Risk Of Central Nervous System Relapse Research Articles

Clinical Outcomes and CNS Relapse Risk in Patients with Primary Cutaneous DLBCL, Leg Type Treated in the Rituximab Era: Long-Term Follow-up of a Single-Center Experience

Clinical Outcomes and CNS Relapse Risk in Patients with Primary Cutaneous DLBCL, Leg Type Treated in the Rituximab Era: Long-Term Follow-up of a Single-Center Experience

Characteristics of Patients with Central Nervous System Relapse in Veterans with Diffuse Large B-Cell Lymphoma within the Veterans Health Administration

IntroductionAround 2-5% of patients with diffuse large B-cell lymphoma (DLBCL) will experience central nervous system (CNS) relapse resulting in a poor prognosis. The Central Nervous System International Prognostic Index (CNS-IPI) is a validated risk model used to help identify DLBCL patients receiving R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone) chemotherapy who are at risk for CNS relapse. CNS prophylaxis is recommended for those with high-risk CNS-IPI scores; however, the role of CNS prophylaxis has been called into question given recent large datasets showing no impact on CNS relapse. The purpose of this study is to evaluate the characteristics of Veterans who experienced CNS relapse within the Veterans Healthcare Administration (VHA) and to validate the CNS-IPI risk stratification within this population.MethodsTrained abstractors performed a retrospective chart review of 3287 lymphoma patients seen in the VHA nationwide between 01/01/2011 and 12/31/2017. Figure 1 describes the selection of the study cohort. We evaluated baseline patient and disease characteristics including CNS-IPI score, performance of diagnostic lumbar puncture (LP) and first-line chemotherapy regimen. Pathology reports to identify cell of origin (COO), and additional risk factors for CNS relapse present at the time of original diagnosis including HIV associated lymphoma, testicular lymphoma, and high-grade B-cell lymphomas (HGBLs) defined as double or triple-hit DLBCL were evaluated. We also assessed response to first-line treatment, type of CNS prophylaxis used, including number of doses, and time to CNS relapse.ResultsA total of 1621 patients met criteria for analysis. Patients were predominately male, white, had a median age of 67, and presented with advanced disease (Table 1). At the time of diagnosis, 81% of the cohort had an ECOG performance status of 0-2, 73% received a CHOP based regimen, and 52% were designated as having a high-risk CNS-IPI score. Patients were about twice as likely to have a germinal center B-cell (GCB) COO rather than activated B-cell (ABC), but the COO was unavailable for almost 30% of the cohort. About 6% of the patients were known to have HGBLs, but the “hit status” of around 65% of the patients was unknown. Diagnostic LP was performed in 10%, 14%, and 19% of patients in the low-, intermediate-, and high-risk CNS-IPI groups respectively.The median follow-up time for the subjects in the study was 44 months. The low-risk group (12% of all patients analyzed), the intermediate-risk group (36%) and the high-risk group (52%) showed rates of CNS relapse of 1% (with a 95% CI: 0% to 2.4%), 2.4% (CI: 1.2% to 3.7%), and 2.4% (CI: 1.3% to 3.4%) respectively with no statistically significant difference across the risk groups (p=0.30). In patients with CNS relapse, only 35% of patients had a diagnostic LP. More than 90% of patients deemed high-risk for CNS relapse did not receive CNS prophylaxis. Among the 36 patients with CNS relapse, only 3 were given CNS prophylaxis at baseline (Table 2). Of the patients with CNS relapse, 75% of patients achieved a complete response with initial treatment. When categorized by the CNS-IPI score, there is no significant difference between intermediate- and high-risk based on type of CNS relapse, type of CNS prophylaxis used, response to first-line therapy, median time to relapse, median survival time, or median time from relapse to death. Those with CNS relapse had a shorter survival time compared to those with systemic relapse or no relapse (Figure 2).ConclusionsWhen compared to the previously validated CNS-IPI study, there were fewer instances of CNS relapse in our patient population in the intermediate- and high-risk groups, however, about a quarter of the patients in these groups did not receive CHOP based therapy. Although there is published data demonstrating COO and HGBLs as contributing factors to CNS relapse, our data did not show any statistically significant difference in relapse rates. Potential limitations include that the study is a retrospective chart review of a predominately male veteran population. Our data suggests the CNS-IPI may not identify patients at risk for CNS relapse with adequate accuracy. [Display omitted] DisclosuresNooruddin: AstraZeneca: Research Funding.

Impact of Double Hit Lymphoma and Cell of Origin in the Risk of Central Nervous System Relapse in Patients with Newly Diagnosed Diffuse Large B-Cell Lymphoma

Introduction: Central nervous system (CNS) relapse is an uncommon but devastating complication occurring in about 2-10% of patients with diffuse large B-cell lymphoma (DLBCL). The CNS-IPI is a validated prognostic tool used to identify patients at high risk of CNS relapse. MYC and BCL2/BCL6 rearrangements (double-hit lymphoma- DHL) and non-GCB (NGCB) cell of origin may be at higher risk of CNS relapse. However, the ability of these molecular data to refine CNS-IPI risk prediction has not been assessed. In this study, we aimed to describe the impact of DHL and NGCB cell of origin in the incidence of CNS relapse in patients with newly diagnosed DLBCL.Methods: A retrospective review was conducted to identify patients with newly diagnosed DLBCL from 01/01/2002 - 06/30/2015 using the University of Iowa/Mayo Clinic Lymphoma Molecular Epidemiology Resource database. Patients with primary CNS lymphoma or with CNS involvement at diagnosis were excluded. All patients received chemoimmunotherapy. Clinical, biological, laboratory and radiological data were abstracted including the occurrence of CNS relapse. CNS IPI risk score categories were defined as low- (≤1) intermediate- (2-3) and high-risk (≥4) as originally described (Schmitz et al, JCO 2016). Cell of origin (COO) classification into GCB and non-GCB subtypes was performed using Hans algorithm and/or NanoString data. Characteristics between groups were compared using Kruskal-Wallis or Chi-squared test as appropriate. Survival analysis was performed using Cox proportional hazards model and the Kaplan Meier method. Statistical analysis was performed using SAS version 9.4M5 and R version 4.0.3.Results: We identified a total of 1,360 patients with newly diagnosed DLBCL. Patients had a median age of 62 years (range 18-93 years), were predominantly male (56%), had a performance status <2 (84%), had stage III/IV disease (61%) and an elevated LDH (56%) at diagnosis. Fluorescent in situ hybridization data was present for 65% of patients. Among patients with available data, DHL and NGCG COO represented 2.8% and 36% of the cohort, respectively. CNS IPI high- and intermediate-risk categories were present in 12.4% and 52% of the patients, respectively. R-CHOP was the most common upfront chemotherapy (n=980, 72%).The median follow-up for the entire cohort was 84.9 months (IQR: 58.9-120.9). Overall, 50 patients (3.6%) had a CNS relapse during the study period. Lymphoma relapsed in the CNS in 3.0% (95% CI:2.1-4.4), 4.7% (95% CI: 3.4-6.3) and 4.9% (95% CI: 3.7-6.6)% of patients with CNS-IPI score of intermediate/high risk at 1, 3 and 5 years following the diagnosis of DLBCL. In patients with low risk CNS-IPI, 1.1% (95% CI: 0.4-2.5), 1.7% (95% CI: 0.9-3.4) and 1.7% (95% CI: 0.9-3.4) had a CNS relapse at 1, 3 and 5 years following DLBC diagnosis. Patients with CNS relapse were more likely to have elevated LDH (76% vs 56%, p=0.008), advanced stage (78% vs 61%, p=0.01), adrenal involvement (8% vs 2.4%, p=0.014) and have a CNS IPI intermediate risk (68% vs 51%), and high risk (16% vs 12.3%, p=0.014) at the time of initial diagnosis compared to patients without CNS relapse. Patients with CNS relapse had similar rates of DHL (4% vs 2.7%, p=0.17) and NGCB cell of origin (42% vs 36.2%, p=0.52) compared to patients without CNS relapse.In the multivariable analysis, the strongest predictors for CNS relapse were CNS IPI high risk (Hazard Ratio [HR]= 3.6, 95%CI= 1.4-9.7) and CNS IPI intermediate risk (HR= 3.15, 95%CI= 1.46-6.81). DHL and NGCB cell of origin were not associated with a significantly higher risk of CNS relapse (HR= 1.79, [95%CI=0.42-7.59] and HR= 1.26, [95%CI=0.62-2.57], respectively).Conclusion: CNS relapse was an uncommon occurrence in patients with DLBCL who were treated with chemoimmunotherapy. CNS IPI intermediate- and high-risk scores remain the strongest predictors of CNS relapse in patients with DLBCL after adjusting to biological high-risk variables including DHL and NGCB cell of origin. Larger studies are required to validate our findings due to the low incidence of CNS relapse in our cohort. [Display omitted] DisclosuresFarooq: Kite, a Gilead Company: Honoraria. Maurer: Kite Pharma: Membership on an entity's Board of Directors or advisory committees; Morphosys: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Research Funding; Genentech: Research Funding; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Nanostring: Research Funding. Witzig: Karyopharm Therapeutics, Celgene/BMS, Incyte, Epizyme: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene/BMS, Acerta Pharma, Kura Oncology, Acrotech Biopharma, Karyopharm Therapeutics: Research Funding. Habermann: Tess Therapeutics: Other: Data Monitoring Committee; Seagen: Other: Data Monitoring Committee; Incyte: Other: Scientific Advisory Board; Morphosys: Other: Scientific Advisory Board; Loxo Oncology: Other: Scientific Advisory Board; Eli Lilly & Co.,: Other: Scientific Advisor. Novak: Celgene/BMS: Research Funding.

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

Retrospective Review of the Safety and Efficacy of High-Dose Methotrexate for Prevention of CNS Relapse in Diffuse Large B-Cell Lymphoma at Kaiser Permanente- Northern California (Jan 2015 - June 2019)

Retrospective review of the safety and efficacy of high-dose methotrexate for prevention of CNS relapse in diffuse large B-cell lymphoma at Kaiser Permanente- Northern California (Jan 2015 - June 2019)Background: Central nervous system (CNS) relapse occurs in 10-12% of high-risk diffuse large B-cell lymphoma (DLBCL) patients. Prophylactic intravenous high-dose methotrexate (HD-MTX) is recommended by international guidelines to reduce this risk despite limited evidence to support such practice. Recent retrospective studies have cast doubt on the clinical benefit of such treatment. There is limited data on safety and efficacy of such treatment in a community oncology setting.Methods: We conducted a retrospective analysis of adults ≥ 18 years diagnosed with DLBCL treated with systemic therapy and HD-MTX as CNS prophylaxis at Kaiser Permanente Northern California from 1/2015 - 6/2019. We abstracted patient demographics, clinical information, treatment, toxicity, and health care utilization from the electronic health record. Descriptive statistics were used to evaluate patients' outcomes.Results: Of 33 patients (median age: 61; range: 23 - 81; age ≥ 60: 57.5%), most had stage IV disease (78.7%) and an ECOG performance status of 0 or 1 (66.5%). Patients with CNS-IPI score of 2-3 (intermediate-risk) was 30.3%, while higher CNS-IPI scores of 4-6 (high-risk) was 51.5%. Other patient characteristics include double hit lymphoma (12.1%), kidney/adrenal gland involvement (33%), and/or epidural involvement (24.2%). Most common therapies were R-CHOP (51.5%) and R-EPOCH (27.2%). The median number of HD-MTX doses was 3 (range 1-4). The median cumulative dose was 7 gm/m2 (range 3-10.5). With regards to the treatment schedule, 63.6% received HD-MTX intercalated with systemic chemotherapy and 36.4% received HD-MTX after completion of preplanned treatment. Overall, renal toxicity was the most common adverse side effect. The rates of grade 1, 2 and 3 renal toxicity were 12.1%, 9% and 6%, respectively. Other notable side effects experienced were neutropenic fever requiring hospitalization (27.2%) and grade 3 transaminitis (6%). No patients experienced grade 3 mucositis. The median duration of hospital stay was 12 days (range 4-37) and 12.1% required suspension of future HD-MTX. With a median follow up of 31.3 months (range: 0.79 - 58.4) 69.6% are alive and 15.1% had CNS relapse despite prophylactic HD-MTX.Conclusions:In this community oncology setting, patients with DLBCL who were deemed high risk for CNS relapse and received HD-MTX for prophylaxis experienced similar CNS relapse rate compared to those who did not in previous studies. Our findings are in line with recent retrospective reviews, which further support the lack of benefit of such prophylactic treatment. This study underscores the need for further research to prevent CNS disease and improved patient selection criteria for prophylactic treatment among high risk DLBCL patients. DisclosuresNo relevant conflicts of interest to declare.

Impact of Choice of Platinum-Based Salvage Therapy on CNS Relapse in Patients with Relapsed or Refractory Diffuse Large B-Cell Lymphoma

Impact of Choice of Platinum-Based Salvage Therapy on CNS Relapse in Patients with Relapsed or Refractory Diffuse Large B-Cell Lymphoma

Central nervous system (CNS) prophylaxis in antiCD20-CHOP treated DLBCL at intermediate to high risk for CNS relapse: A systematic review and meta-analysis.

CNS prophylaxis is commonly used in Diffuse Large B-Cell Lymphoma (DLBCL) patients with risk features for CNS relapse. This systematic review and meta-analysis compares CNS relapse rates with and without CNS prophylaxis, for patients at intermediate to high CNS relapse risk. Studies reporting CNS relapse risk category and CNS outcomes with and without CNS prophylaxis for antiCD20-CHOP treated DLBCL patients were included. 10 studies with 3770 patients at intermediate to high CNS relapse risk were analyzed. No significant difference in the pooled Absolute Risk Difference (ARD 0.01, 95 % CI -0.01 to 0.02, P = 0.61) or Risk (RR 1.22, 95 % CI 0.81-1.83, P = 0.34) was noted in patients with and without CNS prophylaxis. There were also no differences within pre-specified subgroups of IV Methotrexate or IT chemotherapy. However, the quality of evidence supporting these observations was low. A meta-analysis of individual patient data will help evaluate the benefit of CNS prophylaxis strategies.

Single-route CNS prophylaxis for aggressive non-Hodgkin lymphomas: real-world outcomes from 21 US academic institutions

AbstractProphylaxis is commonly used to prevent central nervous sy stem (CNS) relapse in diffuse large B-cell lymphoma (DLBCL), with no clear standard of care. We retrospectively evaluated 1162 adult patients across 21 US academic centers with DLBCL or similar histologies who received single-route CNS prophylaxis as part of frontline therapy between 2013 and 2019. Prophylaxis was administered intrathecally(IT) in 894 (77%) and using systemic high-dose methotrexate (HD-MTX) in 236 (20%); 32 patients (3%) switched route due to toxicity and were assessed separately. By CNS-International Prognostic Index (IPI), 18% were considered low-risk, 51% moderate, and 30% high. Double-hit lymphoma (DHL) was confirmed in 243 of 866 evaluable patients (21%). Sixty-four patients (5.7%) had CNS relapse after median 7.1 months from diagnosis, including 15 of 64 (23%) within the first 6 months. There was no significant difference in CNS relapse between IT and HD-MTX recipients (5.4% vs 6.8%, P = .4), including after propensity score matching to account for differences between respective recipient groups. Weighting by CNS-IPI, expected vs observed CNS relapse rates were nearly identical (5.8% vs 5.7%). Testicular involvement was associated with high risk of CNS relapse (11.3%) despite most having lower CNS-IPI scores. DHL did not significantly predict for CNS relapse after single-route prophylaxis, including with adjustment for treatment regimen and other factors. This large study of CNS prophylaxis recipients with DLBCL found no significant difference in CNS relapse rates between routes of administration. Relapse rates among high-risk subgroups remain elevated, and reconsideration of prophylaxis strategies in DLBCL is of critical need.

Central Nervous System Relapse in HIV Positive Patients Affected By Diffuse Large B Cell Lymphoma. Is the CNS-IPI Score Useful in This Population?

▪Background:Central nervous system (CNS) relapse is an important and most often fatal event in patients (pts) affected by Diffuse Large B cell lymphoma (DLBCL). Identifying high risk pts is critical to guide diagnostic and therapeutic approach.Recently, Schmitz et al. validated a risk score (CNS-IPI) that predicts the risk of CNS recurrence/progression in pts affected by DLBCL treated according to standard chemotherapy. It includes IPI score and kidney and/or adrenal glands involvement (scored 1 point if present or 0 if absent). Three levels of CNS recurrence/progression risk are defined: low (LR: 0-1 points), intermediate (IR: 2-3 points), high (HR: 4-6 points) showing significantly different rates of CNS disease at 2-years follow-up (0,6% for LR group, 3,4% for IR group, and 10.2% for HR group).This score has been validated in HIV negative population. Since DLBCL are more aggressive and at higher risk of CNS relapse/progression in HIV positive (HIV+) pts, studies of the validity of CNS-IPI score in this setting are particularly needed.The aim of our study was to evaluate the rate of CNS relapse in our HIV+ population as regard to CNS-IPI score. Furthermore, we evaluated if HIV-related parameters (such as CD4+ T cell count and HIV-RNA at lymphoma diagnosis) could influence the risk of CNS relapse.Methods: Observational, multicenter, cohort study involving 6 centres in Lombardy, Italy. HIV+ pts with DLBCL diagnosis observed from 2009 to 2015 were included in this analysis. The CNS relapse risk was estimated for all pts based on the CNS-IPI score (LR, IR, HR). Continuous variables were described by median values and first and third quartiles. Chi-square or Fisher's exact test and Kruskal-Wallis test were used for comparison of discrete and continuous variables, respectively.Results: Sixty-one HIV+ pts with DLBCL were included. General characteristics of population showed: 90% male; median age 49 years; median CD4+ T cell count at lymphoma diagnosis 224 cells/mm3; median HIV-RNA log10 4.2; 34% HCV Ab pos; 70.5% on antiretroviral treatment (ART) at the onset of DLBCL; 93.4% treated with R-CHOP like regimen and 6.6% pts with higher-intensity chemotherapeutic regimen; 54% with IPI ≥3 and 46% with IPI <3; 19.7% pts underwent intratechal (IT) prophylaxis. According to CNS-IPI score we defined 13 pts (21,3%) at HR of CNS relapse, 38 pts (62,3%) at IR and 10 pts (16,4%) at LR of CNS relapse. Pts belonging to HR group displayed significantly higher number of extranodal sites (84.6% showing 2-4 extranodal sites) as compared to IR and LR groups (20% and 0% showing 2-4 extranodal sites, respectively, p=0.03). In addition, pts with HR score showed a poor ECOG PS (61.5% showing >2) as compared to intermediate and low CNS relapse risk (20% and 20% showing ECOG PS >2, respectively, p=0.01).In our series, we didn't find any significant association among HIV-related characteristics at lymphoma diagnosis (CD4+ T cell count, nadir CD4+ T cell count, HIV-RNA log10, use of ART) and CNS-IPI risk score. After a median follow-up of 28 months (range 4-96), 6 pts (9.8%) displayed a CNS relapse. We found that CNS relapse was significantly more frequent in CNS-IPI HR pts (4/13, 30.8%) as compared to CNS-IPI IR or LR pts (2/30, 6.7% and 0/10, 0%, respectively, p=0.049). No association was found between HIV-related characteristics and CNS relapse. The risk of death was also significantly higher in CNS-IPI HR group (69.2%) as compared to IR and LR groups (33.3% and 0%, respectively, p<0.0001). As shown in Figure 1, all CNS relapses occurred in the first 12 months after diagnosis. No association was found between IT prophylaxis and CNS relapse, even if very few pts underwent this procedure.Discussion: In our study we found that CNS-IPI score could be considered as a valuable prognostic tool of CNS relapse/progression also in HIV+ pts. We found a higher rough proportion of DLBCL pts belonging to HR CNS-IPI group in our HIV+ cohort as compared to published data on general population, even if no relationship emerged between HIV-related parameters and CNS relapse risk. Further studies on larger HIV+ population are required to confirm the validity of this score; moreover, the integration of HIV-specific markers and histological characteristics of DLBCL could ameliorate the therapeutic approach and finally reduce the risk of CNS disease in HIV+ population. [Display omitted] DisclosuresGambacorti-Passerini:Pfizer: Consultancy, Honoraria, Research Funding; BMS: Consultancy.

CNS Prophylaxis in DLBCL: A Ten Year Single-Center Review in the Rituximab Era

Introduction:The role of prophylactic treatment for central nervous system (CNS) relapse in DLBCL is not clearly established. The selection of patients (pts) and the optimal regimens, including choice of agents, timing of administration, dosing, route, etc., remain unclear. In an effort to develop a uniform approach to this strategy, we have reviewed the practice of CNS ppx in DLBCL at Memorial Sloan Kettering during 2004-2014.Methods:We retrospectively reviewed 1) all newly diagnosed pts with DLBCL from 2004-2014 who received CNS ppx, and 2) all pts with DLBCL who developed CNS relapse/progression during the same period. All pts were treated with rituximab-based chemotherapy. Prophylactic agents included methotrexate (MTX) and/or cytarabine (ara-C). Pts with CNS or ocular involvement upon presentation were excluded. All data was compiled and analyzed using SPSS (IBM).Results:Three hundred and three pts received CNS ppx. CNS-IPI (Schmitz et al. J Clin Oncol, 2016) classified pts as low (18.2%), intermediate (43.6%), or high risk (38.2%) for CNS relapse. Seventy-six percent of pts presented with stage IV disease and a mean of 2.1 EN sites, frequently involving bone (53.8%) (vertebrae specifically, 33.7%), lung/pleura (20.1%), GI tract (18.2%), sinuses (17.5%), testes (10.5%) and others.Thirty-five percent of pts had high risk CNS IPI scores and received ppx. Most frequently, pts received ppx due to the presence of EN disease (36.6%), and of these pts 66.4% had multiple EN sites involved. CNS ppx was also administered to pts with primary testicular (24), sinus (30), and breast (8) DLBCL in addition to pts with isolated bone (21) vertebrae (14), and GI tract (5) lesions. The remaining 3.6% of pts received ppx for other reasons including high risk molecular profiles or bulky disease.Intrathecal (IT) MTX alone was administered to 271 of 303 prophylaxed pts, and 17 (5.9%) developed CNS involvement. High dose intravenous (HD) MTX alone was given to 7 pts; 1 developed CNS involvement. IT MTX and IT ara-C were given to 10 pts; 1 developed CNS involvement. IT and HD MTX plus IT ara-C were given to 2 pts; 1 developed CNS involvement. Additional combinations can been reviewed in Table 1.Twenty pts (6.6%) failed CNS ppx, with a median (mdn) time from diagnosis to detection of CNS involvement of 12.7 months. No pts developed CNS disease while on first-line therapy. Of 20 pts, 11 had isolated CNS relapses (mdn= 8.9 months). 7 relapsed systemically with CNS involvement (mdn =26.8 months). Two had primary refractory disease with CNS involvement detected at 10.2 and 12.7 months. The difference in time to CNS relapse based on involvement pattern (leptomeningeal, parenchymal or both) or the context of CNS involvement (isolated CNS relapse vs systemic relapse with CNS involvement) was not statistically significant. The pt treated with HD and IT MTX and IT ara-C relapsed in the CNS at 3.5 months, significantly earlier than pts treated with IT MTX (mdn 12.7 mo, p=0.02), but notably received only 3 cycles of R-CHOP due to wound dehiscence.There were 776 DLBCL pts from the same time period who were not treated with ppx, and 25 (3.2%) developed CNS involvement. One pt relapsed after 48d during R-CHOP. Three additional pts had primary refractory disease with CNS involvement at a median of 5.2 months. Fifteen had isolated CNS relapses (mdn 8.5 months), and 6 had systemic relapses with CNS involvement (mdn 12.0 months). There was no significant difference in the time to CNS relapse comparing pts who received CNS ppx to pts who did not.Conclusions:In our study, pts with DLBCL at high risk for CNS relapse treated with rituximab-based chemotherapy developed CNS involvement after systemic therapy was complete. Administering CNS ppx concurrently with R-CHOP poses many challenges, often resulting in dose adjustments or delays in treatment. Our results suggest that CNS ppx can be delayed until the completion of R-CHOP without compromising the effects of ppx. [Display omitted] DisclosuresMoskowitz:Seattle Genetics: Consultancy, Other: Ad Board, Research Funding; Genentech BioOncology: Consultancy; Pharmacyclics: Research Funding; Celgene: Consultancy; Merck: Consultancy, Research Funding.

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.

High Density of NRF2 Expression in Malignant Cells Is Associated with Increased Risk of CNS Metastasis in Early-Stage NSCLC

Simple SummaryWe retrospectively analyzed 304 patients with surgically removed non-small cell lung cancer (NSCLC). Multiplex antibody staining of nuclear factor erythroid 2-related factor 2 (NRF2) and thioredoxin reductase 1 (TrxR1) was conducted and scored in cytokeratin-positive (CK+) cells within the whole-tissue core as well as the tumor and stromal compartments of each tissue microarray (TMA) core. A high density of NRF2+/CK+ cells in the whole-tissue core compartment was an independent prognostic factor, with an eightfold increase in odds regarding the risk of relapse in the central nervous system (CNS). This is the first study to report a tumor-cell-associated protein biomarker for CNS relapse in early-stage lung cancer and the first trial to report the correlation between NRF2 expression and risk of CNS relapse. The results of our study may have an impact on the follow-up strategy for early-stage NSCLC patients and eventually improve their prognosis. Nuclear factor erythroid 2-related factor 2 (NRF2) protein expression promotes cancer progression in non-small cell lung cancer (NSCLC). However, its role in the clinical setting has not been established. We retrospectively analyzed data from 304 patients with surgically removed NSCLC. Multiplex antibody staining of NRF2 and thioredoxin reductase 1 (TrxR1) was conducted and scored in cytokeratin-positive (CK+) cells within the whole-tissue core as well as the tumor and stromal compartments of each tissue microarray (TMA) core. A high density of NRF2+/CK+ cells in the whole-tissue core compartment was correlated with a higher risk of central nervous system (CNS) relapse OR = 7.36 (95% CI: 1.64–33.06). The multivariate analysis showed an OR = 8.00 (95% CI: 1.70–37.60) for CNS relapse in NRF2+/CK+ high-density cases. The density of TrxR1+/CK+ cells failed to show any statistically significant risk of relapse. The OS analyses for NRF2+/CK+ and TrxR1+/CK+ cell density failed to show any statistical significance. This is the first study to report a correlation between NRF2+/CK+ cell density and the risk of CNS relapse in early-stage NSCLC. The results of our study may impact the follow-up strategy for early-stage NSCLC patients and eventually improve their prognosis.

A Higher Dose of Dasatinib May Increase the Possibility of Crossing the Blood–brain Barrier in the Treatment of Patients With Philadelphia Chromosome–positive Acute Lymphoblastic Leukemia

Dasatinib is a second-generation tyrosine kinase inhibitor with higher central nervous system (CNS) penetration compared with imatinib and nilotinib in in vitro studies. However, limited clinical data are available regarding the dosage and CNS penetration of dasatinib. The purpose of this study was to investigate the actual ability of dasatinib to cross the blood-brain barrier in patients with Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL). Plasma and cerebrospinal fluid (CSF) samples collected from Ph+ ALL patients treated with dasatinib were analyzed by using an LC-MS/MS assay. Orally administered dasatinib 100 mg once daily was well absorbed by the patient but penetrated poorly into the CSF. The use of a higher drug dosage (140 mg/d) may increase systemic drug exposure and enhance the penetration of dasatinib into the CSF. Based on this study, the use of a higher dosage of dasatinib (140 mg/d) is recommended in patients at high risk of CNS relapse or patients who need treatment for CNS leukemia. ClinicalTrials.gov identifier: NCT02523976.

Prophylaxis with intrathecal or high-dose methotrexate in diffuse large B-cell lymphoma and high risk of CNS relapse

Although methotrexate (MTX) is the most widely used therapy for central nervous system (CNS) prophylaxis in patients with diffuse large B-cell lymphoma (DLBCL), the optimal regimen remains unclear. We examined the efficacy of different prophylactic regimens in 585 patients with newly diagnosed DLBCL and high-risk for CNS relapse, treated with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) or R-CHOP-like regimens from 2001 to 2017, of whom 295 (50%) received prophylaxis. Intrathecal (IT) MTX was given to 253 (86%) and high-dose MTX (HD-MTX) to 42 (14%). After a median follow-up of 6.8 years, 36 of 585 patients relapsed in the CNS, of whom 14 had received prophylaxis. The CNS relapse risk at 1 year was lower for patients who received prophylaxis than patients who did not: 2% vs. 7.1%. However, the difference became less significant over time (5-year risk 5.6% vs. 7.5%), indicating prophylaxis tended to delay CNS relapse rather than prevent it. Furthermore, the CNS relapse risk was similar in patients who received IT and HD-MTX (5-year risk 5.6% vs. 5.2%). Collectively, our data indicate the benefit of MTX for CNS prophylaxis is transient, highlighting the need for more effective prophylactic regimens. In addition, our results failed to demonstrate a clinical advantage for the HD-MTX regimen.

Effectiveness of intravenous high-dose methotrexate for prevention of relapse in patients with DLBCL.

e19562 Background: Central nervous system (CNS) relapse develops in 2-10% of patients with diffuse large B cell lymphoma (DLBCL) and has an adverse prognosis. Tools like IPI and CNS-IPI scores identify patients at high risk of systemic or CNS relapse based on the presence of established risk factors ( Schmitz et al. JCO 2016). International guidelines propose prophylactic intravenous high-dose methotrexate (HD-MTX) for patients at high risk of CNS relapse; however, limited data is backing this approach. Methods: We conducted a retrospective review of newly diagnosed DLBCL patients aged 18-75 years treated with curative intent at large academic medical centers in Riyadh, Saudi Arabia, between 2015-2018. Patients who were planned for CNS HD-MTX after cycles 2, 4, and 6 of R-CHOP and received at least one HD-MTX cycle were included. Results: We identified 35 DLBCL patients who received at least one R-CHOP cycle with one cycle of HD-MTX. The median IPI and CNS-IPI score were 3, (range = 0-4) and 3, (range = 0-5), respectively. The median number of R-CHOP cycles received was 6 (range 3-6) and HD-MTX 3 (range 1-6). The overall response rate was 91%, with 3 (9%) primary refractory patients per interim evaluation on cycle 3 of R-CHOP. Achieving complete remission after six cycles of RCHOP was noted in 80%, with four additional patients showed residual disease at the end of treatment evaluation. The entire cohort's overall survival was not reached, and five years estimated survival is 75%. With a median follow-up duration of 37.3 months, none of the patients relapsed after achieving CR at the end of treatment evaluation. The risk of systemic or CNS relapse in our cohort was 0%. In restricting the analysis to CNS-IPI of ≥ 4, a total of 13 patients with a median follow-up of 42 months were included; four patients did not achieve CR by the end of treatment, while nine patients continue to be in CR without any evidence of relapsed disease. Conclusions: High-dose methotrexate with high-intensity chemoimmunotherapy (R-CHOP) seems to be associated with an improvement in the expected rate of CNS relapse. Our data set is small, and a more extensive study evaluating HD-MTX's effectiveness in high-risk DLBCL is warranted.[Table: see text]

CNS relapse in DLBCL patients below 60 years treated with R-ACVBP, R-CHOEP, or R-CHOP: A joint analysis of LYSA and GLA/DSHNHL.

7543 Background: Central nervous system (CNS) relapse occurs in 2-6% of DLBCL patients (pts) increasing to 10% or more in high-risk groups. Intrathecal (IT) or intravenous high-dose methotrexate (HD MTX) have limited if any prophylactic impact on CNS relapse. To address the role of systemic first-line therapy in pts tolerating intensified strategies (R-ACVBP, R-(Mega)CHOEP, R-CHO(E)P), we compared CNS relapses occurring in a large cohort of pts ≤60 years. Methods: We conducted a retrospective analysis including previously untreated pts with DLBCL by central review, age 18-60 years, from multicenter clinical trials conducted by LYSA and GLA/DSHNHL (Table). We assessed the risk of CNS relapse in matched cohorts based on the aaIPI. Results: A total of 2203 pts were included. Median age was 47 years (18-60). 455 pts were treated with R-ACVBP, 444 with R-(Mega)CHOEP, 1304 with R-CHOP. Distribution of CNS IPI was not significantly different comparing R-ACVBP to R-CHO(E)P groups within aaIPI categories (Table). PFS and OS were comparable according to treatment within aaIPI groups, also adjusted for prognostic factors. No CNS events occured during observation time of 3 years in pts with aaIPI 0. In pts with aaIPI 1, no CNS event occured in the R-ACVPB arm, the 3y-cumulative incidence of CNS relapse for pts treated with R-CHO(E)P group was 1.0% (95%CI 0.3-1.7). In pts with aaIPI 2,3 and intermediate/high CNS IPI, four (1.6%) treated with R-ACVBP experienced relapse in the CNS compared to 15 (3.9%) pts treated with R-(Mega)CHO(E)P (3y-cumulative incidence 1.6% (95%CI 0-3.2) vs. 4.0% (95%CI 2.0-6.0). Conclusions: CNS relapse was extremely rare in younger DLBCL pts with aaIPI 0 or 1; prophylactic measures are not warranted. In pts with aaIPI 2,3 (and intermediate/high CNS-IPI), only 4 (1.6%) CNS relapses were seen with the R-ACVBP while 15 (3.9%) relapses did occur after R-(Mega)CHO(E)P. This analysis underlines the important role of the systemic therapy in controling CNS relapse.[Table: see text]

Safety of same day HD-MTX with induction therapy for DLBCL with concurrent CNS disease or as prophylaxis for high risk of CNS relapse.

e19545 Background: High-dose methotrexate (HD-MTX) at a dose between 2.5 to 5 gm/m2 is commonly administered in conjunction with standard induction chemotherapy to patients with Diffuse Large B Cell Lymphoma (DLBCL) at high risk of central nervous system (CNS) relapse, as defined by the Lymphoma International Prognostic Index (CNS-IPI). Optimal timing of HD-MTX in relation to induction chemotherapy is unknown. A recent study suggested that HD-MTX intercalated with R-CHOP cycles was associated with increased toxicity and treatment delays without improvement in survival or CNS relapse compared with end of treatment MTX (Wilson et al 2020). This retrospective study evaluates the toxicities and treatment delays associated with HD-MTX administered on day 1 of cycles of chemo-immunotherapy. Methods: This single center retrospective cohort study included 45 patients (pts) with DLBCL with concurrent CNS disease or at high risk of CNS relapse who received HD MTX on day 1 of chemo-immunotherapy at our center. Data was abstracted from chart review and included variables describing clinical and treatment characteristics, time to MTX clearance, toxicities experienced and treatment delays. Results: 31 pts received HD-MTX on the day of R-CHOP chemotherapy, 6 pts received HD-MTX on the day of R-EPOCH (Rituximab, Etoposide, Doxorubicin, Vincristine, Cyclophosphamide, and Prednisone), and 8 pts received HD-MTX with R-MiniCHOP (dose reduced R-CHOP). Same day HD MTX with chemo-immunotherapy was associated with acute kidney injury (AKI; 17-25%), treatment delays &gt;7 days (13-17%), and grade 2 mucositis (11-50%). The burden of toxicities was numerically higher in patients treated with R-EPOCH vs. R-CHOP (Table). Clinical outcomes are summarized in table below. Conclusions: In our heterogeneous population of pts, we describe that the incidence of toxicities and treatment delays experienced with same day HD-MTX are higher with R-EPOCH than with R-CHOP. Comparative studies with intercalated or end of treatment MTX will determine if the incidence of treatment delays, toxicities and de-escalations are higher with same day HD-MTX administration. [Table: see text]

Ineffectiveness of high-dose methotrexate for prevention of CNS relapse in diffuse large B-cell lymphoma.

Central nervous system (CNS) relapse affects 5% of diffuse large B-cell lymphoma (DLBCL) patients and portends a poor prognosis. Prophylactic intravenous high-dose methotrexate (HD-MTX) is frequently employed to reduce this risk, but there is limited evidence supporting this practice. We conducted a multicenter retrospective study to determine the CNS relapse risk with HD-MTX in DLBCL patients aged 18-70 years treated in Alberta, Canada between 2012 and 2019. Provincial guidelines recommended HD-MTX for patients at high-risk of CNS relapse based upon CNS-IPI score, double-hit lymphoma, or testicular involvement. Among 906 patients with median follow-up 35.3 months (range 0.29-105.7), CNS relapse occurred in 1.9% with CNS-IPI 0-1, 4.9% with CNS-IPI 2-3, and 12.2% with CNS-IPI 4-6 (p < .001). HD-MTX was administered to 115/326 (35.3%) high-risk patients, of whom 96 (83.5%) had CNS-IPI score 4-6, 45 (39.1%) had double-hit lymphoma, and four (3.5%) had testicular lymphoma. The median number of HD-MTX doses was two (range 1-3). Central nervous system relapse risk was similar with versus without HD-MTX (11.2% vs. 12.2%, p = .82) and comparable to previous reports of high-risk patients who did not receive CNS prophylaxis (10-12%). In multivariate and propensity score analyses, HD-MTX demonstrated no association with CNS relapse, progression-free survival, or overall survival. This study did not demonstrate a benefit of prophylactic HD-MTX in this high-risk patient population. Further study is required to determine the optimal strategy to prevent CNS relapse in DLBCL.

Narrative review: secondary central nervous system lymphoma

: Secondary central nervous system (CNS) lymphomas (SCNSL) include the systemic lymphoproliferative diseases with CNS involvement at presentation or at relapse or at both stages of disease. Potentially all lymphoproliferative diseases can present or relapse in the CNS, although with a different incidence. While for some of these the management of CNS localization can be considered standard for others a worldwide consensus on the management and treatment lacks. The incidence of CNS relapse in diffuse large B-cell lymphoma (DLBCL) is about 5%, and it is possibly slightly reduced over the last decades. Two possible reasons of this reduction are: (I) the improvement of systemic disease control obtained with the addition of rituximab to the chemotherapy; (II) the advances in identifying patients at high risk of CNS relapse and the application of prophylaxis. However, many unanswered questions remain and there is not a worldwide consensus on the criteria identifying patients at high risk of CNS and on the standard prophylaxis therapy. Patients who develop SCNSL have a poor prognosis, and the optimal treatment is unknown, and indeed often unsatisfactory. In this manuscript we report the important advances of the knowledge of this rare and fatal disease, obtained in the last years, thanks to the development of multicenter collaborations. However, this disease remains still highly fatal and the discovery of more and more efficient therapy strategies is becoming a priority. New therapeutic strategies alternative to or in combination with chemotherapy such as target and immunomodulatory therapy are being addressed in future trials. In this regard, a more accurate knowledge of the molecular and biological characteristics of this malignancy is becoming a priority for the development of innovative therapies that will be firstly investigated in refractory/relapsing patients and, if efficient, successively incorporated as part of first-line treatment.

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.