First-line Treatment Of Diffuse Large B-cell Lymphoma Research Articles

The Oncogenic Lipid Sphingosine-1-Phosphate Impedes the Phagocytosis of Tumor Cells by M1 Macrophages in Diffuse Large B Cell Lymphoma.

A total of 30-40% of diffuse large B cell lymphoma (DLBCL) patients will either not respond to the standard therapy or their disease will recur. The first-line treatment for DLBCL is rituximab and combination chemotherapy. This treatment involves the chemotherapy-induced recruitment of tumor-associated macrophages that recognize and kill rituximab-opsonized DLBCL cells. However, we lack insights into the factors responsible for the recruitment and functionality of macrophages in DLBCL tumors. We have studied the effects of the immunomodulatory lipid sphingosine-1-phosphate (S1P) on macrophage activity in DLBCL, both in vitro and in animal models. We show that tumor-derived S1P mediates the chemoattraction of both monocytes and macrophages in vitro and in animal models, an effect that is dependent upon the S1P receptor S1PR1. However, S1P inhibited M1 macrophage-mediated phagocytosis of DLBCL tumor cells opsonized with the CD20 monoclonal antibodies rituximab and ofatumumab, an effect that could be reversed by an S1PR1 inhibitor. Our data show that S1P signaling can modulate macrophage recruitment and tumor cell killing by anti-CD20 monoclonal antibodies in DLBCL. The administration of S1PR1 inhibitors could enhance the phagocytosis of tumor cells and improve outcomes for patients.

Phase II Clinical Trial of R-CHOP Combined with Lenalidomide in the First-Line Treatment for Patients with High Risk Diffuse Large B Cell Lymphoma

Introduction: Diffuse large B cell lymphoma (DLBCL) is the most common type of non-Hodgkin's lymphoma (NHL). Currently, R-CHOP (Rituximab-Cyclophosphamide, Epirubicin, Vincristine and Prednisone) is world-widely used in the first-line treatment for DLBCL, producing a long-term survival rate of approximately 60%. The unmet need is focused on high-risk DLBCL patients, having high International Prognostic Index (IPI) scores, non-germinal center-like B cell (non-GCB) origin, double expression of MYC and BCL2 protein, or TP53 aberrations. Lenalidomide is an active agent in the activated B cell-like (ABC) subtype of DLBCL by increasing interferon-stimulated gene transcription and activation of immunomodulatory mechanisms. At present, it has been approved for the treatment of multiple myeloma with good efficacy and safety. This is a prospective single arm, multi-center, phase II clinical trial and the goal of our trial is to assess the efficacy and safety of R-CHOP combined with lenalidomide in the first-line treatment for patients with high risk diffuse large B cell lymphoma. Methods: We did an investigator-initiated, open-label, phase 2 trial at the Affiliated Cancer Hospital of Zhengzhou University in China. Patients were eligible if they were aged over 18 years, had histologically confirmed DLBCL. The key inclusion criteria included untreated and medium to high /high risk DLBCL (International Prognostic Index (IPI) score 3-5, aaIPI score 2-3 or NCCN-IPI score≥ 4/ Immunohistochemical staining of double expression (BCL2 ≥ 50% and C-MYC ≥ 40%) or P53 protein mutation positive ≥ 50%). Participants in RL-CHOP cohort were given Lenalidomide orally 25 mg per day on days 1 through 10 of each cycle and delivered concomitantly with standard dose R-CHOP-21 chemotherapy. We also set another group treated with conventional R-CHOP-21 used as a matched contemporary cohort. The primary clinical endpoint was 2-year progression-free survival (PFS). The secondary efficacy endpoints were objective response rate (ORR), 2-year overall survival (OS) and safety. This trial is registered with ClinicalTrials.gov, number NCT04214626. Results: Between December 2019 and January 2023, 63 patients with untreated DLBCL enrolled and were evaluable in the investigator-initiated phase II study. The median age was 59 years (range: 25-76 years); 49.2% of patients were older than age 60 years. 46 of 63 patients (73.02%) had a ECOG score of 0-1; 43 of 63 patients (68.25%) had stage III-IV disease, and 33 of 63 patients (52.38%) had ≥2 extranodal localizations. The IPI score was high-intermediate and high in 73.02% (46/63) of patients. 51 of 63 patients (80.95%) were non-GCB subtype; 25 of 63 patients (39.68%) were double expressor. The TP53 protein was positive in 34.55% (19/55) of patients. In RL-CHOP cohort, the complete response rate was 80.95%, with overall response rate achieving 100%. The median follow-up time was 18.25 (3.73-42) months, median PFS and OS were not reached, and 2-year PFS and OS was 71.1% (+-6.7) and 87.4% (+-4.5), respectively. Comparing with historical matched contemporary cohort, the 2-year PFS and OS rates were improved for medium to high /high risk DLBCL. The most common adverse events of treatment were hematologic toxicities. Grade 3/4 AEs occurred in ≥20% patients were neutropenia, leukopenia, anemia, thrombocytopenia and decreased serum potassium, without bleeding complications. No grade 4 non-hematological adverse event was reported. Conclusion: RL-CHOP is effective and safe in patients with newly diagnosed DLBCL with high risk. Relevance of molecular biomarkers on RL-CHOP response warrants further investigation in DLBCL.

REFLECT: prospective multicenter non-interventional study evaluating the effectiveness and safety of Sandoz rituximab (SDZ-RTX; Rixathon®) in combination with CHOP for the treatment of patients with previously untreated CD20-positive diffuse large B-cell lymphoma.

REFLECT is the first prospective study of Sandoz biosimilar rituximab (SDZ-RTX) in patients with diffuse large B-cell lymphoma (DLBCL). To evaluate the 2-year effectiveness and safety of SDZ-RTX as first-line treatment for DLBCL. Real-world, multicenter, open-label, single-arm, non-interventional, post-approval study of SDZ-RTX in combination with cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) in patients with treatment-naïve CD20‑positive DLBCL. Treatment-naïve, CD20-positive adult patients (⩾18 years) with DLBCL eligible for therapy with R-CHOP were treated with SDZ-RTX-CHOP every 2 or 3 weeks for 6-8 cycles. The effectiveness of SDZ-RTX was measured by the complete response (CR) rate at the end of R-CHOP treatment, as assessed by the treating physician. Progression-free survival (PFS) was assessed at 24 months. A total of 169 patients [52.1% female, median (range) age 70 (24-94) years] with DLBCL were included in the full analysis set. At baseline, 19.5% and 24.3% of patients had Ann Arbor disease stage III or IV, respectively, and most patients (80.5%) had Eastern Cooperative Oncology Group Performance Status of 0 or 1. A total of 100 (59.2%) patients completed the 24-month observation period. In total, 110 [65.1%; 95% confidence interval (CI): 57.4-72.3] patients achieved CR as best response and 50 (29.6%; 95% CI: 22.8-37.1) patients achieved partial response. Overall best response rate was 94.7% (95% CI: 90.1-97.5). One-year PFS was 84.9% (95% CI: 78.2-89.6), while 2-year PFS was 78.5% (95% CI: 70.9-84.4); median PFS was not reached within the observational period. A total of 143 (84.6%) patients experienced ⩾1 adverse event, 53 (31.4%) of which were suspected to be related to study drug. This real-world, 2-year study reconfirms that first-line treatment of CD20-positive DLBCL with R-CHOP using SDZ-RTX is effective and well tolerated. N/A.

Diffuse large B-cell lymphoma genetics - simplifying the subtyping.

Diffuse large B-cell lymphoma genetics - simplifying the subtyping.

Three-Year Follow-up on Safety and Effectiveness of Rituximab Plus Chemotherapy As First-Line Treatment of Diffuse Large B-Cell Lymphoma

Background:As the most common subtype of aggressive non-Hodgkin lymphoma (NHL), diffuse large B-cell lymphoma (DLBCL) accounts for approximately 38% of NHL cases in China. Rituximab plus chemotherapy (R-chemo) is widely used by Chinese physicians as the standard of care for patients with DLBCL. The benefits of R-chemo have been well demonstrated in many randomized clinical trials. However, the safety and effectiveness of R-chemo in real clinical setting need to be further investigated.Methods:This study was a multicenter, prospective, single-arm observational study conducted in China. DLBCL patients who were eligible to receive R-chemo (CHOP or non-CHOP) as first-line treatment were enrolled with no specific exclusion criteria. Individual dose and duration of treatment was determined at the investigator's discretion, local labeling information and standard clinical practice. Data on safety and effectiveness were collected from medical records. Patients went through safety and effectiveness assessment after the last rituximab dose was administered, and then followed-up for 3 years. The safety endpoints included adverse events (AEs), severe adverse events (SAEs), adverse drug reactions (ADRs), and adverse events of special interest (AESIs). The effectiveness endpoints included overall response rate (ORR), complete response (CR), unconfirmed CR (CRu), partial response (PR), progression-free survival (PFS), and overall survival (OS). This study was registered in clincialtrials.gov (NCT01340443).Results:In total, 282 DLBCL patients received at least one dose of rituximab. During the study, 271 (96.1%) patients reported 1864 AEs (Table 1). The common drug-related AEs (incidence ≥ 5%) in DLBCL patients were white blood cell count decreased (16.0%), lung infection (6.4%), neutrophil count decreased (5.7%), and infusion related reaction (5.3%). Drug-related AEs of special interest in DLBCL patients were infusion related reactions (6.4%), others (2.5%), other opportunistic infections (1.8%), hypogammaglobulinaemia (1.4%), serum sickness and serum sickness symptoms (1.1%), hepatitis B virus reactivation (0.7%), and prolonged neutropenia (0.4%). Six (2.1%) DLBCL patients died due to AEs. The cause of death included lung infection (2 cases), acute leukemia (1 case), cardiac failure (1 case), acute left ventricular failure (1 case), sepsis (1 case), and multiple organ failure (1 case). Of which, 1 patient died of sepsis and lung infection.Effectiveness assessment was performed in intention to treat (ITT) population, comprising patients who received at least one cycle of rituximab and completed at least one tumor assessment after baseline. Among 258 DLBCL patients in ITT population, the overall response rate were 94.2% [95% CI (90.59%, 96.71%)], and CR, CRu, PR, and stable disease (SD) were 55.0%, 18.2%, 20.9%, and 5.8%, respectively. Subgroup analysis showed that ORR was statistically different in ECOG, IPI, tumor maximum diameter, extra nodal, age, type of hepatitis B, site and total treatment cycles in DLBCL patients. The 2-year PFS rate was 68% (60%, 74%) for DLBCL patients. The COX univariate analysis showed that IPI ,age ,ECOG and LDH were statistically different for PFS while gender, tumor maximum diameter, type of hepatitis B, rituximab treatment cycle, Ann Arbor stage and extra nodal involvement showed no statistically different, while age , ECOG and LDH remained statistically different for PFS for the possible reason of correlation between these factors and short follow-up time in this non-intervention study(Figure 1,2). The average rituximab treatment cycles for early stage (Ann Arbor I+II) and late stage(Ann Arbor III+IV) were 5.6 and 5.9 respectively.Summary and conclusion:Overall, R-chemo as the first-line treatment of DLBCL was well tolerated by patients in China. The effectiveness in real-life clinical practice was consistent with previous studies. This study provides long term safety data and insights into treatment responses and prognostic factors in Chinese patients with DLBCL. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Genomic Characteristics Clinical Phenotype and Disease Course of TP53 Mutated Diffuse Large B Cell Lymphoma at Diagnosis and Relapse

Genomic Characteristics Clinical Phenotype and Disease Course of TP53 Mutated Diffuse Large B Cell Lymphoma at Diagnosis and Relapse

R-CHOP compared to R-CHOP + X for newly diagnosed diffuse large B-cell lymphoma: a systematic review and meta-analysis

Background Treatment with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) is standard of care first line treatment for diffuse large B-cell lymphoma (DLBCL), though outcomes remain suboptimal. Methods We performed a systemic review and meta-analysis of randomized controlled trials comparing the efficacy and safety of R-CHOP vs. R-CHOP + X (addition of another drug to R-CHOP) as first line treatment for DLBCL. We searched Cochrane Library, PubMed and conference proceedings up to September 2020. Results Our search yielded ten trials including 4206 patients. The added drug was bortezomib or lenalidomide in three trials each, and gemcitabine, bevacizumab and ibrutinib, each drug in one trial. R-CHOP + X was associated with statistically significant improved disease control (HR 0.88, 95% CI 0.78–0.99). The point estimate was in favor of improved overall survival with R-CHOP + X (hazard ratio (HR) 0.87, 95% confidence interval (CI) 0.75–1.00), although this was not statistically significant. Subgroup analysis revealed improved disease control with the addition of lenalidomide and in patients younger than 60 years. R-CHOP + X was associated with an increase in serious adverse events and grade III/IV hematologic toxicity. Conclusion The addition of another drug to frontline R-CHOP treatment for DLBCL did not result in a significant improvement in OS, although we did observe improved disease control compared to R-CHOP, perhaps most evident with the addition of lenalidomide. Yet, RCHOP + X was associated with an increased risk for serious and hematological adverse events. Further studies could reveal subgroups that would benefit most from augmentation of standard R-CHOP.

R-CHOP Vs. R-CHOP+X for Newly Diagnosed Diffuse Large B-Cell Lymphoma: A Systematic Review and Meta-Analysis

Introduction: Treatment with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) has remained the standard of care as first line treatment for diffuse large B-cell lymphoma (DLBCL) for almost two decades. Treatment outcomes are still suboptimal, as approximately 40% of patients have refractory disease or relapse. Prospective studies recently examined whether the addition of various drugs to R-CHOP (termed R-CHOP+ X) could improve outcomes. The aim of this study was to compare the efficacy and safety of R-CHOP vs. R-CHOP +X as first line treatment for DLBCL. Methods: Systematic review and meta-analysis of randomized controlled trials including patients with DLBCL, comparing first line treatment with R-CHOP vs. R-CHOP+X (i.e. R-CHOP with the addition of another single drug). The Cochrane Library, MEDLINE, conference proceedings and references were searched until June 2019. Two reviewers appraised the quality of trials and extracted data. Primary outcome was overall survival (OS). Secondary outcomes included overall response rate (ORR), complete response (CR) rate, disease control and safety. Results: Our search yielded seven trials conducted between the years 2010 and 2019, including 2939 patients (three abstracts, and four published in peer review journals). Median age of patients ranged between 50 to 67 years. The added drug was bortezomib and lenalidomide - each drug in two trials; gemcitabine, bevacizumab and ibrutinib - each drug in one trial. Three trials included all DLBCL patients regardless of cell of origin, whereas four trials included only patients with non-GCB DLBCL. Characteristics of trials included in the meta-analysis are described in Table 1. Regarding OS, the point of estimate favored improved OS with R-CHOP+X as compared to R-CHOP, yet without statistical significance, HR 0.87, [95% confidence interval (CI) 0.73-1.04, I2=0, 1984 patients, 5 trials]. The ORR and CR rates were similar in the two arms (RR 0.97 [95% CI 0.93-1.02, I2=65%, 2824 patients, 7 trials], and RR 0.99 [95% CI 0.93-1.05, I2=37%, 2826 patients, 7 trials], respectively). However, there was a trend towards improved disease control in the RCHOP+X arm, HR 0.89 [95% CI 0.78-1.01, I2=36]. Regarding safety, three trials (N=1200) reported serious adverse events. There was a significant increase in adverse events in the R-CHOP+X group, RR 1.42 [95% CI 1.24-1.64. I2=55%]. In addition, there was more hematologic toxicity in the R-CHOP+X arm, as reflected by higher rates of grade III/IV thrombocytopenia, anemia and neutropenia. Conclusions: The addition of an extra drug to the conventional first line R-CHOP regimen in patients with DLBCL resulted in a trend towards improved disease control compared to standard R-CHOP. However, there was no significant change in response rates or OS, and R-CHOP+ X was associated with an increased risk for serious and grade III/IV hematological adverse events. R-CHOP still remains the "gold standard" of treatment for DLBCL. Further analyses could perhaps reveal subgroups that would benefit from the addition of an additional drug to this regimen. Disclosures Gurion: Roche: Consultancy.

R‐CHOP VS. R‐CHOP+X FOR NEWLY DIAGNOSED DIFFUSE LARGE B‐CELL LYMPHOMA: A SYSTEMATIC REVIEW AND META‐ANALYSIS

Introduction: Treatment with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) has remained the standard of care as first line treatment for diffuse large B-cell lymphoma (DLBCL) for almost two decades. Treatment outcomes are still suboptimal, as approximately 40% of patients have refractory disease or relapse. Prospective studies recently examined whether the addition of various drugs to R-CHOP (termed R-CHOP+ X) could improve outcomes. The aim of this study was to compare the efficacy and safety of R-CHOP vs. R-CHOP +X as first line treatment for DLBCL. Methods: Systematic review and meta-analysis of randomized controlled trials including patients with DLBCL, comparing first line treatment with R-CHOP vs. R-CHOP+X (i.e. R-CHOP with the addition of another single drug). The Cochrane Library, MEDLINE, conference proceedings and references were searched until June 2019. Two reviewers appraised the quality of trials and extracted data. Primary outcome was overall survival (OS). Secondary outcomes included overall response rate (ORR), complete response (CR) rate, disease control and safety. Results: Our search yielded seven trials conducted between the years 2010 and 2019, including 2939 patients (three abstracts, and four published in peer review journals). Median age of patients ranged between 50 to 67 years. The added drug was bortezomib and lenalidomide - each drug in two trials; gemcitabine, bevacizumab and ibrutinib - each drug in one trial. Three trials included all DLBCL patients regardless of cell of origin, whereas four trials included only patients with non-GCB DLBCL. Characteristics of trials included in the meta-analysis are described in Table 1. Regarding OS, the point of estimate favored improved OS with R-CHOP+X as compared to R-CHOP, yet without statistical significance, HR 0.87, [95% confidence interval (CI) 0.73-1.04, I2=0, 1984 patients, 5 trials]. The ORR and CR rates were similar in the two arms (RR 0.97 [95% CI 0.93-1.02, I2=65%, 2824 patients, 7 trials], and RR 0.99 [95% CI 0.93-1.05, I2=37%, 2826 patients, 7 trials], respectively). However, there was a trend towards improved disease control in the RCHOP+X arm, HR 0.89 [95% CI 0.78-1.01, I2=36]. Regarding safety, three trials (N=1200) reported serious adverse events. There was a significant increase in adverse events in the R-CHOP+X group, RR 1.42 [95% CI 1.24-1.64. I2=55%]. In addition, there was more hematologic toxicity in the R-CHOP+X arm, as reflected by higher rates of grade III/IV thrombocytopenia, anemia and neutropenia. Conclusions: The addition of an extra drug to the conventional first line R-CHOP regimen in patients with DLBCL resulted in a trend towards improved disease control compared to standard R-CHOP. However, there was no significant change in response rates or OS, and R-CHOP+ X was associated with an increased risk for serious and grade III/IV hematological adverse events. R-CHOP still remains the “gold standard” of treatment for DLBCL. Further analyses could perhaps reveal subgroups that would benefit from the addition of an additional drug to this regimen. Download : Download high-res image (125KB) Download : Download full-size image Disclosures Gurion: Roche: Consultancy.

A comparative study of standardized quantitative and visual assessment for predicting tumor volume and outcome in newly diagnosed diffuse large B-cell lymphoma staged with 18F-FDG PET/CT

BackgroundSemi-automated quantitative measurement of metabolic tumor volume (MTV) for prognosis in diffuse large B-Cell lymphoma (DLBCL) has gained considerable interest lately. However, simple tumor volume measures may be inadequate for assessment of prognosis in DLBCL as other characteristics such as growth pattern and metabolic heterogeneity may be just as important. In addition, MTV measurements require delineation of tumor lesions by semi-automated software, which can be time-consuming. We hypothesized that a simple visual assessment of tumor volume performs as well as standardized MTV measurements in DLBCL prognostication.Materials and methodsQuantitative and visual analyses of pre-therapy 18F-FDG PET/CT scans in 118 patients with newly diagnosed DLBCL were conducted. Quantitative analyses were performed using Hermes TumourFinder® to obtain MTV2.5 (SUV 2.5 cut-off) and MTV41 (41% SUVmax isocontour cut-off). Visual assessments included a binary prediction (good/poor prognosis) as well as tumor burden based on a visual analog scale (MTVVAS) and an estimated volume (eMTV). Three experienced nuclear medicine physicians who were blinded to clinical outcome performed visual evaluations. Progression-free survival was evaluated by Kaplan-Meier curves and log-rank test. Inter-observer variability was evaluated by Fleiss’ kappa for multiple observers.ResultsIn the quantitative analysis, a ROC-determined MTV2.5 cut-off (log-rank p = 0.11) seemed to outperform MTV41 (log-rank p = 0.76) for PFS prediction. TLG2.5 (log-rank p = 0.14) and TLG41 (log-rank p = 0.34) were not associated with outcomes. By visual analysis, all three reviewers were able to stratify patients into good/poor prognosis (reviewer A log-rank p = 0.002, reviewer B log-rank p = 0.016, and reviewer C log-rank p = 0.012) with fair inter-observer agreement (Fleiss’ kappa 0.47). MTVVAS and eMTV were not consistently correlated with the outcome.ConclusionPredictions of outcome after first-line treatment for DLBCL were surprisingly good when left to the unsupervised, subjective judgment of experienced readers of lymphoma 18F-FDG-PET/CT. The study highlights the importance of non-standardized clinical judgments and shows potential loss of valuable prognostic information when relying solely on semi-automated MTV measurements.

Valproate in combination with rituximab and CHOP as first-line therapy in diffuse large B-cell lymphoma (VALFRID)

AbstractThe aims of the present study were to establish the maximally tolerated dose (MTD) of the histone deacetylase inhibitor valproate together with R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) in patients with diffuse large B-cell lymphoma (DLBCL). A phase 1 dose escalation study of valproate together with R-CHOP followed by a dose expansion study using the established MTD of valproate was performed. MTD of valproate together with R-CHOP was established at 60 mg/kg per day, as higher doses resulted in auditory adverse events (AEs). In the study population, 2-year progression-free survival was 84.7% (95% confidence interval [CI], 73.2%-98%). The 2-year overall survival (OS) was 96.8% (n = 31; 95% CI, 90.8%-100%). These data were compared with 2 risk-factor matched populations of R-CHOP–treated patients from the Swedish Lymphoma Registry (cohort A, n = 330 and B, n = 165). As compared with the matched cohorts, we observed a statistically significant (P = .034 and 0.028, respectively) beneficial effect of the addition of valproate to R-CHOP on the OS in the studied population. In conclusion, addition of valproate to R-CHOP is a feasible strategy in first-line treatment of DLBCL. The proposed phase 2 dose is 60 mg/kg per day together with prednisone. Auditory AEs were unexpected and warrant close monitoring. Our findings suggest that drugs that target histone deacetylation may add benefit and are tolerable when combined with standard R-CHOP in DLBCL. The phase 1 trial was registered at www.clinicaltrials.gov as #NCT01622439.

Multi-Database Description of Primary Splenic Diffuse Large B-Cell Lymphoma

Introduction:Although the spleen is involved in about a third of patients with Diffuse Large B-cell Lymphoma (DLBCL), stage I splenic DLBCL is rare and there is little data to guide management. Potential treatment modalities include combinations of splenectomy, radiation and immuno-chemotherapy, but there is no consensus on the optimal approach. Using multiple publically available and propriety databases, we sought to further define the prognosis and outcomes for stage I splenic DLBCL.Methods:We utilized the Surveillance Epidemiology and End Results (SEER) 18 registry to identify patients with stage I splenic DLBCL diagnosed during the years 1973-2013. Appropriate cases were identified using a combination of International Classification of Diseases for Oncology, 3rd edition code DLBCL (9680/3) and location code for spleen (C42.2). These patients were divided into two cohorts based on the year of diagnosis (1983-2005; 2006-2013) as rituximab (R) was approved by the FDA in 2006 for use in the first line treatment of DLBCL. Patient characteristics and survival outcomes were analyzed by GraphPad Prism 6 and Microsoft Excel. Disease specific survival (DSS) and Overall survival (OS) comparisons were made using the Gehan-Breslow-Wilcoxon test. All p-values were 2-sided and results ≤0.05 were considered significant.We queried the Mitelman Database of Chromosome Aberrations and Gene Fusions in Cancer to identify patients with stage I splenic lymphoma during the years 1973-2013. We also searched the Caris Life Sciences database for patients profiled by Caris Molecular Intelligence using the keywords "splenic lymphoma " in the clinical history and diagnosis fields for cases of stage I splenic DLBCL from 2007-2015. All database searches were conducted with IRB approval.Results:107,550 patients with known stage and histologically confirmed DLBCL were identified within the SEER database. 30,455 patients had stage I disease with 470 of them diagnosed as stage I splenic DLBCL. The mean age was 66 years (range, 17-93 years) and the majority were Caucasian (89%). There was equal distribution of patients in the pre-rituximab (pre-R) era and post rituximab (R) era (53% vs 47%). 42% (470/1116) of splenic DLBCL were diagnosed as stage I compared to 28% (29,985/106,434) of all other types of DLBCL (p<0.01). Stage I splenic DLBCL treated in the R-era has better OS than all other stage I DLBCLs treated during the same period (HR = 0.62, 95% CI 0.53-0.86, p<0.01)The rate of splenectomy was lower after the approval of rituximab (82% in pre-R vs 72% in R era, p=0.03). Splenectomy was associated with an improvement in DSS (HR = 0.57, 0.28 - 0.96, p=0.04), but when stratified by pre-R and R era, improved DSS with splenectomy was only seen in the pre-R (HR = 0.51, 0.17-1.08, p =0.04), but not in the R-era (HR =0.62, 0.25 - 1.38 p=0.53). OS advantage with splenectomy was also seen only in the pre-R era (HR = 0.66, 0.32 - 1.14, 106m vs 137m, p=0.03) but splenectomy had no impact on OS in the R-era (HR = 0.74, 0.37 - 1.43, p=0.45). There was a trend toward improved OS with the introduction of rituximab (HR = 0.75, 0.48 - 1.14, p=0.054). There was no difference in the utilization of radiation between these cohorts (6% in pre-R vs 3% in R era, p=0.13).Our search of the Mitelman database found 1413 patients with DLBCL, but none of them had stage I splenic DLBCL. We also identified 20 patients with Non-Hodgkin lymphoma profiled by Caris Life Sciences, of which only one had primary splenic DLBCL. This patient was a 35 year old male who on immunohistochemistry was found to be positive for MGMT, MRP1, PTEN, TOP2A, TOPO1, and TS.Conclusion:The utilization of splenectomy for stage I splenic DLBCL has decreased with the introduction of rituximab without compromise of outcomes. Radiation is rarely used and does not appear to influence outcomes. Splenic DLBCL is more likely to present as stage I disease compared to other types of DLBCLs and Stage I splenic DLBCL appears to have a favorable prognosis relative to other stage I DLBCLs. Alternative databases added little to the understanding of the biology of stage I splenic DLBCL. DisclosuresNo relevant conflicts of interest to declare.

Changes in treatment patterns and impact of radiotherapy for early stage diffuse large B cell lymphoma after Rituximab: A population-based analysis

PurposeUse of Rituximab for diffuse large B cell lymphoma (DLBCL) has improved outcomes and led to further questions regarding the benefit of consolidative radiation therapy (RT). This study sought to determine changes in RT utilization following the incorporation of Rituximab for treatment of early stage DLBCL and to examine survival outcomes. Materials/methodsWe included patients in the Surveillance, Epidemiology, and End Results database, diagnosed with Stage I–II DLBCL between 1992 and 2011. Linear regression was performed to determine rate of RT utilization over time during the pre- and post-Rituximab eras (1992–2001 vs. 2002–2011). Kaplan–Meier and Cox Regression were performed to compare overall survival (OS) for patients treated with or without RT. Propensity-score matching was used to compare survival outcomes to account for indication bias. Results34,680 patients met the specified criteria. RT utilization was 35.2% in the pre-Rituximab era and 29.9% in the post-Rituximab era (​P<0.001). Linear regression revealed that in the pre-Rituximab era the slope of the best fit line for RT utilization by year was positive (m=0.01, ​P=0.0046), while the slope was negative in the post-Rituximab era (m=−0.008, ​P=0.0102). RT use was associated with improved OS in both the pre-Rituximab era (hazard ratio [HR]=0.797; 95% confidence interval [CI] 0.756–0.841) and the post-Rituximab era (HR=0.745; 95% CI 0.702–0.789). Propensity-score matched analysis confirmed that RT use improved OS in the pre-Rituximab era (HR=0.844; 95% CI 0.793–0.897) and post-Rituximab era (0.754; 95% CI 0.703–0.809). ConclusionRT utilization has decreased following incorporation of Rituximab for first line treatment of DLBCL. RT use is associated with improved OS in both pre- and post-Rituximab eras, suggesting that RT should continue to be used for management of early stage DLBCL, even in the era of Rituximab.

Secondary Central Nervous System (CNS) Involvement in Patients Diagnosed with Diffuse Large B-Cell Lymphoma (DLBCL) during the First Line R-CHOP Treatment and after the End of Treatment

Background: Secondary central nervous system (CNS) involvement is an unfavorable risk factor with an impact on overall survival (OS) in malignant lymphoma.Methods: We conducted a retrospective analysis of secondary CNS involvement in patients diagnosed with Diffuse Large B-Cell lymphoma (DLBCL) on the first line treatment and after the end of treatment. We collected data on 361 patients diagnosed with DLBCL.Results: The median age (range) was 66 (17-91) years. All patients received first-line R-CHOP21 (rituximab, cyclophosphamide, vincristine, doxorubicin, prednisone) between 2006-2011. Patients with primary involvement of testis, nasopharynx, orbit and CNS received CNS prophylaxis with 15 mg methotrexate intrathecally (IT). Secondary CNS involvement was confirmed in 18 (4.9%) patients which stands for 24.6% (18/73) patients with relapsed lymphoma. Median time from first R-CHOP to lymphoma relapse was 10 months (range 3-33). CNS involvement in first 12 months of treatment was 3.9% (95% CI: 1.8%, 5.8%). Median (range) OS from diagnosis of CNS involvement was 3 (3-79) months. Clinical stage III/IV, IPI 4, breast, 2 or more extranodal sites and NCCN-IPI unfavorable site involvement increased the risk of CNS involvement. Three patients who had received methotrexate IT prophylaxis had CNS involvement at relapse. No patient with primary testis involvement had CNS relapse.Conclusion: Less than 5% of patients had secondary CNS involvement on first line treatment and after end of treatment. Advanced stage, high-risk IPI, 2 or more extranodal sites of involvement increased the risk of CNS involvement after first-line treatment for DLBCL. CNS prophylaxis appears effective in patients with primary testicular lymphoma DisclosuresWalewski:Karyopharm: Consultancy; Roche: Consultancy, Honoraria, Other: travel, accommodation, Research Funding; Celgene: Honoraria, Other: travel, accommodation, Research Funding; Gilead: Consultancy, Honoraria, Other: travel, accommodation; Takeda: Consultancy, Honoraria, Other; Ariad: Consultancy; Janssen-Cilag: Consultancy; Mundipharma: Consultancy, Honoraria, Research Funding; Genetics: Other: travel, accommodation; Teva: Consultancy, Honoraria; Seattle: Other: travel, accommodation; GSK/Novartis: Research Funding; Boehringer Ingelheim: Consultancy; Sanofi: Honoraria, Other: travel, accommodation; Servier: Consultancy.

Survival Trends Among Very Elderly Patients with Advanced Diffuse Large B-Cell Lymphoma - a Population Based Study

BackgroundRituximab became commercially available in Novermber 1997. It was FDA approved in February 2006 for the first line treatment of patients with advanced diffuse large B cell lymphoma (DLBCL). The incidence of diffuse large B cell lymphoma increases with age, with >100 cases per 100000 persons aged >80 years. There is a limited data on survival very elderly patients with DLBCL. This study was conducted to evaluate survival trends of very elderly (≥80 years) patients with advanced DLBCL in the United States.MethodsWe selected very elderly patients (age ≥80 years) diagnosed with Stage III and IV DLBCL from the Surveillance, Epidemiology, and End Results (SEER) 18 database. We calculated 1- and 2- year relative survival rates of the patients during 1992-1997 (Pre-rituximab era) and 1998-2009 (post –rituximab era). We also analyzed survival rates of patients diagnosed before (1998 – 2005) and after (2006-2009) FDA approval of rituximab for the first line treatment of DLBCL. We used SEER Stat software to calculate relative survival (RS) rates.ResultsThere were 2709 advanced DLBCL patients reported during 1992-2009. Overall median survival of the group was 6±0.240 months. The 1- and 2- year relative survival rates of the patients improved significantly from pre-rituximab era to post-rituximab era (1 year RS: 30±2.0 vs 38.9±1.2; Z value 4.16 and 2 year RS: 19.7±1.8 vs 32.8±1.2; Z 5.16). The survival rates were higher in the post-rituximab era for all the cohorts except the Blacks and Others. However, there was no difference in the survival rates of the patients diagnosed during 2006-2009 compared to those diagnosed during 1998-2005 (Table).ConclusionOur population based study showed that the survival rates of very elderly patients with advanced DLBCL have improved in the post-rituximab era for all groups except the Blacks and Others. There is no significant improvement in survival of patients before- and after approval of rituximab in the post-rituximab era.Abstract 2640. Table:Advanced DLBCL relative survival rates in elderly (age ≥ 80 years)CohortsSurvival1992-19971998-20091998-20052006-2009Z value (92-97 vs 98-09)Zvalue (98-05 vs 06-09)NRS ± SE%NRS ± SE%NRS ±SE %NRS ± SE%Male & Female12 mo63330±2.02,07638.9±1.21,27438.1±1.580240.1±1.94.1590.79624 mo19.7±1.82,07632.8±1.231.2±1.535.3±1.95.1621.166Male12 mo26330.6±3.195039.7±1.758338.3±2.236741.0±2.82.7980.63224 mo18.6±2.795033.7±1.830.6±2.238.4±3.03.7501.304Female12 mo37029.5±2.51,12638.2±1.569137.4±2.043539.4±2.53.0360.47824 mo20.4±2.31,12632.1±1.631.7±2.032.7±2.53.6200.335White12 mo57229.8±2.01,78639.8±1.31,10138.5±1.668541.8±2.04.1451.10624 mo19.9±1.91,78633.7±1.332.0±1.636.4±2.15.0291.266Black12 mo2021.0±9.47727.0±5.44630.9±7.33121.2±7.81.499-1.03024 mo17.3±9.27723.6±5.525.1±7.019.5±8.01.476-0.894Other12 mo4136.1±7.821135.4±3.512636.3±4.58534.1±5.40.3490.02924 mo16.7±6.321128.1±3.425.4±4.131.7±5.41.1140.631 NNumber of patients DisclosuresNo relevant conflicts of interest to declare.

Cost-Effectiveness of the Addition of Rituximab to CHOP Chemotherapy in First-Line Treatment for Diffuse Large B-Cell Lymphoma in a Population-Based Observational Cohort in British Columbia, Canada

Background Diffuse large B-cell lymphoma (DLBCL) has primarily been treated with cyclophosphamide, doxorubicin, vincristine, and predisone (CHOP) chemotherapy since the 1970s. Recently, the addition of rituximab to CHOP (CHOP-R) has been found to improve survival and trial-based results have suggested that it is a cost-effective alternative to CHOP. Objectives The objective in this study was to evaluate the cost-effectiveness of CHOP-R relative to CHOP in first-line treatment of DLBCL in a population-based setting in British Columbia, Canada. Methods We created a patient-level simulation model describing potential pathways for DLBCL patients initiating treatment with either CHOP or CHOP-R. Model parameters were populated with statistical analyses of individual-level treatment and effectiveness data and published cost estimates. All results were stratified by age at treatment initiation (<60 years vs. ≥60 years). The base-case scenario was based on a 15-year time horizon and a 3% discount rate. Probabilistic sensitivity analysis was performed. All costs are reported as 2006 $CDN. Results For the base-case scenario, incremental cost-effectiveness ratios (ICERs) for younger individuals ranged from $11,965 per disease-free life-year gained to $19,144 per quality-adjusted life-year gained. For older individuals, estimated ICERs for all health outcomes were below $10,000 per unit outcome gained for a 15-year time horizon. Conclusions Using population-based data, CHOP-R was found to be a cost-effective alternative to CHOP, particularly for individuals aged 60 years and older. Results from this Canadian observational data source were consistent with international clinical trial-based studies. The use of CHOP-R as a first-line treatment for DLBCL is recommended, with respect to both clinical and cost-effectiveness.