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Editorials
greater problem in real-world practice than observed in clinical trials, and that isolated CNS recurrence is a com- mon cause of treatment failure in adults with BL. The contributing factors are multiple and one should not con- clude that the problem is readily addressed by choice of frontline regimen. In reality, the absence of highly effec- tive CNS-penetrating agents is a major barrier, and new strategies should focus on this limitation (Figure 1). In the meantime, optimal management mandates being ever mindful of CNS detection, prophylaxis, and treatment.
The first important question is whether high-dose methotrexate-containing regimens such as CODOX- M/IVAC or HyperCVAD/MA are superior to DA-EPOCH- R in patients with CNS disease. The inherent selection bias of this retrospective study design precludes a defini- tive answer since the patients who received DA-EPOCH- R were older and were more likely to have a poor per- formance status.5 It is unclear whether these patients would have even been candidates for highly dose-inten- sive regimens since toxicities rise sharply with age.6,7 In a multicenter study of DA-EPOCH-R in 113 adults with BL, we reported that baseline CNS involvement was associat- ed with an inferior progression-free survival.4 Importantly, these patients had equal risk of disease progression as well as early toxic death due to sepsis compared to patients without CNS disease. Intensification of chemotherapy may improve control of CNS disease, but will increase the risk of early toxic death. In reality, only a prospective ran- domized study, such as the HOVON 127 trial (EudraCT number: 2013-004394-27), can adequately address the question of optimal therapy selection for adults with BL across various subsets.
Careful review of the data in the report from Zayac et al. and in the published literature suggests that additional barriers contribute to this complex problem (Figure 1). An important component of proper use of DA-EPOCH-R for BL is a risk-adapted approach that includes a careful analysis of the cerebrospinal fluid (CSF) with flow cytom- etry to detect occult disease. Using this approach, patients who are positive by flow cytometry are treated with an intensive intrathecal chemotherapy schedule while patients who are negative by flow cytometry receive less intrathecal treatment as CNS prophylaxis. Given the nature of the retrospective study by Zayac et al., the prop- er use of CSF flow cytometry to identify and adjust treat- ment with DA-EPOCH-R is unknown as is the use of brain imaging and CSF cytology. The absence of proper CNS evaluation in this series confounds any interpreta- tion that DA-EPOCH-R is less effective than other high- dose regimens. Furthermore, only 45% of the patients received the schedule of intrathecal therapy as published. Lastly, intrathecal chemotherapy alone would not be ade- quate therapy for brain parenchymal lesions and these patients have been excluded from clinical trials of DA- EPOCH-R; yet four patients in the study discussed had brain parenchymal lesions and received DA-EPOCH-R, which contributed to the high rate of CNS recurrence.
The authors adequately address the limitations of their data and should be commended for performing a sobering analysis of outcomes in adults with BL which we com- monly consider “highly curable.” In reality, these data illustrate that we successfully cure fewer adult BL patients than suggested by clinical trials, although the proper implementation of the treatment regimens in general prac- tice likely contributes to this disparity. Advances in the detection of occult CSF disease, including assays for cell- free tumor DNA, may be important in future studies. Perhaps most importantly, these data highlight that no matter which chemotherapy regimen is selected, effective treatment of CNS disease is an unmet need in BL. Novel targeted agents or immunotherapy that can overcome chemotherapy resistance, penetrate the blood-brain barri- er, and are tolerated by adult patients of all ages offer the most promise. Sadly, the patients with the highest risk of treatment failure, such as those with CNS involvement or HIV, are often excluded from clinical trials testing these novel agents.8-10 Until we collectively change our minds about the wisdom of this practice, we should expect to be disappointed with ‘real-world’ outcomes.
Disclosures
No conflicts of interest to disclose.
References
1. Zayac AS, Evens A, Olszewski AJ. Outcomes of Burkitt lymphoma with central nervous system involvement: evidence from a large multi-center cohort study. Haematologica. 2021;106(7):1932-1942.
2. Mead GM, Sydes MR, Walewski J, et al. An international evaluation of CODOX-M and CODOX-M alternating with IVAC in adult Burkitt's lymphoma: results of United Kingdom Lymphoma Group LY06 study. Ann Oncol. 2002;13(8):1264-1274.
3. Thomas DA, Faderl S, O'Brien S, et al. Chemoimmunotherapy with hyper-CVAD plus rituximab for the treatment of adult Burkitt and Burkitt-type lymphoma or acute lymphoblastic leukemia. Cancer. 2006;106(7):1569-1580.
4. Roschewski M, Dunleavy K, Abramson JS, et al. Multicenter study of risk-adapted therapy with dose-adjusted EPOCH-R in adults with untreated Burkitt lymphoma. J Clin Oncol. 2020;38(22):2519-2529.
5. Evens AM, Danilov AV, Jagadeesh D, et al. Burkitt lymphoma in the modern era: real world outcomes and prognostication across 30 US cancer centers. Blood. 2021;137(3):374-386.
6. Costa LJ, Xavier AC, Wahlquist AE, Hill EG. Trends in survival of patients with Burkitt lymphoma/leukemia in the USA: an analysis of 3691 cases. Blood. 2013;121(24):4861-4866.
7. Kelly JL, Toothaker SR, Ciminello L, et al. Outcomes of patients with Burkitt lymphoma older than age 40 treated with intensive chemotherapeutic regimens. Clin Lymphoma Myeloma. 2009;9(4):307-310.
8. Uldrick TS, Ison G, Rudek MA, et al. Modernizing clinical trial eligi- bility criteria: recommendations of the American Society of Clinical Oncology-Friends of Cancer Research HIV Working Group. J Clin Oncol. 2017;35(33):3774-3780.
9. Lin NU, Prowell T, Tan AR, et al. Modernizing clinical trial eligibility criteria: recommendations of the American Society of Clinical Oncology-Friends of Cancer Research Brain Metastases Working Group. J Clin Oncol. 2017;35(33):3760-3773.
10. Lichtman SM, Harvey RD, Damiette Smit MA, et al. Modernizing clinical trial eligibility criteria: recommendations of the American Society of Clinical Oncology-Friends of Cancer Research Organ Dysfunction, Prior or Concurrent Malignancy, and Comorbidities Working Group. J Clin Oncol. 2017;35(33):3753-3759.
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