scan is a powerful predictor of CNS relapse for patients with diffuse large B-cell lymphoma: An international multicenter study of 1532 patients treated with chemoimmunotherapy

Highlights

• Risk of central nervous system (CNS) relapse in diffuse large B-cell lymphoma is predicted by the CNS-IPI.

• The CNS-IPI remains valid in PET/CT staged diffuse large B-cell lymphoma.

• More than two extranodal sites at diagnosis confer increased risk of CNS relapse.

Abstract

Purpose

Development of secondary central nervous system involvement (SCNS) in patients with diffuse large B-cell lymphoma is associated with poor outcomes. The CNS International Prognostic Index (CNS-IPI) has been proposed for identifying patients at greatest risk, but the optimal model is unknown.

Methods

We retrospectively analysed patients with diffuse large B-cell lymphoma diagnosed between 2001 and 2013, staged with PET/CT and treated with R-CHOP(-like) regimens. Baseline clinicopathologic characteristics, treatments, and outcome data were collected from clinical databases and medical files. We evaluated the association between candidate prognostic factors and modelled different risk models for predicting SCNS.

Results

Of 1532 patients, 62 (4%) subsequently developed SCNS. By multivariate analysis, disease stage III/IV, elevated serum LDH, kidney/adrenal and uterine/testicular involvement were independently associated with SCNS. There was a strong correlation between absolute number of extranodal sites and risk of SCNS; the 144 patients (9%) with >2 extranodal sites had a 3-year cumulative incidence of SCNS of 15.2% (95% confidence interval [CI] 9.2–21.2%) compared with 2.6% (95% CI 1.7–3.5) among those with ≤2 sites (P < 0.001). The 3-year cumulative risks of SCNS for CNS-IPI defined risk groups were 11.2%, 3.1% and 0.4% for high-, intermediate- and low-risk patients, respectively. All risk models analysed had high negative predictive values, but only modest positive predictive values.

Conclusions

Patients with >2 extranodal sites or high-risk disease according to the CNS-IPI should be considered for baseline CNS staging. Clinical risk prediction models suffer from limited positive predictive ability, highlighting the need for more sensitive biomarkers to identify patients at highest risk of this devastating complication.

Introduction

Patients with secondary CNS involvement (SCNS) by diffuse large B-cell lymphoma (DLBCL) have a dismal prognosis, highlighting the pressing need for effective preventative strategies [1], [2], [3], [4], [5], [6], [7], [8], [9], [10], [11]. The addition of CNS-penetrating chemotherapeutics such as high-dose methotrexate into frontline protocols appears the most promising prophylactic strategy and has been recommended by recent guidelines [10], [12], [13]. Clinical risk factors for SCNS are well characterised and have been used to construct risk models, which allow targeted application of such prophylaxis [2], [3], [4], [14], [15]. The CNS-IPI, the best validated of these, combines established International Prognostic Index (IPI) risk factors (age >60 years, stage III/IV disease, >1 extranodal site, ECOG performance score >1 and LDH above upper normal limit) with kidney/adrenal involvement into a 6-point score with high-risk patients defined by a total score of ≥4 [16]. Disease stage and extranodal involvement are consistent risk factors for SCNS in most analyses, but their association with SCNS may be influenced by the imaging modality used for baseline staging. In non-hodgkin lymphoma, PET/CT detects more extranodal disease sites than conventional staging, and this leads to upstaging in a relevant number of patients [17]. The aims of this study were to examine risk factors for SCNS and validate the CNS-IPI model in a large independent cohort of PET/CT-staged patients treated with R-CHOP- or R-CHOP-like regimens.