Prophylaxis with high‐dose methotrexate significantly reduces CNS dissemination in patients with diffuse large B ‐cell lymphoma ( DLBCL ) and high‐risk CNS‐IPI score

Abstract

Introduction: CNS relapse is an uncommon but lethal event in DLBCL pts. Early detection and effective CNS prophylaxis reduce related mortality. Evidence supporting the use of intravenous high-dose-methotrexate (HD-MTX)-based prophylaxis is growing; however, prophylaxis cannot be indicated in every DLBCL pt, and risk predictors with high diagnostic sensitivity remain to be defined. Recently, a reproducible model to estimate the risk of CNS relapse in DLBCL pts was reported (Schmitz N, et al. JCO 2016). With this “CNS-IPI,” based on IPI parameters and involvement of adrenal gland and kidney, the CNS relapse rate was >10% in high-risk pts; however, the role of CNS prophylaxis in these pts remains to be defined. On this background, we analysed the value of CNS-IPI and the role of HD-MTXbased prophylaxis in high-CNS-IPI pts in a mono-institutional series of 242 pts with DLBCL treated in the rituximab era. Methods: Consecutive HIV-neg adults with DLBCL treated with RCHOP or similar were considered. CNS, mediastinal and leg-type DLBCL, transformed lymphomas and pts registered in prospective trials were excluded. Following institutional guidelines, pts with high-CNS risk diagnosed after 2007 received CNS prophylaxis, consisting of 3-4 cycles of MTX 3 g/m2 ± intrathecal chemo (IT). CNS-IPI was estimated as reported. For this analysis, pts with testicular involvement were considered at high risk independently of IPI values. Results: 242 pts were analyzed (median age 66, range 18-89). CNS-IPI was 0-1 (low risk) in 77 (32%), 2-3 (intermediate) in 90 (37%) and ≥4 (high) in 75 (31%). Prophylaxis with HD-MTX ± IT was indicated in 36 pts: 5 with low risk, 7 with intermediate risk and 24 with high risk. CNS prophylaxis was well tolerated; unexpected toxicity and interruptions due to toxicity were not recorded. At a median follow-up of 65 months (12-171), 11 (4.5%) pts experienced CNS relapse: 6 in the brain, the others in the meninges. CNS relapse rate was 1% (1/77) in low-risk pts, 0% (0/90) in intermediate-risk pts and 13% (10/75) in high-risk pts (low-intermediate vs high; p = 0.00001), with a 5-year actuarial risk of 2% (95%CI = 0-5), 0% and 19% (95%CI = 10-28), respectively (p = 0.00001). Eight of these pts died of CNS progressive lymphoma. In the 75 pts with high CNS-IPI, CNS relapse occurred in 20% (10/51) of pts who did not receive CNS prophylaxis and in 0% (0/24) of pts who received HD-MTX (p = 0.02), with a 5-year actuarial risk of 32% (95%CI = 18-46) and 0% (p = 0.008). Overall, 33 high-risk pts experienced relapse, and CNS and lymph nodes were the most commonly involved sites. Conclusions: With the limitations of a retrospective series, this study shows that HD-MTX prophylaxis is highly effective in pts with DLBCL and high risk of CNS relapse defined by the CNS-IPI and testicular involvement. CNS prophylaxis may contribute to appreciably improve survival of high-risk pts as the incidence and high mortality of CNS relapse.