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CNS prophylaxis in DLBCL
mg/m2 twice daily for 2 days, followed 3 weeks later by methotrexate at a dose of 3000 mg/m2. Among 156 patients, there were three toxicity-related deaths. The rate of CNS relapse was 4.5%, and all relapses occurred within 6 months of diagnosis; this CNS recurrence rate is compa- rable to that in historical controls. It is interesting to note, however, that all relapses occurred very early in the dis- ease course and the CNS-active agents were administered only following induction therapy. This supports the hypothesis that occult CNS involvement may already have been present early in the disease course, and that ear- lier administration of systemic methotrexate may have conferred greater benefit.
The optimal timing of CNS prophylaxis, particularly with high-dose intravenous methotrexate, remains incom- pletely elucidated. CNS relapse typically occurs during or within 5-6 months of induction treatment.8,28 The inci- dence of early CNS events forms the rationale for intro- duction of CNS-directed therapy concurrently with sys- temic induction treatment, but this must be balanced with risks of toxicity due to concomitant therapy. For high-risk DLBCL patients who are appropriate candidates for high- dose systemic methotrexate, we favor inclusion at a dose of 3500 mg/m2 on day 15 of the 21-day R-CHOP cycle for up to a total of three doses, usually administered in alter- nating R-CHOP cycles. An alternative schedule is to administer three or four doses of intravenous methotrex- ate immediately following completion of R-CHOP, although this risks earlier CNS progression. Methotrexate can be administered at 10- to 14-day intervals when given as monotherapy following completion of R-CHOP. A rec- ommended algorithm for risk stratification and prophy- laxis is shown in Figure 2.
Safe administration of high-dose systemic methotrexate for CNS prophylaxis relies upon careful attention to the selection and supportive care of patients. This treatment should be avoided in patients with a poor performance status, and those with impaired renal function or signifi- cant effusions or ascites which may serve as reservoirs for methotrexate and prolong toxicity. In order to minimize risk of toxicity, patients are pre-treated with hydration and alkalinization, which continues after methotrexate infusion to accelerate clearance. Methotrexate at a dose of 3000-3500 mg/m2 is typically administered over 2-4 h, with leucovorin rescue commencing 24 h after the begin- ning of the methotrexate infusion, and continuing every 6 h for 12-16 doses as the methotrexate clears. It is essential to monitor methotrexate levels along with electrolytes and renal function in order to ensure that the drug is cleared rapidly, which helps to avoid toxicity.
There are no data to support systemic prophylaxis with chemotherapeutic agents other than methotrexate at this time. Cytarabine has activity as a single agent and in com- bination with high-dose methotrexate in primary CNS lymphoma, but has not been validated to add benefit as prophylaxis in systemic DLBCL.74,81 Etoposide is a widely used lymphoma therapy which may attain cytotoxic con- centrations in the CSF and had historically been associated with a reduced risk of CNS recurrence, raising the prospect of benefit in the prophylactic setting.8,82 Subsequent studies of etoposide with rituximab-contain- ing therapy in the modern era, however, found no signifi- cant benefit in reducing CNS risk, so etoposide also can- not be recommended as a component of prophylactic therapy.18,83
Two novel agents, ibrutinib and lenalidomide, have demonstrated activity in relapsed DLBCL, particularly in ABC-like DLBCL which characterizes most cases of pri- mary and secondary CNS lymphoma. Additionally, ibruti- nib appears especially promising in ABC-like DLBCL har- boring both MYD88 and CD79B mutations, a mutational pattern commonly observed in primary CNS DLBCL.84-86 Given this biological rationale, ibrutinib and lenalidomide have both been preliminarily investigated in primary CNS DLBCL in which they have demonstrated the ability to cross the blood-brain barrier and induce remissions.87,88 Based on these findings, BTK inhibitors and lenalidomide warrant evaluation in the therapy of secondary CNS lym- phoma as well. Whether incorporation of one or both of these novel agents into upfront therapy in high-risk patients will reduce the risk of CNS relapse remains unknown, but will likely be elucidated by randomized tri- als adding these agents to R-CHOP in ABC-like DLBCL, which have been completed and await reporting. Two phase II trials in which lenalidomide was added to R- CHOP included 136 patients with CNS-IPI intermediate- and high-risk scores present in 71.3% and 18.4%, respec- tively.89 Prophylactic intrathecal methotrexate was employed in only 14% of patients. At a median follow-up of 48 months, only one of the 136 patients had experi- enced a CNS relapse, which is a promising early result. In addition to evaluating these agents in patients with active CNS DLBCL, studies will be helpful in determining the potential benefit of these agents in preventing CNS relapse, and in determining which patients could derive the most benefit from these novel therapies.
The advent of immune checkpoint inhibitors in the treatment of solid tumors and Hodgkin lymphoma90 has garnered interest in their use for DLBCL. While PD-L1 expression is uncommon in systemic DLBCL,91 higher rates of PD-L1 expression have been noted in primary mediastinal large B-cell lymphoma,92 primary CNS DLBCL, and primary testicular DLBCL.35 A small case series including four patients with relapsed/refractory pri- mary CNS DLBCL and one patient with CNS relapse of primary testicular DLBCL showed clinical and radiograph- ic responses in all patients treated with the PD-1 inhibitor nivolumab.93 These early data warrant further investiga- tion to determine whether select subsets of high-risk DLBCL patients may benefit from immune checkpoint inhibition to reduce the risk of CNS relapse.
Conclusions
In patients with DLBCL, relapse within the CNS remains a rare but devastating complication. There are significant limitations to determining the optimal methods of risk stratification and prophylaxis against CNS relapse, includ- ing the infrequency of the event, heterogeneity of existing literature, and inability to enroll sufficient numbers of patients in appropriately powered clinical trials with the primary outcome of CNS relapse. As a result, recommenda- tions and guidelines remain largely empiric in nature.
Based on the available data and clinical experience, the optimal approach is to first consider patient- and disease- specific risk factors and identify patients at highest risk for CNS relapse. Proper risk stratification should include cal- culation of patients’ CNS-IPI score, consideration of extra- nodal sites of disease, and identification of disease-specific
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