Early-stage Diffuse Large B-cell Lymphoma Research Articles

Clinical characteristics and outcome of early-stage diffuse large B cell lymphoma of female genital track: A retrospective study of the Hellenic cooperative lymphoma group.

Involvement of female genital track (FGT) by diffuse large B cell lymphoma (DLBCL) represents an extremely rare diagnosis. Especially data regarding early-stage disease (i.e., IE, IIE) is very limited. Importantly, previous studies showed controversial results about the risk of central nervous system (CNS) relapse in this entity. Herein, we describe one of the largest reported real-world series of patients with early-stage FGT DLBCL aiming to investigate the clinicopathological characteristics, response to therapy and survival outcomes in the era of immunochemotherapy. We analyzed 21 consecutive patients with biopsy proven DLBCL from uterus or ovary classified as stage IE or IIE out of 1905 newly diagnosed DLBCL patients (1.1%). Uterine and ovarian localization was observed in 14 and seven patients, respectively. Median age was 66years (range 33-96); 9/21 (43%) were <55years. Regarding Cell of Origin DLBCL subtype, Germinal Center B-cell subtype was found in seven patients, non-GCB in 10 and non-classified in 4 patients. Median follow-up was 57months and 5-year overall survival, lymphoma specific survival and Freedom from Progression were 78%, 89% and 90%, respectively. There was no correlation of patients' characteristics with survival parameters. Interestingly, none of the patients experienced CNS relapse. Our results indicate that localized FGT DLBCL exhibits a good prognosis and may not increase the risk for secondary CNS involvement.

Definition of bulky disease in early stage diffuse large B-cell lymphoma in computed tomography on coronal and transverse planes

BackgroundIn early stage diffuse large B-cell lymphoma (ESDLBL), tumor bulkiness is an important determinant of treatment and prognosis. Tumor bulk is usually measured on transverse computed tomography (CT) plane and variably defined from 5 to 10 cm.ObjectivesOur study aims to investigate the prognostic significance of bulky disease measured on CT coronal and transverse planes and to evaluate the outcome of patients with bulky disease.MethodsPatients with ESDLBL and treated with rituximab, cyclophosphamide, doxorubicin, and prednisolone (RCHOP) with or without radiotherapy were included. Receiver Operating Characteristic (ROC) analysis was used to identify the optimal tumor dimension that correlated with progression, relapse, or death. Correlation between different variables and progression-free survival (PFS) and overall survival (OS) were analyzed using log-rank (Mantel–Cox) test and Cox proportional hazard models.ResultsA total of 127 patients with a median age of 47 (range: 18–90) years were included. Eighty-two (64.6%) patients treated with combined modality treatment (CMT) [RCHOP + radiotherapy]. After a median follow-up of 40 (range: 2–114) months, 3-year PFS and OS were 83.9% (95% CI: 76.759%–89.981%), and 80.6% (95% CI: 72.499%–87.531%), respectively. Tumor dimension of &amp;gt;7.5 cm measured on either CT plane was the optimal cutoff point to define bulky disease. Three-year PFS and OS were inferior in the group of patients with no bulky disease on transvers plane (n = 84) but had bulky disease on coronal plane (n = 9,10.7%); (94.2% vs. 75%, p = 0.017 and 90.5% vs. 56.3%, p = 0.002), as well as in patients with no bulky disease on coronal plane (n = 89), but had bulky disease on transverse plane (n = 14, 15.7%); (94.1% vs. 62.3%, p &amp;lt; 0.001, and 90.4% vs. 63.5%, p = 0.002). Compared to RCHOP alone, 3-year PFS and OS were better in patients with bulky disease treated with CMT (78% vs. 52.5%, p = 0.018 and 81.8% vs. 38.7%, p = 0.003) but not in patients with non-bulky disease (96.2% vs. 93%, p = 0.691 and 87.6% vs. 91.5%, p = 0.477).ConclusionIn ESDLBL, measurement of tumor mass on transverse and coronal CT planes may help in better identification of patients with bulky disease. The use of CMT was associated with better survival outcomes in patients with bulky disease.

Outcomes and Toxicities in Patients with Diffuse Large B-Cell Lymphoma of the Gastrointestinal Tract.

Diffuse large B-cell lymphoma (DLBCL) involving the gastrointestinal (GI) tract is rare and long-term outcomes are not well defined. Combined modality therapy (CMT) with radiotherapy (RT) in addition to systemic therapy in this setting is not commonly pursued. We aim to characterize outcomes in patients with GI DLBCL treated with systemic therapy, with or without RT. Patients diagnosed with DLBCL of the GI tract (with or without mesenteric involvement) treated at a single institution from 1988-2022 were retrospectively reviewed on an IRB-approved protocol. Clinical and treatment data were collected including adverse events (AE; acute vs late defined as before or 4 weeks after therapy end). Kaplan-Meier and Cox regression models were used to estimate survival. Of 207 patients, 62% were male and median age at diagnosis was 63 (IQR 52-73). Gastric involvement was most common (n = 130, 63%), followed by small intestines (n = 48, 23%) and colon/rectum (n = 24, 12%). Most presented with early-stage disease (n = 124, 60%), with a median IPI score of 1. All patients received chemotherapy. Of 182 treated with CHOP/EPOCH, 36 (20%) were treated in the pre-rituximab era while 146 (80%) received rituximab. 66 patients (32%) were treated with RT, 89% as part of first line CMT. 50 cases (76%) received consolidative RT, while 10 (15%) targeted residual gross disease and 4 (6%) targeted distant sites. Median dose and fractionation were 36Gy (IQR 30.6-39.6) in 18 fractions (IQR 17-22). Over half (n = 132, 64%) developed grade 3+ acute chemotherapy AEs, and the most common were anemia (n = 64), febrile neutropenia (n = 40), and neutropenia (n = 20). Grade 3+ late chemotherapy AEs occurred in 14 patients (7%). Acute grade 3+ radiation AEs were uncommon (n = 2, 3%; colitis, emesis). No grade 3+ late radiation AEs were noted. Median follow-up was 46 months (IQR 16-97). 169 (81.6%) had a complete response (CR), with 154 (91%) after first line chemotherapy, 9 (5%) after second line, and 6 (4%) after RT. CR was defined by PET (62%), endoscopy (22%), CT (9%), or other methods (7%). The 5-year progression-free survival for those treated with one line of chemotherapy with or without RT was 95%. Median overall survival (OS) was not reached. Improved OS was associated with early-stage disease (p = 0.003), low IPI (p = 0.001), fewer chemotherapy lines (p<0.001), and CR (p<0.001). OS did not differ by gender, age, immunophenotype, GI site, SUVmax, or RT. Patients with early stage DLBCL treated with RT in the post-rituximab era received fewer chemotherapy cycles compared to those treated without RT (p = 0.02; median of 4 (IQR 3-6) vs 6 cycles (IQR 4-6)), with no OS difference. GI DLBCL patients have favorable outcomes after CMT with minimal late toxicity. CMT with RT to the GI tract is well tolerated with no OS difference compared to chemotherapy alone, and may mitigate risks from additional chemotherapy cycles for selected early-stage patients.

Radiotherapy Effect on Long-Term Net Survival Benefit for Early-Stage Diffuse Large B-Cell Lymphoma in the Rituximab Era

It is controversial whether to add consolidative radiotherapy (RT) after chemoimmunotherapy in the first-line treatment for diffuse large B-cell lymphoma (DLBCL). This study aimed to investigate the long-term net survival benefit of RT for early-stage DLBCL in the rituximab era. The data of 10,841 adult patients with early-stage DLBCL from the Surveillance, Epidemiology, and End Results (SEER) database between 2002 and 2015 were extracted and analyzed. The patients had received combined modality treatment (CMT, chemotherapy plus RT) or chemotherapy alone. Linear regression analysis was performed for RT utilization by year of diagnosis. Competing risk analysis was used to evaluate the cumulative incidence of mortality according to the cause of death. Inverse probability of treatment weighting (IPTW) was used to balance the distribution of covariates between treatment arms. Relative survival (RS), standardized mortality ratio (SMR), and transformed Cox regression were performed to estimate the net survival benefit of RT by controlling for background mortality. Linear regression revealed that the slope of the best-fit line for RT utilization over time was negative between 2002 and 2015 (m = -0.006, P = 0.003). A total of 4,648 deaths were recorded among 10,841 patients; 55.6% were lymphoma-related death (LRD), and 44.4% were attributed to other causes. Patients initially treated with CMT had a lower cumulative incidence of LRD than chemotherapy alone (HR 0.63, 95% CI: 0.57-0.69; P < 0.001). The 10-year overall survival (OS) rate of 66.1%, RS rate of 85.0%, and SMR of 1.71 achieved with CMT were significantly better than chemotherapy alone (OS, 53.0%; RS, 69.8%; SMR, 2.62; P < 0.001). By IPTW and multivariable analysis, the addition of RT remained associated with better OS (HR 0.67, 95% CI: 0.62-0.71; P < 0.001) and RS (HR 0.69, 95% CI: 0.65-0.74; P < 0.001). RT was associated with better long-term net survival in patients with early-stage DLBCL in the rituximab era.

Decreased lymphoma-related deaths and improved long-term relative survival with radiotherapy for early-stage diffuse large B-cell lymphoma in the rituximab era

BackgroundWe aimed to investigate the incidence of lymphoma-related death (LRD) and the long-term net survival benefit of radiotherapy (RT) for early-stage diffuse large B-cell lymphoma (DLBCL) in the rituximab era. Methods10,841 adults diagnosed with early-stage DLBCL between 2002–2015 were retrospectively analyzed using data from the Surveillance, Epidemiology, and End Results database. Primary therapy was categorized into combined-modality treatment (CMT, n = 3,631) and chemotherapy alone (n = 7,210). Competing risk analysis was used to evaluate the cumulative incidence of mortality. Inverse probability of treatment weighting (IPTW) was used to balance groups. The net survival benefit of RT was estimated through relative survival (RS), standardized mortality ratio (SMR), and transformed Cox regression, while controlling for background mortality. ResultsPatients initially treated with CMT had a lower cumulative incidence of LRD compared to those who received chemotherapy alone (HR 0.63, 95%CI: 0.57–0.69; P < 0.001). The 10-year overall survival (OS), RS, and SMR for CMT were 66.1%, 85.0%, and 1.71 respectively, which were significantly better than those for chemotherapy alone (53.0%; 69.8%; 2.62; all P < 0.001). IPTW and multivariable analysis revealed that the addition of RT led to better OS (HR 0.67, 95%CI: 0.62–0.71; P < 0.001) and RS (HR 0.69, 95%CI: 0.65–0.74; P < 0.001). Moreover, compared with chemotherapy alone, the benefit of OS and RS for CMT increased over time within 10 years of diagnosis. ConclusionRT reduced LRD and improved the long-term net survival in early-stage DLBCL in the rituximab era. Further prospective studies are warranted to assess the specific patient population that would benefit the most from consolidative RT in early-stage DLBCL.

Outcome and patterns of relapse in primary gastric diffuse large B cell lymphoma treated with RCHOP

ABSTRACTObjectivesPatterns and predictors of relapse in primary gastric diffuse large B cell lymphoma (DLBCL) were variably reported. Our study aims to evaluate the patterns and predictors of relapse in early-stage gastric DLBCL treated with Rituximab, Cyclophosphamide, Doxorubicin, Vincristine, and Prednisolone (RCHOP).MethodsFrom 2005 to 2019, the medical records of 72 patients with stage I or stage II gastric DLBCL treated with six cycles of RCHOP without radiotherapy were reviewed. Different variables were correlated with progression free survival (PFS), overall survival (OS), and local relapse free survival (LRFS).Results64 (88.1%) patients achieved a complete response (CR), while 8 (11.9%) had refractory disease. After CR, 9 (14%) patients relapsed; 7 (78%) relapses were loco-regional. Abnormal LDH (p = 0.028), H. pylori negative (p = 0.032) and, stage adjusted international prognostic index (sa-IPI) > 1 (p = 0.013) correlated with loco-regional failure. The 5-year PFS, OS, and LRFS were 74.8%, 75.3%, and 87.5%, respectively, after a median follow-up of 58 (range: 6–185) months. The median time to progression or relapse was 9 months (range: 5–54 months). In multivariate analysis, a sa-IPI >1 (HR: 3.56, CI: 1.35–8.8, p = 0.01) was associated with PFS while low albumin (HR: 8.85, CI: 1.09–71.4, p = 0.041) was associated with worse OS. None of the variables were associated with LRFS.ConclusionTreatment of primary gastric DLBCL with RCHOP results in a high CR rate. The majority of treatment failures were loco-regional. Sa-IPI and H. pylori status may be used to identify patients who may benefit from combined modality treatment.

PET-Driven Radiotherapy (RT) in Patients with Low Risk Diffuse Large B-Cell Lymphoma (DLBCL): 5-Year Results of the DLCL10 Multicenter Phase 2 Trial By Fondazione Italiana Linfomi (FIL)

Background Recent data show that RT on PET-negative sites after chemo-immunotherapy in early stage DLBCL can be avoided. Nevertheless, bulky sites at diagnosis are still irradiated after rituximab-chemotherapy (R-CT), whereas residual uptake area (RUA at other sites are considered as failure. As PET negativity is mandatory to define complete remission (CR), we hypothesized that PET-neg areas after R-CT do not need consolidation RT independently from their size at onset Aims: To assess the role of RT in PET-neg and in PET-pos low-risk DLBCL patients after R-CT Methods: The DLCL10 protocol was a phase II study of patients (pts) >=18 years with low risk DLBCL according to the MiNT trial, (aa IPI 0 and bulky, aa IPI 1 +/- bulky) conducted in 19 FIL centers. Pts were treated with 6 courses of RCHOP and final response was evaluated with FDG-PET. Both pre and post treatment PET scans were centrally reviewed through the Widen web platform by a panel of 5 nuclear medicine experts. Positive scans were those centrally classified with Deauville score 3-4-5 by the first 2 concordant reviewers. Pts with one RUA received RT, 36 Gy involved-site, regardless of bulky disease at onset, while those with multiple RUA were shifted to salvage systemic therapy. Primary aim was to obtain a 2-year PFS of at least 85% for post R-CT PET-neg pts. Secondary endpoints were OS and response. Results: From January 2012 to December 2017, 115 consecutive pts were screened, and 110 were evaluable. Median age 58 years (47-65); M:F 61 /49; DLBCL de novo 90%, aa IPI 0 16 , aa IPI 1 94 (20% with bulky mass), bulky disease in the whole series 35 pts ; RCHOP-14 /RCHOP-21 73/37. At the time of the present analysis median follow-up was 63 months and 13 pts died (3 lymphoma, 2 acute toxicitiy, 2 late toxicity, 2 secondary neoplasm, 2 complication from allo-transplant, 1 other causes, 1 unknown). A total of 105 pts completed the R-CT program, while five were discontinuated for lymphoma progression (1), toxicity (2, both died), histological review (1) and patient dispersion (1). At end of treatment, 83 patients had PET-neg, whereas 17 had single RUA and received involved -site RT. In PET-neg patients, PFS was 90.6% (95% CI 81.1-95.4) at 2 years and 82.48% (95% CI 78.4-94.3) at 5 years. OS was 96.37% (95% CI 89.17-98.81) at 2 years and 87.81% (95% CI 77.62-93.54) at 5 years. After RT, 15 pts reached CR, one PR and one was not evaluable. None of them relapsed. Thus, all patients with positive focal RUA after R-CT were cured with involved-site RT. Concerning the 35 pts with bulky disease, 21 reached PET-neg and 14 had single RUA after R-CT and were thus irradiated (1 PD). There were two relapses in the PET-neg/not irradiated group, but only one in previously bulky site. In the PET-pos /RT group no relapse occurred. In the total population, 5 -year PFS and OS are 80.9% (95%, CI 79.28-92.18) and 87.1% (95%, CI 78.66- 92.38), respectively. Conclusion: Our data suggest that irradiating only sites of unique PET RUA, regardless of bulky at onset, can be considered as a reasonable strategy for low risk DLBCL pts. In cases with bulky disease, PET-driven RT allowed RT sparing in approximately half of patients in this small series. Moreover, consolidation RT in those with focal residual PET positivity, guaranteed excellent prognosis (17/17 cured) and can be considered as a valid option Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Nanochip Technology for Monitoring Chemotherapy Response Using Extracellular RNAs and Proteins in Patient Plasma with Diffuse Large B-Cell Lymphoma As Biomarkers

Introduction Diffuse large B-cell lymphoma (DLBCL) is the most common subtype of non-Hodgkin lymphoma. Assessment of therapeutic response and monitoring for relapse are important components of clinical care in this entity. Although circulating tumor DNA (ctDNA) has shown to be a potential biomarker, it is affected by gene dysregulation and limited by cost, as it requires high amplification, especially in early stage DLBCL since only ~100 ng free DNA fragments are detected in 1 mL blood. Extracellular vesicles (EVs), on the other hand, are abundant in the blood (1011 - 1012 in 1 mL blood), making quantitative analysis easier and less expensive. This OSU based technology has been extensively studied in lung and pancreatic cancer as well as chronic lymphocytic leukemia and multiple myeloma with promising results. Hence, we sought to evaluate whether Immune Lipoplex Nanoparticle (ILN) biochip-based testing (the first of its kind to monitor patients with lymphomas) can serve as a useful means to follow select biomarkers for monitoring therapeutic response. Methods This is a single-center prospective study of de-novo DLBCL patients wherein the patient samples were longitudinally collected before, during, and after chemotherapy upto 2 years every 3 months. The patients were classified as responders if they achieved complete remission (CR) to chemotherapy following cycle 6 (C6), and non-responders/primary progressors if they had progression. In ILN biochip assay, tethered antibodies on the chip surface can capture and sort an EV subpopulation rich with specific membrane proteins after washing. The fluorescence labeled antibodies or cationic lipoplex nanoparticles (CLNs) containing molecular beacons (MBs) are then added to fuse with captured EVs for the detection of membrane protein or mRNA targets respectively. Well known B-cell markers (CD10, CD19, CD20, MUM1, BCL2, BCL6, and cMYC) and a relatively new lymphoma biomarker, CD47 was measured in plasma samples from DLBCL patients before and after chemotherapy with ILN biochips. EV subpopulations rich in CD20 and/or CD19 (DLBCL markers) or CD63/CD9/CD81 (exosome markers) were captured by antibodies tethered on the biochip surface. Subsequently, ILN biomarker measurements were obtained for CD10, CD19 and CD20 protein expressions by fluorescence-labeled antibodies on anti-CD19/CD20 captured B-cell dominated EV subpopulation; MUM1, BCL2, BCL6, cMYC, and PRMT5 mRNA expressions by MBs encapsulated in CLNs in anti-CD63/CD9/CD81 captured exosome-dominated EV subpopulation; and CD47 protein expression by fluorescence-labeled antibodies on the anti-CD47 captured/ CD47-rich EV subpopulation. Results For plasma samples taken before treatment (C0), the exosomal cMYC, BCL2, and BCL6 mRNA expressions could discriminate between healthy donors (HDs, n=17) and patients (n=27), while other B-cell markers did not perform well (Figure 1A). Since BCL2 and BCL6 detection demonstrated similar trends with BCL2 performing slightly better, exosomal cMYC and BCL2 mRNA expressions were selected as the biomarker classifiers. CD47 protein expression by CD47-rich EVs also discriminated between HDs and patients well in pre-treatment (C0) samples (Figure 1A). During chemotherapy, the EV CD47 expression demonstrated a greater decrease in responder samples (n=20) than in non-responder samples (n=7) obtained after C3 showing a statistically significant difference (Figure 1B). Longitudinal CD47 expression (i.e., C1 and C3) on CD47+ EVs could serve as a potential biomarker to discriminate between responders and non-responders of DLBCL patients undergoing chemotherapy with AUC~0.80 (Figure 2). The results of the longitudinal tri-biomarkers, i.e., CD47(C3)/cMYC(C0)/BCL2(C0) expressions will be presented at the meeting. Conclusions We discovered a new longitudinal tri-biomarker classifier based on CD47/cMYC/BCL2 expression after early chemotherapy treatment (C0 and C3) for monitoring chemotherapy response in DCBCL. However, the sample size, particularly in the non-responder cohort (n=7) is small to make any statistically meaningful conclusions. Additional patient samples are being collected to validate these findings. Lastly, to improve the biomarker classifier performance for chemotherapy monitoring (and maybe relapse surveillance), we are conducting an EV mRNA profiling study to identify novel biomarker candidates. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Outcomes with Immunochemotherapy Plus Radiation Versus Immunochemotherapy Alone in Stage I Diffuse Large B-Cell Lymphoma: A Retrospective Study

Introduction Diffuse Large B-cell lymphoma (DLBCL) is the most common subtype of non-Hodgkin lymphoma with a prognosis highly dependent on the stage of the disease. The mainstay of front-line therapy for limited-stage DLBCL is R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) or R-CHOP-like immunochemotherapy (IC). The impact of combined modality therapy (CMT) with radiation therapy (RT) after IC remains uncertain in the rituximab era. In the pre-rituximab era, studies comparing the efficacy of chemotherapy with or without RT showed heterogenous results. To date, only a few single institutional studies have compared IC versus CMT. The aim of this study is to evaluate the efficacy of standard IC compared to CMT in patients with stage I DLBCL in the rituximab era. Methods Adult patients with stage I DLBCL diagnosed between 2002 to 2015 and seen at Mayo Clinic Rochester were identified. Data were obtained from medical records. All patients were treated with IC (R-CHOP or R-CHOP-like), or IC followed by radiation (CMT). The student's t-test or the Wilcoxon rank-sum test was used to analyze between-group differences, as appropriate. Chi-square or Fisher's exact test was used for categorical variable comparisons. Progression-free survival (PFS) was defined as the time from the date of diagnosis to the date of relapse, death or the date of the last follow-up and was analyzed using the Kaplan-Meier method. Overall survival (OS) was defined as the time from the date of diagnosis to the date of last follow-up or death. Response to treatment was evaluated by treating physicians. Results The study included 123 patients diagnosed with stage I DLBCL with a median follow-up time of 65.9 months for IC arm and 56.2 months for CMT arm. Overall, 78 patients were treated with six cycles of IC, and 45 patients were treated with 2-4 cycles of IC followed by involved-site radiation (2 cycles in 4 patients, 3 cycles in 25 patients, 4 cycles in 16 patients). There were no significant differences in age, sex, or extranodal involvement. In the IC group, 59 patients had cell of origin data available: 44 (56.41%) were GCB subtype and 15 patients (19.23%) were non-GCB subtype. In the CMT group, 21 patients (47%) and 9 patients (20%) had GCB and non-GCB subtypes, respectively. Double-hit lymphoma (defined as rearrangement of MYC together with rearrangement of BCL2 and/or BCL6) was reported in 4 out of 78 patients in the IC arm and 2 out of 45 patients in the CMT arm. There was no significant difference in response rates to frontline treatment between groups. In the IC group, the overall response rate (ORR) was 92% (n=72), and the rate of complete response (CR) was 87% (n=68), partial response (PR) was 5% (N=4), stable disease (SD) was 5% (n=4), and progressive disease (PD) was 5% (n=4). In the CMT group, the ORR was 96% (n=43, all CR); 2 patients achieved SD (4%) and no patients had a PR or PD. With a median follow-up time of 65.9 months for IC arm, 14 patients had died. With a median follow-up of 56.2 months for the CMT arm, 14 patients had died. Median PFS was not reached in the IC group while PFS was more than 10 years in the CMT group (p=0.7851) [Figure 1]. There was no significant OS difference observed in both groups (p=0.2561) [Figure 2]. Conclusion Our study showed no significant difference in OS and PFS between patients with stage I DLBCL treated with IC or CMT. Future research on a larger patient population is needed to evaluate the role of consolidation radiotherapy in early stage DLBCL. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

ABCL-242 Definition of Bulky Disease in Early-Stage Diffuse Large B-Cell Lymphoma on Longitudinal and Axial Planes

In early-stage diffuse large B-cell lymphoma (DLBCL), tumor bulkiness and stage-adjusted International Prognostic Index (sa-IPI) are the main determinants of treatment and prognosis. Bulky disease is variably defined from 5 to 10 cm. The aim of our study is to investigate the prognostic significance of bulky disease measured on longitudinal and axial planes on computed tomography (CT) imaging. Medical records of patients diagnosed with early-stage DLBCL and treated in King Hussein Cancer Center were reviewed. Maximal longitudinal and axial planes on initial CT scans were reviewed by two radiologists; sa-IPI was calculated as previously described. Correlation between tumor dimensions and relapse-free survival (RFS) and overall survival (OS) was done using the Pearson correlation test. Survival analyses were performed using the Kaplan-Meier method. A total of 127 patients were included with a median age of 47 years. Fifty-one (40.2%) patients were having extranodal involvement, and sa-IPI was 0-1 in 73 (57.4%). Eighty-two (64.6%) patients were treated with combined modality treatment (RCHOP followed by radiotherapy), and the remaining were treated with RCHOP only. A cut-off of 5 cm correlated with RFS in both the longitudinal and axial dimensions and was used to define bulky disease. Seventy-eight (61.5%) patients with bulky disease in either dimension had 3-year RFS of 76.4% versus 95.4% for patients with non-bulky disease (P=0.0045) and 3-year OS of 71.8% versus 93.2% (P=0.0043), respectively. On multivariate analysis, bulky disease (P=0.028) and sa-IPI >1 (P=0.044) were significantly associated with RFS, whereas OS significantly correlated with sa-IPI >1 (P=0.014). In patients with bulky disease, the use of combined modality treatment resulted in better RFS (62.9% vs. 83.3%, P=0.0157) and OS (81.6% vs. 52.1%, P=0.0042). Tumor bulk of more than 5 cm in the longitudinal or axial dimensions on CT scan should be considered in treatment decisions of patients with early-stage DLBCL, including the use of consolidative radiotherapy. More studies are needed to define the best treatment approach in such patients.

Patient Survival With and Without Radiation Therapy for Early-Stage Diffuse Large B-Cell Lymphoma in the Era of PET and Rituximab

PurposeThe benefit of radiation therapy (RT) becomes uncertain in the treatment of early stage diffuse large B-cell lymphoma (DLBCL) in the era of rituximab, positron emission topography (PET), and computed tomography (CT). We sought to retrospectively review modern patients with early stage I-II DLBCL treated with rituximab and staged by PET-CT to better define which patients benefit from consolidative RT. Methods and MaterialsPatients with early stage I-II DLBCL from 1998 to 2017 were reviewed coinciding with our institutional utilization of rituximab with the standard regimen of cyclophosphamide, doxorubicin, vincristine, and prednisone and PET-CT. Relevant clinical information was used to calculate National Comprehensive Cancer Network international prognostic index (IPI) scores. Kaplan-Meier survival analysis and a Cox proportional hazards model were used for overall survival (OS). ResultsSeventy-seven patients received chemoimmunotherapy alone, and 41 received chemoimmunotherapy plus RT. Median follow-up time was 9.5 years. On univariate analysis, extranodal disease (P = .04) and National Comprehensive Cancer Network IPI (P < .001) were significantly correlated with OS. Five-year OS was 87% versus 67%, and 10-year OS was 67% versus 58%, numerically higher favoring RT (P = .16). On multivariate Cox regression analysis of OS controlling for IPI and extranodal disease, the addition of RT was associated with improved OS (hazard ratio of 0.4, P = .01). ConclusionsThe current analysis supports the use of consolidative RT in early stage DLBCL given an OS benefit on multivariate analysis. Further prospective randomized data are needed to confirm these findings.

Clinical and Survival Outcomes in Patients with Supra-Diaphragmatic Vs İnfra-Diaphragmatic Diffuse Large B Cell Lymphoma

Limited-stage diffuse large B-cell lymphoma (DLBCL) accounts for approximately 30% of all DLBCL cases. This study aimed to investigate the impact of the lymphoma involvement side relative to the diaphragm on clinical and survival outcomes in patients with limited-stage DLBCL treated with first-line rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP). Data from 93 patients with limited-stage DLBCL between 2010 and 2019 receiving R-CHOP were retrospectively analyzed. Patients were divided into two subgroups according to the side of the diaphragm: 29 patients with infradiaphragmatic (InD) and 64 patients with supradiaphragmatic (SpD). There were no significant differences in survival outcomes [5-year PFS rate of SpD and InD groups, 76.7% and 85.7%, respectively (P =0.553); 5-year OS rates of SpD and InD groups, 82.1% and 89.1%, respectively (P = 0,524)] and clinical characteristics, except that extra nodal involvement was dominant in the InD group and the SpD group had a higher IPI. In conclusion, in early-stage DLBCL, extra nodal involvement is expected more if the primary involvement area is below the diaphragm, however whether the primary involvement area is below or above the diaphragm has no effect on survival outcomes. The results of this study need to be confirmed by further studies with a larger case group.

Abstract TP194: Radiation And Stroke Death Risk In Diffuse Large B-cell Lymphoma Patients, A Population Based Study.

Objective: Radiation (RT) is associated with vascular changes, which carotid studies have linked with stroke risk. Previous studies have reported an increased risk of stroke following RT for squamous cancers of head &amp; neck (HN), or Hodgkin’s lymphomas, though with variations in dose and anatomical radiation targets. Hence the effects of low dose radiation to only the HN remains unclear. We used a national database with long-term follow up to quantify the association of RT and stroke death (SD) in patients with diffuse large B cell lymphoma (DLBCL) of the HN. Materials/Methods: Patients 30 or older with DLBCL, stage I-II of a known primary site besides CNS or mediastinum from 1983-2013 were obtained for analysis from the SEER database. Cause of death coding was filtered for Cerebrovascular Disease. Chi square, T-test, and Kaplan-Meier analysis were performed with log-rank test and Cox accounting for age, sex, RT, and year of diagnosis. Results: 33945 patients met inclusion criteria with a median follow up of 44 months. SD occurred in 410 patients in median time 62 months. RT was given in 3855 of 8312 (46%) HN and 7686 of 25633 (30%) of non-HN patients. The 10 year-SD rate was 2.2 / 2.8 % (p=0.77) for HN receiving/ not receiving RT (noRT), and 1.8 / 2.1 % for non-HN patients (p=0.40). When combining both RT and noRT patients, HN patients did show a trend towards higher SD risk compared with non-HN patients, 2.5 vs 2.0%, (p=0.053), though this did not appear to be driven by RT. On univariate analysis of HN patients, there was no difference in the effects of RT on the SD rate in any subgroup. Multivariate analysis did not identify any increased risk of SD associated with RT, either (HR = 0.87, p=0.63). Conclusions: This study did not identify any increased risk of stroke death from RT in patients with early stage DLBCL of the head &amp; neck, although there was a trend suggesting stroke rates may be higher in patients with disease located in head &amp; neck compared to other sites regardless of whether they received RT. Higher chemotherapy doses for non-RT patients may be a relevant confounding variable. Confirmation with pooled analyses and meta-analysis may be useful.

Efficacy and safety comparison between R-CHOP and modified NHL-BFM-90 regimens in children and adolescents with diffuse large B-cell lymphoma.

Studies comparing the efficacy and safety of R-CHOP and modified non-Hodgkin lymphoma Berlin-Frankfurt-Münster-90 (NHL-BFM-90) regimens in children and adolescents with diffuse large B-cell lymphoma (DLBCL) are lacking. Thus, we retrospectively analyzed 85 DLBCL patients aged ≤18 years from 2000 to 2020; 74 patients received the modified NHL-BFM-90 regimen, and 11 received the R-CHOP regimen. The 5-year OS and event-free survival (EFS) rates between the modified NHL-BFM-90 and R-CHOP regimens were 91.0% vs. 90.9% (P = 0.466) and 89.8% vs. 68.6% (P = 0.055), respectively. In the stratified analysis, the survival outcome of pediatric patients treated with the modified NHL-BFM-90 regimen was not significantly different from that of adolescent patients. The OS and EFS rates of patients with early-stage disease were both 100%. Patients in the advanced-stage group who were treated with the modified NHL-BFM-90 regimen had superior EFS rates (P < 0.05). The frequency of severe adverse events from the two regimens was similar. There were no treatment-related deaths. We concluded that the modified NHL-BFM-90 regimen has better efficacy than R-CHOP in DLBCL patients with advanced-stage disease. However, the R-CHOP regimen might be an option for early-stage DLBCL. Further prospective studies are needed to guide clinical decisions about treatment.

Biological and Classical Prognostic Factors with Impact on Overall Survival in Patients with Early Stage (I/II) Diffuse Large B-Cell Lymphoma: A Study from the Grupo De Estudio Latinoamericano De Linfoproliferativos (GELL)

Background: Diffuse large B-cell lymphoma (DLBCL) is the most common non-Hodgkin lymphoma subtype. Early stage (I/II) disease is seen in up to 30% of all DLBCL cases, and although outcomes in this subgroup have been reported as optimal, relapses can still occur. Prognostic models such as the International Prognostic Index (Miller, NEJM, 1998) continues to be utilized for risk stratification in DLBCL. However, despite its limitations and lack of validation in specific demographic groups such as Latin American patients, no prognostic models exist for the evaluation of limited stage DLBCL. Therefore, we aim to investigate different clinico-epidemiological and laboratory variables and its impact on survival in early stage DLBCL.Methods: We conducted a retrospective study of newly diagnosed patients with early stage DLBCL. Using the Grupo de Estudio Latinoamericano de Linfroproliferativos (GELL) database, we selected patients that had early stage disease, defined as non-bulky stage I or II. The variables analyzed included demographic and clinical variables (e.g., age, ECOG performance status), the International Prognostic Index (IPI), and laboratory variables such as serum albumin, serum lactate dehydrogenase (LDH), serum beta-2-microglobulin, the lymphocyte-monocyte ratio (LMR), the neutrophil-lymphocyte ratio (LNR), and the platelet-lymphocyte ratio (PLR). To determine the variables associated with mortality, univariate and multivariate Cox regression (step-wise type) analysis was performed. Kaplan-Meier and log-rank test were used for survival analysis. Outcomes with a p-value <0.05 were considered statistically significant.Results: We identified 1,375 patients with DLBCL; 503 were identified as early stage DLBCL of whom 498 had sufficient data for analysis. Almost all cases (n=483, 96%) had nodal disease as the primary site, and 15 (4%) extranodal, all within the gastrointestinal tract. There was a slight female predominance (51.8%). The median age at diagnosis was 64 (IQR: 50 -73) with 57.4% older than >65 years. ECOG performance status of <2 was seen in 77.2% of cases; elevated serum LDH in 32.4%; and elevated serum beta-2-microglobulin in 5.6% (n=11/192). Based on previous data, we evaluated and calculated variables that have been suggested as independent negative prognostic factors for overall survival; the proportion of patients with serum albumin <3.5 mg/dL; LMR <2, NLR >4, and PLR >376 was 34.4%, 10.3%, 9.2%, and 4.7% respectively. With a median follow-up of 45 months, the median 5-year overall survival (OS) rate was 72%. The therapy approaches used, response rates and outcomes with these approaches will be presented at the meeting. Results of the univariate and multivariate analysis are summarized in Table 1. We found that age over 65, ECOG performance status, serum albumin level, beta-2-microglobulin level, LDH ratio, LMR, NLR, PLR, and BCL-2 positivity by immunohistochemistry (IHC) were prognostic factors for OS in the univariate analysis. However, in the multivariate analysis, only NLR, serum albumin level and ECOG performance status were independent factor for worse prognosis. Survival rates were significantly shorter in patients with serum albumin <3.5 g/dL (5-year OS of 49% versus 79%, respectively; p<0.0001); NLR >4 (5-year OS of 46% versus 73%, respectively: p=0.0013); and ECOG performance status ≥2 (5-year OS of 51% versus 74%, respectively; p<0.0001) (Figures 1 to 3).Conclusion: In this large cohort of Latin American patients with early stage DLBCL most patients were older than 65, had nodal disease as the primary site, good performance status, with only a third of patients exhibiting elevated LDH. Moreover, we found serum albumin <3.5 g/dL, NLR >4 and ECOG ≥2 as negative prognostic factors for poor survival in early stage DLBCL. We are currently validating our findings in a prospective cohort of Latin American DLBCL patients and to improve clinical decision-making in those deemed at high-risk for early mortality. [Display omitted] DisclosuresOtero: Astra Zeneca: Current Employment. Oliver: Roche: Other: conference support and fees ; Abbvie: Other: conference support and fees . Castillo: Abbvie: Consultancy, Research Funding; BeiGene: Consultancy, Research Funding; Pharmacyclics: Consultancy, Research Funding; Janssen: Consultancy; Roche: Consultancy; TG Therapeutics: Research Funding.

Treatment Outcomes of Consolidative Radiation in Extranodal Early-Stage Diffuse Large B-Cell Lymphoma

IntroductionDiffuse large B-cell lymphoma (DLBCL) is the most common subtype of Non-Hodgkin Lymphoma, with approximately 25-30% of patients presenting as early or limited-stage (stage I and II). Though treatment with chemoimmunotherapy is standard of care, the role of consolidative radiotherapy (RT) in limited-stage (LS) patients is not well defined. Recent studies have attempted to shorten chemotherapy courses and eliminate RT for LS patients. Additionally, recent single institutional data has suggested LS patients with extranodal (EN) disease may have better outcomes if treated with RT. We aimed to investigate whether the addition of RT provided a survival benefit in early-stage DLBCL patients based on primary site at presentation comparing nodal to EN disease.MethodsThe National Cancer Database was utilized to identify patients diagnosed with LS-DLBCL from 2004 to 2015. Only patients treated with multiagent chemotherapy were included. Patients with international prognostic index (IPI) score available were separated into low (0-1 factors) or high-risk (2-4) groups. Landmark analysis was performed to exclude patients with last contact, including death, within 12 months of diagnosis. Kaplan-Meier survival analysis was used to compare overall survival (OS). Cox regression analysis was used to identify hazard ratios for survival using RT between subgroups.ResultsOf the 39,745 LS patients identified, 62.9% had nodal disease and 37.1% had EN disease with stage I disease accounting for 51.5% of patients. Only 6,628 patients had reported IPI scores with the majority having low-risk IPI (69.2%). Compared to patients with only nodal disease, patients with EN involvement were more likely to receive consolidative RT (42.9% vs 37.2%; p<0.05). EN patients were most likely to receive RT with primary bone (67.7% of 1526 patients), skin/soft tissue (60.3% of 1353), breast (58.6% of 652), testes (58.4% of 950) and thyroid (56.6% of 1059) involvement (all p<0.05). GI (18.1% of 4652) and lung (23.3% of 614) primaries were least likely to receive RT (p<0.05). With a median follow up of 58.8 months, the addition of RT was associated with improved 5-year OS for all LS patients as compared to those treated with chemotherapy alone (68 vs. 62%, p<0.001). While RT was associated with improved 5-year OS in both the nodal and EN disease patients, nodal patients had a greater benefit of receiving RT as compared to EN patients (nodal: 71% vs. 63%, p<0.001; EN: 64% vs. 62%; p<0.001). Specifically, in EN patients, the addition of RT significantly increased 5-year OS for skin/soft tissue (60% vs. 57%, p<.001), head and neck (63% vs. 60%, p<0.02), testicular (63% vs. 45%, p<.001), and thyroid sites (73% vs. 67%, p <0.02). Furthermore, RT slightly improved 5-year OS outcomes for patients with both low-risk (75% vs. 73%; p<0.01) and high-risk IPI (52% vs. 50%; p<0.04). On multivariate analysis, adjusting for age, stage, and Charlson-Deyo comorbidity score, the addition of RT was an independent factor for improved survival for all LS patients (Hazard Ratio [HR] 0.84, 95% Confidence Interval [CI] 0.81-0.88; p<0.001) along with EN sites of skin/soft tissue (HR 0.72, 95% CI 0.58-0.88; p<0.01), testicle (HR 0.70, 95% CI 0.54-0.90, p<0.01) and thyroid (HR 0.68, 95% CI 0.51-0.90; p<0.01). No significant survival differences were observed in patients with EN involvement of the lung, bone, breast, or GI tract when RT was added to their treatment.ConclusionsWe report the largest retrospective study on EN outcomes utilizing consolidative RT in early-stage DLBCL. Though there is no consensus on optimal treatment indications for RT in LS-DLBCL, this data shows improved OS in both nodal only disease and within specific EN disease subgroups when RT is added to front-line chemotherapy. As recent studies have attempted to shorten chemotherapy cycles and limit the use of RT, these results suggest caution against omission of RT in select patients. [Display omitted] DisclosuresShah: AstraZeneca: Research Funding; Seattle Genetics: Research Funding; Epizyme: Research Funding. Stephens: TG Therapeutics: Membership on an entity's Board of Directors or advisory committees; Novartis: Research Funding; Abbvie: Consultancy; JUNO: Research Funding; Innate Pharma: Membership on an entity's Board of Directors or advisory committees; Adaptive: Membership on an entity's Board of Directors or advisory committees; Arqule: Research Funding; Mingsight: Research Funding; Beigene: Membership on an entity's Board of Directors or advisory committees; Epizyme: Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Consultancy; CSL Behring: Consultancy; Celgene: Consultancy; Karyopharm: Membership on an entity's Board of Directors or advisory committees, Research Funding.

Updates in the Management of Early-Stage Diffuse Large B-Cell Lymphoma

Several important updates have emerged in the management of early-stage diffuse large B-cell lymphoma. Three trials resulted in the approval of rituximab + cyclophosphamide/doxorubicin/vincristine/prednisone (R-CHOP) for use in these patients internationally. Furthermore, studies have been initiated to determine whether 4 or 6 cycles of this regimen should be administered without radiation therapy (RT). Six cycles of R-CHOP plus central nervous system (CNS) prophylaxis and prophylactic testicular RT are recommended for patients with extranodal disease occupying the testicles. Although controversial, there is a reasonable consensus in the literature to consider 6 cycles of R-CHOP plus involved-site RT and CNS prophylaxis for patients with extranodal disease of the breast. Patients with primary bone and gastric extranodal disease do not seem to derive a significant survival benefit from RT. Molecular subtype evaluations may change treatment approaches.

Treatment Outcomes of Consolidative Radiation in Extranodal Early-Stage Diffuse Large B-Cell Lymphoma

By Daniel A. Ermann, Victoria A. Vardell & 5 more. Whether the addition of RT provided a survival benefit in early-stage DLBCL patients based on primary site at presentation comparing nodal to EN disease.

HGAL inhibits lymphoma dissemination by interacting with multiple cytoskeletal proteins

AbstractHuman germinal center–associated lymphoma (HGAL) is an adaptor protein specifically expressed in germinal center lymphocytes. High expression of HGAL is a predictor of prolonged survival of diffuse large B-cell lymphoma (DLBCL) and classic Hodgkin lymphoma. Furthermore, HGAL expression is associated with early-stage DLBCL, thus potentially limiting lymphoma dissemination. In our previous studies, we demonstrated that HGAL regulates B-cell receptor signaling and cell motility in vitro and deciphered some molecular mechanisms underlying these effects. By using novel animal models for in vivo DLBCL dispersion, we demonstrate here that HGAL decreases lymphoma dissemination and prolongs survival. Furthermore, by using an unbiased proteomic approach, we demonstrate that HGAL may interact with multiple cytoskeletal proteins thereby implicating a multiplicity of effects in regulating lymphoma motility and spread. Specifically, we show that HGAL interacts with tubulin, and this interaction may also contribute to HGAL effects on cell motility. These findings recapitulate previous observations in humans, establish the role of HGAL in dissemination of lymphoma in vivo, and explain improved survival of patients with HGAL-expressing lymphomas.

Prognostication of Primary Tumor Location in Early-Stage Nodal Diffuse Large B-Cell Lymphoma: An Analysis of the SEER Database.

Simple SummaryFew studies have examined the impact of primary tumor location on clinical outcome in patients with early-stage nodal diffuse large B-cell lymphoma (DLBCL). The objective of this study was to identify the association between primary tumor location and early-stage nodal DLBCL patient prognosis using a large population-based cohort and make an effort to uncover its underlying molecular mechanism using a public database. Our result shows that the prognosis of early-stage nodal DLBCL patients with tumors growing under the diaphragm is poorer. After screening DEGs and carrying out enrichment analysis, we found early-stage nodal diffuse large B-cell lymphoma located in different sites having different genetic characteristics. These results emphasize the importance of the primary tumor site on clinical decision-making and prognosis of patients with early-stage nodal diffuse large B-cell lymphoma.The prognostic role of primary tumor location for clinical outcomes of patients with early-stage nodal diffuse large B-cell lymphoma (DLBCL) remains uncertain. We evaluated the relationship between primary tumor site and overall survival (OS) in 9738 early-stage nodal DLBCL patients from the Surveillance, Epidemiology, and End Results (SEER) database. The primary site of the tumors was characterized as supradiaphragm and subdiaphragm according to the definition of lymph node distribution in the Ann Arbor staging. The OS was significantly better for patients of the supradiaphragm group (n = 6038) compared to the ones from the subdiaphragm group (n = 3655) (hazard ratio (HR) 1.24; 95%CI: 1.16–1.33; P < 0.001), and it was preserved after propensity score matching (PSM) (HR 1.15; 95% CI: 1.07–1.24; P < 0.001). Gene enrichment analyses demonstrated that the subdiaphragm group has an upregulated extracellular matrix (ECM)-related signaling, which reportedly can promote growth, invasion, and metastasis of the cancer, and downregulated interferon response, which is considered to have anti-tumor function. Our results indicate the two tumor locations (supradiaphragm and subdiaphragm) presented different prognostic implications for the overall survival, suggesting that the tumor’s location could serve as a prognostic biomarker for early-stage nodal DLBCL patients.