Page 18 - 2021_02-Haematologica-web

332
Editorials
Central nervous system prophylaxis in diffuse large B-cell lymphoma: a race to the bottom
Mark Roschewski
Lymphoid Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
E-mail: MARK ROSCHEWSKI - mark.roschewski@nih.gov doi:10.3324/haematol.2020.266635
In this issue of Haematologica, Bobillo et al. address the controversial topic of chemotherapy as central nerv- ous system (CNS) prophylaxis during front-line man- agement of diffuse large B-cell lymphoma (DLBCL).1 Despite the fact that CNS spread is a feared and often ter- minal complication of DLBCL treatment, there is no broad consensus regarding which patients should receive CNS prophylaxis or which is the most effective delivery method.2 Overall, the incidence of CNS relapse across all DLBCL subsets is only approximately 5%, but clinical risk factors, including the involvement of specific anatomic sites, are associated with a significantly higher rate of CNS spread. Further, we are beginning to uncover the biological basis for DLBCL involving the CNS, as spe- cific genetic subtypes demonstrate an inherently higher rate of CNS tropism.3-5 The CNS International Prognostic Index (CNS-IPI) is a commonly used risk model that strat- ifies patients into risk categories,6 and combining this model with the cell-of-origin phenotype may improve patient selection.7 However, even the most robust predic- tive models cannot overcome the fundamental problem that the chemotherapy agents most effective for the cure of systemic DLBCL do not reliably penetrate the blood- brain barrier (Figure 1).8 Conversely, methotrexate (MTX), which reliably penetrates the CNS, is not highly effective for DLBCL. The most commonly used prophy- lactic strategy is repeated intrathecal (IT) injections of chemotherapy such as MTX during front-line therapy, but since brain parenchymal sites are the commonest site of CNS relapse, some advocate the use of deeply pene- trant drugs such as high-dose methotrexate (HD- MTX).9,10 No randomized prospective study has directly addressed this specific question, and, as a result, practice patterns rely on consensus guidelines and vary widely across institutions and individual providers.11 In essence, the debate about optimal delivery methods is essentially a 'race to the bottom' that compares two strategies that do not adequately address the clinical problem.
Bobillo et al. utilize this lack of consensus to retrospec- tively compare clinical outcomes in 585 patients with DLBCL considered high-risk for CNS relapse (29% of all DLBCL cases screened) treated at their own institution with a variety of CNS prophylactic strategies including no prophylaxis at all.1 Most (86%) of the 295 patients who received CNS prophylaxis were treated with a median of four IT injections of MTX or cytarabine during front-line therapy while a significant minority (14%) of patients were treated with a median of two cycles of HD- MTX at a median dose of 3.5g/m2 either during front-line therapy (45% of cases) or immediately following (55% of cases). Notably, 11 (26%) patients who received HD- MTX also received concomitant IT chemotherapy. Importantly, 290 (50%) patients received no form of CNS
prophylaxis and these patients were significantly older (median age 72 years). This observation highlights the fact that patient-related factors such as age and perceived ability to tolerate treatment-related toxicity greatly influ- ence treatment decisions beyond prognostic scores and/or involvement of extranodal sites. Since all forms of CNS prophylaxis have clinically meaningful toxicities, this underscores the fact that an important limitation of all available datasets is patient selection bias.
Bobillo et al. first confirmed the expected finding that patients with relapse in the CNS had a worse median overall survival of only 4.9 months compared to 17.1 months for those with systemic-only relapse (P=0.03).1 Regarding efficacy, after a median follow-up of 6.8 years, the 5-year CNS relapse rate was still 5.6% in patients who received any form of CNS prophylaxis, confirming that currently employed chemotherapy strategies are not uni- versally effective. An important observation in this study was that CNS relapses in patients treated with prophylax- is occurred a median of 19 months after front-line therapy compared to only 8 months in patients who received no prophylaxis. As a result, even though CNS prophylaxis appeared to reduce the risk of CNS relapse at 1 year, there was no difference in the 5-year CNS relapse rate between patients who received prophylaxis compared to those who received no CNS prophylaxis (5.6% vs. 7.5%) (Risk Ratio 0.76, 95% Confidence Interval: 0.35-1.50). Further, there was no difference in the 5-year CNS relapse risk in patients who received IT MTX compared to those who received HD-MTX, although the number of events was small. Taken together, these data suggest that actual risk reduction of any form of CNS prophylaxis with chemotherapy is likely to be modest at best and currently employed strategies may simply delay the timing of CNS recurrence. These findings also have implications for the reporting of CNS relapse. It is well-described that patients with primary DLBCL of the CNS (PCNSL) often have late relapses, and early reporting of clinical outcomes will miss a significant number of events and may overestimate the true cure rate in subsets of DLBCL with the highest CNS tropism.12 Many retrospective studies that have described the incidence of CNS relapse do not include long-term fol- low-up beyond 2 or 3 years and therefore may be under- reporting the true incidence.2
However, the risk of CNS involvement is not equally distributed across all subsets of DLBCL, which may allow for precision medicine strategies. In fact, DLBCL is not a singular disease but comprises a spectrum of aggressive lymphomas with striking underlying genetic diversity. The current classification system recognizes both ABC DLBCL and GCB DLBCL as distinct molecular subtypes and introduced a new entity, high-grade B-cell lym- phoma, defined by the presence of MYC and BCL2
haematologica | 2021; 106(2)