Is there still a need for specific central nervous system directed prophylaxis for diffuse large B-cell lymphoma in the rituximab era?

Central nervous system (CNS) relapse remains an important cause of treatment failure in patients with diffuse large B-cell lymphoma (DLBCL) treated with rituximab, cyclophosphamide, doxorubicin, vincristine and prednisolone (R-CHOP). The frequency with which it occurs depends upon the population studied, the duration of follow-up and the degree of scrutiny applied. In unselected patients with DLBCL, CNS relapse rates of 2–9.9% have been reported [1,2], whilst in a selected high-risk minority the actuarial 2-year incidence is as high as 33.5% [3]. Although infrequent, CNS relapse has devastating consequences and is rarely salvageable; hence, prevention is the best approach. However, the use of, appropriate selection of patients for and most effective form of prophylaxis all remain contentious issues. Rituximab (Mabthera; Hoffman La-Roche, Basel, Switzerland; and Rituxan; Genentech, San Francisco, CA) has markedly improved outcomes in patients with DLBCL [4,5], but prior studies evaluating its impact on CNS relapse have had conflicting results.

Helping to clarify our understanding, in this issue of Leukemia and Lymphoma Zhang et al. report a meta-analysis of eight randomized studies comprising 4911 patients, in which patients with newly diagnosed DLBCL received chemotherapy with or without rituximab [6]. The risk factors for CNS relapse identified in this study included a list of the usual suspects: advanced stage, International Prognostic Index (IPI) ≥ 2, performance status > 1, elevated serum level of lactate dehydrogenase (LDH), more than one extranodal site of involvement, bone marrow involvement, the presence of B symptoms and testicular involvement. Intrathecal (IT) prophylaxis was not associated with reduced risk of CNS relapse, although in the included studies use of IT chemotherapy was not randomly allocated, and was presumably used in those patients perceived to be at higher risk of CNS relapse; thus the apparent equivalent risk for CNS relapse in patients receiving IT prophylaxis (hazard ratio [HR] 1.03) could be interpreted as consistent with some degree of risk reduction, although even if present such a benefit is insufficient on its own. [7] The main finding of the study was that the addition of rituximab showed a modest reduction of CNS relapse in DLBCL, from 5.7% to 4.7%, a relative risk reduction of 30% (HR 0.7; 95% confidence interval [CI] 0.54–0.91), or an absolute risk reduction of 1% in the total population.

How should we incorporate the findings from this into clinical practice? It appears that the addition of rituximab to CHOP affords a modest reduction in CNS relapse, and this likely provides sufficient protection for those patients without identified high risk factors. However, we argue that for patients at high risk of CNS relapse (predicted > 10%), the use of R-CHOP without specific CNS-directed prophylaxis is insufficient. A number of the risk factors identified in this meta-analysis are markers of high tumor burden and/or highly proliferative disease. In addition to the risk factor of testicular involvement identified in this meta-analysis, other retrospective studies have identified specific high-risk extranodal sites including kidney [8], breast [9,10], adrenal gland [10] and epidural space [11,12]. We believe that patients with one or more of these factors also warrant consideration of CNS-directed therapy. Although paranasal sinus involvement increased risk of CNS dissemination in the pre-rituximab era, a recent German analysis of patients treated with R-CHOP has found no such increase [13]. This meta-analysis confirms the finding of prior studies that IT chemotherapy alone as prophylaxis is either ineffective or has insufficient utility [3,7–9,14]. The practice of IT prophylaxis is extrapolated from its successful use in acute lymphoblastic leukemia and Burkitt lymphoma, where the risk of CNS involvement is high and the distribution is leptomeningeal in 74% of instances [15]. In contrast, meta-analysis of 28 studies of DLBCL found that CNS relapse was manifest as parenchymal involvement in 59% of cases [16]. This, combined with uneven distribution of chemotherapy injected by lumbar puncture around the neuroaxis and limited penetration into the deep parenchymal structure, constitutes one potential explanation for the frequent failure of this approach [17]. Hence, there is conceptual appeal in treating patients with doses of methotrexate and cytarabine capable of penetrating brain parenchyma. Pharmacokinetic studies have shown that continuous infusion intravenous (IV) methotrexate results in a “therapeutic” serum level for longer than bolus administration [18].

We highlight three studies which have examined the addition of high doses of systemic methotrexate to anthracycline based chemotherapy in patients with DLBCL. Tilly et al. conducted a prospective randomized comparison of four cycles of doxorubicin, cyclophosphamide, vindesine, bleomycin and prednisolone (ACVBP) with eight cycles of CHOP in intermediate grade lymphoma [19]. The ACVBP arm included a dose of IT methotrexate with each of the induction cycles and a consolidation phase, which consisted of two cycles of methotrexate (3 g/m²), etoposide, ifosfamide and low dose cytarabine. No CNS prophylaxis was delivered on the CHOP arm. Patients allocated to the intensive arm had a marked reduction in CNS relapse from 8.3% to 2.8% (p = 0.004). Abramson et al. treated 65 patients with DLBCL considered to be at high risk of CNS relapse with the addition of methotrexate 3.5 g/m² with a median of 3 (range 1–8) cycles following completion of primary chemotherapy, which was predominantly R-CHOP [20]. The large majority of patients had one or more risk factors (raised serum LDH, multiple extranodal sites, advanced stage and IPI 3–5), but with the addition of a median of 3 cycles of methotrexate, only two patients (3%) developed CNS relapse. Finally, Holte et al. conducted a phase II study of 156 patients with age adjusted (aa) IPI 2–3 aged < 65 with rituximab, cyclophosphamide, doxorubicin, vincristine, etoposide and prednisolone at 14-day intervals (R-CHOEP14) with the addition of a cycle of methotrexate and cytarabine (both at 3 g/m² at the completion of primary therapy, with dose reductions permitted for patients aged 60–65). A single dose of IT chemotherapy was permitted at the time of staging lumbar puncture prior to the commencement of therapy [21]. The study population was also high risk (nearly all stage III/IV, raised serum LDH, aaIPI 2–3 by inclusion criteria), and the reported CNS relapse rate of 4.5% was lower than expected for such a group. These studies suggest that high dose antimetabolite therapy is an effective strategy for reducing the risk of CNS relapse. However, neither form of CNS-directed prophylaxis is free from adverse effects. IT methotrexate can cause chemical arachnoiditis resulting in nausea, vomiting, fever and headache; lumbar puncture can result in post-lumbar puncture headache, and in the absence of fluoroscopic guidance, ectopic administration of methotrexate in addition to the usual potential side effects of lumbar puncture. Intravenous high dose methotrexate (particularly in the setting of pre-existing renal impairment) can be complicated by delayed clearance, acute renal tubular necrosis, mucositis, transaminitis, myelosuppression and sepsis [22]. These factors typically result in prolonged hospitalizations, and therefore it is critical that only patients at high risk of CNS relapse are selected for such a prophylactic strategy.

Our unit policy is to define patients with DLBCL at high risk of CNS involvement by the presence of any one or more of the following factors: aaIPI > 2 (incorporating LDH, stage and performance status); multiple or specific extranodal sites of involvement (testis, breast, kidney, adrenal, bone marrow and epidural). We perform lumbar puncture with cerebrospinal fluid analysis using conventional cytology, flow cytometry and biochemistry at the time of diagnosis and with each cycle of chemoimmunotherapy. Intrathecal methotrexate 12 mg is administered with each lumbar puncture, optimally for a total of six doses, acknowledging that anatomic barriers or patient tolerance can limit the number achieved in standard practice. At the completion of chemoimmunotherapy, patients undergo restaging with positron emission tomography–computed tomography (PET-CT); those achieving a complete response are admitted for two sequential cycles of methotrexate 1–3 g/m² with a 2-week interval between cycles (with dose reductions based on age and renal impairment). Careful attention is paid to urinary alkalinization, avoidance of medications which may interact with and delay methotrexate excretion, including proton pump inhibitors and herbal remedies [11,23–25], and fluid balance. Using this combination we thus direct prophylaxis at both the parenchymal and leptomeningeal compartments, and hope to strike the balance between preventing this deadly complication in those at substantial risk and avoiding unnecessary harm in those patients unlikely to benefit. So, is there still a role for specific CNS-directed prophylaxis in patients treated with R-CHOP? We think the answer is yes.

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