Rituximab-based Immunochemotherapy Research Articles

Primary follicular lymphoma of the duodenum as an incidental finding on upper gastrointestinal endoscopy.

Primary follicular lymphoma of the duodenum (FLD) is a rare variant of follicular lymphoma (FL), which represents only 1-4% of gastrointestinal non-hodgkin lymphomas (NHL). It usually appears in the second portion of the duodenum as micronodular lesions and the diagnosis is often incidental. Unlike other NHLs, the prognosis is excellent and the treatment ranges from "watch and wait" to rituximab-based immunochemotherapy regimens, depending on the symptoms and the presence of systemic involvement.

CD79 Expression Is Associated with Cell-of-Origin and Outcome in Diffuse Large B-Cell Lymphoma

Introduction: CD79B is a target of polatuzumab vedotin, an antibody-drug conjugate, which significantly improved the prognosis of both previously untreated and relapsed/refractory patients with diffuse large B-cell lymphoma (DLBCL). However, the biological and clinical significance of CD79B protein and gene expression have not been fully explored in DLBCL, thus we aimed at examining these relationships. Methods: We retrospectively analyzed de novo DLBCL patients, who were diagnosed and received rituximab-based immunochemotherapy from 2008 through 2018 in the Okayama Hematology Study Group from Japan. Immunohistochemistry (IHC) staining was performed using a CD79B antibody (AT107-2), and protein expression was assessed based on H-score as described in a previous study (Sehn LH et al. JCO 2020), integrating with publicly available representative bulk RNA sequencing DLBCL datasets (BCC cohort from Ennishi D et al. JCO 2019 and NCI cohort from Schmitz R et al. NEJM 2018). We also performed CD8 and MHC class-I IHC to evaluate the tumor microenvironment. Gene expression profile-based cell-of-origin (COO) classification was performed including double-hit signature (DHITsig), recently renamed the dark zone signature (DZsig), using the NanoString DLBCL90 assay. In addition, simultaneous epitope and transcriptome measurement in single cells from lymphoid tissues was conducted. Results: CD79B IHC was evaluable in 576 cases. DLBCL90 assay classified the entire cohort into 293 ABC (50.9 %), 189 GCB (32.8 %), 31 DZsig-positive (5.4 %) and 63 unclassified (10.9 %). Furthermore, we dichotomized the cohort into 288 CD79B high cases and 288 CD79B low cases according to the median CD79B H-score. A dynamic range of CD79B protein expression was observed across COO, where ABC-DLBCL showed the lowest values followed by GCB-DLBCL and DZsig-positive-DLBCL, in ascending order (Kruskal-Wallis test, P < .00001; Figure A). Indeed, CD79B low cases were significantly enriched in ABC-DLBCL (58 %) compared to GCB-DLBCL (26 %) and DZsig-positive-DLBCL (2 %), respectively (Chi-squared test, P < .001). Consistently, we revealed that CD79B expression was the lowest in ABC-DLBCL compared to GCB-DLBCL and DZsig-positive-DLBCL at the transcriptomic level (Kruskal-Wallis test, P = .011 for BCC cohort and P = .022 for NCI cohort). In addition, we identified different CD79B staining patterns, composed of 433 with cytoplasmic pattern (75 %), 86 with membranous pattern (14.9 %), and 52 cases being IHC negative. These patterns significantly varied across COO (Fisher's exact test, P = .015) and CD79B H-score was the highest in the membranous pattern followed by the cytoplasmic pattern (Kruskal-Wallis test, P < .0001). Of note, the composition of CD8 positive T-cells in CD79B low tumors was significantly higher than that of CD79B high tumors (Wilcoxon rank sum test, P < .0001). However, MHC class-I expression was decreased in CD79B low cases compared to CD79B high (Wilcoxon rank sum test, P = .0002), suggesting an immune escape mechanism with downregulation of MHC class-I in the presence of cytotoxic T-cells, which is often seen in solid cancers. Significant association of CD79B expression with COO further prompted us to evaluate CD79B expression in normal germinal center B cells. Notably, the single-cell simultaneous epitope and transcriptome analysis (CITEseq, n = 2) and single-cell RNAseq analysis (n = 6) of reactive lymph nodes revealed that both CD79B gene and protein expression were the lowest in cells exhibiting plasmablastic signatures, followed by light zone and dark zone B cells (Kruskal-Wallis test, P < .0001; Figure B), supporting the relation of CD79B expression to COO subtype in DLBCL. Regarding prognostic impact, CD79B low group had significantly poorer prognosis in the entire DLBCL cohort (Log-rank test, P = .0005 for overall survival (OS) and P = .008 for progression-free survival (PFS)) and in ABC-DLBCL (Log-rank test, P = .003 for OS and P = .031 for PFS). Moreover, CD79B protein expression was significantly associated with OS after adjusting for International Prognostic Index in the entire DLBCL cohort (Cox regression model; P = .035). Conclusion: Our study identifies distinct CD79B expression patterns across COO subtypes, with CD79B low cases enriched in ABC-DLBCL and demonstrating poorer prognosis, suggesting its potential as a prognostic marker and for targeted therapies.

Clinicopathological analysis of diffuse large B-cell lymphoma using molecular biomarkers: a retrospective analysis from 7 Hungarian centers.

The clinical and genetic heterogeneity of diffuse large B-cell lymphoma (DLBCL) presents distinct challenges in predicting response to therapy and overall prognosis. The main objective of this study was to assess the application of the immunohistochemistry- and interphase fluorescence in situ hybridization (FISH)-based molecular markers in the diagnosis of DLBCL and its prognostic value in patients treated with rituximab-based immunochemotherapy. This is a multicenter, retrospective study, which analyzed data from 7 Hungarian hematology centers. Eligible patients were adults, had a histologically confirmed diagnosis of DLBCL, were treated with rituximab-based immunochemotherapy in the first line, and had available clinicopathological data including International Prognostic Index (IPI). On the specimens, immunohistochemistry and FISH methods were performed. Germinal center B-cell like (GCB) and non-GCB subtypes were classified by the Hans algorithm. Outcomes included overall survival (OS), event-free survival (EFS), and EFS at 2 years (EFS24). For survival analysis, we used Kaplan-Meier curves with the log-rank test and multivariate Cox regression. A total of 247 DLBCL cases were included. Cases were positive for MYC, BCL2, BCL6, and MUM1 expression in 52.1%, 66.2%, 72.6%, and 77.8%, respectively. BCL6 translocation, BCL2 gene copy number (GCN) gain, IGH::MYC translocation, MYC GCN gain, IGH::BCL2 translocation, and BCL6 GCN gain were detected in 21.4%, 14.1%, 7.3%, 1.8%, 7.3%, and 0.9%, respectively. At a median follow-up of 52 months, 140 patients (56.7%) had disease progression or relapse. The Kaplan-Meier estimate for EFS24 was 56.2% (CI: 50.4-62.8%). In univariate analysis, only IPI and BCL6 expression were significant predictors of both OS and EFS, whereas MUM1 predicted EFS only. In multivariate analysis, the IPI score was a significant independent negative, whereas MIB-1 and BCL6 protein expressions were significant independent positive predictors of both OS and EFS. In our study, we found that only IPI, BCL6 protein expression and MIB-1 protein expression are independent predictors of survival outcomes in DLBCL. We did not find any difference in survival by GCB vs. non-GCB subtypes. These findings may improve prognostication in DLBCL and can contribute to designing further research in the area.

Obinutuzumab Versus Rituximab Immunochemotherapy in Previously Untreated iNHL: Final Results From the GALLIUM Study

The phase III GALLIUM trial assessed the safety and efficacy of obinutuzumab-based versus rituximab-based immunochemotherapy in patients with previously untreated follicular lymphoma (FL) or marginal zone lymphoma (MZL). At the primary analysis, the trial met its primary end point, demonstrating improvement in investigator-assessed progression-free survival (PFS) with obinutuzumab-based versus rituximab-based immunochemotherapy in patients with FL. We report the results of the final analysis in the FL population, with an additional exploratory analysis in the MZL subgroup. Overall, 1202 patients with FL were randomized 1:1 to obinutuzumab- or rituximab-based immunochemotherapy followed by maintenance with the same antibody for up to 2 years. After a median 7.9 (range, 0.0–9.8) years of follow-up, PFS remained improved with obinutuzumab- versus rituximab-based immunochemotherapy, with 7-year PFS rates of 63.4% versus 55.7% (P = 0.006). Time-to-next antilymphoma treatment was also improved (74.1% versus 65.4% of patients had not started their next antilymphoma treatment at 7 y; P = 0.001). Overall survival was similar between the arms (88.5% versus 87.2%; P = 0.36). Irrespective of the treatment received, PFS and OS were higher in patients with a complete molecular response (CMR) versus those with no CMR (P < 0.001). Serious adverse events were reported in 48.9% and 43.4% of patients in the obinutuzumab and rituximab arms, respectively; there was no difference in the rate of fatal adverse events (4.4% and 4.5%, respectively). No new safety signals were reported. These data demonstrate the long-term benefit of obinutuzumab-based immunochemotherapy and confirm its role as a standard-of-care for the first-line treatment of advanced-stage FL, taking into account patient characteristics and safety considerations.

17th International Conference on Malignant Lymphoma, Palazzo dei Congressi, Lugano, Switzerland, 13 - 17 June, 2023.

Introduction: MZL is a heterogeneous disease comprising 3 subtypes, extra-nodal MZL of mucosa-associated lymphoid tissue, nodal MZL, and splenic MZL. Treatment of R/R MZL is similar to other indolent B-cell non-Hodgkin lymphoma (B-NHL) subtypes (e.g., follicular lymphoma [FL]), comprising rituximab-based immunochemotherapy regimens that achieve an objective response rate (ORR) of ∼45%–80%. Options after progression on rituximab-based regimens include the BTK inhibitor ibrutinib, which demonstrated an ORR of 46%, but a compete response (CR) rate of only 3%, in its pivotal trial in R/R MZL. Overall, limited options are available after progression on current therapies, and a need remains for more effective treatments for R/R MZL. Odronextamab is a bispecific antibody that binds CD20-expressing B-NHL cells and CD3 on T cells. In the Phase 1 ELM-1 study, odronextamab monotherapy showed antitumor activity and a manageable safety profile in a range of R/R B-NHL subtypes, including MZL (n = 6; ORR 67%) (Bannerji et al. Lancet Haematol, 2022). In the Phase 2 ELM-2 study, odronextamab elicited an ORR of 82% and CR rate of 75% in patients with heavily pretreated R/R FL (Kim, et al. ASH, 2022). These positive data in an indolent B-NHL subtype support evaluation of odronextamab in R/R MZL. Methods: ELM-2 (NCT03888105) is an open-label study of odronextamab in patients with R/R B-NHL comprising 5 disease-specific cohorts: FL, diffuse large B-cell lymphoma, mantle cell lymphoma, MZL, and other B-NHLs. Each cohort will be evaluated separately, and patients recruited from sites across North America, Europe, and Asia-Pacific regions. The MZL cohort is planned to include 78 patients, who will receive IV odronextamab monotherapy until disease progression or other protocol-defined reason for treatment discontinuation. Odronextamab is administered according to a step-up regimen during the first 21-day cycle (C), consisting of 0.7 mg split over C1 Day (D) 1 (0.2 mg) and C1D2 (0.5 mg), 4 mg split over C1D8 and C1D9, and 20 mg split over C1D15 and C1D16. The full 80 mg dose is given QW during C2 to C4, then 160 mg Q2W from C5 onwards. If a patient achieves a CR and has a durable response for ≥9 months after initial determination of the CR, then dosing interval will be decreased from Q2W to Q4W. Patients eligible for the MZL cohort will be ≥18 years of age; relapsed/refractory to ≥2 prior lines of systemic therapy; ECOG performance status ≤1; and have adequate bone marrow and hepatic functions. Patients with prior allogeneic stem cell transplant or CAR T treatment will be excluded. Primary endpoint is ORR (Lugano classification; assessed by independent central review). Key secondary endpoints include ORR (investigator evaluation); CR rate; progression-free survival; overall survival; duration of response; safety; pharmacokinetics; and patient-reported quality of life outcomes. As of January 2023, 19 patients with MZL had enrolled. Encore Abstract—previously submitted to ASCO 2023 and EHA 2023 The research was funded by: Regeneron Pharmaceuticals, Inc. Keywords: indolent non-Hodgkin lymphoma, immunotherapy, ongoing trials Conflicts of interests pertinent to the abstract. T. M. Kim Consultant or advisory role Boryung, AstraZeneca/MedImmune, Takeda, Novartis, Janssen, Hanmi, and Regeneron Pharmaceuticals, Inc Honoraria: Takeda, Janssen, Regeneron Pharmaceuticals, Inc, Samsung Bioepis, and AstraZeneca Research funding: Celgene, Boryung, Boehringer-Ingelheim, BMS, Bayer, AstraZeneca/MedImmune, Takeda, Roche/Genentech, Novartis, Janssen, Hanmi, Genmab, Merck Serono, Merck Sharp & Dohme, Regeneron Pharmaceuticals, Inc, and Sanofi M. Taszner Consultant or advisory role Roche and Takeda Honoraria: Roche, Takeda, Novartis, and Servier Educational grants: Roche A. Chaudhry Employment or leadership position: Regeneron Pharmaceuticals, Inc Stock ownership: Regeneron Pharmaceuticals, Inc M. Ufkin Employment or leadership position: Regeneron Pharmaceuticals, Inc Stock ownership: Regeneron Pharmaceuticals, Inc A. Uppala Employment or leadership position: Regeneron Pharmaceuticals, Inc Stock ownership: Regeneron Pharmaceuticals, Inc A. Sabir Employment or leadership position: Regeneron Pharmaceuticals, Inc Stock ownership: Regeneron Pharmaceuticals, Inc H. Mohamed Employment or leadership position: Regeneron Pharmaceuticals, Inc Stock ownership: Regeneron Pharmaceuticals, Inc S. Ambati Employment or leadership position: Regeneron Pharmaceuticals, Inc Stock ownership: Regeneron Pharmaceuticals, Inc E. Bachy Consultant or advisory role Roche, Gilead, ADC Therapeutics, Takeda, Novartis, and Incyte Honoraria: Kite, Gilead, Novartis, Roche, Incyte, Miltenyi Biotech, Takeda, and Sanofi Research funding: Amgen and BMS

17th International Conference on Malignant Lymphoma, Palazzo dei Congressi, Lugano, Switzerland, 13 - 17 June, 2023.

Introduction: CD79B is a target of polatuzumab vedotin, an antibody–drug conjugate, which may improve the prognosis of both previously untreated and relapsed/refractory patients with diffuse large B-cell lymphoma (DLBCL). However, the biological and clinical significance of CD79B protein and gene expression in DLBCL is largely unknown. Methods: We retrospectively analyzed de novo DLBCL patients, who were diagnosed and received rituximab-based immunochemotherapy from 2008 through 2018 in the Okayama Hematology Study Group from Japan. Immunohistochemistry (IHC) staining was performed using a CD79B antibody (AT107-2), and protein expression was assessed based on H-score according to a previous study (Sehn L et al. JCO 2020). We also performed gene expression profile-based cell-of-origin (COO) classification, including double-hit signature (DHITsig) which has been renamed to dark zone signature (DZsig) (Waleed A et al. Blood 2022), using the NanoString DLBCL90 assay. Results: CD79B IHC expression was evaluable in 602 cases. We idefined two groups according to median H-score of CD79B expression: CD79Bhigh and CD79Blow. The COO subtypes were assigned as follows: 308 patients (51%) with activated B-cell-like (ABC)-DLBCL, 196 (33%) with germinal center B-cell-like (GCB)-DLBCL, 32 (5%) with DZsig-pos DLBCL and 66 (11%) with unclassified (UNC). H-score of CD79B was the lowest in patients with ABC-DLBCL followed by GCB-DLBCL and DZsig-pos DLBCL in ascending order (Kruskal–Wallis test P < .00001; Figure A). Indeed, CD79Blow tumors were significantly enriched in ABC-DLBCL (57%) compared to GCB-DLBCL (40%) and DZsig-pos DLBCL (22%), respectively (both, P < .001). Consistently, using publicly available DLBCL datasets (Schmitz et al. NEJM 2018 and Ennishi et al. JCO 2019), we revealed that CD79B gene expression was the lowest in ABC-DLBCL compared to GCB- and DHITsig-DLBCL (Kruskal–Wallis test P = .01; Figure B and C). The association of CD79B expression with COO prompted us to evaluate CD79B expression in normal germinal center B cells. Notably single-cell transcriptomic analyses of six reactive lymphoid tissues from publicly available datasets revealed that the lowest expression of CD79B was found in plasmablasts followed by light zone B cells and dark zone B cells in ascending order (Kruskal–Wallis test P < .0001), supporting the differential expression of CD79Baccording to COO subtype. CD79Blow group had significantly shorter overall survival (OS) in the total DLBCL cohort (log-rank, P < .001) and within ABC-DLBCL (P = .001, Figure D and E). Moreover, CD79B protein expression was significantly associated with OS after adjusting for International Prognostic Index in the total cohort (Cox regression model; P< .001). Keywords: Aggressive B-cell non-Hodgkin lymphoma, Diagnostic and Prognostic Biomarkers Conflicts of interests pertinent to the abstract. K. Sunami Honoraria: Celgene, Sanofi, BMS, Ono, Janssen Research funding: Takeda, AbbVie, GSK, Chugai, Otsuka, MSD, Novartis, Astellas Amgen, Pfizer, Parexel, Kyowa Kirin, Symbio, Agios Y. Hiramatsu Honoraria: Chugai Pharmaceutical Co, Nippon Shinyaku Co, Bristol Myers Squibb, Sanofi K.K. I. Yoshida Honoraria: Kyowa Kirin, Chugai, Eisai, Jannsen, Nippon-shinyaku, Otsuka, Symbio, Takeda, Sumitomo Pharma, Meiji Research funding: Kyowa Kirin, Chugai Y. Maeda Research funding: Chugai, Nippon-shinyaku Other remuneration: Chugai, Eisai, Otsuka, Kyowa Kirin, Takeda D. W. Scott Consultant or advisory role: Abbvie, AstraZeneca, Janssen, Incyte Honoraria: AstraZeneca Research funding: Janssen, Roche/Genentech D. Ennishi Honoraria: Chugai, Eisai, Kyowa Kirin Research funding: Nipponshinyaku, Chugai

Reverse effect of Semaphorin-3F on rituximab resistance in diffuse large B-cell lymphoma via the Hippo pathway.

Exploring the underlying mechanism of rituximab resistance is critical to improve the outcomes of patients with diffuse large B-cell lymphoma (DLBCL). Here, we tried to identify the effects of the axon guidance factor semaphorin-3F (SEMA3F) on rituximab resistance as well as its therapeutic value in DLBCL. The effects of SEMA3F on the treatment response to rituximab were investigated by gain- or loss-of-function experiments. The role of the Hippo pathway in SEMA3F-mediated activity was explored. A xenograft mouse model generated by SEMA3F knockdown in cells was used to evaluate rituximab sensitivity and combined therapeutic effects. The prognostic value of SEMA3F and TAZ (WW domain-containing transcription regulator protein 1) was examined in the Gene Expression Omnibus (GEO) database and human DLBCL specimens. We found that loss of SEMA3F was related to a poor prognosis in patients who received rituximab-based immunochemotherapy instead of chemotherapy regimen. Knockdown of SEMA3F significantly repressed the expression of CD20 and reduced the proapoptotic activity and complement-dependent cytotoxicity (CDC) activity induced by rituximab. We further demonstrated that the Hippo pathway was involved in the SEMA3F-mediated regulation of CD20. Knockdown of SEMA3F expression induced the nuclear accumulation of TAZ and inhibited CD20 transcriptional levels via direct binding of the transcription factor TEAD2 and the CD20 promoter. Moreover, in patients with DLBCL, SEMA3F expression was negatively correlated with TAZ, and patients with SEMA3F low TAZ high had a limited benefit from a rituximab-based strategy. Specifically, treatment of DLBCL cells with rituximab and a YAP/TAZ inhibitor showed promising therapeutic effects in vitro and in vivo . Our study thus defined a previously unknown mechanism of SEMA3F-mediated rituximab resistance through TAZ activation in DLBCL and identified potential therapeutic targets in patients.

Total Metabolic Tumor Volume Is Confirmed As Independent Prognostic Factor in Treatment Naïve Follicular Lymphoma Patients and Can be Combined with FLIPI2 to Improve Prognostic Accuracy. a FOLL12 Substudy By the Fondazione Italiana Linfomi

Aim/Introduction: The prognostic role of FDG PET/CT parameters before first line therapy in patients with Follicular Lymphoma (FL) remains unclear, with conflicting data published in the literature. To this end we evaluated the prognostic value of baseline Total Metabolic Tumor Volume (TMTV) in a large cohort of treatment-naïve FL patients enrolled in the FOLL12 trial (NCT02063685). Materials and Methods: FOLL12 is a multicenter, randomized, phase III trial that compared standard (Arm A) vs response adapted maintenance (Arm B) in patients with grade 1-3a advanced stage FL who achieved complete (CR) or partial response (PR) to induction rituximab based immunochemotherapy (R-ICT). In the current study we included patients for whom baseline FDG PET/CT was available and centrally reviewed. The TMTV was obtained by expert nuclear physicians from baseline scans by summing the metabolic volumes of all individual nodal and extra nodal lesions, using the 41% SUVmax threshold method. Univariate and multivariate analyses were performed using Cox proportional hazard model. Main study endpoint was Progression Free Survival (PFS). Results: starting from the FOLL12 trial population, 692/807 patients were included in this study; 48% were older than 60 years, 89% had stage III-IV disease and 40% had a high-risk FLIPI-2 score(3-5 risk factors). Overall, the 5-year PFS was 79% (95% CI, 76 to 82%) and the median TMTV was 242 mL (IQR=446). The optimal cutoff identified for TMTV was 200ml. TMTV values were higher in association with unfavorable prognostic features (Hb <12 g/dl, LoDLIN > 6cm, elevated beta2 microglobulin and LDH, and number of nodal areas >4) whereas were similar between study arms, and ICT regimens. In univariate analysis, 5-year PFS was significantly lower for patients with high vs low TMTV (60% vs 75%; HR=1.87 [95%CI: 1.41-2.49], p<0.001). The correlation between TMTV and PFS was confirmed both in the standard maintenance arm and in the response adapted arm of the FOLL12 trial and the independent prognostic role of TMTV was confirmed when adjusted by study arm, FLIPI-2, and type of ICT. In multivariate analysis, high TMTV (HR 1.47 (1.09 - 2.00); p=0.012) and high risk FLIPI2 (3-5 RFs: HR2.05 (1.54 - 2.73) p<0.001) retained their independent prognostic role for predicting PFS. Three groups of patients were identified which were associated with different 5-year PFS rates; TMTV < 200ml and intermediate FLIPI2: N=241 (35%), 5yr PFS 78% (95% CI 71-83); TMTV > 200ml or high risk FLIPI2: N=237 (34%), 5yr PFS 68% (60-74), HR 1.53 (1.06 - 2.22); TMTV >200ml and high risk FLIPI2: N=214 (31%) 5-yr PFS 51% (43-58), HR 2.96 (2.10-4.19). The combined TMTV + FLIPI2 model was internally validated with 1000 bootstrap resampling (c-Harrel 0.616) Conclusion: Pre-treatment TMTV is confirmed as a strong independent predictor of PFS in patients with FL receiving frontline R-based ICT The combination of TMTV and FLIPI2 may contribute to improve risk stratification in guiding risk adapted therapy. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Rituximab Maintenance Benefits Less for Follicular Lymphoma Patients with Low Risk of the Follicular Lymphoma International Index

Background Follicular lymphoma (FL) is an incurable indolent disease with a heterogeneous course. The Follicular Lymphoma International Prognostic Index (FLIPI) is the most commonly used prognostic system to predict survival. Rituximab-based immunochemotherapy is now the standard choice for the first-line therapy of FL, followed by rituximab maintenance (RM) in patients with response, which prolongs the progression-free survival (PFS). However, the role of RM in different FLIPI risk groups has never been studied as we know. In this study, we aimed to illustrate the effect of RM in FLIPI risk groups.Methods Newly diagnosed FL patients at our center were enrolled in this analysis. All the patients received the rituximab-based chemoimmunotherapy induction regimens. Response assessments were determined according to Lugano's 2014 criteria. Patients who didn't respond to induction were excluded. Categorical variables were compared using Fisher's exact test. Overall survival (OS) and progression-free survival (PFS) were estimated using the Kaplan-Meier method and compared with the log-rank test.Results From May 2003 to September 2020, 203 newly diagnosed FL were included. 192 patients (95.0%) achieved remission (complete response, CR/partial response, PR) after immunochemotherapy induction, of whom 96 patients continued rituximab maintenance therapies every 3 months for 1-2 years (RM group) (median 7 times，range 4 to 12). 96 patients received no maintenance or fewer than 4 times (control group) (median 0 times, range 0-3). There were no significant differences in baseline characteristics other than the Ann Arbor stage and pathological grade. The RM group patients were more likely to be at low grade (71.8% vs 54.9%, P = 0.042) and advanced stage (90.6% vs 78.7% , P = 0.027) (Table 1). After a median follow-up of 36.4 months (95% confidence interval [CI], 32.2 to 40.6), median OS and PFS were not reached. The 5-year OS rates and PFS rates were 95.1% (95%CI, 90.2%-100%) and 83.0% (95%CI, 75%-91%)(Fig 1). And RM significantly prolonged the PFS, with 5-year PFS rates 92.2% (95%CI, 85.1%-99.3%) and 70.3%(95%CI, 55%-85.6%) (P = 0.0003) (Fig 2). According to FLIPI risk stratification, patients were classified into low-risk, intermediate-risk, and high-risk groups. The 5-year PFS rates were 97.7% (95%CI, 93.2%-100%), 84.7% (95%CI, 70.4%-99%), and 67.8% (95%CI, 49%-86.6%), respectively (Fig 3). For low-risk patients, there was no significant difference in PFS for the RM group vs the control group. However, for both intermediate risk and high-risk patients, PFS was significantly longer in the RM group compared to the control group (P < 0.0001). The PFS rates at 5 years in intermediate-risk patients were 100% and 77.8% (95%CI, 40.8%-92.6%), for the RM group vs control group, high risk 76.4% (95%CI, 54.3%-98.5%), and 54.9% (95%CI, 21.6%-88.2%), respectively (Fig 4).Conclusion Standard rituximab maintenance significantly prolongs progression-free survival in FLIPI intermediate risk and high-risk patients with FL, but not in the FLIPI low risk group. [Display omitted] DisclosuresWang: AbbVie: Consultancy; Astellas Pharma, Inc.: Research Funding.

The prognostic value of end-of-treatment FDG-PET/CT in diffuse large B cell lymphoma: comparison of visual Deauville criteria and a lesion-to-liver SUVmax ratio-based evaluation system.

The aim of this study was to determine a better criterion for end-of-treatment PET (EoT-PET) assessment and prognostic evaluation of patients with diffuse large B cell lymphoma (DLBCL). EoT-PET scans were assessed using the visual Deauville 5-point scale (5PS) and LLR, the maximum standard uptake value ratio between the lesion and the liver. The cutoff value of LLR was obtained by receiver operator characteristic curve analysis. Patient outcomes were compared using Kaplan-Meier survival analysis. Prognostic indexes of different criteria were compared. Multivariate Cox regression analysis was performed to evaluate the prognostic factors. Four hundred forty-nine newly diagnosed DLBCL patients who received rituximab-based immunochemotherapy were included, and the median follow-up duration was 41.4months. Patients with Deauville score (DS) 4 displayed significantly longer PFS and OS compared with patients with DS 5 (both p < 0.001), and they had significantly shorter PFS (p < 0.01) but similar OS (p = 0.057) compared with patients with DS 1-3. The differences in PFS and OS between groups were all significant whether positive EoT-PET was defined as DS 4-5 or DS 5 (all p < 0.001). The optimal cutoff of LLR was 1.83, and both PFS and OS were significantly different between EoT-PET-positive and EoT-PET-negative patients as defined by the cutoff (both p < 0.001). LLR-based criterion displayed higher specificity, positive predictive value, and accuracy than 5PS-based criterion in the prediction of disease progression and death events. In the multivariate analysis, positive EoT-PET (as defined by LLR) was related to unfavorable PFS and OS (both p < 0.001). Additional treatment was not correlated with outcomes of EoT-PET-negative patients either defined by LLR or 5PS or EoT-PET-positive patients classified by 5PS, but it was the only beneficial factor for OS (p < 0.05) in EoT-PET-positive patients with LLR ≥ 1.83. The optimal cutoff of LLR may be superior to Deauville criteria in identifying low-risk DLBCL patients with negative EoT-PET after the first-line immunochemotherapy and sparing them the cost and toxicity of additional treatment.

Real-World Patterns of Care for Patients with Follicular Lymphoma Treated with Lenalidomide and Rituximab (R2) in the US Medicare Population

Introduction: Follicular lymphoma (FL) is the most common indolent lymphoma and the second most common subtype of non-Hodgkin lymphoma (NHL). While rituximab-based immunochemotherapy remains a standard in front-line and relapsed FL settings, novel therapies hold the potential for chemotherapy-free treatment and may offer particular clinical benefit in the subgroup of patients with early relapse following immunochemotherapy. Rituximab with lenalidomide (R2) represents one such chemotherapy-free regimen currently in late-stage clinical trials for indolent lymphoma. While we await final reports from these ongoing trials, little is known about the current use of R2 in the routine care of patients with FL.M ethods: Our population-based cohort study utilized 100% Medicare claims data from January 2009 through December 2014. We selected a population of patients with FL (ICD-9: 202.0x) with at least one claim for rituximab during the identification period (January 1, 2010 through October 31, 2014). We then identified the subgroup of patients who received R2 by requiring claims for at least two consecutive cycles of lenalidomide and rituximab. The first prescription date for lenalidomide was defined as the index date. Patients were required to have continuous medical and pharmacy benefits for ≥ 12 months pre-index date (the baseline period), and ≥ 2 months post-index date (the follow-up period). Treatment discontinuation was defined as a gap in therapy of > 60 days. Patients initiating R2 within 90 days of a prior treatment were considered refractory to previous therapy. Patient demographics, clinical characteristics, and previous treatment regimens were recorded throughout the pre-index period. Patients receiving R2 were followed until the end of data availability.Results: Of 18,199 patients with FL receiving rituximab-based therapy during our study period, 226 (1.2%) were identified as receiving R2. The median age at the time of receiving R2 was 75 years (interquartile range [IQR] = 9 years); patients were mostly male (56.2%) and white (89.8%). Comorbid conditions at the initiation of R2 therapy were common, with a mean Charlson comorbidity index score of 5.1. Medical claims related to anemia (65.5%), chronic obstructive pulmonary disease (36.7%), and kidney dysfunction (30.5%) were the most prevalent comorbid conditions. The median time from the first identifiable FL claim until R2 initiation was 589 days (IQR = 895 days). Almost all patients (n = 224) showed evidence of previous FL-related treatment, with 39% showing evidence of at least two prior lines of treatment during the study period before initiating R2 therapy. A significant proportion of patients were refractory to their previous therapy (57.5%), and of those patients 35.3% were receiving R-chemotherapy, 26.2% were receiving rituximab monotherapy, and the remaining 38.5% were receiving other chemotherapy agent or regimens. The most frequent treatment regimens received in the pre-R2 period were rituximab monotherapy (42.5%), rituximab + bendamustine (38.9%), R-CHOP (rituximab + cyclophosphamide, doxorubicin, vincristine, and prednisone [24.4%]), and rituximab + cyclophosphamide (20.4%). Additionally, 26.1% of patients had prior radiotherapy use. The median treatment gap between previous FL therapy and R2 was 124 days (IQR = 293 days). The median duration of R2 therapy was 100 days (IQR = 99 days).Conclusions: In our large US population-based study of older patients with FL receiving therapy between 2009 and 2014, R2 therapy was used infrequently compared with rituximab monotherapy and standard immunochemotherapy. R2 was nearly exclusively administered in the relapsed setting, with almost half of patients receiving R2 immediately being refractory to other rituximab-based treatments. With claims through the end of 2014, our study does not account for the impact of other recently approved novel FL therapies. Overall, R2 therapy has historically been limited to the relapsed/refractory FL setting and future observational studies will be important to assess whether upcoming R2 trial results impact FL treatment and outcomes in the real-world setting. DisclosuresHuntington:Pharmacyclics: Honoraria; Janssen: Consultancy; Celgene: Consultancy, Other: Travel. Keshishian:Celgene: Other: Employee of STATinMED Research, which is a paid consultant to Celgene Corporation. Xie:Celgene: Other: Employee of STATinMED Research, which is a paid consultant for Celgene Corporation. Baser:Celgene: Other: Employee of STATinMED Research, which is a paid consultant for Celgene Corporation. McGuire:Celgene: Employment, Equity Ownership.

Phase III Clinical Trials in First-Line Follicular Lymphoma: A Review of Their Design and Interpretation.

Follicular lymphoma (FL) is one of the most common subtypes of non-Hodgkin lymphoma worldwide. Improved survival outcomes with rituximab-based therapy in clinical trials led to the establishment of rituximab-based immunochemotherapy as standard of care for first-line (1L) treatment of FL. In the GALLIUM trial, obinutuzumab-based immunochemotherapy demonstrated improved progression-free survival (PFS), prolonged time-to-next antilymphoma treatment (TTNT) and comparable overall survival (OS) compared with rituximab-based immunochemotherapy as 1L treatment for FL. Using GALLIUM as an example, this article aims to explain how improved outcomes in 1L treatment of FL have changed the landscape for the design and interpretation of future trials. As approved therapies for 1L FL already achieve good responses, it is becoming more difficult to design trials that demonstrate further treatment benefits with the currently accepted primary endpoints. New endpoints are needed to reflect the long remission times, low relapse rates, and impact of subsequent therapies in FL. PFS is used as a primary efficacy endpoint in registrational clinical trials for indolent malignancies like FL, where improvement in OS is not always observed due to the large number of patients and long study duration required to demonstrate a clear survival benefit. However, there are limitations to using PFS as the primary endpoint. Other potential endpoints, including TTNT, progression of disease within 2 years, response rate, and minimal residual disease status are explored.

Berberine exerts anti-tumor activity in diffuse large B-cell lymphoma by modulating c-myc/CD47 axis

Diffuse large B-cell lymphoma (DLBCL) is the most common subtype of non-Hodgkin lymphoma (NHL) with high clinical heterogeneity and poor prognosis. Immune escape mediated by CD47 overexpression contributes to the limited efficacy of rituximab, an anti-CD20 antibody, which indicates a target to improve the efficacy of DLBCL treatment. Here, we validated berberine, a natural compound, as a suppressor of CD47 and revealed the involved mechanism and biological function in DLBCL. Berberine downregulated the expression of CD47 in DLBCL at the transcriptional level by suppressing c-myc expression. Berberine-induced CD47 inhibition enhanced the phagocytosis of macrophages, thereby eliminating DLBCL cells in vitro and in vivo. Interestingly, berberine enhanced the efficiency of anti-CD47 antibody and rituximab-mediated phagocytosis. Moreover, a novel prognostic model based on the combination of CD47 and CD68, a biomarker of macrophages, was established in DLBCL. Our results highlighted for the first time that berberine could restore macrophage function in the tumor microenvironment, enhance rituximab-mediated phagocytosis and promote anti-CD47 antibody function via suppressing CD47 expression, which revealed a new anti-tumor mechanism of berberine and provided novel insights into the rituximab-based immunochemotherapy and CD47-targeted immunotherapy in DLBCL.

Outcomes in refractory diffuse large B‐cell lymphoma: results from a multicenter real‐world study in China

BackgroundDiffuse large B‐cell lymphoma (DLBCL) patients refractory to rituximab‐based immunochemotherapy have a dismal prognosis. However, the definition of refractory DLBCL remains inconsistent and no large cohort study data is available from Asian countries. To validate the definition and outcomes of refractory DLBCL in China, we conducted a multicenter, retrospective cohort study.MethodsThe REtrospective AnaLysis of Treatment REspoNse of refractory DLBCL (REAL‐TREND) study was performed using real‐world data from 8 centers in China. DLBCL patients with curative intent were included in the REAL‐TREND dataset. Overall survival (OS) was estimated using the Kaplan‐Meier method and compared by the log‐rank test. Due to heterogeneity in response rates among different centers, the response rates of refractory patients were pooled using random‐effect models. Multivariate survival analysis was performed using the Cox regression model.ResultsA total of 2778 DLBCL patients diagnosed between January, 2010 and December, 2015 were enrolled to this study. After validating previous definitions, the SCHOLAR‐1 study was most suitable to define refractory DLBCL. The estimated 5‐year cumulative incidence of refractory patients was 20% (95% confidence Interval [CI] = 18%‐22%). After the determination of refractory disease, overall response rate and complete remission rate were 30% (95% CI = 22%‐38%) and 9% (95% CI = 4%‐15%), respectively. Patients with either no response to immunochemotherapy or relapse within 12 months after stem‐cell transplantation had inferior survival with a median OS of 5.9 months (95% CI = 5.5‐7.1 months) and 2‐year OS rate of 16% (95% CI = 12%‐20%). International prognostic index score 4‐5 (hazard ratio [HR] = 2.22; 95% CI = 1.47‐3.35), central nervous system relapse (HR = 1.43; 95% CI = 1.04‐1.97), and best response status (HR = 2.68; 95% CI = 1.42‐5.03 for partial remission. HR = 5.97, 95% CI = 3.21‐11.11 for stable disease/progressive disease) were independent unfavorable prognostic factors.ConclusionsThis is the first large‐scale Asian cohort study focusing on outcomes of refractory DLBCL. The definition of the SCHOLAR‐1 study identifies patients with homogenously inferior survival, thus is appropriate to select refractory DLBCL. Due to poor clinical outcomes in the rituximab era, patients with refractory DLBCL may be potential candidates for novel treatment modalities.

Absolute Monocyte and Platelet Counts May Provide Additional Prognostic Information in Primary Gastric Diffuse Large B-cell Lymphoma Patients Treated with Rituximab and CHOP.

Primary gastric diffuse large B cell lymphoma (PG-DLBCL) is the most common histological subtype of primary gastric lymphoma. The standard of care of PG-DLBCL patients is the combination rituximab-based immunochemotherapy (R-CHOP). Re-cently, different host-related factors have been shown to have significant prognostic significance in non-Hodgkin lymphoma. However, data regarding their prognostic contribution to PG-DLBCL are limited. To assess the prognostic impact of a panel of simple, cost-effective laboratory variables which are easy to apply in routine labora-tory use for R-CHOP-treated PG-DLBCL patients in an attempt to identify those among them that are high-risk category. We retrospectively assessed the possible prognostic impact of different laboratory markers in 42 R-CHOP treated PG-DLBCL patients treated between 2004 and 2014 and followed at a single institution. The estimated 5-year overall (OS) and progression-free survival (PFS) of the whole group were 80.9% and 78%, respectively. The absolute monocyte and platelet counts in univariate analysis predicted PFS and OS when analyzed as continuous and dichotomized variables. On multivariate analysis performed with factors included in the stage-modified International Prognostic Index (m-IPI), the absolute monocyte and platelet counts remained independent predictors of PFS and OS. Therefore, the absolute monocyte and platelet counts were combined to generate a prognostic index that identified patients with an especially poor overall survival. This prognostic index was independent of the m-IPI and could provide additional prognostic information for better stratification of these patients.

Association of early disease progression and very poor survival in the GALLIUM study in follicular lymphoma: benefit of obinutuzumab in reducing the rate of early progression.

We evaluated early disease progression and its impact on overall survival (OS) in previously untreated follicular lymphoma patients in GALLIUM (clinicaltrials.gov identifier: 01332968), and investigated the effect on early disease progression of the two randomization arms: obinutuzumab-based versus rituximab-based immunochemotherapy. Cause-specific Cox regression was used to estimate the effect of treatment on the risk of disease progression or death due to disease progression within 24 months of randomization and to analyze OS in patients with or without disease progression after 24 months. Mortality in both groups was analyzed 6, 12, and 18 months post randomization (median follow up, 41 months). Fewer early disease progression events occurred in obinutuzumab (57 out of 601) versus rituximab (98 out of 601) immunochemotherapy patients, with an average risk reduction of 46.0% (95%CI: 25.0-61.1%; cumulative incidence rate 10.1% vs. 17.4%). At a median post-progression follow up of 22.6 months, risk of mortality increased markedly following a progression event [HR of time-varying progression status, 25.5 (95%CI: 16.2-40.3)]. Mortality risk was higher the earlier patients progressed within the first 24 months. Age-adjusted HR for OS after 24 months in surviving patients with disease progression versus those without was 12.2 (95%CI: 5.6-26.5). Post-progression survival was similar by treatment arm. In conclusion, obinutuzumab plus chemotherapy was associated with a marked reduction in the rate of early disease progression events relative to rituximab plus chemotherapy. Early disease progression in patients with follicular lymphoma was associated with poor prognosis, with mortality risk higher after earlier progression. Survival post progression did not seem to be influenced by treatment arm.

Absolute monocyte count as a prognostic parameter in diffuse large B cell lymphoma

Background Prognosis of patients with Diffuse Large B Cell Lymphoma (DLBCL) is highly variable, and despite the use of modern immunochemotherapy regimens, almost 50% of patients will eventually relapse. Standard risk models, like the International Prognostic Index or the Revised International Prognostic Index (R_IPI) incorporate patient and tumor characteristics but do not consider variables related to host adaptive immunity which have been shown to be of significant prognostic value in non-Hodgkin lymphomas. Aim To analyze the prognostic significance of the absolute monocyte count at diagnosis in diffuse large-B-cell lymphoma in a retrospective setting. Material and Methods We reviewed data of 171 patients with DLBCL treated with Rituximab-based immunochemotherapy at two reference public Hospitals in Montevideo-Uruguay. The outcome measures were overall and relapse free survival. Results The absolute monocyte count, analyzed as a dichotomized variable predicted progression-free and overall survival in low risk patients according to the R-IPI score. Worse outcomes were observed in those with high monocyte count al diagnosis. Conclusions Absolute monocyte count could help in the identification of high-risk patients otherwise expected to have a good prognosis according to traditional scores.

The Risk of Hepatitis B Reactivation Is Controllable in Patients with Concomitant Hepatitis B Virus Infection during Chimeric Antigen Receptor T-Cell Therapy

Background: Among patients with non-Hodgkin lymphoma (NHL) and concomitant chronic or resolved hepatitis B virus (HBV) infection, HBV reactivation is an identified risk associated with chemotherapy, especially after rituximab-based immunochemotherapy. Chimeric antigen receptor (CAR) T-cell targeting CD19 can also cause B-cell aplasia as seen in patients receiving rituximab, and the risk of HBV reactivation during CAR T-cell therapy is still unknown. We performed a retrospective study to explore the risk of HBV reactivation in patients with concomitant HBV infection who had received anti-CD19 CAR T therapy at our hospital. Methods: Patients with relapse or refractory B-cell lymphoma who were treated with CNCT19 (second-generation anti-CD19 CAR T-cell provided by Juventas) at Blood Disease Hospital were retrospectively analyzed. All patients were screened for hepatitis B surface antigen (HBsAg), hepatitis B surface antibody (HBsAb) and hepatitis B core antibody (HBcAb) at the time of evaluation for CNCT19 therapy, and those with positive HBsAg or positive HBcAb were eligible for this retrospective study. This study was approved by Blood Diseases Hospital Internal Review Board. Results: Between June 2017 and May 2019, 17 patients with relapsed or refractory B-cell lymphoma and concomitant HBV infection who were treated with CNCT19 therapy alone (n=14) or CNCT19 therapy following high-dose chemotherapy and autologous stem cell transplantation (HDT/ASCT, n=3) were included in this study. The median age was 53 years (range: 31-71years), with 53% were male. 6 patients (35%) had chronic HBV infection, defined as positive HBsAg, 11 patients (65%) had resolved HBV infection, defined as negative HBsAg and positive HBcAb. At the time of CNCT19 infusion, HBV DNA levels of all patients were lower than the normal limit (&lt;1000IU/ml). All 6 patients with chronic HBV infection received prophylactic anti-HBV nucleos(t)ide therapy (NAT) of entecavir, 5/11(45%) patients with resolved HBV infection received prophylactic NAT of entecavir or lamivudine, and the other 6/11(55%) patients with resolved HBV infection did not receive any prophylactic anti-HBV therapy. With median follow-up of 8 months (range: 1-24 months) from CNCT19 infusion, including 9 patients who had been followed up for more than 6 months, no HBV reactivation occurred (defined as HBV-DNA level exceeding 1000IU/ml). 6 patients with chronic HBV infection remained on NAT at the time of last follow-up, and among the 5 patients with resolved HBV infection who had received prophylactic NAT during CNCT19 therapy, 1 patient was still on NAT at 3 months after CNCT19 infusion following HDT/ASCT, 4 patients stopped NAT at 1, 2, 6, 6months after CNCT19 infusion, respectively. Cytokine release syndrome (CRS) occurred in 59% of patients and CAR-T-cell-related encephalopathy syndrome (CRES) occurred in 12% of patients, with 2 patients received short term of corticosteroids for grade 4 CRES. Conclusions: Our results showed that CAR T therapy could be safely administered in patients with chronic or resolved HBV infection. Considering the small sample size and the retrospectively analysis, the risk of HBV reactivation and the recommendation for prophylactic anti-HBV NAT during CAR T therapy should be further evaluated in large and prospective studies. Disclosures Lv: Juventas Cell Therapy Ltd.: Employment.

Clinical features and survival of patients with T-cell/histiocyte-rich large B-cell lymphoma: analysis of the National Cancer Data Base

Using data from the National Cancer Data Base, 2010–2015, we examined characteristics and outcomes of T-cell/histiocyte-rich large B-cell lymphoma (THRLBCL, N = 622) relative to unspecified diffuse large B-cell lymphoma (DLBCL-NOS, N = 91,588) and nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL, N = 2240). Socio-demographic characteristics of patients with THRLBCL resembled more NLPHL than DLBCL-NOS. Five-year overall survival in THRLBCL was 66% (95% confidence interval [CI], 60–71%). Adjusting for clinical and socio-economic covariates, THRLBCL was associated with better survival than DLBCL-NOS (adjusted hazard ratio, 0.80; 95%CI, 0.67–0.94). This association was similar in academic and community hospitals and consistent in a model stratified by the revised International Prognostic Index. Prognostic factors in THRLBCL included age, comorbidity index, and extranodal primary site, but not stage. Adjusted odds of prior NLPHL were 18.2 higher for THRLBCL (95%CI, 7.2–45.7) than DLBCL-NOS. These large-scale epidemiologic data support the relationship between THRLBCL and NLPHL, and suggest improved prognosis with modern rituximab-based immunochemotherapy.

The expression level of hsa-miR-146a-5p in plasma-derived exosomes of patients with diffuse large B-cell lymphoma.

Background:The standard treatment for patients with diffuse large B-cell lymphoma (DLBCL) had been rituximab-based immunochemotherapy. However, the biological and clinical heterogeneity within DLBCL seems to affect treatment outcome. Therefore, the evaluation of miRNA levels might be useful in predicting treatment response and relapse risk. miR-146a is a modulator of innate and acquired immunity and may play an important role in predicting treatment response. The aim of the present study was to compare the expression level of miR-146a in plasma-derived exosomes of responsive DLBCL patients (response to R-CHOP (Rituximab, and Cyclophosphamide, Hydroxydaunorubicin, Oncovine and Prednisone)), refractory DLBCL patients (resistant to R-CHOP), patients receiving R-CHOP, and healthy donors.Materials and Methods:After the preparation of plasma and isolation of exosomes, the presence of plasma-derived exosome was confirmed by Zetaseizer, electron microscope, and Western blot. The patients’ medical records were collected and analyzed. The expression level of exosomal miR-146a was evaluated in DLBCL patients and healthy donors using real-time polymerase chain reaction (PCR). The −ΔCt values of miR-146a were compared among responsive patients (n = 17), refractory patients (n = 16), patients receiving R-CHOP therapy (n = 15), and healthy donors (n = 6).Results:The presence and size of plasma-derived exosomes were confirmed. Our findings did not show any significant difference in the expression level of exosomal miR-146a between DLBCL patients and healthy donors (P = 0.48). As well, the clinical and histopathological parameters were not correlated with the expression level of exosomal miR-146a or plasma miR-146a. The expression level of plasma miR-146 was lower than the expression level of exosomal miR-146 (P = 0.01).Conclusion:Exosomal miR-146a might be useful as a promising “liquid biopsy” biomarker in predicting treatment response and relapse risk; however, we could not find significant differences due to small sample size.