Identification of Neoplastic Infiltration of the Cerebrospinal Fluid (CSF) in Patients with Aggressive B-Cell Non-Hodgkin’s Lymphoma (B-NHL) without Clinical Evidence of Leptomeningeal Disease: A Comparative Analysis of the Utility of Flow Cytometry (FCM) Versus Conventional Cytology (CC).

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 4605-4605 ◽  
Author(s):  
A. Orfao ◽  
S. Quijano ◽  
A. Lopez ◽  
G. Deben ◽  
A. Salar ◽  
...  
Keyword(s):  
B Cells ◽  
High Risk ◽  
B Cell ◽  
B Cell Lymphoma ◽  
Lower Percentage ◽  
Leptomeningeal Disease ◽  
Neoplastic Cells ◽  
Cns Relapse ◽  
Phenotypic Characterisation ◽  
Meningeal Disease

Abstract Introduction: CC analysis of the CSF is considered as the reference method to diagnose meningeal disease in patients with B-NHL. However, recent studies suggest that in patients with B-NHL who are at high risk of CNS relapse, FCM could be more sensitive than CC for detecting meningeal disease in CSF. Objective: To evaluate the sensitivity and specificity of a standardized FCM immunophenotypic approach vs CC for detecting the presence of neoplastic cells in CSF, in patients with aggressive B-NHL who are at high risk of CNS relapse. Patients and methods: A total of 29 CSF samples were analysed (total volume: 0.8 to 4ml; median: 2.4) in newly diagnosed patients with aggressive B-NHL, from a total of 14 different hospitals (diffuse large B cell lymphoma-DLBCL: 17; Burkitt’s lymphoma-BL: 9; follicular lymphoma transformed to DLBCL -tFL: 2; and T-cell-rich B-NHL: 1). Of the 29 patients studied, 15 were men (52%) and 14 women (48%) with a mean age of 55 ± 19 years (range: 16–86). In all cases, the CSF samples were analysed simultaneously by CC at the institution of origin and FCM, centrally one institution. For the FCM analysis of the CSF, stabilised samples (Transfix, CYTOMARK) were systematically stained with the following combination of monoclonal antibodies: CD8-sIgl/CD56-sIgk/CD4-CD19/CD3/CD20/CD45 (FITC/PE/PERCPCY5.5/PECY7/APC/APCCY7). If the FCM test showed infiltration, an additional 6-color antibody panel was used for full phenotypic characterisation of the disease. Results: Haematopoietic cells were detected in all cases (mean: 2.2 ± 4 cells/μl; range: 0.2–14). Systematically, these cells included T cells (mean: 0.6±0.8/μl; range: 0.1–4) and monocytes (mean: 1±2/μl; range: 0.1–9). Furthermore, in 31%, 3%, 3% and 14% of cases the following cell populations were also detected: polyclonal B-lymphocytes (mean: 0.06±0.07/μl; range: 0.01–0,2), plasma cells (0.09/μl), natural killer cells (0.03/μl) and neutrophils (mean: 0.6±1/μl; range: 0.03–2), respectively. Of the 29 cases studied, 5 (17%) showed infiltration by neoplastic B-cells by FCM, while CC only showed infiltration in two of these patients (7%). Cases with CNS infiltration by both methods included one tFL (82%; 14 neoplastic cells/μl by FCM) and one BL (68%; 8 neoplastic cells/μl using FCM). The three patients with FCM+/CC- presented a lower percentage of pathological B-cells (2% in one DLBCL and 1% and 0.1% in two BL, respectively). One of these three patients presented neurological symptoms (meningism). Conclusion: Although preliminary, these results suggest that FCM is more sensitive that CC in detecting CSF infiltration by neoplastic B-cells in aggressive B-NHL, especially when these cells are present in a relatively low numbers.

scholarly journals Integration of cell of origin into the clinical CNS International Prognostic Index improves CNS relapse prediction in DLBCL

Blood ◽  
2019 ◽  
Vol 133 (9) ◽  
pp. 919-926 ◽  
Author(s):  
Magdalena Klanova ◽  
Laurie H. Sehn ◽  
Isabelle Bence-Bruckler ◽  
Federica Cavallo ◽  
Jie Jin ◽  
...  
Keyword(s):  
High Risk ◽  
B Cell ◽  
International Prognostic Index ◽  
Prognostic Index ◽  
B Cell Lymphoma ◽  
Cell Of Origin ◽  
Cns Relapse ◽  
Relapse Prediction ◽  
Expression Status ◽  
Dual Expression

Abstract Central nervous system (CNS) relapse carries a poor prognosis in diffuse large B-cell lymphoma (DLBCL). Integrating biomarkers into the CNS–International Prognostic Index (CNS-IPI) risk model may improve identification of patients at high risk for developing secondary CNS disease. CNS relapse was analyzed in 1418 DLBCL patients treated with obinutuzumab or rituximab plus cyclophosphamide, doxorubicin, vincristine, prednisone chemotherapy in the phase 3 GOYA study. Cell of origin (COO) was assessed using gene-expression profiling. BCL2 and MYC protein expression was analyzed by immunohistochemistry. The impact of CNS-IPI, COO, and BCL2/MYC dual-expression status on CNS relapse was assessed using a multivariate Cox regression model (data available in n = 1418, n = 933, and n = 688, respectively). High CNS-IPI score (hazard ratio [HR], 4.0; 95% confidence interval [CI], 1.3-12.3; P = .02) and activated B-cell‒like (ABC) (HR, 5.2; 95% CI, 2.1-12.9; P = .0004) or unclassified COO subtypes (HR, 4.2; 95% CI, 1.5-11.7; P = .006) were independently associated with CNS relapse. BCL2/MYC dual-expression status did not impact CNS relapse risk. Three risk subgroups were identified based on the presence of high CNS-IPI score and/or ABC/unclassified COO (CNS-IPI-C model): low risk (no risk factors, n = 450 [48.2%]), intermediate risk (1 factor, n = 408 [43.7%]), and high risk (both factors, n = 75 [8.0%]). Two-year CNS relapse rates were 0.5%, 4.4%, and 15.2% in the respective risk subgroups. Combining high CNS-IPI and ABC/unclassified COO improved CNS relapse prediction and identified a patient subgroup at high risk for developing CNS relapse. The study was registered at www.clinicaltrials.gov as #NCT01287741.

Validation of a Prognostic Model to Assess the Risk of CNS Disease in Patients with Aggressive B-Cell Lymphoma

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 394-394 ◽  
Author(s):  
Kerry J. Savage ◽  
Samira Zeynalova ◽  
Roopesh R. Kansara ◽  
Maike Nickelsen ◽  
Diego Villa ◽  
...  
Keyword(s):  
High Risk ◽  
B Cell ◽  
Research Funding ◽  
Prognostic Model ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Chop Chemotherapy ◽  
Relapse Risk ◽  
Cns Disease ◽  
Cns Relapse

Abstract Introduction: Despite the improvement of outcome of aggressive B-cell lymphomas in the rituximab treatment era, central nervous system (CNS) relapse continues to pose a significant management problem. It remains a challenge to select patients (pts) in whom specific diagnostic procedures to identify CNS disease at diagnosis should be performed and to target a high risk group in whom a CNS prophylaxis strategy is warranted. The German High-Grade Non-Hodgkin Lymphoma Study Group (DSHNHL) recently proposed a new prognostic model incorporating the 5 IPI factors (age > 60 y, LDH > N, stage 3 or 4, extranodal (EN) sites > 1) in addition to kidney/adrenal gland involvement to predict the risk of secondary CNS disease in pts with aggressive B-cell lymphoma. This model effectively stratified patients into 3 risk groups: low risk (0-1 factors, 2 y CNS relapse risk .6% (95% CI 0.0-1.2); intermediate risk (2-3 factors, 2 y CNS relapse risk 3.4 %( 95% CI 2.2-4.6)) and high risk (4-6 factors, 2 y CNS relapse risk of 10.2% (95% CI 6.3-14.1)) (Schmitz et al. Hematol. Oncol. 2013: 31, 047a). Herein, we sought to validate this model in an independent cohort of DLBCL treated with R-CHOP chemotherapy at the British Columbia Cancer Agency (BCCA). Methods: The DSHNHL dataset on which the model was initially developed was comprised of 2164 patients with aggressive B-cell lymphomas (n= 1735, 80.2% diffuse large B-cell lymphoma (DLBCL)), 18-80 years of age who were treated with rituximab with (CHO(E) P-like chemotherapy on prospective studies. The BCCA Lymphoid Cancer Database was screened to identify all patients with DLBCL treated with curative intent R-CHOP chemotherapy. Results: In total, 1597 patients were diagnosed with DLBCL at the BCCA and received at least one cycle of curative intent R-CHOP chemotherapy. The median follow-up for living patients was 4.2 years. Pts in the BCCA population-based DLBCL cohort were more likely to have poor risk features including PS >1, advanced age and a high IPI score (Table 1). Applying the 6 factor model, very similar risk groups were identified: low risk (0-1 factors 2 year CNS relapse risk .8% (95% CI 0.0-1.6%).; intermediate risk (2-3 factors 2 year CNS relapse risk 3.9% (95% CI 2.3-5.5%); and high risk (4-6 factors 2 y CNS relapse risk 12% (95% CI 7.9-16.1%) (Figure 1). The median time to CNS relapse was 6.7 months from the time of diagnosis in the BCCA group and was 7.2 months in the DSHNHL group highlighting that this event typically occurs early in the disease course. In both datasets kidney/adrenal involvement was highly associated with CNS relapse (2 year CNS risk BCCA 33%; 14% DSHNHL), the difference likely reflecting the higher risk pts in the BCCA population-based setting. Conclusions: We have validated the proposed DSHNHL prognostic model for CNS relapse in an independent dataset. The model identifies a high risk group in which diagnostic procedures to rule out CNS disease are highly recommended at diagnosis including MRI head, and cerebrospinal fluid analysis by cytology and flow cytometry and consideration of CNS-directed therapies. Kidney/adrenal involvement is consistently associated with a high risk of CNS relapse in the rituximab treatment era for which CNS prophylaxis should be incorporated into front-line therapy. Table 1 Clinical factor BCCA N=1597 DSHNHL N=2164 Age > 60 years * Median age 1035 (65%) 65 years (16-94) 974 (45%) 58 years (18-80) Median follow-up 4.6 years 2.9 years Male sex 915 (57%) 1244 (57.5%) PS > 1* 584 (37%) 247 (11%) Elevated LDH 1147 (53.0%) 737 (49.0%) EN > 1 396 (25%) 479 (22%) Stage 3 or 4 916 (57%) 1148 (53%) IPI * 0,1 2 3 4,5 463 (31%) 359 (24%) 350 (23%) 329 (22%) 1009 (47%) 523 (24%) 398 (18%) 231 (11%) Bulky disease > 7cm 636 (41%) 1027 (47.5%) * P< 0.05 Figure 1 Figure 1. Disclosures Savage: F Hoffmann-La Roche: Other. Villa:F Hoffmann-La Roche: Other. Sehn:Roche: Research Funding. Pfreundschuh:Roche: Advisory Board Other, Research Funding. Gascoyne:Hoffman La-Roche: Research Funding. Connors:Seattle Genetics, Inc.: Research Funding; Roche: Research Funding.

CNS International Prognostic Index: A Risk Model for CNS Relapse in Patients With Diffuse Large B-Cell Lymphoma Treated With R-CHOP

2016 ◽  
Vol 34 (26) ◽  
pp. 3150-3156 ◽  
Author(s):  
Norbert Schmitz ◽  
Samira Zeynalova ◽  
Maike Nickelsen ◽  
Roopesh Kansara ◽  
Diego Villa ◽  
...  
Keyword(s):  
High Risk ◽  
B Cell ◽  
Risk Model ◽  
Risk Group ◽  
International Prognostic Index ◽  
Prognostic Index ◽  
B Cell Lymphoma ◽  
Intermediate Risk ◽  
Data Set ◽  
Cns Relapse

Purpose To develop and validate a risk score for relapse in the CNS in patients with diffuse large B-cell lymphoma (DLBCL). Patients and Methods A total of 2,164 patients (18 to 80 years old) with aggressive B-cell lymphomas (80% DLBCL) treated with rituximab and CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone)-like chemotherapy, who were enrolled in studies from the German High-Grade Non-Hodgkin Lymphoma Study Group and the MabThera International Trial, were analyzed for occurrence of relapse/progression in the CNS. The resulting risk model was validated in an independent data set of 1,597 patients with DLBCL identified in the British Columbia Cancer Agency Lymphoid Cancer database. Results The risk model consists of the International Prognostic Index (IPI) factors in addition to involvement of kidneys and/or adrenal glands (CNS-IPI). In a three-risk group model, the low-risk group (46% of all patients analyzed), the intermediate-risk group (41%), and the high-risk group (12%) showed 2-year rates of CNS disease of 0.6% (CI, 0% to 1.2%), 3.4% (CI, 2.2% to 4.4%), and 10.2% (CI, 6.3% to 14.1%), respectively. Patients from the validation British Columbia Cancer Agency data set showed similar rates of CNS disease for low-risk (0.8%; CI, 0.0% to 1.6%), intermediate-risk (3.9%; CI, 2.3% to 5.5%), and high-risk (12.0%; CI, 7.9% to 16.1%) groups. Conclusion The CNS-IPI is a robust, highly reproducible tool that can be used to estimate the risk of CNS relapse/progression in patients with DLBCL treated with R-CHOP (rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone) chemotherapy. Close to 90% of patients with DLBCL belong to the low- and intermediate-risk groups and have a CNS relapse risk < 5%; they may be spared any diagnostic and therapeutic intervention. In contrast, those in the high-risk group have a > 10% risk of CNS relapse and should be considered for CNS-directed investigations and prophylactic interventions.

scholarly journals Secondary CNS relapse in diffuse large B-cell lymphoma: defining high-risk patients and optimization of prophylaxis strategies

Hematology ◽  
2017 ◽  
Vol 2017 (1) ◽  
pp. 578-586 ◽  
Author(s):  
Kerry J. Savage
Keyword(s):  
High Risk ◽  
B Cell ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
High Risk Patients ◽  
Clinical Risk ◽  
Large B Cell Lymphoma ◽  
Cns Relapse ◽  
Risk Patients ◽  
Large B Cell

Abstract Despite improvement in survival in diffuse large B-cell lymphoma (DLBCL) with the introduction of rituximab, central nervous system (CNS) relapse continues to represent a clinical challenge. A number of studies have evaluated clinical risk factors in an attempt to identify high-risk patients to direct CNS staging investigations and consider prophylaxis strategies. The CNS International Prognostic Index is a robust and reproducible risk model that can identity patients at high risk of CNS relapse, but its specificity remains limited. Studies are emerging of biomarkers that predict CNS relapse that can be integrated with clinical risk models to better identify high-risk patients for CNS-directed prophylaxis strategies. Because CNS parenchymal disease is the predominant compartment, prophylaxis should include deeply penetrant drugs such as high-dose methotrexate. However, this has been associated with toxicity and has limited use in older patients. Novel therapies are being tested in primary CNS lymphoma with encouraging results and may represent rational strategies to be further explored in the prophylaxis setting.

scholarly journals PD-L1 Expression Identifies High Risk Diffuse Large B-Cell Lymphoma and Is Associated with Several Genomic Markers

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 153-153 ◽  
Author(s):  
Imran N Siddiqi ◽  
Venkata Thodima ◽  
Julia Friedman ◽  
Adames Violeta ◽  
Anil Tulpule ◽  
...  
Keyword(s):  
High Risk ◽  
B Cell ◽  
Cancer Genetics ◽  
Pearson Correlation ◽  
B Cell Lymphoma ◽  
T Test ◽  
Phase Ii Trials ◽  
Neoplastic Cells ◽  
Positive Correlation ◽  
Large B Cell

Abstract Diffuse large B-cell lymphomas (DLBCLs) are aggressive tumors and the most common form of non-Hodgkin lymphoma (NHL). DLBCLs arise from germinal center (GC) or post-GC B cells and display marked heterogeneity in genetic features and clinical outcomes DLBCLs, similar to other NHL and to solid tumors, are known to evade host immune response by usurping immune checkpoint pathways such as CTLA4 and PD-1. The initial Phase I and Phase II trials of checkpoint inhibitors in NHL revealed promising results, but rational and reliable biomarkers for selecting patients that benefit from such therapies is missing. Even in the case of the better-studied PD1-PD-L1 pathway, the characterization of expression of those proteins in DLBCLs is not standardized, and their relationship with molecular and clinical features in DLBCLs are still largely unknown. We set out to study PD-L1 expression using three commonly used anti-PD-L1 antibodies in a well-characterized single-institutional cohort of 52 primary DLBCLs from Keck School of Medicine of USC treated with R-CHOP or R-CHOP-like therapy with clinical follow up. All cases were characterized by aCGH; Focus::Lymphoma NGS test (Cancer Genetics Inc), which includes 220 most commonly mutated genes in B NHL; FISH including bcl2 and c-myc; and immunohistochemical staining to define cell of origin (Hans classification) and with three anti-PD-L1 antibodies (Abcam EPR1161, Abcam 28-8 and Ventana SP263 clones). We observed variable sensitivity, specificity and dynamic range of three anti-PD-L1 antibodies. EPR1161 and SP263 clones had highest correlation (Pearson correlation=0.69) and similar staining characteristics demonstrating robust linear membranous staining on neoplastic cells and on reactive infiltrating Immune Cells (IC). PD-1 expression on IC had inverse correlation with PD-L1 expression on neoplastic cells, suggesting immunosuppressive effect of PD-L1 positive neoplastic cells on tumor microenvironment. Non-GCB DLBCLs had higher PD-L1 positivity than GCB DLBCLs (p=0.0001, 0.01 and 0.06 respectively for EPR1161, DAKO 28-8 and Ventana SP263 Abs, t-test). Using molecular characterization, we observed that PD-L1 expression marked high risk aggressive DLBCLs, which also had higher TP53 expression, TP53 mutation and/or del 17p13 (Pearson correlation= 0.176). Moreover, higher expression of PD-L1 had negative correlation with mutations associated with GCB-like DLBCLs including BCL2, FOXO1, KMT2D, EZH2 (p=0.003, 0.01, 0.06, 0.08; t-test) and positive correlation with mutations associated with ABC-like DLBCLs including FAT2 (p=0.04, t-test). Interestingly, while PD-L1 expression correlated with high risk molecular and cytogenetic groups of DLBCL, it did not show correlation with BCL2 or C-MYC expression nor with BCL2/C-MYC double expressors. Most importantly, Kaplan Meyer analysis showed that even in the settings of chemotherapy, higher PD-L1 expression correlated with more aggressive disease, using all three antibodies ( p=0.03, 0.01, 0.04 respectively for Abcam EPR1161, Abcam 28-8 and Ventana SP263 clones). We conclude that PD-L1 expression reflects the biology of aggressive subsets of DLBCLs, which are also characterized by high risk cytogenetic and molecular biomarkers. PD-L1 expression can be measured by several antibody clones, which have different performance characteristics but show positive correlation. Disclosures No relevant conflicts of interest to declare.

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

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 2501-2501
Author(s):  
Amy M Horowitz ◽  
Madison H. Williams ◽  
Ryan A. Williams ◽  
Jean Pierre Blaize ◽  
Snegha Ananth ◽  
...  
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
High Risk ◽  
B Cell ◽  
Risk Group ◽  
B Cell Lymphoma ◽  
First Line ◽  
Cns Prophylaxis ◽  
Cns Relapse ◽  
Significant Difference

Abstract Introduction Around 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. Methods Trained 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. Results A 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). Conclusions When 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. Figure 1 Figure 1. Disclosures Nooruddin: AstraZeneca: Research Funding.

Evaluation of Dose-Adjusted EPOCH-R Compared with R-CHOP for the Treatment of High-Risk, Aggressive B-Cell Lymphomas: A Single-Center Experience

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 3-4
Author(s):  
Sarah J. Rockwell ◽  
Katherine A. Richter ◽  
Ryan J. Caddell ◽  
Julio C. Chavez
Keyword(s):  
High Risk ◽  
B Cell ◽  
Relapse Rate ◽  
International Prognostic Index ◽  
B Cell Lymphoma ◽  
Hematologic Toxicity ◽  
B Cell Lymphomas ◽  
Cns Relapse ◽  
Significant Difference ◽  
Grade 3

Introduction High-risk subtypes of DLBCL, including high-grade B-cell lymphomas (HGBCL) with rearrangements of c-MYC (MYC-R), BCL2 and/or BCL6 [or double hit and triple hit lymphomas (DHL/THL)], double expressor lymphoma (DEL), and patients with International Prognostic Index (IPI) scores of 3-5 have a poor prognosis with standard R-CHOP chemotherapy. Treatment intensification with DA-EPOCH-R did not improve outcomes when compared to R-CHOP in the CALGB 50303 trial (Bartlett et al JCO 2019). However, high-risk patients were underrepresented as 36% of patients had IPI scores of 3-5, 0.61% of patients had DHL or THL, 2.6% of patients had MYC-R, and 8.6% of patients had DEL (Bartlett et al JCO 2019). Our purpose was to retrospectively compare DA-EPOCH-R to R-CHOP in the treatment of high-risk DLBCL. Methods Patients ≥ 18 years old who received either DA-EPOCH-R or R-CHOP at Moffitt Cancer Center between 1/2010 - 9/2019 were included. Patients with a diagnosis of DLBCL with IPI score of 3-5, DHL/THL, and/or DEL were included. Patients with primary mediastinal B-cell lymphoma (PMBCL), DLBCL with testicular or central nervous system (CNS) involvement, grade 3b follicular lymphoma, Richter's transformation or IPI score &lt; 2 were excluded. The primary endpoint was complete response (CR) rate and secondary endpoints included progression-free survival (PFS), overall survival (OS), CNS relapse rate, and adverse events (AE). PFS and OS were estimated using Kaplan-Meier curves and differences were established using the log-rank test. Statistically significant difference was considered if p &lt; 0.05. Results The study included 128 patients: DA-EPOCH-R (n=36) and R-CHOP (n=92). General characteristics were similar between groups and included: median age = 66 years (33-85), stage III/IV = 89%, IPI score 3-5 = 87.6%, non-germinal center B-cell (GCB) = 32.8%, DEL = 26.6%, and DHL/THL = 18%. Of note, more patients in the DA-EPOCH-R group were &lt; 60 years old, had MYC-R, and/or were DHL/THL or HGBCL, NOS cases. The CR rates for DA-EPOCH-R and R-CHOP were 72.2% (95% CI: 54.8, 85.8) vs. 68.5% (95% CI: 57.8,78.0), respectively (p=0.831). In a pre-planned subgroup analysis, the CR rates across subgroups, including IPI score 3-5, DEL, and DHL/THL, were not different. There was no difference in PFS between DA-EPOCH-R and R-CHOP (p= 0.33; Figure 1). The 1-year (y) PFS for DA-EPOCH-R and R-CHOP was 69% (95% CI: 56.0, 86.0) and 62% (95% CI: 52.0, 73.0), respectively. The 3 y PFS for DA-EPOCH-R and R-CHOP was 66% (95% CI: 53.0, 84.0) and 46% (95% CI: 35.0, 59.0), respectively. PFS was higher in the DA-EPOCH-R arm for patients with MYC-R (p=0.0224) and DHL/THL (p=0.045). There was no difference in OS between DA-EPOCH-R and R-CHOP (p=0.83). The 1 y OS was 77% (95% CI: 65.0, 92.0) for the DA-EPOCH-R group compared with 81% (95% CI: 73.0, 90.0) for the R-CHOP group. The 3 y OS was 71% and 65% for the DA-EPOCH-R and R-CHOP groups, respectively. The CNS relapse rate was 6.2% in the DA-EPOCH-R group and 2.4% in the R-CHOP group (p=0.301). Of the 4 patients with CNS relapse, 3 were DHL, THL or DEL. There were more grade ≥ 3 AEs in DA-EPOCH-R vs. R-CHOP (97.2% vs. 77.2%; p=0.003). There was significantly more grade ≥ 3 hematologic toxicity in the DA-EPOCH-R group regarding neutropenia (DA-EPOCH-R 91.7% vs. R-CHOP 69.6%; p=0.017) and thrombocytopenia (DA-EPOCH-R 50% vs. R-CHOP 16.3%; p=0.0003). Neuropathy and mucositis were significantly more common in the DA-EPOCH-R arm. Conclusions R-CHOP remains standard of care for high-risk DLBCL subgroups when compared to DA-EPOCH-R (such as non-GCB DLBCL, DEL, and patients with IPI score &gt; 3). Patients with DHL/THL or MYC-R had greater benefit from DA-EPOCH-R compared to R-CHOP. DA-EPOCH-R was associated with increased rates of AEs, including significantly more hematologic toxicity. Disclosures Chavez: AstraZeneca: Speakers Bureau; Celgene: Consultancy; Bayer: Consultancy; Kite, a Gilead Company: Consultancy, Speakers Bureau; Novartis: Consultancy; Merck: Research Funding; Morphosys: Consultancy, Speakers Bureau; BeiGene: Speakers Bureau; Karyopharm: Consultancy; Genentech: Speakers Bureau; AbbVie: Consultancy; Verastem: Consultancy; Pfizer: Consultancy; Epizyme: Speakers Bureau; Gilead: Consultancy.

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

2021 ◽  
Vol 11 (6) ◽  
Author(s):  
Sabela Bobillo ◽  
Erel Joffe ◽  
David Sermer ◽  
Patrizia Mondello ◽  
Paola Ghione ◽  
...  
Keyword(s):  
High Risk ◽  
B Cell ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
High Dose ◽  
Relapse Risk ◽  
Cns Prophylaxis ◽  
Large B Cell Lymphoma ◽  
Cns Relapse ◽  
Large B Cell

AbstractAlthough 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.

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