Risk Factors For Central Nervous System Relapse Research Articles

Incidence of Central Nervous System Relapse in Patients with Primary Mediastinal Large B-Cell Lymphoma: A Retrospective Study

Background Primary mediastinal large B-cell lymphoma (PMBCL) is an uncommon type of non-Hodgkin lymphoma. Clinicopathologic features are distinct from diffuse large B cell lymphoma, but it shares some clinical and biologic features with Nodular sclerosis classic Hodgkin lymphoma. Central nervous system (CNS) relapse appears to be rare in patients with PMBCL, with limited literature reporting a rate of approximately 1.5% to 4%. We examined the incidence of CNS relapse, treatment approaches and survival outcomes in patients with PMBCL. Methods Patients with newly diagnosed PMBCL seen at Mayo Clinic between 2002 and 2022 were identified using the prospective Mayo Clinic Lymphoma Database. Clinical features, treatment details and outcomes were abstracted from the medical record. Cumulative incidence of CNS relapse was analyzed with death as a competing risk. The association of CNS-IPI, systemic treatment, and CNS prophylaxis approach with CNS relapse rate was analyzed using competing risk models and descriptively. Event-free survival (EFS) for the cohort was defined as time from PMBCL diagnosis to first recorded CNS and/or systemic relapse or death from any cause. Overall survival (OS) was defined as time from PMBCL diagnosis (or CNS relapse) to death from any cause. Survival analysis was performed using the Kaplan-Meier method. Results A total of 124 PMBCL cases were identified. The median age at diagnosis was 37 years and 61% were female. The distribution of CNS-IPI was low-risk in 67 (61%), intermediate-risk in 41 (37%), and high-risk in 2 (2%). 64 patients (52%) received R-CHOP and 54 patients (44%) received R-DA-EPOCH as frontline therapy. High-dose methotrexate (HD-MTX) for CNS prophylaxis was administered to 6 patients (5%), 5 with R-CHOP and 1 with R-DA-EPOCH. 16 patients received intrathecal (IT) chemotherapy (methotrexate and/or cytarabine) for CNS prophylaxis, 3 with R-CHOP and 13 with R-DA-EPOCH. The median follow-up was 56.0 months. The 5-year EFS rate was 75.1% and the 5-year OS rate was 90.7% for the entire cohort. 20 patients had systemic relapse only and 3 had CNS relapse. The cumulative incidence of CNS relapse was 1.84% (95% CI 0.46%-7.17%) at 2 years and 2.92% (95% CI 0.50%-8.84%) at 5 years (Figure 1). No statistically significant association of CNS-IPI, systemic therapy or CNS prophylaxis regimen with CNS relapse rate was found in competing risk models; however, this analysis was limited by a small event number (n=3). Among the 3 patients with CNS relapse, 1 had high-risk CNS-IPI and 2 had intermediate risk. All 3 patients were treated initially with R-CHOP. Two patients did not receive any CNS prophylaxis and 1 patient received IT CNS prophylaxis. All three patients who had CNS relapse were female. Patient #1 was diagnosed at age 48 and had simultaneous CNS and systemic relapse 6 months later. The patient was treated with HD-MTX, temozolomide and rituximab for CNS relapse, and subsequently received multiple therapies for systemic disease including R-DHAP, R-ICE, and died 17 months after CNS relapse. Patient #2 was diagnosed at age 22 and had CNS relapse after 8.7 months, followed by systemic relapse 2 months later. The patient received HD-MTX, temozolomide and rituximab for CNS relapse, followed by systemic and whole-brain radiation therapy (RT) for both systemic and CNS relapse. Subsequently the patient received salvage chemotherapy, autologous and allogeneic stem cell transplant for systemic relapse. The patient died 26.8 months after CNS relapse. Patient #3 was diagnosed at age 24 and had systemic relapse after 20.7 months, followed by CNS relapse 5.4 months later. The patient received methotrexate and whole-brain RT following CNS relapse and died 1.2 months after CNS relapse. Besides these 3 patients, we identified 6 PMBCL patients with CNS relapse who were diagnosed at other medical centers and subsequently referred to our institution for management of refractory disease. The survival after CNS relapse was poor, with a median OS of 10.4 months (95% CI 5.6-15.2). Conclusion Our study showed that the CNS relapse rate (1.84% at 2 years and 2.92% at 5 years) was overall low in patients with PMBCL, consistent with previous reports. CNS relapse was associated with poor survival despite aggressive treatment approaches. Novel approaches utilizing biological risk factors for CNS relapse, such as circulating tumor DNA, are needed to identify patients with CNS relapse.

Model for Predicting Central Nervous System Relapse in Diffuse Large B-Cell Lymphoma and Discussion of Prophylaxis Measures

Relapse of the central nervous system (CNS) is a rare but fatal complication in diffuse large B-cell lymphoma (DLBCL). The purpose of this study is to learn how to identify high-risk patients and take effective preventive measures. We retrospectively analyzed 1,290 adult patients with DLBCL at Peking University Cancer Hospital and Shanxi Bethune Hospital between 2010 and2020. There were 55 patients with CNS relapse who had a median follow-up of 5years. The risk of CNS relapse was 1.58% in the low-risk group, 5.66% in the moderate-risk group, and 11.67% in the high-risk group based on CNS International Prognostic Index (CNS-IPI). We found that CNS-IPI and testicular involvement were risk factors for CNS relapse, with OR 1.913 (95% CI: 1.036∼3.531; P= 0.038) versus. OR 3.526 (95% CI: 1.335∼9.313; P= 0.011), respectively. Intrathecal MTX and/or cytarabine prophylaxis was used in 166 patients (13.94%), intravenous (IV) high-dose methotrexate (HD-MTX) prophylaxis in 8 patients (0.67%), and intrathecal plus intravenous prophylaxis in 15 patients (1.26%). There was no significant difference in CNS relapse risk between IT, HD-MTX, and no prophylaxis recipients (12.7% vs. 0% vs. 23.6%, respectively, P=0.170). The risk of CNS relapse was similar whether or not patients accepted prophylaxis (5-year risk 4.1% vs. 2.2%, P= 0.140). Central nervous system (CNS) relapse isassociated with high risk CNS-IPI and testicular involvement. Therefore, it is necessary to pursue novel prophylactic strategies for CNS relapse.

Biosimilar Rituximab (Redditux) Added to CHOP Chemotherapy for De Novo Diffuse Large B-Cell Lymphoma Patients: Real-Life Single-Center Experience

Redditux® (RED), as a biosimilar rituximab, was approved in Turkey for all indications of the original Mabthera® (MAB) in March 2018. The aim of our study was to evaluate the efficacy and safety of RED in de novo diffuse large B-cell lymphoma. Fifty-one patients received RED combined with the CHOP regimen. The median follow-up was 31 months. The historical control group included 219 patients treated with the MAB-CHOP regimen and the median follow-up time was 38 months. We compared the response rates and survival outcomes of these RED-CHOP and MAB-CHOP cohorts. In the RED cohort, the overall response rate (ORR) at the end of the treatment protocol was 86%, with 37 (72.5%) cases of complete response (CR) and 7 (13.5%) cases of partial response (PR). In the historical MAB cohort, the ORR was 84%, with CR and PR rates of 82% and 2%, respectively. The 24-month progression-free survival (PFS) rates were 73.76% (95% confidence interval [CI]: 0.59-0.84) and 85.2% (95% CI: 0.79-0.90) for the RED and MAB cohorts, respectively (p=0.0106). The 24-month overall survival rates were 78.4% (95% CI: 0.64-0.87) and 81.4% (95% CI: 0.75-0.86) for the RED and MAB cohorts, respectively (p=0.7461). For patients with high revised International Prognostic Index scores, 24-month PFS was 45.5% (95% CI: 0.17-0.71) and 63% (95% CI: 0.37-0.80) for the RED and MAB cohorts, respectively (p=0.0711). In the RED cohort, central nervous system (CNS) relapse was significantly increased compared to the MAB cohort (10% vs. 1.83%, p=0.004). Among the RED cohort, bone involvement at the time of diagnosis was a risk factor for CNS relapse (p=0.028). Thirteen patients died in follow-up. There were no serious adverse events causing the cessation of the drugs. RED has an ORR similar to that of MAB. However, PFS rates were worse in the RED cohort. Additionally, CNS relapse ratio was a major concern for our RED cohort. Large prospective controlled studies and real-life data with longer follow-up are needed to document the non-inferiority of RED compared to MAB.

Outcomes of high‑dose methotrexate for CNS prophylaxis in diffuse large B‑cell lymphoma with an intermediate or high CNS‑International Prognostic Index: A single‑center retrospective cohort study.

Central nervous system (CNS) relapse in patients with diffuse large B-cell lymphoma (DLBCL) is rare (2-5% of cases), but is a devastating complication with a poor survival rate. The administration of high-dose methotrexate (HDMTX) for CNS prophylaxis in patients with DLBCL is controversial and variable in the literature. The present study aimed to evaluate the clinical outcomes of HDMTX CNS prophylaxis in patients with intermediate and high CNS-International Prognostic Index (IPI) DLBCL using real-world data. An observational retrospective cohort study was conducted of all patients with intermediate and high CNS-IPI DLBCL treated at Princess Noorah Oncology Center (King Abdulaziz Medical City, Jeddah, Saudi Arabia) between January 2010 and December 2020. Patients were treated with HDMTX either intravenously or intrathecally, according to the physician's evaluation of the patient. Data on patient clinical characteristics, CNS relapses, risk factors and survival rates were obtained from hospital records. Data were analyzed using Student's unpaired t-test and the χ2 test to compare the two subgroups, the Kaplan-Meier survival method with log-rank test to calculate and compare the survival rates, and regression analysis to determine the risk factors for CNS relapse and death. The study included 358 patients (n=32 with HDMTX CNS prophylaxis and n=326 without CNS prophylaxis). Patients in the CNS prophylaxis group had a significantly higher CNS relapse rate than those in the non-CNS prophylaxis group (12.5% vs. 1.8%; P=0.008). Patients who received CNS prophylaxis were younger and had an advanced stage of disease, with extranodal involvement and a high serum lactate dehydrogenase level at presentation. CNS prophylaxis was significantly associated with CNS relapse, while relapsed disease was associated with the risk of death (all P<0.05). In conclusion, the present study found that patients with intermediate and high CNS-IPI who received HDMTX CNS prophylaxis did not have fewer CNS relapses; however, those without CNS relapse had higher survival rates. In addition to CNS prophylaxis, Stage of DLBCL and IPI were significantly associated with CNS relapse. Future randomized control trials are needed to evaluate the efficacy of HDMTX CNS prophylaxis in patients with DLBCL.

P362: MINIMAL-LOSS-CYTOMETRY FOR EVALUATION OF CEREBROSPINAL FLUID IN PEDIATRIC ACUTE LYMPHOBLASTIC LEUKEMIA. SINGLE CENTER STUDY.

Background: Central nervous system (CNS) involvement at diagnosis of acute lymphoblastic leukemia (ALL) represents a risk factor for CNS relapse. Currently, examination of the cerebrospinal fluid (CSF) is performed and evaluated quantitatively using a counting chamber and qualitatively using cytomorphological analysis of cytospin. Recently, flow cytometry (FC) evaluation of CSF was shown to provide more reliable results and to predict relapse risk (de Haas et al., 2021, Thastrup et al., 2020). Independently of these studies, we applied a lyse-no wash technique aiming at minimizing cell loss during preparation and at improved cell concentration estimate. Aims: Our aim was to compare our findings with morphological criteria and published data and correlate them with clinical outcome in pediatric patients with ALL. Methods: We included pediatric patients with newly diagnosed ALL (04/2014 – 01/2022), whose CSF examination was performed in CLIP laboratory (n=208). Patients were classified as B cell precursor ALL (BCP ALL; 85%) and T ALL (15%) and treated according to following protocols: AIEOP-BFM ALL 2009 (n=118), AIEOP-BFM ALL 2017 (n=71), EsPhALL(n=8), Interfant06 (n=5), off-protocol (n=6). During follow up, 14 patients relapsed (5 CNS incl. combined, 9 non-CNS). CSF (drawn into tube with no fixative agent and processed within 2 hours) was concentrated by centrifugation and incubated with combination of antibodies (CD20/CD10/CD45/CD34/CD19/CD3/Syto41 in BCP ALL and CD4/CD99/CD5/CD3/CD7/CD16 + 56/CD8/CD45/Syto41 in T ALL). Residual erythrocytes were lysed with NH4Cl solution, followed by immediate acquisition on BD FACS Lyric or BD LSRII cytometers. Blasts were quantified to initial CSF volume. Cluster of 20 events was required to assign samples as FC positive (FC+). In parallel, CNS status was concluded according to morphological criteria, being classified as CNS1 (no blasts), CNS2a/b (≤5 WBC/μL with blasts), CNS2c/CNS3 (≥5 WBC/μL with blasts) according to treatment protocol guidelines. Continuous variables were compared with the Mann–Whitney test, survival data were analyzed using Mantel-Cox test. P values<0.05 were considered as significant. Results: Using FC, we identified atypical blasts in 50 out of the 208 analyzed samples (24%). Median of analyzed CSF volume was 367µL (range 143-1033µL), which enabled median sensitivity 0.054 events/µL (range 0.02-0.14ev/µL). Mean blast concentration was 0.47ev/µL (range 0-25ev/µL) in all samples and 2 ev/µL (range 0.01-25ev/µL, median 0.53ev/µL) in FC+ samples. We observed significantly higher blast concentration in patients with T ALL, in patients with CNS2 and CNS3 and those who subsequently relapsed. Patients with FC+ had significantly lower relapse-free survival than FC- patients (55% vs 94%), which provided better separation than CNS status (68% vs.85% for CNS2/3 vs. CNS1, respectively). Image:Summary/Conclusion: Using fresh CSF sample with lyse-no wash protocol enabled us to detect approximately 10x higher blast count (0.24ev/µL in FC+CNS1 and 1.25ev/µL in FC+CNS2/3) than was recently published (0.015ev/µL in FC+CNS1 and 0.073ev/µL in FC+CNS2/3 in Thastrup et al., 2020), and thus it better correlates to cytomorphological data. Interestingly, the proportion of FC+ patients in our cohort is comparable to (24% vs 25%), showing that although in our method we lose fewer cells, we identify the same proportion of FC+ patients. The presented study shows a higher impact of FC positivity on relapse risk than described previously. The disadvantage of our method is a need for a fresh sample, which is investigated locally. Supported by UNCE/MED/015, NU20J-07-00028.

Long-term outcomes and central nervous system relapse in extranodal natural killer/T-cell lymphoma.

To elucidate the long-term outcomes of non-anthracycline-containing therapies and central nervous system (CNS) events in patients with extranodal NK/T-cell lymphoma, nasal type (ENKTL), the clinical data of 313 patients with ENKTL diagnosed between 2000 and 2013 in a nationwide retrospective study in Japan were updated and analyzed. At a median follow-up of 8.4years, the 5-year overall survival (OS) and progression-free survival (PFS) were 71% and 64%, respectively, in 140 localized ENKTL patients who received radiotherapy-dexamethasone, etoposide, ifosfamide, and carboplatin (RT-DeVIC) in clinical practice. Nine (6.4%) patients experienced second malignancies. In 155 localized ENKTL patients treated with RT-DeVIC, 10 (6.5%) experienced CNS relapse (median, 12.8months after diagnosis). In five of them, the events were confined to the CNS. Nine of the 10 patients who experienced CNS relapse died within 1year after CNS relapse. Multivariate analysis identified gingival (hazard ratio [HR], 54.35; 95% confidence interval [CI], 8.60-343.35) and paranasal involvement (HR, 7.42; 95% CI, 1.78-30.89) as independent risk factors for CNS relapse. In 80 advanced ENKTL patients, 18 received steroid (dexamethasone), methotrexate, ifosfamide, L-asparaginase, and etoposide (SMILE) chemotherapy as first-line treatment. Patients who received SMILE as their first-line treatment tended to have better OS than those who did not (p=0.071). Six (7.5%) advanced ENKTL patients experienced isolated CNS relapse (median, 2.6months after diagnosis) and died within 4months of relapse. No second malignancies were documented in advanced ENKTL patients. In the entire cohort, the median OS after first relapse or progression was 4.6months. 12 patients who survived 5years after PFS events were disease-free at the last follow-up. Of those, 11 (92%) underwent hematopoietic stem cell transplantation. Our 8-year follow-up revealed the long-term efficacy and safety of RT-DeVIC and SMILE. The risk of CNS relapse is an important consideration in advanced ENKTL.

Predictive impact of soluble interleukin-2 receptor and number of extranodal sites for identification of patients at very high risk of CNS relapse in diffuse large B-cell lymphoma.

There remains an unmet clinical need to identify which patients with diffuse large B‐cell lymphoma (DLBCL) would benefit from central nervous system (CNS) prophylaxis, due to the low positive predictive value (PPV; 10%–15%) of the currently available predictive models. To stratify patients at high risk of developing CNS relapse, we retrospectively analyzed 182 patients with DLBCL initially treated with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R‐CHOP), or a R‐CHOP‐like regimen. Among them, 17 patients relapsed with CNS involvement, and the 2‐year rate of CNS relapse was 7.9%. Upon carrying out multivariate analysis, ≥3 extranodal sites and elevated soluble interleukin‐2 receptor (sIL‐2R) levels at diagnosis were identified as independent risk factors for CNS relapse. The 2‐year and 3.5‐year rates of CNS relapse were 57.1% and 78.6%, respectively, in patients with both elevated sIL‐2R and ≥3 extranodal sites. Furthermore, combined use of these risk factors of both elevated sIL‐2R and ≥3 extranodal sites resulted in a high PPV (71.4%), negative predictive value (93.1%), and overall accuracy (92.3%) for undergoing CNS relapse. In conclusion, we propose a simple and valuable tool to predict patients with DLBCL at very high risk of CNS relapse.

Timing of high-dose methotrexate CNS prophylaxis in DLBCL: a multicenter international analysis of 1384 patients

AbstractProphylactic high-dose methotrexate (HD-MTX) is often used for diffuse large B-cell lymphoma (DLBCL) patients at high risk of central nervous system (CNS) relapse, despite limited evidence demonstrating efficacy or the optimal delivery method. We conducted a retrospective, international analysis of 1384 patients receiving HD-MTX CNS prophylaxis either intercalated (i-HD-MTX) (n = 749) or at the end (n = 635) of R-CHOP/R-CHOP-like therapy (EOT). There were 78 CNS relapses (3-year rate 5.7%), with no difference between i-HD-MTX and EOT: 5.7% vs 5.8%, P = .98; 3-year difference: 0.04% (−2.0% to 3.1%). Conclusions were unchanged on adjusting for baseline prognostic factors or on 6-month landmark analysis (n = 1253). In patients with a high CNS international prognostic index (n = 600), the 3-year CNS relapse rate was 9.1%, with no difference between i-HD-MTX and EOT. On multivariable analysis, increasing age and renal/adrenal involvement were the only independent risk factors for CNS relapse. Concurrent intrathecal prophylaxis was not associated with a reduction in CNS relapse. R-CHOP delays of ≥7 days were significantly increased with i-HD-MTX vs EOT, with 308 of 1573 (19.6%) i-HD-MTX treatments resulting in a delay to subsequent R-CHOP (median 8 days). Increased risk of delay occurred in older patients when delivery was later than day 10 in the R-CHOP cycle. In summary, we found no evidence that EOT delivery increases CNS relapse risk vs i-HD-MTX. Findings in high-risk subgroups were unchanged. Rates of CNS relapse in this HD-MTX-treated cohort were similar to comparable cohorts receiving infrequent CNS prophylaxis. If HD-MTX is still considered for certain high-risk patients, delivery could be deferred until R-CHOP completion.

Early Integration of High Dose Methotrexate to Frontline DLBCL Therapy Does Not Impact CNS Relapse Compared to End of Treatment Delivery: A Multicentre International Analysis of 1384 Patients

Early Integration of High Dose Methotrexate to Frontline DLBCL Therapy Does Not Impact CNS Relapse Compared to End of Treatment Delivery: A Multicentre International Analysis of 1384 Patients

An Analysis Of Mechanisms Of Central Nervous System Infiltration In Acute Lymphoblastic Leukaemia Using Primary Cells Xenografted Into Immunodeficient Mice

Despite great advances in the treatment of paediatric acute lymphoblastic leukaemia (ALL), disease in the central nervous system (CNS) continues to pose challenges. Current diagnostic tests are insensitive and risk factors for CNS relapse are poorly understood. This results in all children receiving intensive CNS-directed therapy which may be associated with acute and/or chronic neurotoxicity. A better understanding of the mechanisms of CNS engraftment is a necessary pre-requisite for diagnostic and therapeutic advances. To investigate if primary cells infiltrate the CNS, and whether this property resides in any particular sub-clonal compartment we undertook a comprehensive analysis of the CNS engrafting potential of primary ALL cells in immunodeficient NOD.Cg-PrkdcscidIl2rgtm1Wjl/SzJ (NSG) mice. In addition, we used this model to investigate whether chemokine receptor expression drives CNS infiltration in pre-B ALL, as previously shown for T-ALL.CNS engraftment was seen in 18/23 pre-B ALL samples (78%). A consistent pattern of engraftment was observed with plaques of disease in the leptomeninges, relative sparing of the ventricles and complete absence of parenchymal infiltration. This implies ALL transit across the blood-CSF barrier rather than the blood-brain barrier – an important distinction, as leucocytes utilise distinct physiological trafficking mechanisms to cross these two barriers. To examine the frequency of cells with CNS-engrafting potential, intra-femoral transfer of 10 to 10,000 cells was performed. CNS engraftment was seen with as few as 10 initial cells. In addition, the ability to engraft the CNS was not restricted to any particular immunophenotypic compartment and was seen in CD19+CD10high, CD19+CD10low, CD19+CD20low, CD19+CD20high, CD19+CD34high, CD19+CD34low fractions. These data suggest that CNS engraftment potential is present at high-frequency in the bulk leukaemic population at diagnosis. To examine candidate trafficking molecules governing CNS entry, we investigated chemokine receptor expression on pre-B ALL blasts using quantitative PCR and flow cytometry. The chemokine receptors CXCR3, CXCR4 and CXCR7 were expressed by pre-B ALL but were not up-regulated in cells retrieved from the CNS compared to the bone marrow (BM).In conclusion, in xenograft models of pre-B ALL, CNS engrafting potential is present at high frequency in patient diagnostic BM specimens and does not appear to be restricted to sub-clonal compartments. These findings have important implications for the design of risk-adapted CNS therapy. Firstly, our studies indicate that CNS entry is a common property of leukaemic blasts and therefore the current dogma of CNS-directed therapy for all patients appears to have a rational scientific basis. Secondly, it is unlikely that chemokine receptor expression profiling will be a useful biomarker for CNS disease in pre-B ALL. Finally, identifying factors that facilitate long-term survival of cells in the CNS (which may also enhance long-term survival in the bone marrow) may be a better therapeutic strategy than attempts to block cell entry. Disclosures:No relevant conflicts of interest to declare.

Central Nervous System Relapse in Diffuse Large B Cell Lymphoma—Predictors at Diagnosis

Background Central nervous system (CNS) relapse of diffuse large B cell lymphoma (DLBCL) is an infrequent outcome with very poor prognosis. Initial studies have identified risk factors for CNS relapse and the CNS international prognostic score ((CNS-IPI) (Schmitz et al, JCO 2016) has been validated in various cohorts. Biologic characteristics of the disease are not included in the derivation of this model. We sought to validate this risk factor model in our single center DLBCL population in search for additional disease - specific factors that could further improve prediction of CNS relapse.Methods The hematologic malignancies database of the University Hospitals Seidman Cancer Center was accessed to identify newly diagnosed DLBCL patients between 2002 and 2014. Patients with extra-nodal CNS involvement at diagnosis were excluded. Through retrospective chart review data, we identified patient and disease characteristics, and outcomes data including response, relapse and death was collected. Patients who underwent therapy and had follow up data were included for final analysis. Univariate Cox proportional hazards analysis was conducted on the risk factors and those reaching statistical significance (p < 0.05) were selected for inclusion in multivariate proportional hazards model to help identify predictors for CNS relapse. CNS IPI score was applied to our population and cumulative incidence (with death as competing risk) was used to estimate the incidence of CNS relapse with the Gray test performed for comparisons between groups.Results: Five hundred and twenty-four patients were included for final analysis. Median age in our cohort was 64 years, with 312 (59.5 %) patients above the age of 60 years. 322 (63 %) patients had stage (III-IV), and 220 patients (37%) had elevated LDH at diagnosis. Two hundred and eighty five patients had extra-nodal disease involvement at the time of diagnosis with 88 patients involving more than one site. Baseline patient and disease characteristics are listed in Table 1. Four hundred (76%) patients received R CHOP as first line therapy, 395 patients achieved complete remission with first line therapy. At a median follow up of 64 months, 187 patients died and 171 patients had relapsed.Twenty-one patients developed CNS relapse in the follow up period, at median of 8.2 months after treatment initiation (95% CI 6.2-9.6) months. Applying the CNS-IPI risk scoring among the evaluable patients, 149 patients (36%) were found to be low risk (0-1 factors), 222 patients (53%) were intermediate risk (2-3 factors) and 47 patients (9%) were high risk (4-6 factors) for CNS relapse. Univariate analysis showed advanced stage (stage III-IV), number of extra-nodal sites involved, liver involvement, non- GCB subtype, translocation t (14; 18) and body mass index were significantly associated with CNS relapse (p<0.05). In multivariate analysis, only non- GCB subtype and translocation t (14; 18) (p = 0.023 and 0.028 respectively) were significant. Table 2 summarizes the results of Cox proportional hazards analysis.We evaluated the cumulative incidence of CNS relapse in the high-risk group, defined as CNS-IPI >1, (n=269, 64%). The 2-year CNS relapse cumulative incidence was at 5.1 % (95% CI: 2.8- 9%) compared to 0% for patients with CNS IPI ≤ 1 (p=0.027) (Figure 1).Median survival after CNS relapse was 3.6 months (0 - 150.2 months). Overall survival from start of initial therapy was 16 months (95% CI 9.5 -81.9 months) for patients with CNS relapse vs 170 months (95% CI 120.3 months - not reached), p<0.001]. (Figure 2)SummaryPrognosis of CNS relapsed of DLBCL is very poor. CNS IPI score helps identify a cohort that may benefit from CNS prophylaxis, and may help avoid unnecessary diagnostic and therapeutic intervention in the low risk cohort, i.e., CNS- IPI score <1. Hepatic involvement at diagnosis may be an additional clinical characteristic associated with high risk of CNS relapse. Biological features including non-GCB subtype and translocation t (14; 18) are novel risk factors that should be considered in the development of future risk models. [Display omitted] DisclosuresMalek:Takeda: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sanofi: Membership on an entity's Board of Directors or advisory committees; Celgene: Speakers Bureau. Cooper:Novartis: Research Funding. de Lima:Celgene Corporation: Research Funding; Pfizer: Membership on an entity's Board of Directors or advisory committees. Caimi:Seattle Genetics: Equity Ownership; Abbvie: Equity Ownership; Incyte: Equity Ownership; Celgene: Speakers Bureau.

Lack of Effectiveness of Intravenous High-Dose Methotrexate for Prevention of CNS Relapse in Patients with High-Risk DLBCL: A Retrospective Analysis from Alberta, Canada

Introduction: Central nervous system (CNS) relapse occurs in 2-10% of patients with diffuse large B cell lymphoma (DLBCL) and carries a poor prognosis. The CNS-IPI score identifies patients at high-risk (10-12%) of CNS relapse based on the presence of 4-6 risk factors: age &amp;gt;60 years, ECOG performance status &amp;gt;1, elevated LDH, stage III to IV, &amp;gt;1 extranodal site, and renal or adrenal involvement. International guidelines recommend prophylactic intravenous high-dose methotrexate (HD-MTX) for patients at high-risk of CNS relapse. However, there is limited evidence supporting this practice, and prophylactic HD-MTX requires hospital admission and increases the risk of treatment-related toxicity. Therefore, we conducted a real-world study to determine the effectiveness of HD-MTX for prevention of CNS relapse in high-risk DLBCL. Methods: We performed retrospective chart reviews of patients aged 18-70 years with DLBCL treated with curative intent at two academic medical centers in Alberta, Canada between 2012-2019. Since 2015, the Alberta Provincial Lymphoma Clinical Practice Guideline (APLCPG) has recommended CNS prophylaxis with HD-MTX 3.5g/m2 IV after cycles 2, 4, and 6 of R-CHOP for patients with the following high-risk criteria: CNS-IPI 4-6, double hit lymphoma, or testicular involvement. Between 2012-2015, HD-MTX was recommended for patients with elevated LDH, ECOG &amp;gt;1, and &amp;gt;1 extranodal site. In addition, eligible patients at risk of poor outcomes (e.g. double hit lymphoma or IPI score 4-5) could be offered higher intensity chemoimmunotherapy (e.g. da-EPOCH-R or R-CODOXM/R-IVAC) or R-CHOP followed by consolidative autotransplant. The log-rank test was applied to determine risk of CNS relapse and the Cox proportional-hazards model was used to determine factors associated with CNS relapse, progression-free survival (PFS), and overall survival (OS). Analyses were performed using SPSS version 25 and GraphPad Prism 8 statistical software. Results: We included 906 patients with a median follow-up time of 35.3 months (range 0.29-105.7). Risk of CNS relapse was 1.9% (95% C.I. 0.0-30.7%) for patients with CNS-IPI 0-1, 4.9% (95% C.I. 0.5-18.0%) for CNS-IPI 2-3, and 12.2% (95% C.I. 4.0-25.2%) for CNS-IPI 4-6 (p&amp;lt;0.0001). Risk factors for CNS relapse included APLCPG high-risk criteria (HR 4.69, 95% C.I. 2.51-8.76), CNS-IPI score 4-6 (HR 4.26, 95% C.I. 2.22-8.16), and testicular involvement (HR 3.45, 95% C.I. 0.43-27.34). Among the 326 patients meeting APLCPG high-risk criteria, median CNS-IPI was 4 (range 0-6), 67 (20.6%) had double hit lymphoma, and 17 (5.2%) had testicular involvement. Risk of CNS relapse was significantly increased for patients meeting APLCPG high-risk criteria (11.8% vs 3.0%, p&amp;lt;0.0001). Prophylactic HD-MTX was administered to 115 (35.3%) high-risk patients; median number of doses given was 2 (range 1-3). The risk of CNS relapse was 11.2% (95% C.I. 2.1-28.9%) for patients who received HD-MTX versus 12.2% (95% C.I. 2.8-28.8%) for those who did not (p=0.82). Patients who underwent higher intensity chemoimmunotherapy (n=35) or consolidative autotransplant (n=68) tended to have a lower risk of CNS relapse than patients treated with conventional R-CHOP (6.0% vs. 14.6%, p=0.09). In multivariate analyses, HD-MTX and higher intensity chemoimmunotherapy demonstrated no significant association with CNS relapse, PFS, or OS; however, consolidative autotransplant was associated with a tendency toward lower risk of CNS relapse (HR 0.30, 95% C.I. 0.09-1.01) and a significantly improved PFS (HR 0.41, 95% C.I. 0.24-0.71) and OS (HR 0.56, 95% C.I. 0.32-0.98). Conclusion: The APLCPG high-risk criteria of CNS-IPI 4-6, double hit lymphoma, or testicular involvement identify patients with DLBCL at significantly increased risk of CNS relapse. The risk of CNS relapse was similar for all high-risk patients (11.8%) and those who received prophylactic HD-MTX (11.2%) in our study relative to previously published data for patients who did not receive CNS prophylaxis (10-12%). Based on this analysis, we could not demonstrate a benefit to the current practice of prophylactic HD-MTX. However, the lower rate of CNS relapse and improved PFS and OS in patients who received consolidative autotransplant in our study suggests that optimizing frontline therapy to achieve better systemic disease control may be a more effective strategy to reduce the risk of CNS relapse than prophylactic HD-MTX alone. Disclosures Stewart: Teva: Honoraria; Sandoz: Honoraria; Novartis: Honoraria; AstraZeneca: Honoraria; Amgen: Honoraria; Roche: Honoraria; Janssen: Honoraria; Abbvie: Honoraria; Gilead: Honoraria; Celgene: Honoraria.

Impact of prophylactic intrathecal chemotherapy on CNS relapse rates in AML patients presenting with hyperleukocytosis

Central nervous system (CNS) relapse in acute myeloid leukemia (AML) confers a poor prognosis. Despite the identification of risk factors for CNS relapse (e.g. hyperleukocytosis), there is no standard practice for CNS relapse risk reduction with intrathecal (IT) chemotherapy in patients. We compared outcomes of 50 patients who did not receive IT chemotherapy with 18 patients who did receive IT chemotherapy with a hyperleukocytosis at diagnosis (defined as white blood cell count ≥100,000 cells/mcL). There were three occurrences of CNS relapse, all within patients who did not receive prophylaxis. There was no difference in the incidence of CNS relapse between the patient cohorts (p = .560). These results highlight the low incidence of CNS relapse in our patient population that received and survived induction chemotherapy despite selecting for a high risk cohort. Furthermore, there is a need for a CNS relapse registry to standardize treatment approaches in this high-risk patient population.

Molecular Correlates of Central Nervous System Relapse in Diffuse Large B-Cell Lymphoma

Introduction: Central nervous system (CNS) relapse is a rare phenomenon in diffuse large B-cell lymphoma (DLBCL), occurring in less than 5% of all patients, but is associated with disproportionate morbidity and mortality. Indeed, the median survival of patients diagnosed with CNS relapse is as low as 2-4 months. Individual risk factors for CNS relapse are well established, and include clinical parameters such as stage, number/type of extranodal sites and elevated lactate dehydrogenase. These and other clinical risk factors have been integrated into a risk score that is reproducible and easy to calculate (CNS International Prognostic Index). Moreover, molecular attributes such as double-hit translocation status, MYC/BCL2 dual protein expression and the activated B-cell-like subtype have been associated with a higher risk of CNS relapse. However, while experts recommend prophylactic interventions for high-risk patients, the major shortcoming of available risk tools is their limited sensitivity. Herein, we evaluated whether gene expression and/or mutational profiles can identify those patients that will ultimately experience CNS relapse, and whether intratumoral heterogeneity impedes accurate prognostication. Methods: We accrued diagnostic FFPET samples from 230 newly diagnosed DLBCL patients, selected to fall into 3 clinical groups: 1) cases with CNS relapse/CNS involvement at diagnosis (n=58); 2) cases with systemic relapse but without CNS relapse (n=64) and 3) cases without any relapse (n=108). These 230 samples were subjected to microarray-based gene expression profiling and differential gene expression analysis. Pathway analysis was performed using Gene Set Enrichment Analysis on ranked gene lists. We assembled a partially overlapping dataset with mutation data of 45 genes in 213 diagnostic samples (n=65 with CNS relapse, 62 with systemic relapse and 86 without relapse). Lastly, we performed exome sequencing in 5 pairs (peripheral and CNS parenchymal tumors) of patients with CNS relapse or CNS involvement at diagnosis, and reconstructed clonal phylogenies using PyClone. Results: Focusing on gene expression data at first, we did not observe significant differential expression between CNS relapse and non-relapse cases at the individual gene level. This was in contrast to the comparison between systemic relapse vs. non-relapse cases where 368 genes were differentially expressed (adjusted P&lt;0.05). In terms of pathway analysis, minimal gene set enrichment was seen in CNS relapse cases, whereas functional annotations such as translation, ribosome biogenesis and MYC targets were significantly enriched in cases with systemic relapse. In keeping with these observations, the percentage of cases that were positive for the recently published double hit signature was highest in cases with systemic relapse (64% vs. 39% in CNS relapse cases and 27% in cases without relapse, P=0.012). However, CNS relapsing cases were defined by down-regulation of numerous immune signatures (e.g. interferon and multiple T cell signatures), suggesting that an intact immune response may have a protective effect on CNS relapse. Considering mutation data, we found that TP53 and SGK were most commonly mutated in systemic relapse cases, while TNFRSF14 and KTM2D were most commonly mutated in non-relapse cases (all adjusted P&lt;0.05). The only gene mutation with a borderline significant trend for enrichment in CNS relapse cases was MYD88 (adjusted P=0.05). We then performed exome sequencing of 5 tumor pairs. A subset of high-confidence somatic variants and tumor purity were used as input for PyClone to infer clonal population structures. In all pairs, we documented the existence of common ancestral mutations, as well as significant clonal divergence, with CNS-exclusive mutations not identified in diagnostic specimens. Conclusion: In summary, we have documented that CNS and systemic relapse result from distinct biological processes that, in part, may be associated with the underlying taxonomy of DLBCL. Our findings further show that CNS relapse results from the dissemination of sub-clones that may not be readily sampled at the time of diagnosis, and that intratumoral heterogeneity may limit our ability to predict CNS relapse. Large-scale, integrative analyses and in-depth characterization of clonal trajectories hold the promise to increase our ability to predict dissemination of DLBCL into the CNS. Disclosures Kridel: Gilead Sciences: Research Funding. Villa:Roche, Abbvie, Celgene, Seattle Genetics, Lundbeck, AstraZeneca, Nanostring, Janssen, Gilead: Consultancy, Honoraria. Steidl:Nanostring: Patents &amp; Royalties: Filed patent on behalf of BC Cancer; Juno Therapeutics: Consultancy; Bristol-Myers Squibb: Research Funding; Roche: Consultancy; Tioma: Research Funding; Bayer: Consultancy; Seattle Genetics: Consultancy. Savage:BMS, Merck, Novartis, Verastem, Abbvie, Servier, and Seattle Genetics: Consultancy, Honoraria; Seattle Genetics, Inc.: Consultancy, Honoraria, Research Funding. Scott:Celgene: Consultancy; Roche/Genentech: Research Funding; NanoString: Patents &amp; Royalties: Named inventor on a patent licensed to NanoSting [Institution], Research Funding; Janssen: Consultancy, Research Funding.

The Magnitude of Lactate Dehydrogenase Elevation As a Predictive Factor for Central Nervous System Relapse in Diffuse Large B-Cell Lymphoma

Introduction: The incidence of central nervous system (CNS) relapse in diffuse large B-cell lymphoma (DLBCL) is approximately 5%. Although the introduction of rituximab for the treatment of DLBCL has reduced the risk of CNS relapse, the median overall survival of these patients remains only few months, emphasizing the need to accurately identify at-risk patients, screen for CNS disease, and develop effective therapeutic/prophylactic strategies. Aim: To identify risk factors for CNS relapse in patients with DLBCL. Methods: Retrospective analysis of patients with DLBCL diagnosed from January 2012 to December 2017 at a Cancer Institute. Patients with exclusive extranodal (EN) disease were excluded. Factors associated with CNS relapse were evaluated using Chi-square, Fisher's Exact Test, Mann-Withney U or T-Test, according to variable types and distributions. Survival was evaluated by Kaplan-Meier method and groups were compared by Log-rank test. Independent predictive factors were identified using Logistic Regression. A p value &lt; 0.05 was considered statistically significant. Results: Four hundred and seventy-nine patients were identified, 122 were excluded due to exclusive EN disease, and 357 patients were included in the study. With a median follow-up of 33 months, there were 10 (3%) CNS relapses. According to International Prognostic Index (IPI) factors in addition to involvement of kidneys and/or adrenal glands (CNS-IPI), 5 (50%) of these patients were classified as high risk, 4 (40%) intermediate risk and 1 (10%) low risk. Patients who development CNS involvement were significantly younger (57 vs. 65 years, p=0.036), presented higher levels of lactate dehydrogenase (LDH) (median 738 vs. 282 U/L, p&lt;0.001) and lower levels of hemoglobin (median 10,3 vs. 12,1 g/dL, p=0.010) at diagnosis. No differences were found regarding to performance status, stage or number of EN areas. Two patients (18%) in the CNS relapse group had done CNS prophylaxis versus twenty two (6,3%) patients in the group without CNS relapse. In multivariate analysis, LDH &gt;600 was the only independent predictive factor (HR 15.3, CI 95% 3.5 - 65.8, p&lt;0.001). Overall survival in CNS relapse group was 22 months, versus not reached (p&lt;0.001). Conclusion: Although CNS-IPI is a robust model to estimate the risk of CNS relapse, it does not capture the full spectrum of those at high risk. Other clinical risk factors and biomarkers beyond this model might play an important role in this setting, such as the magnitude of LDH elevation Disclosures No relevant conflicts of interest to declare.

The Predictors and Prevention of the Central Nervous System Relapse in Patients with Extranodal NK/T Cell Lymphoma, Nasal Type

Background: The incidence of central nervous system (CNS) involvement is rare ranging from 0 to 6% in patients with extranodal NK/T cell lymphoma, nasal type. A few studies have suggested that CNS prophylaxis should be considered in the high PINK group, but it is unclear because of relatively small numbers of patients. However, non-anthracycline-based chemotherapy with L-asparaginase improved the survival outcome, and the frequency of CNS relapse is expected to increase. Therefore, we aimed to identify the incidence and risk factors for CNS relapse and to evaluate the need for CNS prophylaxis with high-dose methotrexate (HD MTX) regimens. Patients and methods: We retrospectively reviewed 399 patients who had diagnosed with extranodal NK/T-cell lymphoma, nasal type, and received non-anthracycline based chemotherapy from January 2000 to January 2019 at multicenter in Korea. The CNS relapse was defined as a brain parenchymal or leptomeningeal involvement confirmed either by MRI or CSF study during chemotherapy or follow-up period. For subgroup analysis, we used the prognostic index of natural killer lymphoma (PINK), and the prognostic index of natural killer lymphoma with Epstein-Barr virus DNA (PINK-E), which includes age, Ann Arbor stage, lymph node involvement, and EBV DNA. Patients were divided into two groups, according to whether the chemotherapy regimen included HD-MTX. Results: Twenty-seven patients (6.8%, 27/399) experienced CNS relapse during chemotherapy or follow-up period. The median overall survival of all patients was 93.7 months [95% confidence interval (CI) 72.53-114.95], and the median time to CNS relapse of 27 patients was 10.1 months (range 0.0-42.0). The clinical variables associated with CNS relapse were BM involvement (HR 4.026, p=0.002), extranodal involvement≥2 (HR 8.198, p&lt;0.001), EBV DNA (HR 3.90, p=0.013), Ann Arbor stage III/IV (HR 9.397, p&lt;0.001), PINK [intermediate (HR 4.700, p=0.009), high (HR 9.554, p&lt;0.001)], and PINK-E [intermediate (HR 6.032, p=0.001), high (HR 6.775, p&lt;0.001)]. In multivariate analysis, PINK was the powerful predictor of CNS relapse (HR 3.486, p=0.019). The cumulative incidence of CNS relapse was significantly different between groups of Ann Arbor stage (p&lt;0.001), PINK (p=0.004), or PINK-E (p=0.002). The incidence of CNS relapse in patients with/without HD-MTX regimens was six patients (6/101, 5.9%) and 21 patients (21/298, 7.0%). Although there was no significant difference between both treatment groups in all patients, the patients who received chemotherapy with HD MTX regimens had a lower incidence of CNS relapse than those who received other regimens in Ann Arbor stage III/IV (p=0.033). Conclusions: We demonstrate the strong predictability of PINK and PINK-E for CNS relapse in patients with extranodal NK/T-cell lymphoma, nasal type. HD MTX regimens reduced the incidence of CNS relapse in Ann Arbor stage III/IV groups, and CNS prophylaxis should be considered for these patients. Disclosures Kim: F. Hoffmann-La Roche Ltd: Research Funding; Celltrion: Research Funding; Novartis: Research Funding; Donga: Research Funding; Kyowa-Kirin: Research Funding; Novartis: Research Funding; J + J: Research Funding.

Abstract PD3-12: Central nervous system as first site of relapse in patients with HER2 positive early breast cancer treated in the BCIRG-006 trial

Abstract Introduction: Central Nervous System (CNS) metastases as first site of relapse is seen in 2-3% of patients with HER2+ early breast cancer (EBC) during or after treatment with adjuvant trastuzumab. Data about long-term follow-up outcomes in this population is scarce. Methodology: BCIRG-006 was designed to assess the efficacy and safety of two trastuzumab-based regimens compared to a standard (non-trastuzumab) regimen in the adjuvant treatment of HER2+ EBC. 3,222 patients were randomized to standard AC-T or two trastuzumab-based regimens (AC-TH or TCH). Ten year follow-up outcomes were previously presented; we have used this data to assess the frequency and course of CNS relapses as first site of distant recurrence. DFS and OS in these patients were estimated and compared using the Kaplan-Meier method and Log-Rank test respectively. Univariate and multivariate analyses for DFS were conducted considering patient's age, nodal status, tumor size and estrogen receptor (ER) status in the primary tumor. Results: Of the 3,222 patients randomized, 575 (17.8%) experienced a distant relapse and in 17.5% of these (n=101) CNS was the first site of recurrence. With a median follow-up of 10.3 years, the frequency of CNS relapses did not differ when comparing the trastuzumab containing arms with the control arm (OR 0.86, 95% CI: 0.56-1.33; p= 0.519). No difference was observed either between AC-TH and TCH (OR 1.14, 95% CI: 0.67-1.94; p= 0.704). There were no differences in DFS (HR 1.21, 95% CI: 0.74-1.99; p= 0.621) nor in OS (HR 0.74, 95% CI: 0.43-1.27; p= 0.377) between AC-T, AC-TH and TCH arms. Positive axillary nodes (≥4 nodes) and ER negative status at baseline remained independent risk factors for CNS relapse after univariate and multivariate analysis (HR 0.60, 95% CI: 0.8-0.95; p= 0.007 for nodal status and HR 0.56, 95% CI: 0.37-0.85; p= 0.029 for ER status). Conclusion: Among the pivotal adjuvant trastuzumab trials, BCIRG-006 is the one with the longest median FUP in which data about CNS relapses has been presented. CNS relapse in patients in this trial was an infrequent event. Its frequency and outcomes were similar across the three treatment arms. Patients with ER negative and/or ≥ 4 positive nodes are at higher risk of CNS relapse irrespective of trastuzumab therapy and may be the patient population where research efforts should be focused. BC outcomes in patients with CNS metastases per treatment arm in the BCIRG-006 trial AC-T N=1073 n(%)AC-TH N=1074 n(%)TCH N=1075 n(%)p valueFrequency of CNS relapse37 (3.44%)30 (2.79%)34 (3.16%)0.519 ^Median DFS (months; 95% CI)23.8 (13.3-30.4)19.9 (16.6-25.1)19.9 (15.0-27.2)0.621 ⫲Median OS (months; 95% CI)42.5 (28.3-62.7)53.2 (31.2-103.6)30.3 (23.4-39.0)0.377 ⫲ ^ comparing control vs. trastuzumab-containing arm using Fisher's Exact test. ⫲ comparing control vs. trastuzumab-containing arms using Log Rank test. Citation Format: Chan A, Spera G, Machado A, Fung H, Bee V, Fresco R, Slamon DJ. Central nervous system as first site of relapse in patients with HER2 positive early breast cancer treated in the BCIRG-006 trial [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr PD3-12.

Incidence and Risk Factors of Central Nervous System Relapse in Localized Extranodal NK/T-Cell Lymphoma, Nasal Type: An Analysis of Nkea Study

Incidence and Risk Factors of Central Nervous System Relapse in Localized Extranodal NK/T-Cell Lymphoma, Nasal Type: An Analysis of Nkea Study

Central Nervous System Involvement in Peripheral T Cell Lymphoma.

Central nervous system (CNS) involvement in peripheral T cell lymphoma (PTCL) is a difficult condition to treat, both as a primary and a secondary disease. Primary CNS lymphoma (PCNSL) in PTCL is very rare, making up only 2% of all PCNSLs. The incidence of CNS relapse is generally 2-6% in all cases of PTCL, but the risk may vary by histologic subtype, and extranodal involvement > 1 has been consistently found to be a risk factor for CNS relapse. Currently, there is no consensus about indications for CNS prophylactic treatment. A high-dose systemic methotrexate-based regimen is the most commonly used treatment, with or without consolidation with high-dose chemotherapy with autologous stem cell transplantation for both primary and secondary CNS involvement. This approach, however, is generally toxic for older patients. New therapeutic approaches against PTCL are therefore needed.

Frequency, risk factors, and outcomes of central nervous system relapse in lymphoma patients treated with dose-adjusted EPOCH plus rituximab.

Central nervous system (CNS) relapse in non-Hodgkin lymphoma (NHL) is a rare but serious complication that carries a poor prognosis. The use of infusional etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, and rituximab (EPOCH-R) for frontline treatment of diffuse large B cell lymphoma (DLBCL) is increasing, though little is known about incidence of and risk factors for CNS relapse with this regimen PATIENTS AND METHODS: We completed a chart review of patients with NHL who received EPOCH-R as front line therapy. Data obtained included baseline and treatment characteristics including if patients received CNS directed therapy. We measured overall survival (OS), progression free survival (PFS), and progression to CNS involvement. We identified 223 patients who met the inclusion criteria, 72% had DLBCL. Of all the patients, 5.8% experienced CNS relapse, and 38.6% were treated with CNS prophylaxis. There was no difference in rate of CNS relapse, OS, or PFS between patients who had and had not received CNS prophylaxis. Patients whose serum lactate dehydrogenase was greater than twice the upper limit of normal at diagnosis and those with extranodal disease were significantly more likely to have CNS relapse (P = .0247 and 0.022, respectively) than their counterparts. The rate of CNS relapse in this patient population approaches 6%, not significantly different from reports on those receiving R-CHOP. The results of this study suggest that CNS prophylaxis might be more selectively used among patients treated with EPOCH-R with certain high-risk features.