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Real-world CNS outcomes in Burkitt lymphoma
disease had significantly lower rates of complete response (59% vs. 77% for patients with and without CNS involvement, respectively; P<0.001), worse 3-year progression-free survival (adjusted hazard ratio [aHR]=1.53, 95% confidence interval [95% CI]: 1.14-2.06; P=0.004) and overall survival (aHR=1.62, 95% CI: 1.18-2.22; P=0.003). The 3-year cumulative incidence of CNS recurrence was 6% (95% CI: 4-8%) and was significantly lower among patients receiving other regimens (CODOX-M/IVAC, 4%, or hyperCVAD/MA, 3%) compared with DA-EPOCH-R (13%; adjusted sub-distribution HR=4.38, 95% CI:, 2.16-8.87; P<0.001). Baseline CNS involvement in Burkitt lymphoma is relatively common and portends inferior prognosis independently of the first-line treatment regimen selected. In real-world practice, regi- mens including intravenous systemic agents with pronounced CNS penetrance were associated with a lower risk of CNS recurrence. This finding may be influenced by observed suboptimal adherence to the strict CNS staging and intrathecal therapy procedures incorporated in the DA-EPOCH-R regimen.
Introduction
Central nervous system (CNS) involvement is a serious complication of Burkitt lymphoma (BL), with an incidence ranging from 5% to 40%.1-7 Most first-line regimens employ dedicated CNS-directed strategies which typically include intrathecal and systemic chemotherapy capable of penetrat- ing the blood-brain barrier. The need for multiple intrathe- cal injections and potential severe toxicities of high-dose methotrexate (HDMTX) pose challenges to effective CNS- directed therapy, requiring expertise from the clinician and strict adherence by the patient. It is uncertain whether the application and outcomes of CNS-directed treatments in routine clinical practice correspond to those in clinical trials.
Short-cycle, dose-intensive immunochemotherapy regi- mens achieve progression-free survival (PFS) rates of 70- 80% in BL.8-11 Adverse effects associated with high-intensity regimens have limited the use of such regimens among the elderly or patients positive for human immunodeficiency virus (HIV), leading to interest in less aggressive options. The DA-EPOCH-R regimen (dose-adjusted etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, and rituximab) has demonstrated excellent survival and rel- atively low toxicity in single-arm trials, indicating that treat- ment for BL can be de-escalated without apparent loss of efficacy.12,13 Whereas DA-EPOCH-R involves the same or larger numbers of intrathecal chemotherapy administra- tions as those in common high-intensity regimens, it notably lacks classical CNS-penetrant systemic agents (HDMTX, cytarabine, ifosfamide) used for prophylaxis against CNS disease.14 DA-EPOCH-R requires strict CNS staging procedures (using flow cytometry of the cere- brospinal fluid [CSF] and brain imaging) and specific proto- cols for prophylactic or therapeutic intrathecal therapy to control the CNS invasion. Although the National Comprehensive Cancer Network (NCCN) guidelines rec- ommend DA-EPOCH-R as a first-line option for BL along with R-CODOX-M/IVAC (rituximab, cyclophosphamide, doxorubicin, vincristine, and HDMTX, alternating with ifosfamide, etoposide, and cytarabine) and R- hyperCVAD/MA (rituximab, cyclophosphamide, vin- cristine, doxorubicin, and dexamethasone alternating with HDMTX/cytarabine), there are limited data about the effi- cacy of DA-EPOCH-R in individuals with CNS involve- ment. The guidelines point out that high-risk patients pre- senting with symptomatic CNS disease should start treat- ment with the portion of systemic therapy that contains CNS-penetrating drugs, and that patients with parenchy- mal brain involvement were not included in the clinical tri- als of DA-EPOCH-R.15
Our objective was to describe factors associated with CNS involvement in BL using a large, multi-institutional dataset designed to study practice patterns and outcomes of adult BL.16 We examined real-world practice of CNS- directed management, and also compared CNS-related outcomes among patients treated with DA-EPOCH-R or with ‘high-intensity’ regimens.
Methods
Study cohort
In this multicenter retrospective study, we included patients aged ≥18 years diagnosed with BL between 2009 and 2018 in 30 institutions throughout the USA. The study was approved by the institutional review boards of all the institutions and waiver of informed consent was accepted. Of 702 identified subjects, 641 had complete clinicopathological data and were entered into a centralized database. Sixty-one patients were excluded because of pathology inconsistent with BL (n=21), inadequate follow-up (n=15), treatment dates out of range (n=13), or lack of clinical details (n=12).
The diagnosis was established by local review of pathology reports. BL was defined according to the World Health Organization (WHO) criteria,17 excluding other entities such as high-grade B-cell lymphoma, not otherwise specified, or dou- ble/triple-hit lymphoma. We included cases without known MYC rearrangement if they fulfilled other criteria for BL: small- cell morphology with tingible body macrophages, BCL2-nega- tive, CD10/BCL6-positive immunophenotype, and Ki67 stain- ing at ~100%. Staging evaluations and therapy were completed at the discretion of treating physicians.
Variables and endpoints
Investigators collected data using a standardized protocol. Performance status (PS) was assigned according to the Eastern Cooperative Oncology Group (ECOG) scale. CNS involvement was classified as leptomeningeal (based on CSF evaluation, radiological invasion of meninges or cavernous sinus, or clinical cranial nerve palsy) or parenchymal (radiological or biopsy- proven invasion of the brain, eye, or spinal cord), and always classified as stage 4 lymphoma. All CNS evaluations were per- formed according to institutional standards; specific use of imaging, CSF cytology, flow cytometry, or IGH polymerase chain reaction was not recorded. Serum lactate dehydrogenase (LDH) level was standardized relative to institutional upper limit of normal (ULN). Details about the location of CNS recur- rence and schedules of intrathecal therapy were collected for a subset of patients who either experienced a CNS recurrence, or who received DA-EPOCH-R with known baseline CNS
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