Page 15 - 2021_07-Haematologica-web

Editorials
Be mindful of the central nervous system in Burkitt lymphoma
Mark Roschewski
Lymphoid Malignancies Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA E-mail: MARK ROSCHEWSKI - mark.roschewski@nih.gov
doi:10.3324/haematol.2020.278181
In this issue of Haematologica, Zayac et al. illustrate the adverse prognostic impact of central nervous system (CNS) involvement for adult patients with Burkitt lym- phoma (BL).1 The authors reported data from a retrospec- tive series of 641 patients treated at 30 institutions in the USA and identified 120 (19%) patients with baseline CNS involvement. In the majority of cases (81%), the lep- tomeninges were involved, 17% had brain parenchymal lesions, and the site was unspecified in 2%. The risk was not uniformly distributed as patients with concomitant human immunodeficiency virus (HIV) infection had CNS involvement in 30% of cases whereas extranodal disease (particularly testicular involvement), poor performance status, and markedly elevated lactate dehydrogenase level were strongly correlated with CNS spread in HIV-negative patients. Most patients (89%) were treated with one of three standard frontline BL regimens: CODOX-M/IVAC, HyperCVAD/MA, and DA-EPOCH-R, presumably all with curative intent.2-4 Notably, active CNS involvement was evenly distributed across the three regimens, although this was not the case for other risk factors. The data clearly demonstrated that baseline CNS involvement
identified patients who are difficult to cure with standard frontline approaches as they had lower rates of complete response (59% vs. 77%; P<0.001) and a significantly lower 3-year overall survival (49% vs. 74%; P<0.001) compared to patients without baseline CNS involvement. Importantly, the negative prognostic impact of baseline CNS involvement was significant for all three regimens.
A second focus of the study was predictors of CNS recurrence in 570 patients treated with the three standard regimens. The overall rate of disease recurrence was 26% and the recurrence involved the CNS in 23% of cases. Most of these recurrences (82%) were isolated to the CNS without concomitant systemic recurrence and 87% occurred within the first year of treatment. These data strongly suggest that current strategies typically fail to eradicate active baseline CNS disease rather than the CNS being a sanctuary site for late relapses. Indeed, patients with baseline CNS involvement had the highest CNS recurrence rate of 18%. Considered by regimen, patients who received DA-EPOCH-R had a 35% rate of CNS recurrence among those with baseline CNS disease. These data illustrate that baseline CNS involvement is a
Figure 1. Multiple barriers prevent current strategies from effectively treating and preventing central nervous system disease in adults with Burkitt lymphoma.
Routine cytology is insufficiently sensitive for the detection of occult lymphoma cells in the cerebrospinal fluid (CSF) and widespread adoption of more sensitive tech- niques such as CSF flow cytometry or the development of assays that detect cell-free tumor DNA in the CSF are potential solutions. Therapy intolerance is a barrier unique to adults since pediatric regimens that employ high intensity chemotherapy and are highly effective in children and young adults with central nervous system (CNS) disease are often not tolerated by older patients or those with co-morbid conditions. Treating “possible Burkitt lymphoma (BL)” as a medical emergency with rapid employment of aggressive supportive care can improve performance status to allow for proper CNS-directed interventions and reduce the risk of early toxic death. The blood-brain barrier limits the use of many chemotherapy agents, but novel pathway inhibitors and immunotherapy agents with activity in BL are in clinical development, are often more tolerable, effectively cross the blood-brain barrier, and may overcome chemotherapy resistance. A more complete understanding of the genetic basis for mechanisms of drug resistance in BL may allow the development of additional novel agents that penetrate the CNS.
haematologica | 2021; 106(7)
1785