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A.S. Zayac et al.
with stage 4 disease. Of note, over half of CNS recurrences emerged in patients who did not attain complete response, suggesting primary refractory disease or inadequate control of baseline CNS involvement. Clinical trials have reported lower incidences (0-4%) of CNS recurrence,8,12,13,21,22,27,28 which may reflect selective enrollment of lower-risk patients in trials, or suboptimal CNS-directed therapy in our real-world sample. Despite high rates of intrathecal therapy, one in five patients with baseline CNS involve- ment succumbed to a CNS recurrence, which was predom- inantly leptomeningeal. Survival after CNS recurrence was dismal and consistent with generally poor outcomes of recurrent BL.7,29-31 HDMTX salvaged a few patients, but mainly those who did not receive it as part of their initial treatment regimen.
An emerging finding was the lower risk of CNS recur- rence among patients treated with regimens that contain high-dose systemic CNS-penetrant agents compared with DA-EPOCH-R, which relies solely on intrathecal chemotherapy for CNS management. Our observation could not be explained by stage distribution or prevalence of baseline CNS involvement, which were similar among patients receiving these strategies. Although patients selected for DA-EPOCH-R were older and had a worse PS, possibly compromising the intensity of treatment and adherence to CNS prophylaxis, the increased risk persisted after adjustment for these factors. In this context, it is important to note that we could not ascertain specific CNS staging procedures performed in our cohort. Patients enrolled in the clinical trials of DA-EPOCH-R uniformly underwent CSF evaluations using flow cytometry.12,13 Underdiagnosis of occult leptomeningeal disease might result in suboptimal intrathecal treatment, as DA-EPOCH- R relies on an intensive intrathecal regimen (starting with twice-weekly administration) in cases with CSF involve- ment, whether detected by cytology or flow cytometry. The NCI-9177 study enrolled no patients with parenchy- mal CNS disease, and out of 11 subjects with CSF involve- ment, six (55%) experienced relapse or death.12,13 Considering this experience and the outcomes observed in our series, DA-EPOCH-R should likely be avoided for treatment of BL with parenchymal CNS involvement. Among 81 high-risk patients without baseline CSF involve- ment, two developed a parenchymal CNS recurrence despite prophylaxis with eight intrathecal injections. In contrast, we observed CNS recurrence in 18% of patients with stage 4 BL receiving DA-EPOCH-R and in 35% among those with baseline CNS involvement. We could not discern the reasons for the lower intensity of the intrathecal administration schedule during DA-EPOCH-R (median 6 doses), which possibly contributed to the high failure rate of CNS control; adherence was poor even in academic centers. Because of unavoidable immortal-time bias, we could not compare outcomes based on degree of adherence in our retrospective data. It is possible that with stricter adherence the difference in CNS recurrence between patients treated with the different regimens would not have been significant. However, 37% of recur- rences involved the parenchymal CNS compartment, which may not be prevented with intrathecal therapy. On the other hand, reassuringly, there were no instances of CNS recurrence in patients with disease stages 1-3, sup- porting the observation of 100% PFS in low-risk BL after three cycles of DA-EPOCH-R without any CNS prophy- laxis.13 Because most patients in our study received
intrathecal chemotherapy, we could not identify a sub- group that could omit it. We highlight an unmet need for prospective studies of augmentation of DA-EPOCH-R for patients with CNS involvement using a CNS-directed strategy that is more efficacious and feasible to execute in routine clinical practice. The few attempts at “consolida- tive” HDMTX (± cytarabine) after DA-EPOCH-R observed in our sample do not enable any true interpretation of treatment effect, as these patients had CNS involvement and were likely at particularly high perceived risk of recur- rence. The unfavorable outcomes of this approach may reflect the delayed HDMTX administration, lack of added benefit beyond that of intensive intrathecal therapy in lep- tomeningeal disease, or simply a matter of bias. The need to adjust doses based on degree of cytopenias, early emer- gence of CNS recurrences, and high failure rate of “consol- idative” HDMTX prophylaxis in our admittedly small sam- ple illustrate the challenges of designing such an augmen- tation.32,33 We point out that an analysis of this dataset, as well as other retrospective studies, does not suggest signif- icant differences in the overall PFS or OS according to the first-line treatment regimen used in BL.4,5,16
The strengths of this study include its multicenter scope encompassing academic and community-based practices, HIV-associated BL, and a large subset with CNS involve- ment to allow for an in-depth analysis. Limitations include the retrospective design, rarity of CNS recurrence, and vari- ation in CNS-directed staging or treatment, particularly lim- ited information on the use of CSF flow cytometry, intensi- ty of intrathecal regimens and mode of delivery (intraven- tricular catheter or lumbar puncture). We also lacked molec- ular data that could provide insights into the biology of CNS invasion and inform future treatment strategies.
In conclusion, despite the success of immunochemother- apy in BL, patients with CNS involvement constitute a high-risk group in need of better management. In this large real-world dataset, CNS involvement was associated with worse prognosis regardless of first-line regimen applied, and independently of other factors. Regimens incorporat- ing high-dose systemic CNS-penetrant agents were associ- ated with a lower risk of CNS recurrence when adminis- tered to patients with baseline CNS involvement in routine clinical practice. Selective use of DA-EPOCH-R for patients with advanced age and worse PS, who could not maintain the intrathecal administration schedule inherent to this protocol, may have influenced our findings. An important insight from our analysis is that when clinicians apply the DA-EPOCH-R regimen, they should strictly follow the pre-specified CNS staging procedures (including CSF flow cytometry) and adequately tailored intrathecal administra- tion schedules, as frequent deviations from the protocol may lead to suboptimal CNS control. CNS-related out- comes from the ongoing HOVON-127BL randomized trial comparing DA-EPOCH-R with CODOX-M/IVAC (EudaraCT 2013-004394-27) will be critical to further define optimal therapy, provided that sufficient numbers of patients with baseline CNS involvement are enrolled. Further prospective studies are needed to optimize realis- tic delivery of CNS-directed prophylaxis with all standard regimens and to mitigate the incidence of CNS recurrence.
Disclosures
AE has received research funding from Takeda and Merck; has received honoraria from Research to Practice; has received honorar- ia from and provided consultancy services for Seattle Genetics,
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haematologica | 2021; 106(7)