Zelenetz, Andrew D.

Abstract Since the publication of the Revised European-American Classification of Lymphoid Neoplasms in 1994, subsequent updates of the classification of lymphoid neoplasms have been generated through iterative international efforts to achieve broad consensus among hematopathologists, geneticists, molecular scientists, and clinicians. Significant progress has recently been made in the characterization of malignancies of the immune system, with many new insights provided by genomic studies. They have led to this proposal. We have followed the same process that was successfully used for the third and fourth editions of the World Health Organization Classification of Hematologic Neoplasms. The definition, recommended studies, and criteria for the diagnosis of many entities have been extensively refined. Some categories considered provisional have now been upgraded to definite entities. Terminology for some diseases has been revised to adapt nomenclature to the current knowledge of their biology, but these modifications have been restricted to well-justified situations. Major findings from recent genomic studies have impacted the conceptual framework and diagnostic criteria for many disease entities. These changes will have an impact on optimal clinical management. The conclusions of this work are summarized in this report as the proposed International Consensus Classification of mature lymphoid, histiocytic, and dendritic cell tumors.

Abstract Introduction: Non-Hodgkin lymphoma (NHL) constitutes ~40% of hematologic malignancies and, in 2020, resulted in 19,940 deaths in the USA. The most common NHL subtypes are diffuse large B-cell lymphoma (DLBCL), including primary mediastinal large B-cell lymphoma (PMBCL), and follicular lymphoma (FL). Although a majority of patients respond to standard-of-care therapy, many patients with NHL eventually relapse, highlighting the need for additional treatments. Real-world data regarding the safety and efficacy of emerging therapies in the relapsed/refractory (R/R) population, and the association between treatment patterns and patient outcomes, are limited. These data could provide unique insights to clinical and health-related quality of life (HRQoL) outcomes in patients with DLBCL, FL, or PMBCL treated with emerging therapies, especially novel options such as chimeric antigen receptor (CAR) T cell therapies. Methods: The Connect ® Lymphoma Disease Registry (NCT04982471) is a US-based, multicenter, prospective observational cohort study of patients with R/R NHL (DLBCL, FL, and PMBCL). Approximately 2100 patients ≥ 18 years of age from ~200 community oncology (~80%) or academic (~20%) sites will be enrolled over a ~3-year period. Patients with histologically confirmed NHL subtypes will be enrolled into 1 of 4 cohorts: first R/R DLBCL, second R/R DLBCL, first R/R FL, or first R/R PMBCL (Figure). Patients will be required to have begun second- (first R/R) or third- (second R/R) line systemic treatment within 60 days prior to enrollment. Patients receiving treatment for any active malignancy other than DLBCL, FL, or PMBCL at the time of enrollment, or who are diagnosed with any other malignancy in the 6 months prior to enrollment, will be excluded. All treatment and management decisions will be determined by the practicing clinicians. Patients may undergo hematopoietic stem cell transplantation, CAR T cell therapy, or other treatments at other sites while participating in this study. Patients will be followed from enrollment for up to 5 years or until death, withdrawal of consent, loss to follow-up, or study termination, whichever occurs first. Data collection will occur at enrollment (baseline) and then every ~3 months. The main objectives of the Connect ® Registry are to describe patient characteristics, practice patterns, and factors associated with treatment choice, sequencing, and effectiveness in NHL subtypes. Secondary objectives include describing treatment regimen safety, patient-reported outcomes (PROs) including HRQoL, and healthcare resource utilization outcomes. Exploratory objectives include tumor and blood biomarker evaluation and understanding the availability of social support and its impact on long-term treatment decision-making. Case report forms will be used to collect clinical and treatment data, including baseline demographics, clinical characteristics, treatment details and response, and socioeconomic factors. Outcome measures for efficacy will be progression-free survival, event-free survival, objective response rate, time to next treatment, and overall survival. The availability of social support will be assessed via a specific questionnaire administered at baseline. General (EQ-5D-5L) and disease-specific (FACT-Lym) questionnaires will also be administered. Patients may also optionally agree to release tumor biopsies and blood samples for biomarker analysis. Clinicians will be required to report serious adverse events (AEs), secondary primary malignancies, and confirmed COVID-19 infections within 24 hours. Non-serious AEs of interest include grade 1-3 cytokine release syndrome, grade 1-3 neurotoxicity, grade 3 colitis, grade 3 arrhythmia, grade 3 hemorrhage. Other AEs of interest to be collected include grade 3 hypogammaglobulinemia, prolonged grade 3 cytopenia, and grade 3 infections. Data collected in the Connect ® Registry will increase understanding of the association between emerging therapies and patient outcomes for R/R DLBCL, FL, and PMBCL. Study support: Bristol Myers Squibb Figure 1 Figure 1. Disclosures Flowers: Amgen: Research Funding; Janssen: Research Funding; Biopharma: Consultancy; Ziopharm: Research Funding; Burroughs Wellcome Fund: Research Funding; Nektar: Research Funding; Karyopharm: Consultancy; Iovance: Research Funding; Allogene: Research Funding; AbbVie: Consultancy, Research Funding; Cellectis: Research Funding; Pfizer: Research Funding; Sanofi: Research Funding; BeiGene: Consultancy; Kite: Research Funding; EMD: Research Funding; Genentech/Roche: Consultancy, Research Funding; Morphosys: Research Funding; Adaptimmune: Research Funding; Novartis: Research Funding; Epizyme, Inc.: Consultancy; Spectrum: Consultancy; Pharmacyclics/Janssen: Consultancy; Acerta: Research Funding; 4D: Research Funding; Denovo: Consultancy; Celgene: Consultancy, Research Funding; Guardant: Research Funding; Genmab: Consultancy; Gilead: Consultancy, Research Funding; Bayer: Consultancy, Research Funding; SeaGen: Consultancy; Cancer Prevention and Research Institute of Texas: CPRIT Scholar in Cancer Research: Research Funding; Takeda: Research Funding; National Cancer Institute: Research Funding; TG Therapeutics: Research Funding; Eastern Cooperative Oncology Group: Research Funding; Xencor: Research Funding; Pharmacyclics: Research Funding. Andorsky: Celgene/Bristol Myers Squibb: Research Funding; AbbVie: Consultancy; Celgene/Bristol Myers Squibb: Consultancy; AstraZeneca: Other: served on steering committees; Epizyme: Research Funding; AbbVie: Research Funding. Burke: SeaGen: Consultancy, Speakers Bureau; X4 Pharmaceuticals: Consultancy; Bristol Myers Squibb: Consultancy; Verastem: Consultancy; AstraZeneca: Consultancy; MorphoSys: Consultancy; Adaptive Biotechnologies: Consultancy; Roche/Genentech: Consultancy; Epizyme: Consultancy; Kura: Consultancy; AbbVie: Consultancy; Beigene: Consultancy, Speakers Bureau; Kymera: Consultancy. Cerhan: Genentech: Research Funding; NanoString: Research Funding; Celgene/BMS: Other: Connect Lymphoma Scientific Steering Committee, Research Funding; Regeneron Genetics Center: Other: Research Collaboration. Grinblatt: Astellas Pharma, Inc.: Consultancy; Bristol Myers Squibb: Consultancy; Astra Zeneca: Consultancy; AbbVie: Consultancy. Toomey: Bristol Myers Squibb: Consultancy. Zelenetz: Gilead: Honoraria, Research Funding; Verastem: Honoraria; Novartis: Honoraria; MEI Pharma: Honoraria, Research Funding; SecuraBio: Honoraria; Abbvie: Honoraria, Research Funding; MorphoSys: Honoraria; Pharmacyclics: Honoraria; AstraZeneca: Honoraria; LFR: Other; Genentech/Roche: Honoraria, Research Funding; NCCN: Other; MethylGene: Research Funding; Beigene: Honoraria, Other, Research Funding; BMS/Celgene/JUNO: Honoraria, Other; Amgen: Honoraria; Gilead: Honoraria; Janssen: Honoraria. Sullivan: Bristol Myers Squibb: Current Employment, Current holder of individual stocks in a privately-held company. Flick: Bristol Myers Squibb: Current Employment. Kiselev: Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company, Current holder of individual stocks in a privately-held company. Kaplan: Bristol Myers Squibb: Current Employment. Ahn: Bristol Myers Squibb: Current Employment.

Abstract Background: Diffuse large B-cell lymphoma (DLBCL) is frequently curable after frontline therapy, however, relapses can occur after achievement of a PET-negative complete remission (CR). Early detection of relapse may be associated with improved outcomes, particularly given the development of more active therapies for relapsed, refractory DLBCL. Controversy exists regarding the utility of post-therapy surveillance imaging which is associated with patient (pt) anxiety, radiation exposure, false-positive results, and cost, without clear overall survival benefit in retrospective studies (Thompson JCO 2014). A retrospective study found that serial minimal residual disease (MRD) monitoring during DLBCL surveillance could identify pts at risk of relapse before clinical evidence of disease (Roschewski Lancet Oncol 2015). In this multicenter prospective study, we assessed whether a next-generation immunosequencing (IS) MRD assay could be used for early detection of molecular relapse in DLBCL. Methods: Eligible pts with DLBCL or high-grade B-cell lymphoma (HGBCL) who received anthracycline-containing chemotherapy were enrolled across five cancer centers. In pts who achieved a PET-negative CR, serial peripheral blood samples were obtained every 3 months (mos) and CT scans every 6 mos for 2 years (yrs) post-treatment. The IS MRD assay (Adaptive Biotechnologies, Seattle, WA) that leverages multiplex PCR followed by NGS to identify and track rearrangements of IgH, V-J, D-J and IgK/L loci and translocations in Bcl1/2-IgH was used. MRD positive was defined as any detectable rearrangement and MRD undetectable as no evidence of rearrangement. Results: 500 pts were enrolled and 400 were evaluable (pre-treatment tumor pathology available, completed frontline treatment, and achieved PET-negative CR at end-of-treatment). Baseline characteristics were median age of 62 yrs (range 19-95), male sex 58%, advanced stage 61%, and poor-risk by R-IPI 42%. Histologies included DLBCL, NOS (88%), primary mediastinal B-cell lymphoma (6%), HGBCL (5%), T-cell rich B-cell lymphoma (3%), and other (1%). Pts received regimens including RCHOP x 6 cycles (37%), REPOCH x 6 cycles (20%), clinical trial (15%), combined modality therapy (RCHOP+RT) (9%), and other RCHOP variations (19%). Among the 400 evaluable pts, 44 relapses have occurred as of July 1, 2021. In 45% of pts (20/44), clinical relapse was detected using surveillance imaging alone (typically CT CAP with IV contrast) in an otherwise asymptomatic pt with a normal physical exam and laboratory evaluation . In 10% of pts (4/44), relapse was detected by patient-reported clinical symptoms alone. In 45% of pts (20/44), relapse was detected by imaging, clinical symptoms, and/or evaluation by an oncologist. With a median follow-up of 34 months, the 2-year PFS was 88.9% (85.8, 92.1). Advanced age, advanced stage, and poor-risk R-IPI were associated with inferior PFS. Of the 44 relapses, tumor-specific clonotypes were identified in 39 pts (4 failed quality control (QC), 1 failed calibration) and 38 pts had ≥1 sample available within 90 days of relapse. Of 356 patients in ongoing CR, tumor-specific clonotypes were identified in 279 patients (29 failed QC, 33 failed calibration, and 15 are pending sequencing). The patient-level prospective MRD results are shown in Figure 1. The overall sensitivity, specificity, positive predictive value, and negative predictive value of the IS MRD assay was 63% (24/38), 78% (218/279), 28% (24/85), and 94% (218/232), respectively. Plasma MRD detection had improved sensitivity and specificity compared with circulating cells. Among the 24 relapsed patients with a positive MRD result at or before relapse, the median anticipation of the test was 3 months (range 0 to 24 months). Conclusion: Overall outcomes are excellent for DLBCL and HGBCL pts who achieve PET-negative CR. In this multicenter prospective analysis with standardized follow up, a substantial proportion (45%) of clinical relapses are detected radiographically in asymptomatic pts, supporting the value of CT surveillance imaging in DLBCL, particularly for pts with advanced stage or high-risk disease. MRD assessment using the IS MRD assay had suboptimal sensitivity and specificity in the post-treatment surveillance setting in DLBCL. Further study of the clinical context and its correlation with test performance is ongoing. Figure 1 Figure 1. Disclosures Kumar: Kite Pharmaceuticals: Other: advisory board , Research Funding; Abbvie Pharmaceuticals: Research Funding; Celgene: Honoraria, Other: advisory board, Research Funding; Adaptive Biotechnologies, Celgene, Abbvie Pharmaceticals, Pharmacyclics, Seattle Genetics: Research Funding; Pharmacyclics: Research Funding; Astra Zeneca: Honoraria, Other: Advisory Board, Research Funding; Seattle Genetics: Research Funding. Westin: Novartis: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; Curis: Research Funding; Morphosys: Research Funding; ADC Therapeutics: Consultancy, Research Funding; Iksuda Therapeutics: Consultancy; Umoja: Consultancy; MorphoSys: Consultancy, Research Funding; Kite, a Gilead Company: Consultancy, Research Funding; AstraZeneca: Consultancy, Research Funding; Bristol Myers Squibb: Consultancy, Research Funding; 47 Inc: Research Funding. Schuster: TG Theraputics: Research Funding; Incyte: Research Funding; Adaptive Biotechnologies: Research Funding; Pharmacyclics: Research Funding; Merck: Research Funding; Genentech/Roche: Consultancy, Research Funding; Tessa Theraputics: Consultancy; Loxo Oncology: Consultancy; Juno Theraputics: Consultancy, Research Funding; BeiGene: Consultancy; Alimera Sciences: Consultancy; Acerta Pharma/AstraZeneca: Consultancy; Novartis: Consultancy, Honoraria, Patents & Royalties, Research Funding; Abbvie: Consultancy, Research Funding; Nordic Nanovector: Consultancy; Celgene: Consultancy, Honoraria, Research Funding. Nowakowski: Celgene, NanoString Technologies, MorphoSys: Research Funding; Celgene, MorphoSys, Genentech, Selvita, Debiopharm Group, Kite/Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees. Lossos: Lymphoma Research Foundation: Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Consultancy; Janssen: Consultancy, Honoraria; NCI: Research Funding; University of Miami: Current Employment; NIH grants: Research Funding; Stanford University: Patents & Royalties; Verastem: Consultancy, Honoraria. Jacob: Adaptive Biotechnologies: Current Employment. Mullins: Adaptive Biotechnologies: Current Employment. Zelenetz: AstraZeneca: Honoraria; Amgen: Honoraria; Beigene: Honoraria, Other, Research Funding; Gilead: Honoraria, Research Funding; SecuraBio: Honoraria; Genentech/Roche: Honoraria, Research Funding; BMS/Celgene/JUNO: Honoraria, Other; Janssen: Honoraria; LFR: Other; MEI Pharma: Honoraria, Research Funding; Abbvie: Honoraria, Research Funding; Verastem: Honoraria; MethylGene: Research Funding; NCCN: Other; Pharmacyclics: Honoraria; Novartis: Honoraria; Gilead: Honoraria; MorphoSys: Honoraria.

In the last decade, a better understanding of the molecular pathogenesis of B-cell non-Hodgkin lymphomas has resulted in the development of novel targeted therapies, such as small molecule inhibitors of select kinases in the B-cell receptor pathway, antibody–drug conjugates, and small molecules that target a variety of proteins (eg, CD-19, EZH2, and XPO-1–mediated nuclear export). Anti-CD19 CAR T-cell therapy, first approved for relapsed/refractory (R/R) diffuse large B-cell lymphoma, has also emerged as a novel treatment option for R/R follicular lymphoma and mantle cell lymphoma. These NCCN Guideline Insights highlight the new targeted therapy options included in the NCCN Guidelines for B-Cell Lymphomas for the treatment of R/R disease.

Background: Diffuse large B-cell lymphoma (DLBCL) is frequently curable after frontline therapy, however, relapses can occur after achievement of a PET-negative complete remission (CR). Early detection of relapse may be associated with improved outcomes with second-line curative intent therapy or novel therapies. Controversy exists regarding the utility of post-therapy surveillance imaging which is associated with patient (pt) anxiety, radiation exposure, false-positive results, and cost. A retrospective study found that serial minimal residual disease (MRD) monitoring during DLBCL surveillance could identify pts at risk of relapse before clinical evidence of disease (Roschewski, Lancet Oncol, 2015). In this multicenter prospective study, we assessed whether a next-generation sequencing (NGS)-based MRD assay could be used for early detection of molecular relapse in DLBCL. Methods: Eligible pts with DLBCL or high-grade B-cell lymphoma (HGBCL) who received anthracycline-containing chemotherapy were enrolled across five cancer centers. In pts who achieved a PET-negative CR, serial peripheral blood samples were obtained every 3 months (mos) and CT scans every 6 mos for 2 years (yrs) post-treatment. The clonoSEQ® next generation sequencing (NGS) MRD assay (Adaptive Biotechnologies, Seattle, WA) that leverages multiplex PCR followed by NGS to identify and track rearrangements of IgH, V-J, D-J and IgK/L loci and translocations in Bcl1/2-IgH was used. MRD positive was defined as any detectable rearrangement and MRD negative as no evidence of rearrangement. We also reported MRD positivity above the limit of detection (LOD) (observations required to have 95% reproducibility). Interim futility analysis was performed after approximately 50% of anticipated relapses occurred to assess the preliminary sensitivity of the assay. Progression-free survival (PFS) was defined as time from treatment start date to relapse or death. Results: 501 pts were enrolled and 401 were evaluable (pre-treatment tumor pathology available, completed frontline treatment, and achieved PET-negative CR at end-of-treatment). Baseline characteristics were median age of 62 yrs (range 19-95), male sex 58%, advanced stage 61%, and poor-risk by R-IPI 40% (Table 1). Histologies included DLBCL, NOS (86%), primary mediastinal B-cell lymphoma (6%), HGBCL (5%), T-cell rich B-cell lymphoma (1%), and other (1%). Pts received regimens including RCHOP x 6 cycles (36%), REPOCH x 6 cycles (20%), clinical trial (15%), combined modality therapy (RCHOP+RT) (10%), and other RCHOP variations (19%). Among the 401 evaluable pts, 44 relapses have occurred as of June 1, 2020. In 47% of pts (18/38), clinical relapse was detected using surveillance imaging alone (typically CT CAP with IV contrast) in an otherwise asymptomatic pt with a normal physical exam and laboratory evaluation. Clinical relapse was detected by clinical symptoms alone in 11% (4/28), by the evaluation of an oncologist alone in 0%, and by imaging and clinical symptoms and/or evaluation by an oncologist in 42% (16/38) (missing data in 6 pts). With a median follow-up of 2.2 yrs, the 2-yr PFS was 88.1% (84.8, 91.4) (Figure 1). Advanced age, advanced stage, and poor-risk R-IPI were associated with inferior PFS. Of the 44 relapses, 43 pts were included in the interim analysis and tumor-specific clonotypes were identified in 39 pts (91%). In 56% (22/39), the MRD assay was positive at or before clinical relapse. In 38% (15/39), the MRD assay was positive above the limit of detection at or prior to clinical relapse, with only 10 relapses detected more than 3 mos prior to relapse, reflecting the poor clinical sensitivity of the assay. The NGS-MRD assay was more sensitive in the acellular (plasma cell-free DNA) than in the cellular (circulating leukocytes) compartment. Results: Overall outcomes are excellent for DLBCL and HGBCL pts who achieve PET-negative complete remission. In interim analysis, surveillance MRD assessment using the clonoSEQ® assay fails to consistently identify pts at risk of recurrence before clinical evidence of relapse in DLBCL. In a prospective analysis, a substantial proportion (47%) of clinical relapses are detected by imaging in asymptomatic pts, supporting the value of CT surveillance imaging in DLBCL, particularly for pts with advanced stage or high-risk disease. Additional analyses are forthcoming for MRD assessment in all pts, including those in remission. Disclosures Kumar: Celgene: Research Funding; Pharmacyclics: Research Funding; Adaptive Biotechnologies,: Research Funding; AbbVie: Research Funding; Seattle Genetics: Research Funding; Celgene: Honoraria, Other: Honoraria for Advisory Board; Astra Zeneca: Honoraria, Other: Honoraria for Advisory Board; Kite Pharmaceuticals: Honoraria, Other: Honoraria for Advisory Board. Westin:Kite: Consultancy, Research Funding; Curis: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Amgen: Consultancy; Astra Zeneca: Consultancy, Research Funding; Morphosys: Consultancy, Research Funding; 47: Research Funding; Janssen: Consultancy, Research Funding; BMS: Consultancy, Research Funding. Nowakowski:Curis: Consultancy; Seattle Genetics: Consultancy; Nanostrings: Research Funding; MorphoSys: Consultancy, Research Funding; Roche: Consultancy, Research Funding; Celgene/BMS: Consultancy, Research Funding; Kite: Consultancy; Denovo: Consultancy; Kymera: Consultancy; Ryvu: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other. Lossos:Verastem: Consultancy, Honoraria; Seattle Genetics: Consultancy, Other; NCI: Research Funding; Stanford University: Patents & Royalties; Janssen Biotech: Honoraria; Janssen Scientific: Consultancy, Other. Batlevi:Life Sci, GLG, Juno/Celgene, Seattle Genetics, Kite: Consultancy; Janssen, Novartis, Epizyme, Xynomics, Bayer, Autolus, Roche/Genentech: Research Funding. Drullinsky:Roche: Research Funding; Novartis: Research Funding. Gerecitano:Janssen: Current Employment. Hamlin:Celgene: Consultancy; Karyopharm: Consultancy; Juno Therapeutics: Consultancy; Portola: Research Funding; Molecular Templates: Research Funding; Incyte: Research Funding; J&J Pharmaceuticals: Research Funding; Portola Pharmaceutics: Consultancy. Horwitz:ASTEX: Consultancy; Affirmed: Consultancy; Vividion Therapeutics: Consultancy; Verastem: Consultancy, Research Funding; Myeloid Therapeutics: Consultancy; Miragen: Consultancy; Kura Oncology: Consultancy; Janssen: Consultancy; GlaxoSmithKline: Consultancy; Daiichi Sankyo: Research Funding; C4 Therapeutics: Consultancy; Beigene: Consultancy; Portola: Consultancy, Research Funding; Mundipharma: Consultancy; Innate Pharma: Consultancy; Corvus: Consultancy; Trillium: Consultancy, Research Funding; Seattle Genetics: Consultancy, Research Funding; Millenium/Takeda: Consultancy, Research Funding; Kyowa Hakka Kirin: Consultancy, Research Funding; Infinity/Verastem: Research Funding; Forty Seven: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Aileron: Consultancy, Research Funding; ADCT Therapeutics: Consultancy, Research Funding. Jacob:Adaptive Biotechnologies: Current Employment, Current equity holder in publicly-traded company. Joffe:AstraZeneca: Membership on an entity's Board of Directors or advisory committees; Epizyme: Membership on an entity's Board of Directors or advisory committees. von Keudell:Bayer: Research Funding; Pharmacyclics: Research Funding; Genentech: Research Funding. Lahoud:MorphoSys: Other: Advisory Board. Matasar:Bayer: Consultancy, Honoraria, Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; Rocket Medical: Consultancy, Research Funding; Teva: Consultancy; F. Hoffmann-La Roche Ltd: Consultancy, Honoraria, Research Funding; GlaxoSmithKline: Honoraria, Research Funding; Takeda: Consultancy, Honoraria; Daiichi Sankyo: Consultancy; IGM Biosciences: Research Funding; Janssen: Honoraria, Research Funding; Pharmacyclics: Honoraria, Research Funding; Immunovaccine Technologies: Honoraria, Research Funding; Merck: Consultancy; Juno Therapeutics: Consultancy; Genentech, Inc.: Consultancy, Honoraria, Research Funding. Mullins:Adaptive Biotechnologies: Current Employment, Other: shareholder. Noy:Pharmacyclics: Research Funding; NIH: Research Funding; Rafael Pharma: Research Funding; Janssen: Consultancy; Pharmacyclics: Consultancy; Medscape: Consultancy; Targeted Oncology: Consultancy; Morphosys: Consultancy. Straus:Seattle Genetics: Consultancy, Membership on an entity's Board of Directors or advisory committees; ASH: Other: Conference in December 2019 on HL to other physicians during ASH; Elsevier: Membership on an entity's Board of Directors or advisory committees, Other: CME writer; OncLive: Speakers Bureau; Takeda Pharmaceuticals: Research Funding, Speakers Bureau; NY Lymphoma Rounds: Consultancy; Targeted Oncology: Consultancy, Speakers Bureau; Imedex, Inc.: Speakers Bureau; Karyopharm Therapeutics: Membership on an entity's Board of Directors or advisory committees. Younes:Takeda: Consultancy; HCM: Consultancy; AstraZeneca: Current Employment; Novartis: Consultancy; Daiichi Sankyo: Consultancy; Janssen: Consultancy; Epizyme: Consultancy; BMS: Consultancy; BioPath: Consultancy; Curis: Consultancy. Zelenetz:MEI Pharma: Research Funding; MorphoSys: Research Funding; Sandoz: Research Funding; Celgene: Research Funding; Roche: Research Funding; Gilead: Research Funding; Genentech/Roche: Consultancy; Gilead: Consultancy; Celgene: Consultancy; Janssen: Consultancy; Amgen: Consultancy; Novartis: Consultancy; Adaptive Biotechnology: Consultancy; BeiGene: Membership on an entity's Board of Directors or advisory committees.

Background: With the incorporation of positron emission tomography (PET) imaging as part of the standard staging evaluation of follicular lymphoma (FL), it is generally recommended to obtain the diagnostic biopsy from a lesion with the highest standardized uptake value (SUV) to rule out de novo histologic transformation (HT). In some cases such an approach might be impractical, while in other cases a biopsy from a diseased area with a high SUV may still demonstrate an indolent histology. To date, there is no data to guide treatment choices in patients (pts) with FL with high SUVmax but with no documented evidence of HT. Specifically, it remains unclear whether anthracycline-containing regimens, such as R-CHOP, provide a better outcome than R-Bendamustine (BR). Furthermore, it is unknown whether rituximab (R) maintenance is beneficial in this setting. Therefore, we aimed to compare the efficacy of R-CHOP vs BR in newly diagnosed FL pts with high SUVmax at baseline PET and to clarify the role of maintenance. Patients and Methods: We retrospectively identified 261 consecutive pts with newly diagnosed biopsy-proven FL1-3A and a SUVmax≥13 on baseline PET, who were treated with frontline R-CHOP (n=183) or BR (n=78) at 7 US cancer centers based on the physician's choice. Progression-free survival (PFS) was calculated from starting treatment until progression, relapse or death. Cut-offs of SUVmax ≥13≤18 and SUVmax>18 were used for sub-analysis (Haematologica;2020;105:1907-1913). Results: Median age was 59 years. The baseline characteristics of the two groups differed significantly for a younger age (58 vs 62 years, p=0.009), a higher rate of B-symptoms (26% vs 10%, p=0.005) and baseline SUVmax>18 (49% vs 36%, p=0.04) in the R-CHOP group. A diagnostic biopsy was obtained from the site at the highest SUV in 129 (71%) and 43 (55%) pts, respectively (p=0.01). These suggest a potential selection of R-CHOP in pts with adverse features. At the end of therapy (EoT), R-CHOP treated pts achieved higher PET-CT complete response rates (CR 82% vs 69%, p=0.02). This superiority held in pts with diagnostic biopsy at the highest SUV site (CR 83% vs 67%, p=0.03), but not in the others (CR 80% vs 71%, p=0.37). Progression occurred at EoT in 11 and 14 pts receiving R-CHOP and BR (6% vs 18%, p=0.02), with a higher rate of HT in the BR group (13% vs 4%, p=0.006). After a median follow-up of 76 months (range, 4-208 months), there was no significant difference in PFS between R-CHOP and BR treated pts (hazard ratio [HR] 1.22, p=0.34). PFS was strongly associated with FLIPI 2 (HR 2.32, p=0.01) and 3-5 (HR 2.69, p=0.003) in the univariate as well as in the multivariate analysis (FLIPI 2 HR 2.19, p=0.02; FLIPI 3-5 HR 2.51, p=0.01). There was a trend toward overall survival (OS) benefit in the R-CHOP group (Fig.1A). In the univariate analysis for OS, BR regimen (HR 2.12, p=0.03), age >60 (HR 2.54, p=0.006), FLIPI 3-5 (HR 5.13, p=0.03) and biopsy at the highest SUV site (HR 0.44, p=0.01) were prognostic, however none of those remained significant in the multivariate analysis (BR regimen HR 1.84, p=0.09; age >60 HR 1.92, p=0.08; FLIPI 3-5 HR 3.11, p=0.14; biopsy at the highest SUV site HR 0.60, p=0.13; SUVmax>18 HR 1.87, p=0.055). Among pts with EoT response after R-CHOP or BR (n=170 and n=64, respectively), one third in each group (36% vs 41%, respectively) received R-maintenance for a median of 8 administrations (range, 2-12). A significant PFS advantage (landmark analysis) was observed with R-maintenance (Fig.1B; HR 0.53, p=0.02); however, this did not translate in survival benefit (HR 0.67, p=0.49). In a multivariable model, R-maintenance (HR 0.53, p=0.02), FLIPI 2 (HR 2.47, p=0.03) and 3-5 (HR 2.79, p=0.01) remained independent prognosticators of PFS, while no parameters significantly affected OS. The 2-year HT rate (10% vs 17%) and cumulative incidence did not statistically differ between R-CHOP and BR groups (Fig.1C, p=0.159). Early progression (POD24) occurred in 43 and 22 pts who received R-CHOP and BR, respectively (24% vs 28%) and resulted in a significantly higher risk of death (HR 4.12, p=0.006). Conclusion: In newly diagnosed FL pts with SUVmax≥13 at baseline PET, R-CHOP was more effective in achieving CR and reducing the risk of early HT compared with BR, and it was associated with a trend toward survival advantage. Rituximab maintenance significantly prolonged PFS. A prospective evaluation with a larger population will be needed to confirm our findings. Disclosures Joffe: Epizyme: Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Membership on an entity's Board of Directors or advisory committees. Ruella:Abclon, BMS, NanoString: Consultancy; Abclon: Consultancy, Research Funding; UPenn/Novartis: Patents & Royalties. Svoboda:Adaptive: Consultancy; Astra-Zeneca: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Imbrium: Consultancy; Incyte: Research Funding; Pharmacyclics: Consultancy, Research Funding; Merck: Research Funding; Seattle Genetics: Consultancy, Research Funding; TG: Research Funding; Genmab: Consultancy; Atara: Consultancy. Witzig:Immune Design: Research Funding; Spectrum: Consultancy; Karyopharm Therapeutics: Research Funding; Acerta: Research Funding; Celgene: Consultancy, Research Funding; AbbVie: Consultancy; MorphSys: Consultancy; Incyte: Consultancy. Smith:TG Therapeutics: Consultancy, Research Funding; Janssen: Consultancy; BMS: Consultancy; Celgene: Consultancy, Research Funding; Pharmacyclics: Research Funding; Karyopharm: Consultancy, Research Funding; FortySeven: Research Funding; Acerta: Research Funding; Genentech/Roche: Consultancy, Other: Support of parent study and funding of editorial support, Research Funding. Armand:Affimed: Consultancy, Research Funding; Otsuka: Research Funding; Bristol-Myers Squibb: Consultancy, Honoraria, Research Funding; IGM: Research Funding; Infinity: Consultancy; Genentech: Research Funding; Sigma Tau: Research Funding; Celgene: Consultancy; Adaptive: Consultancy, Research Funding; Tensha: Research Funding; Roche: Research Funding; Merck & Co., Inc.: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy; ADC Therapeutics: Consultancy. Nastoupil:Janssen: Honoraria, Research Funding; LAM Therapeutics: Research Funding; Gilead/KITE: Honoraria; Gamida Cell: Honoraria; TG Therapeutics: Honoraria, Research Funding; Merck: Research Funding; Novartis: Honoraria, Research Funding; Genentech, Inc.: Honoraria, Research Funding; Karus Therapeutics: Research Funding; Bayer: Honoraria; Celgene: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding. Ansell:Takeda: Research Funding; Regeneron: Research Funding; Bristol Myers Squibb: Research Funding; Seattle Genetics: Research Funding; Trillium: Research Funding; Affimed: Research Funding; AI Therapeutics: Research Funding; ADC Therapeutics: Research Funding. Zelenetz:Novartis: Consultancy; Adaptive Biotechnology: Consultancy; Genentech/Roche: Consultancy; Gilead: Consultancy; Gilead: Research Funding; Celgene: Consultancy; Roche: Research Funding; Amgen: Consultancy; BeiGene: Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy; Sandoz: Research Funding; Celgene: Research Funding; MorphoSys: Research Funding; MEI Pharma: Research Funding. Younes:BioPath, Xynomic, Epizyme, and F. Hoffmann-La Roche: Consultancy; Janssen, Curis, Merck, Bristol-Myers Squibb, Syndax Pharmaceuticals, F. Hoffmann-La Roche, Curis (Inst), Johnson & Johnson (Inst), Novartis (Inst): Research Funding; Janssen, AbbVie, Merck, Curis, Epizyme, F. Hoffmann-La Roche, Takeda, Bristol-Myers Squibb, Bayer HealthCare Pharmaceuticals, Celgene, Incyte, Janssen Pharmaceuticals, Merck, Sanofi, Seattle Genetics, Takeda Millennium: Honoraria; AstraZeneca: Current Employment; MSKCC: Ended employment in the past 24 months.

e13535 Background: Pediatric patients (pts) receiving long-term vincristine treatment for acute lymphoblastic leukemia (ALL) who carry two variant alleles of CEP72 rs924607 experience more severe peripheral neuropathy (PN) at lower cumulative vincristine doses. The objective of this retrospective pharmacogenetic analysis was to determine if pts homozygous for rs924607 have increased PN risk when receiving short-term vincristine treatment for diffuse large B-cell lymphoma (DLBCL). Methods: Caucasian pts with DLBCL randomized to either of two vincristine-containing regimens (R-CHOP or DA-EPOCH-R) on the CALGB 50303 (Alliance) trial were genotyped for germline rs924607 via TaqMan. Vincristine was administered intravenously 1.4 mg/m2 (2 mg cap) on day 1 of each R-CHOP cycle (1.4 mg/m2/cycle) or 0.4 mg/m2/day (no cap) on days 1-4 of each DA-EPOCH-R cycle (1.6 mg/m2/cycle). Dosing was repeated every 21 days for 6 treatment cycles, for a maximum cumulative vincristine dose of 8.4 (R-CHOP) or 9.6 (DA-EPOCH-R) mg/m2 over 18 weeks. The primary analysis compared risk of NCI CTCAE grade 3 or higher PN in rs924607 homozygous variant pts versus wild-type allele carriers using multivariable Cox proportional hazards regression adjusted for treatment received (R-CHOP vs. DA-EPOCH-R), age (continuous), and sex (male vs. female). A secondary analysis was conducted only in pts assigned to the DA-EPOCH-R arm. Results: Of 307 pts included in the analysis, 32 (10.4%) experienced grade 3+ PN. PN occurrence was nominally lower in homozygous pts (5/59 = 8.5%) than wild-type carriers (27/248 = 10.9%). In the primary analysis, homozygous pts did not experience PN earlier in treatment (Hazard ratio (HR) = 1.04, (95% confidence interval: 0.39-2.75), one-sided p-value = 0.47). There was no significant difference between groups in dose-at-PN occurrence (homozygous (n = 5): 8.81 mg/m2 vs. wild-type carrier (n = 27):6.74 mg/m2, p > 0.05). The secondary analysis in pts on the DA-EPOCH-R arm (n = 147), in which the majority of PN events occurred (n = 27/32 = 84%), homozygous pts (n = 26) did not have significantly increased PN risk (HR = 1.30, p = 0.56). Conclusions: This retrospective analysis of the prospective CALGB 50303 trial did not find that pts homozygous for CEP72 rs924607 had increased PN risk during short-term vincristine treatment for DLBCL. Support: U10CA180821, U10CA180882, U24CA196171; https://acknowledgments.alliancefound.org . ClinicalTrials.gov Id: NCT00118209.

Abstract Background: FL comprises one quarter of lymphoma in the United States, presents in a heterogeneous fashion, and generates substantial debate regarding optimal management strategies. The recently published clinical prognostic index (FLIPI, BLOOD104:1258) facilitates outcome evaluation and may guide therapeutic strategy. The National LymphoCare Study (NLCS) is an ongoing disease-based longitudinal observational study designed to assess patterns of initial disease presentation including prognosis, long term treatment choices, and clinical outcomes in FL patients. Methods: Beginning March, 2004, pts were recruited from U.S. community practices and academic centers. Pts with FL diagnosed within 6 months with no prior lymphoma history are eligible for enrollment. Collected data includes histology, staging and prognostic evaluation, serial management strategies including drug choices but not doses, response to treatment, and events including relapses and death. There is no study-specific prescribed treatment regimen or intervention. The treating physician determines management for FL according to clinical judgment. Results: 992 pts were enrolled from 207 sites through April, 2005. 182 community sites enrolled 86% of subjects. Pt characteristics include median age 62y, 52.5% female, 90.6% Caucasian, 40% Gr1, 26% Gr2, 19% Gr3, 13% NOS, with highest determined Ann Arbor stage = 17% I, 15%II, 26% III, 33%IV, 8% Unk. The demographic characteristics are similar to pts in the national SEER registry (median age 64, 51% F, 91.3% Caucasian) but clinical characteristics are notable for a higher fraction of advanced stage disease. 686/992 (69%) patients had calculable FLIPI scores based on initial investigator workup. Of factors contributing to FLIPI scores, LDH was collected by investigators in 78% of pts. When correlated with age, geography, and academic/community sites, LDH collection rates differ with 90% in academic sites vs 76% in community sites (p = .0002). Distribution of FLIPI among 686 pts with complete scores are shown in Table1, and show remarkable consistency across grades. Summary: The NLCS is an ongoing study with a large and rapidly growing database combining clinical and treatment data and is the first database investigating initial workup, prognosis, and outcomes of pts in a predominantly community based U.S. population. FL pts enrolled in NLCS are similar to those in the SEER database, and should be widely generalizable to the US population. FLIPI continues to define three distinct groups in the NLCS and is independent of histologic grade. Current evaluation patterns result in 31% incomplete FLIPI scores, suggesting this useful prognostic index is underutilized. FLIPI distribution (%) Low 36 37 37 38 34 81 14 Intermed 37 31 32 28 37 14 40 High 27 32 31 34 29 5 46 Solal Celigny n=1795 NLCS n=686 NLCS Gr1 n=276 NLCS Gr2 n=188 NLCS Gr3 n=136 Stage I/II n=234 Stage III/IV n=452

Abstract Two death receptors, TRAIL-R1 (DR4) and TRAIL-R2 (DR5), expressed in a wide variety of cancer cell types including lymphoma, enable TRAIL (TNF related apoptosis inducing ligand), a member of the TNF ligand superfamily, to induce apoptosis. HGS-ETR1 (TRM-1, mapatumumab) is a fully human monoclonal antibody agonistic to TRAIL-R1 with preclinical evidence of anti-tumor activity in vitro and in vivo. We conducted a phase 2 multicenter study of HGS-ETR1 in 40 subjects with relapsed or refractory NHL. Patients were included on the study if they had relapsed/refractory NHL of any histologic subtype, irrespective of the number of previous treatment regimens. HGS-ETR1 was administered at 2 dose levels: 3 mg/kg (8 subjects) or 10 mg/kg (32 subjects) every 21 days in the absence of disease progression or prohibitive toxicity for up to 6 cycles. The primary endpoint was tumor response evaluated with the International Working Group Criteria after every third treatment. Responses were confirmed between 4 and 8 weeks after initial documentation of response. Secondary endpoints included safety and tolerability. The median age of subjects was 62 years (range 32–81) (24M:16F) with an ECOG performance status 0–2. Subjects had received up to 12 previous therapeutic regimens (69% received 3 or more prior regimens). Original histologic classification is presently available for 34 subjects (14 follicular, 7 diffuse large B-cell, 6 mantle cell, 1 small lymphocytic, 2 peripheral T-cell, 1 anaplastic large cell, 3 lymphomas not classified). Preliminary response data are available for all 40 subjects. 3 subjects (8%), all with follicular lymphoma, had clinical responses (1CR, 2PR). Additionally, 12/40 subjects (30%) had stable disease, and the remainder had progressive disease at the time of first evaluation. 8 subjects (7 follicular) remain on study without disease progression for >5 to >13 months. One subject with a PR (special permission) has continued to receive HGS-ETR1 (10 cycles to date). Subjects tolerated therapy well with no subjects discontinuing therapy due to toxicity related to drug. There have been 10 reported SAEs, 2 of which were considered possibly/probably related to HGS-ETR1 administration (shingles, fever). In conclusion, HGS-ETR1 can be safely administered to heavily treated NHL patients. Clinical responses were seen in 3/14 follicular lymphoma subjects to date. Final data for all subjects will be reported at the meeting. These data suggest that HGS-ETR1 has activity in heavily pretreated lymphoma patients and further studies in combination with agents active in lymphoma are justified.

Abstract As part of a randomized, prospective clinical trial in large cell lymphoma, we conducted serial fluorodeoxyglucose positron emission tomography (FDG-PET) at baseline, after 2 cycles of chemotherapy (interim PET [i-PET]), and at end of treatment (EoT) to identify biomarkers of response that are predictive of remission and survival. Scans were interpreted in a core laboratory by 2 imaging experts, using the visual Deauville 5-point scale (5-PS), and by calculating percent change in FDG uptake (change in standardized uptake value [ΔSUV]). Visual scores of 1 through 3 and ΔSUV ≥66% were prospectively defined as negative. Of 524 patients enrolled in the parent trial, 169 agreed to enroll in the PET substudy and 158 were eligible for final analysis. In this selected population, all had FDG-avid disease at baseline; by 5-PS, 55 (35%) remained positive on i-PET and 28 (18%) on EoT PET. Median ΔSUV on i-PET was 86.2%. With a median follow-up of 5 years, ΔSUV, as continuous variable, was associated with progression-free survival (PFS) (hazard ratio [HR] = 0.99; 95% confidence interval [CI], 0.97-1.00; P = .02) and overall survival (OS) (HR, 0.98; 95% CI, 0.97-0.99; P = .03). ΔSUV ≥66% was predictive of OS (HR, 0.31; 95% CI, 0.11-0.85; P = .02) but not PFS (HR, 0.47; 95% CI, 0.19-1.13; P = .09). Visual 5-PS on i-PET did not predict outcome. ΔSUV, but not visual analysis, on i-PET predicted OS in DLBCL, although the low number of events limited the statistical analysis. These data may help guide future clinical trials using PET response-adapted therapy. This trial was registered at www.clinicaltrials.gov as #NCT00118209.