It’s not all about the CNS. High dose methotrexate in DLBCL

Abstract

Diffuse large B cell lymphoma (DLBCL) is an aggressive B cell lymphoma that carries with it a low but inherent risk of central nervous system (CNS) involvement at presentation or relapse [1]. While the risk of CNS involvement is relatively low, if diagnosed, the prognosis is poor with median survival of less than 6 months [2,3]. In the rituximab era, meta-analyses from prospective trials have demonstrated the overall incidence of CNS relapse to approach 5% in unselected populations, with a statistically lower percentage of relapse in patients who received CNS prophylaxis, 2.97% versus 6.12%, respectively [4]. Identification of patients at highest risk of CNS relapse and who would benefit most from intensification of prophylactic treatment has for years been complicated by lack of large uniformly treated patient cohorts and conflicting results regarding efficacy of preventing CNS relapse [5,6]. Generally in routine clinical practice, patients are considered high risk for CNS relapse if they have extranodal involvement of the bone marrow, testes, orbit/sinuses, epidural, adrenal, kidney, liver, or breast involvement [7,8]. Recently, the CNS International Prognostic Index (IPI) has been validated as a tool to identify patients at high risk of CNS relapse and in whom CNS prophylactic measures should be considered. This scoring system takes into consideration the standard IPI with the addition of points if there is involvement of kidneys and or adrenal glands. The system can risk stratify patients into three groups of high, intermediate, or low risk for CNS relapse with relapse rates of 10.2%, 3.4%, 0.6%, respectively, with the authors suggesting that high risk patients should be considered for CNS prophylactic strategies [9]. In this issue of leukemia lymphoma, Goldschmidt et al. provide retrospective evidence from two independent centers, concluding that addition of high dose methotrexate (HDMTX) to standard R-CHOP in patients with DLBCL at high risk for systemic or CNS relapse resulted in improved progression free survival (PFS) and overall survival (OS), compared to high risk patients that did not receive systemic intensification of prophylactic therapy [10]. Goldschmidt et al., identified high risk patients by the presence of any one of the following parameters; stage IV, LDH> normal, >1 extranodal site, bone marrow, testicular, orbital, or breast involvement. Of 480 patients identified as high risk, 130 (27%) were treated with HDMTX prophylaxis. At a median follow-up of 9 months, treatment with HDMTX significantly improved PFS and OS in patients receiving HDMTX compared to those who did not, PFS HR: 0.56 (0.4–0.78), OS HR: 0.39 (0.25–0.6). Of interest, treatment with HDMTX did not result in decreased incidence of CNS relapse. This supports the notion that improvement in patient outcomes was not due to decreased CNS disease, but rather to an impact on systemic disease. Notably this improvement in outcomes was observed despite the group receiving HDMTX having significantly more adverse features at baseline. Several studies, all retrospective, support the conclusion that high dose methotrexate is beneficial. Melen et al., studied outcomes of Swedish patients as reported to a national lymphoma registry and found the best outcomes in high risk patients were obtained with a regimen containing at least one cycle of high dose cytarabine and HDMTX [11]. Similarly, Ferreri et al. found a PFS and OS benefit associated with HDMTX, but attributed it solely to its protective effect on CNS relapses [12]. Recently Strussman et al., reported a retrospective study demonstrating improved outcomes in patients receiving