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CNS prophylaxis in DLBCL
ed in a broader analysis of 2210 patients treated on addi- tional prospective clinical trials by the DSHNHL, 620 of whom received rituximab-based treatment: intrathecal methotrexate again yielded no reduction in risk of CNS events.64
Similarly, a randomized controlled trial comparing R- CHOP-14 versus R-CHOP-21 (cyclophosphamide, doxoru- bicin, vincristine and prednisolone plus rituximab at 21- day intervals) included 984 patients, of whom 177 received CNS prophylaxis with the vast majority (92%) receiving intrathecal methotrexate. When stratified based on CNS-IPI, patients treated with intrathecal methotrex- ate had similar rates of CNS relapse, progression-free and overall survival compared with those not given prophy- laxis.19 Several additional retrospective analyses involving large numbers of patients treated with rituximab-based chemoimmunotherapy in the modern era have likewise failed to demonstrate an association between intrathecal methotrexate use and reduction in CNS relapse rates.22,65-67
The lack of clinical benefit observed with intrathecal methotrexate may be explained by the pharmacokinetics of this drug. Historic experiments found that methotrex- ate concentrations within the neuroaxis varied widely between different patients when the drug was adminis- tered via lumbar puncture. In one study, two of nine patients given intrathecal methotrexate did not meet the target therapeutic concentration at any time, and five of the nine did not sustain therapeutic concentrations for 24 hours.68 Another study monitoring the distribution of radionuclide Indium showed that it could take up to 24 hours for intrathecal injections of Indium to appear in the ventricles, suggesting that intrathecal therapy injected at the lumbar sac may fail to protect the cerebral lep- tomeninges due to uneven distribution.69 Furthermore, intrathecal methotrexate fails to achieve therapeutic con- centrations within the brain parenchyma,70 which could lead to reduced efficacy in this site where the majority of CNS relapses occur in the rituximab era.6,7,20,21
It is important to note the significant limitations of stud- ies evaluating the efficacy of intrathecal methotrexate. While available data including non-randomized prospec- tive and retrospective studies have not reliably demon- strated lower CNS relapse rates in patients receiving intrathecal therapy, these data are heterogeneous and can- not be considered definitive in their conclusions. Only appropriately powered randomized trials can truly exclude the possibility that intrathecal methotrexate reduces the risk of CNS relapse, although such trials would be extremely difficult to conduct. In cases in which alternative therapies, such as high-dose intravenous methotrexate, cannot be administered, intrathecal methotrexate remains a reasonable option.
One scenario in which intrathecal methotrexate remains an appropriate standard therapy is when administered with the dose-adjusted EPOCH-R regimen in patients with Burkitt lymphoma or high grade B-cell lymphoma (including double-hit and triple-hit lymphoma), in which it has been the exclusively studied method of CNS protec- tion. Intrathecal methotrexate has been demonstrated to improve the clinical outcome in these histological types of lymphoma which frequently relapse in the CSF.47,71
Systemic chemotherapy
Effective systemic therapy which crosses the blood- brain barrier may overcome the liabilities of intrathecal
therapy and achieve even and predictable concentrations throughout the entire neuroaxis, including both the lep- tomeningeal and parenchymal compartments.72
Consideration of systemic CNS prophylaxis is derived largely from experience in primary CNS DLBCL, in which high-dose systemic methotrexate improves progression- free and overall survival and remains the standard back- bone of first-line treatment.73,74 The efficacy of systemic methotrexate as prophylactic therapy for the CNS has also been validated in acute lymphoblastic leukemia75 and Burkitt lymphoma76,77 in which it remains an accepted standard of care.
These results have been corroborated in DLBCL with the phase III GELA trial comparing CHOP-21 (cyclophos- phamide, doxorubicin, vincristine and prednisolone at 21- day intervals) against the intensive ACVBP regimen (dox- orubicin, cyclophosphamide, vindesine, bleomycin, pred- nisone induction followed by sequential consolidation therapy) in patients with aggressive non-Hodgkin lym- phoma and IPI >1.58 The ACVBP arm included four doses of intrathecal methotrexate, plus two infusions of high- dose systemic methotrexate at 3000 mg/m2. Results of the trial were notable for significantly fewer CNS recurrences in the ACVBP arm compared to the CHOP arm (2.7% ver- sus 8%; P=0.004), as well as an overall survival benefit. Greater systemic disease control with the more intensive ACVBP regimen may well account for some of the observed benefit over CHOP, but the lower rate of isolat- ed CNS relapse suggests that CNS prophylaxis may also have played an important role. Given the lack of apprecia- ble benefit in numerous prior studies evaluating intrathe- cal methotrexate alone, it is reasonable to consider that the intravenous methotrexate contributed to the reduction in the rate of CNS recurrence.
We described our retrospective experience adding sys- temic high-dose methotrexate to R-CHOP as CNS prophy- laxis in selected high-risk patients with DLBCL.80 Patients received at least one dose of intravenous methotrexate at a dose of 3500 mg/m2 administered on day 15 of alternating cycles (i.e. cycles 2, 4, and 6) of R-CHOP. The population had a significant proportion of high-risk patients with IPI scores of 3-5 in 68%, elevated lactate dehydrogenase con- centration in 73%, more than one extranodal site of involvement in 62% of subjects, and frequent involvement of high-risk locations including the kidneys, adrenal glands, testes, bone marrow, or the epidural space. Among 65 high-risk patients, two CNS recurrences (3%) occurred (one at 4 months and the other at 9 months). The median follow-up for the entire population was 33 months, and the 3-year progression-free survival was 76%. Toxicities noted within this population included 26 patients (39%) with creatinine elevation above the upper limit of normal, although only one patient required temporary hemodialy- sis and subsequently recovered renal function. Renal toxic- ity led to discontinuation of methotrexate in nine patients (14%), all of whom recovered baseline renal function. In eight patients (12%) the subsequent R-CHOP cycle had to be delayed by 1-3 weeks because of toxicity (nephrotoxic- ity in 4, mucositis in 2, and cytopenias in 2). Despite these adverse events, the study demonstrated that patients with normal baseline renal function could tolerate high-dose methotrexate treatment intercalated with R-CHOP thera- py, and that this was associated with a lower rate of CNS relapse than may be expected based on their high-risk fea- tures at baseline.18
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