Abstract: BACKGROUND: T-cell/histiocyte-rich large B-cell lymphoma (T/HRLBCL) is an aggressive morphological variant of diffuse large B cell lymphoma (DLBCL), which often presents with advanced stage disease, extra-nodal involvement, an association with nodular lymphocyte predominant Hodgkin lymphoma (NLPHL) and has poor outcomes compared to patients (pts) with other DLBCL subtypes. METHODS: We conducted a retrospective, single institution study of pts with newly diagnosed T/HRLBCL and reviewed demographic variables, clinical and pathological characteristics, treatment patterns and outcomes. Pts who were treated/ referred to MD Anderson Cancer Center from 2005-2020 were included in the analysis. We excluded cases without pathologic confirmation by a hematopathologist, missing treatment information, lack of appropriate follow up, or previous treatment with anthracycline containing chemotherapy for unrelated diagnosis. Fisher's exact test or Chi-square test was used to evaluate the association between two categorical variables, Kaplan-Meier method used to estimate the time-to-event endpoints including progression free survival (PFS) and overall survival (OS). RESULTS: A total of 172 patients were reviewed, 65 pts were excluded due to aforementioned reasons. A total of 107 newly diagnosed patients met morphological diagnostic criteria. Seventy four pts (70%) were less than 60 years of age at diagnosis with median age of 49 (18-89 years). Seventy two were male (68%) and 37 pts (34%) had documented NLPHL prior to or at the time of T/HRLBCL diagnosis. Ninety pts (89%) were diagnosed with advance stage disease (stage 3/4) with 59pts (55%) with ≥ 1 extra nodal site. Thirty-seven pts (35%) had associated splenomegaly and/or FDG avid splenic involvement. Common extra nodal sites included bone (26%), bone marrow (19%) and liver (17%). On univariate analysis for survival outcomes, there was not a statistical significant association with any of the following: age, gender, association with NLPHL, presence of B symptoms, performance status, elevated lactate dehydrogenase, extra nodal sites, spleen involvement/ splenomegaly, involvement of liver, and type of front-line treatment. Majority of patients (73%) received front line treatment with R-CHOP, followed by Dose Adjusted R-EPOCH (15%) and other regimens in 11%. Central nervous system prophylactic therapy was given in 24 pts (intrathecal) and 3 pts (high dose methotrexate). One pt had an autologous stem cell transplant consolidation as part of frontline treatment. Seventy (69%) pts achieved complete response (CR), with an overall response rate of 75%, and 25 pts progressed on frontline treatment. Complete remission rates were higher with R-EPOCH (81%) than RCHOP (70%) (p=0.57), with 2 year PFS to first line treatment at 38% and 46% respectively (P=0.20). In the whole cohort, 2-year PFS was 48% and 2-year OS was 83%. Of the 53 patients who relapsed, 48 patients received salvage chemotherapy, 26 pts went on to receive high dose chemotherapy and autologous transplant, and only 4 patients relapsed after transplant. Three patients in the whole cohort who received CD19 CAR-T and all 3 had disease progression. Conclusions: This study demonstrates the generally poor outcomes in pts with T/HRLBCL despite the use of monoclonal antibodies and intensive cytotoxic therapies. T/HRLBCL remains a high unmet need for novel therapies. Figure 1 Figure 1. Disclosures Fowler: Bristol Myers Squibb, F. Hoffmann-La Roche Ltd, TG Therapeutics and Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; BostonGene, Corp: Current Employment, Current holder of stock options in a privately-held company. Steiner: BMS: Research Funding; Rafael Pharmaceuticals: Research Funding; Seattle Genetics: Research Funding. Strati: Astrazeneca-Acerta: Research Funding; Roche-Genentech: Consultancy. Chihara: Astrazeneca: Honoraria. Jain: kite: Consultancy; Lilly: Consultancy. Flowers: Morphosys: Research Funding; Ziopharm: Research Funding; Pfizer: Research Funding; Cancer Prevention and Research Institute of Texas: CPRIT Scholar in Cancer Research: Research Funding; Takeda: Research Funding; Janssen: Research Funding; Acerta: Research Funding; Kite: Research Funding; EMD: Research Funding; Xencor: Research Funding; Cellectis: Research Funding; SeaGen: Consultancy; BeiGene: Consultancy; Eastern Cooperative Oncology Group: Research Funding; Spectrum: Consultancy; Genentech/Roche: Consultancy, Research Funding; Burroughs Wellcome Fund: Research Funding; Allogene: Research Funding; Denovo: Consultancy; Biopharma: Consultancy; Epizyme, Inc.: Consultancy; Genmab: Consultancy; Gilead: Consultancy, Research Funding; Karyopharm: Consultancy; Pharmacyclics/Janssen: Consultancy; Nektar: Research Funding; Amgen: Research Funding; Adaptimmune: Research Funding; National Cancer Institute: Research Funding; Guardant: Research Funding; Sanofi: Research Funding; Novartis: Research Funding; TG Therapeutics: Research Funding; Celgene: Consultancy, Research Funding; Iovance: Research Funding; 4D: Research Funding; Bayer: Consultancy, Research Funding; AbbVie: Consultancy, Research Funding; Pharmacyclics: Research Funding. Neelapu: Takeda Pharmaceuticals and related to cell therapy: Patents & Royalties; Kite, a Gilead Company, Bristol Myers Squibb, Merck, Poseida, Cellectis, Celgene, Karus Therapeutics, Unum Therapeutics (Cogent Biosciences), Allogene, Precision BioSciences, Acerta and Adicet Bio: Research Funding; Kite, a Gilead Company, Merck, Bristol Myers Squibb, Novartis, Celgene, Pfizer, Allogene, Kuur, Incyte, Precision BioSciences, Legend, Adicet Bio, Calibr, and Unum Therapeutics: Other: personal fees; Kite, a Gilead Company, Merck, Bristol Myers Squibb, Novartis, Celgene, Pfizer, Allogene Therapeutics, Cell Medica/Kuur, Incyte, Precision Biosciences, Legend Biotech, Adicet Bio, Calibr, Unum Therapeutics and Bluebird Bio: Honoraria. Nastoupil: IGM Biosciences: Research Funding; Denovo Pharma: Other: DSMC; Epizyme: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding; ADC Therapeutics: Honoraria; TG Therapeutics: Honoraria, Research Funding; Caribou Biosciences: Research Funding; Bristol Myers Squibb/Celgene: Honoraria, Research Funding; MorphoSys: Honoraria; Gilead/Kite: Honoraria, Research Funding; Bayer: Honoraria; Genentech: Honoraria, Research Funding; Takeda: Honoraria, Other: DSMC, Research Funding; Janssen: Honoraria, Research Funding. Wang: Celgene: Research Funding; Loxo Oncology: Consultancy, Research Funding; Miltenyi Biomedicine GmbH: Consultancy, Honoraria; Clinical Care Options: Honoraria; VelosBio: Consultancy, Research Funding; BioInvent: Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Anticancer Association: Honoraria; AstraZeneca: Consultancy, Honoraria, Research Funding; CAHON: Honoraria; Moffit Cancer Center: Honoraria; BeiGene: Consultancy, Honoraria, Research Funding; Mumbai Hematology Group: Honoraria; Epizyme: Consultancy, Honoraria; Hebei Cancer Prevention Federation: Honoraria; Chinese Medical Association: Honoraria; Dava Oncology: Honoraria; Acerta Pharma: Consultancy, Honoraria, Research Funding; Molecular Templates: Research Funding; Kite Pharma: Consultancy, Honoraria, Research Funding; Imedex: Honoraria; Lilly: Research Funding; Newbridge Pharmaceuticals: Honoraria; OMI: Honoraria; Physicians Education Resources (PER): Honoraria; Pharmacyclics: Consultancy, Research Funding; Scripps: Honoraria; The First Afflicted Hospital of Zhejiang University: Honoraria; Oncternal: Consultancy, Research Funding; BGICS: Honoraria; Bayer Healthcare: Consultancy; CStone: Consultancy; DTRM Biopharma (Cayman) Limited: Consultancy; Genentech: Consultancy; InnoCare: Consultancy, Research Funding; Juno: Consultancy, Research Funding. Vega: i3Health, Elsevier, America Registry of Pathology, Congressionally Directed Medical Research Program, and the Society of Hematology Oncology: Research Funding; CRISPR Therapeutics and Geron: Research Funding. Iyer: CRISPRX: Research Funding; Seattle Genetics: Research Funding; Rhizen: Research Funding; Merck: Research Funding; Legend: Research Funding; Innate: Research Funding; Spectrum: Research Funding; Trillium: Research Funding; Astra Zeneca: Research Funding; Yingli: Research Funding; Cyclacel: Research Funding. Westin: Morphosys: Research Funding; 47 Inc: Research Funding; AstraZeneca: Consultancy, Research Funding; MorphoSys: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Kite, a Gilead Company: Consultancy, Research Funding; Bristol Myers Squibb: Consultancy, Research Funding; Curis: Research Funding; Genentech: Consultancy, Research Funding; Iksuda Therapeutics: Consultancy; Umoja: Consultancy; ADC Therapeutics: Consultancy, Research Funding.

Abstract: Diffuse large B-cell lymphoma (DLBCL) can be cured with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP); however, one-third of patients experience refractory or relapsed disease. Studies comparing R-CHOP with modified regimens replacing R with obinutuzumab (O) or adding lenalidomide (L) did not result in improved outcomes; however, L and O together may enhance natural killer-cell mediated antibody-dependent cellular toxicity when paired with CHOP. Here, we report on a phase 1b/2 study of 53 patients with newly diagnosed DLBCL who received 6 cycles of LO-CHOP. The end of treatment overall and complete response rates of the 50 evaluable patients were 98% and 90%, respectively. After a median follow-up of 4.5 years, the 4-year progression free and overall survival rates were 87.4% and 91.3%, respectively. Grade 3 to 4 adverse events were experienced by 70% of patients, including neutropenia (38%), thrombocytopenia (17%), fatigue (13%), and neutropenic fever (13%). Of the 33 patients profiled with circulating tumor DNA (ctDNA) sequencing, 31 (94%) had detectable pretreatment ctDNA with cancer personalized profiling by deep sequencing, 24 (73%) were classifiable by the LymphGen classifier, and 15/20 (75%) and 12/17 (71%) patients achieved early and major molecular responses after 1 and 2 cycles, respectively. Using phased variant enrichment and detection sequencing, 16/18 evaluable patients (89%) showed no detectable ctDNA after at least 5 cycles of LO-CHOP. LO-CHOP demonstrates high efficacy and tolerability in newly diagnosed DLBCL, leading to a high rate of undetectable minimal residual disease by ctDNA. This trial has been registered at www.clinicaltrials.gov as NCT02529852.

Abstract: Follicular lymphoma (FL) is a B-cell malignancy with a complex tumor microenvironment that is rich in nonmalignant immune cells. We applied single-cell RNA sequencing to characterize the diverse tumor and immune cell populations of FL and identified major phenotypic subsets of FL T cells, including a cytotoxic CD4 T-cell population. We characterized four major FL subtypes with differential representation or relative depletion of distinct T-cell subsets. By integrating exome sequencing, we observed that somatic mutations are associated with, but not definitive for, reduced MHC expression on FL cells. In turn, expression of MHCII genes by FL cells was associated with significant differences in the proportions and targetable immunophenotypic characteristics of T cells. This provides a classification framework of the FL microenvironment in association with FL genotypes and MHC expression, and informs different potential immunotherapeutic strategies based upon tumor cell MHCII expression. Significance: We have characterized the FL-infiltrating T cells, identified cytotoxic CD4 T cells as an important component that is associated with tumor cell–intrinsic characteristics, and identified sets of targetable immune checkpoints on T cells that differed from FLs with normal versus low MHC expression. See related commentary by Melnick, p. 374. This article is highlighted in the In This Issue feature, p. 369

Abstract: Limited data exist regarding the outcome of patients with follicular lymphoma (FL) who relapse or progress after frontline lenalidomide and rituximab (R2). Moreover, mechanisms of resistance to R2 in FL remain unclear, with increased protumoral macrophages suspected as a major contributory culprit to this phenomenon. This retrospective study analyzed the outcome of patients with advanced-stage FL grade 1 to 3A who relapsed or progressed after frontline R2. A multiplex immunofluorescence macrophage panel, including CD47, CD14, CD68, CD115 (also known as colony-stimulating factor 1 receptor [CSF1R]), CD163, CD172a (also known as signal regulatory protein α [SIRPα] ), and CD274 (also known as programmed cell death-ligand 1 [PDL1]), was used to stain tissue biopsy specimens collected before initiation of R2 and at the time of progression. Among 156 patients with advanced-stage FL treated with frontline R2, 33 (21%) relapsed or progressed and required second-line therapy, after a median of 33 months (range, 1-122 months). Second-line therapy was chemoimmunotherapy in 16 (48%) patients and other therapy in 17 (52%). The overall response rate was 78%, and complete response rate was 72%. Median progression-free survival was significantly longer in patients who received chemoimmunotherapy compared with other therapy (99 vs 25 months; P = .004). Three macrophage populations were significantly increased in tissue samples collected at progression compared with before frontline treatment: CD68+CD115+ (P = .02), CD68+CD115+CD172a+ (P = .02), and CD68+CD163+CD172a+ (P = .01). Chemoimmunotherapy is an effective treatment strategy for patients with FL who relapse after frontline R2. Therapies targeting specific macrophage populations may yield novel approaches for improving outcomes with frontline R2.

Abstract: To explore the role of clonal hematopoiesis (CH) in chimeric antigen receptor (CAR) T-cell therapy outcomes, we performed targeted deep sequencing on buffy coats collected during the 21 days before lymphodepleting chemotherapy from 114 large B-cell lymphoma patients treated with anti-CD19 CAR T cells. We detected CH in 42 (36.8%) pretreatment samples, most frequently in PPM1D (19/114) and TP53 (13/114) genes. Grade ≥3 immune effector cell-associated neurotoxicity syndrome (ICANS) incidence was higher in CH-positive patients than CH-negative patients (45.2% vs. 25.0%, P = 0.038). Higher toxicities with CH were primarily associated with DNMT3A, TET2, and ASXL1 genes (DTA mutations). Grade ≥3 ICANS (58.9% vs. 25%, P = 0.02) and ≥3 cytokine release syndrome (17.7% vs. 4.2%, P = 0.08) incidences were higher in DTA-positive than in CH-negative patients. The estimated 24-month cumulative incidence of therapy-related myeloid neoplasms after CAR T-cell therapy was higher in CH-positive than CH-negative patients [19% (95% CI, 5.5–38.7) vs. 4.2% (95% CI, 0.3–18.4), P = 0.028]. Significance: Our study reveals that CH mutations, especially those associated with inflammation (DNMT3A, TET2, and ASXL1), are associated with severe-grade neurotoxicities in lymphoma patients receiving anti-CD19 CAR T-cell therapy. Further studies to investigate the mechanisms and interventions to improve toxicities in the context of CH are warranted. See related content by Uslu and June, p. 382. This article is highlighted in the In This Issue feature, p. 369

Abstract: Introduction. The combination of lenalidomide and rituximab (or R2) has been demonstrated to be an effective frontline treatment for patients with advanced stage follicular lymphoma (FL), and it has been increasingly used over the last few years. However, limited data exist regarding the management and outcome of patients who relapse and/or progress after frontline R2. Methods. In a retrospective study of patients with advanced stage FL grade 1-3A treated with frontline R2 at MD Anderson Cancer Center between 08/2008 and 01/2020, we examined treatment strategies and outcomes for patients who progressed/relapsed and required salvage therapy. Response was retrospectively assessed according to 2014 Lugano response criteria. Survival outcomes were calculated from time of first salvage therapy. Results. Among 156 patients with advanced stage FL treated with frontline R2, 33 (21%) relapsed/progressed and required salvage therapy, with a median time to first salvage therapy of 33 months (range, 1-122 months); 12 (8%) patients relapsed within 24 months, and no patients showed transformation at time of first relapse. At time of first relapse/progression, 12 (36%) patients were older than 60 years, 19 (57%) were male, 9 (27%) had high risk FLIPI, and 1 relapsed with localized disease. Overall, the median number of salvage systemic therapies after R2 was 1 (range, 0-4), and maintenance following any line of salvage was used in 7 (21%) patients; 1 (3%) patient each had autologous or allogeneic stem cell transplant, both had progressed within 24 months of frontline R2. First salvage therapy was: bendamustine with an anti-CD20 monoclonal antibody (MAb) in 8 (24%) patients, RCHOP in 8 (24%), an anti-CD20 MAb alone in 8 (24%), a clinical trial in 6 (18%), repeated R2 in 2 (7%), and radiotherapy (XRT) in 1 patient with localized disease. Thirty-two patients were evaluable for response after first salvage therapy: the overall response rate was 78% and complete response rate was 72%. After a median follow-up of 51 months (95%CI, 27-75 months) from time of first salvage therapy initiation, 17 patients progressed/died, and median PFS was 38 months (95% CI, 1-82 months). None of the baseline characteristics collected at time of first salvage therapy were significantly associated with PFS. Median PFS was significantly longer in patients who received chemoimmunotherapy (CIT) as compared to biological therapy (BIO) at relapse (99 vs 25 months, p=0.004)(Figure). Transformation was identified in 2 (7%) patients, 2 and 20 months after initiation of first salvage therapy. At most recent follow-up, 2 (7%) patients died (1 of unknown cause, 1 of transformed FL), and median OS has not been reached (Figure). Second cancers (excluding transformation) were diagnosed in 1 (2%) patient after first salvage chemotherapy, and was represented by a pancreatic adenocarcinoma, after 74 months. Discussion. Chemoimmunotherapy is an effective treatment strategy for patients with FL who relapse after frontline R2. The optimal salvage therapy for these patients needs to be prospectively investigated. Tissue samples derived from patients included in this study are being analyzed at our institution, and changes occurring in the tumor microenvironment are being characterized. Figure Disclosures Westin: Kite: Consultancy; Genentech: Consultancy; 47 Inc: Consultancy; MorphoSys: Consultancy; Unum: Consultancy; Juno: Consultancy; Curis: Consultancy; Novartis: Consultancy; Janssen: Consultancy. Lee:Guidepoint Blogal: Consultancy; Celgene: Research Funding; Oncternal Therapeutics: Research Funding; Takeda: Research Funding; Seattle Genetics: Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Aptitude Health: Speakers Bureau. Neelapu:Celgene: Other: personal fees, Research Funding; Bristol-Myers Squibb: Other: personal fees, Research Funding; Merck: Other: personal fees, Research Funding; Kite, a Gilead Company: Other: personal fees, Research Funding; Takeda Pharmaceuticals: Patents & Royalties; Cellectis: Research Funding; Adicet Bio: Other; Calibr: Other; Unum Therapeutics: Other, Research Funding; Poseida: Research Funding; Incyte: Other: personal fees; Precision Biosciences: Other: personal fees, Research Funding; Legend Biotech: Other; Acerta: Research Funding; Allogene Therapeutics: Other: personal fees, Research Funding; Karus Therapeutics: Research Funding; Pfizer: Other: personal fees; N/A: Other; Novartis: Other: personal fees; Cell Medica/Kuur: Other: personal fees. Vega:NCI: Research Funding. Fowler:TG Therapeutics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Research Funding. Nastoupil:Karus Therapeutics: Research Funding; Gamida Cell: Honoraria; Celgene: Honoraria, Research Funding; Gilead/KITE: Honoraria; Novartis: Honoraria, Research Funding; Merck: Research Funding; TG Therapeutics: Honoraria, Research Funding; LAM Therapeutics: Research Funding; Pfizer: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Genentech, Inc.: Honoraria, Research Funding; Bayer: Honoraria.

Abstract: Background Primary mediastinal large B-cell lymphoma (PMBL) is a rare and distinct subtype of diffuse large B-cell lymphoma and affects primarily young adults. PMBL has a unique genomic profile that has similarities to classic Hodgkin lymphoma (cHL). The aberrancies amenable to targeted therapy include CD30 expression in up to 86% of cases and genomic alterations in the programmed T-cell death-ligand 1 (PD-L1) locus 9p24.1 in up to 75% of cases. The anti-CD30 antibody-drug conjugate brentuximab vedotin (A) induces apoptosis and immunogenic cell death and is approved for the treatment of frontline and relapsed/refractory (rr) cHL. Nivolumab (O) is a monoclonal antibody that binds to immune checkpoint PD-1, abrogates tumor inhibitory signals, augments host antitumor immune response, and is FDA approved for multiple malignancies. The trial CheckMate-436, including rr-PMBL patients treated with nivolumab and brentuximab vedotin (A-O), demonstrated synergistic activity with an overall response rate (ORR) of 70-73% and complete response rate (CRR) of 37-43% (Zinzani et al. JCO 2019). Although most PMBL patients can be cured with frontline R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) with radiotherapy or R-EPOCH (Rituximab, Etoposide, Prednisone, Vincristine, Cyclophosphamide, Doxorubicin), these regimens are toxic. The outcome of patients having rr-PMBL treated with intensive regimens is generally unfavorable. The discovery of new frontline regimens to decrease chemoresistance and toxicities represents an urgent unmet clinical need for PMBL patients. Study Design and Methods: We are conducting a phase II, open-label, single-center clinical trial combining A-O alone and then combined with rituximab, cyclophosphamide, doxorubicin, and prednisone (R-CHP) for patients with previously untreated PMBL (NCT04745949; PACIFIC: Primary Mediastinal large B-cell lymphoma treated with Antibody therapy, Checkpoint Inhibitor in Frontline with ImmunoChemotherapy). Patients 18 years or older with previously untreated PMBL, stage I (≥ 5 cm in the greatest dimension) to stage IV disease are eligible; patients will need adequate renal and liver function and hematological parameters. Patients with human immunodeficiency virus and/or hepatitis B/C virus infection without active viremia are potentially eligible. However, patients with an urgent need for cytoreductive treatment will be excluded. As represented in the figure below, patients will receive Brentuximab vedotin 1.8 mg/Kg IV and Nivolumab 240 mg flat dose IV day 1 for cycles 1 and 2, in a 21-day cycle (A-O). During cycles 3 and 4, R-CHP (standard dose similar to R-CHOP) will be added to A-O. Patients who will have achieved complete response (CR) at PET/CT before cycle 5 will receive 2 more cycles of A-O-R-CHP (cycle 5 and 6) and A-O only for cycles 7 and 8 (group A). In case of CR on PET/CT after cycle 8, therapy will be considered completed. If stable disease or progressive disease on PET/CT after cycle 4, patients will be taken off the trial. Patients in PR on PET/CT before cycle 5 will receive 4 more cycles of A-O-R-CHP (cycles 5-8; group B). Consolidative radiotherapy is not allowed. The primary endpoint is CRR at the end of therapy (EOT). The maximum sample size for the PMBL cohort is 40 patients, with a target CRR at EOT of 70%. The null hypothesis is that the true CRR at EOT is 50%, and the alternative hypothesis is that the true CRR at EOT is 70%. The Simon's optimal two-stage design controls the one-sided type I error rate at 0.06 and yields the power of 0.8. The secondary endpoints will include the response rate of A-O at the end of the immune lead-in, landmark survival outcomes, and the safety of the combination. The Health-Related Quality of Life EORTC QLQ-C30 instruments will be utilized to evaluate the quality of life. Exploratory analyses include assessing molecular response by sequencing cell-free DNA and multiplexed ion beam imaging to analyze lymphoma tumor tissue sections to investigate the cellular makeup and spatial organization of the tumor microenvironment and quantify PD-L1 and PD-L2 protein expression. The trial was activated in May 2021 and is actively enrolling at MD Anderson Cancer Center. Figure 1 Figure 1. Disclosures Steiner: BMS: Research Funding; Rafael Pharmaceuticals: Research Funding; Seattle Genetics: Research Funding. Strati: Astrazeneca-Acerta: Research Funding; Roche-Genentech: Consultancy. Flowers: Amgen: Research Funding; Eastern Cooperative Oncology Group: Research Funding; Genmab: Consultancy; Janssen: Research Funding; Gilead: Consultancy, Research Funding; Genentech/Roche: Consultancy, Research Funding; Pharmacyclics/Janssen: Consultancy; Xencor: Research Funding; SeaGen: Consultancy; Cancer Prevention and Research Institute of Texas: CPRIT Scholar in Cancer Research: Research Funding; Karyopharm: Consultancy; National Cancer Institute: Research Funding; Pfizer: Research Funding; Denovo: Consultancy; AbbVie: Consultancy, Research Funding; Epizyme, Inc.: Consultancy; Biopharma: Consultancy; Ziopharm: Research Funding; Burroughs Wellcome Fund: Research Funding; Celgene: Consultancy, Research Funding; Bayer: Consultancy, Research Funding; BeiGene: Consultancy; TG Therapeutics: Research Funding; Takeda: Research Funding; Iovance: Research Funding; Guardant: Research Funding; Nektar: Research Funding; Novartis: Research Funding; Morphosys: Research Funding; 4D: Research Funding; Kite: Research Funding; EMD: Research Funding; Sanofi: Research Funding; Spectrum: Consultancy; Cellectis: Research Funding; Allogene: Research Funding; Acerta: Research Funding; Adaptimmune: Research Funding; Pharmacyclics: Research Funding. Neelapu: Takeda Pharmaceuticals and related to cell therapy: Patents & Royalties; Kite, a Gilead Company, Bristol Myers Squibb, Merck, Poseida, Cellectis, Celgene, Karus Therapeutics, Unum Therapeutics (Cogent Biosciences), Allogene, Precision BioSciences, Acerta and Adicet Bio: Research Funding; Kite, a Gilead Company, Merck, Bristol Myers Squibb, Novartis, Celgene, Pfizer, Allogene, Kuur, Incyte, Precision BioSciences, Legend, Adicet Bio, Calibr, and Unum Therapeutics: Other: personal fees; Kite, a Gilead Company, Merck, Bristol Myers Squibb, Novartis, Celgene, Pfizer, Allogene Therapeutics, Cell Medica/Kuur, Incyte, Precision Biosciences, Legend Biotech, Adicet Bio, Calibr, Unum Therapeutics and Bluebird Bio: Honoraria. Nastoupil: MorphoSys: Honoraria; IGM Biosciences: Research Funding; TG Therapeutics: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding; Bayer: Honoraria; Novartis: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Gilead/Kite: Honoraria, Research Funding; Genentech: Honoraria, Research Funding; Epizyme: Honoraria, Research Funding; Caribou Biosciences: Research Funding; ADC Therapeutics: Honoraria; Bristol Myers Squibb/Celgene: Honoraria, Research Funding; Takeda: Honoraria, Other: DSMC, Research Funding; Denovo Pharma: Other: DSMC. Ahmed: Merck: Research Funding; Seagen: Research Funding; Tessa Therapeutics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Xencor: Research Funding. Westin: Umoja: Consultancy; Morphosys: Research Funding; 47 Inc: Research Funding; Kite, a Gilead Company: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Bristol Myers Squibb: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; MorphoSys: Consultancy, Research Funding; AstraZeneca: Consultancy, Research Funding; ADC Therapeutics: Consultancy, Research Funding; Iksuda Therapeutics: Consultancy; Curis: Research Funding.

Abstract: Introduction: The standard of care for patients with stage IE indolent B-cell lymphoma (BCL) of the ocular adnexa is external beam radiotherapy (RT) to 24-30 Gy. Even with these moderate doses, ocular morbidity is common. Indolent BCL is radiosensitive, with reports of complete response (CR) to 4 Gy. We sought to evaluate the efficacy of a response adapted strategy for the treatment of orbital indolent BCL with upfront ultra-low dose (ULD) orbital RT (4 Gy) and an additional 20 Gy for incomplete responders. Methods: We conducted a phase II single arm study in patients with stage I-IV indolent BCL involving the orbit. Patients were treated with ULD RT to 4 Gy in 2 fractions to the affected orbit(s). Response was assessed clinically and/or radiographically 3 months after ULD RT. Patients with a CR were observed. Patients without CR were evaluated in 3-4 month intervals and offered an additional 20 Gy if they had two consecutive visits with no tumor reduction. The primary endpoint was local control (LC) within the RT field defined from the last day of RT. Secondary endpoints included CR rate, freedom from distant relapse (for stage I patients) and overall survival. We hypothesized that this response adapted strategy would yield equivalent LC to that of standard therapy (24 Gy up front). CR was defined as clinical and/or radiographic resolution of orbital disease. In patients with pre-therapy PET-CT avid disease, CR was defined as a 5PS of 1-3 with or without a residual mass. Partial response (PR) was defined as a decrease in clinical or radiographic disease burden by ≥50% by sum of the disease parameters. Minimal response (MR) was defined as & lt; 50% in orbital disease burden. Stable disease (SD) and progressive disease (PD) were defined as no change or increasing disease, respectively. Results: Between July 2015 and January 2021, 51 patients were enrolled. The median age was 63 years (range 29-88); 62% were female (n=31). Diagnoses included MALT lymphoma (65%, n=33), follicular lymphoma (FL) (24%, n=12), and unclassified low-grade BCL (12%, n=6). Thirty-two patients (63%) had disease confined to one or both orbits at enrollment (stage I); 37 (73%) had newly diagnosed, untreated lymphoma. All patients received 4 Gy in 2 fractions to the affected orbit(s) (bilateral, n=8). Treatment was well tolerated without grade 3 or higher toxicity. One patient did not return for follow up. For 50 evaluable patients, at a median follow up of 21.9 months (95% CI 16.2 - 27.6), 44 patients achieved a CR to ULD therapy (88%) at a median time of 3.4 months (IQR 3, 3.9). Nine patients (20%) had residual disease at the first follow up visit but subsequently had resolution of orbital lymphoma in future follow up. No patient who experienced CR to ULD RT had an in-field orbital relapse (freedom from local relapse rate = 100%, Figure 1a). At the time of follow up #3, 7 patients had not experienced CR and had evidence of disease (Figure 2). Among these 7 patients, 1 achieved CR with continued observation (without intervening therapy) and 2 are being observed with stable disease. Ultimately 4 patients were recommended additional RT to 20 Gy; two patients received the recommended RT, one refused additional RT, one was treated with rituximab for systemic disease progression. After an additional 20 Gy, one patient has stable disease at 21 months and the other patient has pending follow-up. Of the 50 evaluable patients, 31 had stage I disease (MALT = 25, FL=4, low grade BCL =2) that was either untreated (n=25) or had relapsed or progressed in the orbit (n=6) after rituximab (n=2), surgical excision (n=2) or contralateral RT (n=2). Twenty-eight stage I patients (90%) had a CR to ULD RT; of these, the 2-year freedom from local recurrence rate was 100% (Figure 1b) and the freedom from distant relapse rate was 87% (Figure 1b). Distant relapses in the mediastinum, lung, contralateral orbit and mesentery were salvaged successfully with bendamustine/rituximab, rituximab, contralateral 4 Gy orbital RT and rituximab, respectively. None of the 3 patients that did not completely respond to ULD RT experienced distant relapse. Conclusions: In the first prospective study evaluating this novel approach of response adapted ULD orbital RT, orbital outcomes were compelling with minimal toxicity. Additional follow up is required to evaluate long term LC. Response adapted ULD orbital RT is an effective and promising strategy for the definitive management of indolent BCL of the ocular adnexa. Figure 1 Figure 1. Disclosures Pinnix: Merck Inc: Research Funding. Nastoupil: Bristol Myers Squibb/Celgene: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Takeda: Honoraria, Other: DSMC, Research Funding; MorphoSys: Honoraria; Gilead/Kite: Honoraria, Research Funding; Genentech: Honoraria, Research Funding; Epizyme: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding; IGM Biosciences: Research Funding; TG Therapeutics: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Denovo Pharma: Other: DSMC; ADC Therapeutics: Honoraria; Bayer: Honoraria; Caribou Biosciences: Research Funding. Strati: Astrazeneca-Acerta: Research Funding; Roche-Genentech: Consultancy. Ahmed: Seagen: Research Funding; Tessa Therapeutics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Merck: Research Funding; Xencor: Research Funding. Steiner: Rafael Pharmaceuticals: Research Funding; BMS: Research Funding; Seattle Genetics: Research Funding. Jain: kite: Consultancy; Lilly: Consultancy. Westin: Kite, a Gilead Company: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Bristol Myers Squibb: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; MorphoSys: Consultancy, Research Funding; AstraZeneca: Consultancy, Research Funding; ADC Therapeutics: Consultancy, Research Funding; Umoja: Consultancy; Iksuda Therapeutics: Consultancy; Curis: Research Funding; Morphosys: Research Funding; 47 Inc: Research Funding. Neelapu: Kite, a Gilead Company, Merck, Bristol Myers Squibb, Novartis, Celgene, Pfizer, Allogene Therapeutics, Cell Medica/Kuur, Incyte, Precision Biosciences, Legend Biotech, Adicet Bio, Calibr, Unum Therapeutics and Bluebird Bio: Honoraria; Takeda Pharmaceuticals and related to cell therapy: Patents & Royalties; Kite, a Gilead Company, Bristol Myers Squibb, Merck, Poseida, Cellectis, Celgene, Karus Therapeutics, Unum Therapeutics (Cogent Biosciences), Allogene, Precision BioSciences, Acerta and Adicet Bio: Research Funding; Kite, a Gilead Company, Merck, Bristol Myers Squibb, Novartis, Celgene, Pfizer, Allogene, Kuur, Incyte, Precision BioSciences, Legend, Adicet Bio, Calibr, and Unum Therapeutics: Other: personal fees. Wang: BioInvent: Research Funding; Celgene: Research Funding; Molecular Templates: Research Funding; Lilly: Research Funding; VelosBio: Consultancy, Research Funding; Pharmacyclics: Consultancy, Research Funding; Oncternal: Consultancy, Research Funding; Loxo Oncology: Consultancy, Research Funding; Juno: Consultancy, Research Funding; InnoCare: Consultancy, Research Funding; Genentech: Consultancy; DTRM Biopharma (Cayman) Limited: Consultancy; CStone: Consultancy; Bayer Healthcare: Consultancy; BGICS: Honoraria; The First Afflicted Hospital of Zhejiang University: Honoraria; Scripps: Honoraria; Physicians Education Resources (PER): Honoraria; OMI: Honoraria; Newbridge Pharmaceuticals: Honoraria; Mumbai Hematology Group: Honoraria; Moffit Cancer Center: Honoraria; Miltenyi Biomedicine GmbH: Consultancy, Honoraria; Kite Pharma: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Imedex: Honoraria; Hebei Cancer Prevention Federation: Honoraria; Epizyme: Consultancy, Honoraria; Dava Oncology: Honoraria; Clinical Care Options: Honoraria; Chinese Medical Association: Honoraria; CAHON: Honoraria; BeiGene: Consultancy, Honoraria, Research Funding; AstraZeneca: Consultancy, Honoraria, Research Funding; Anticancer Association: Honoraria; Acerta Pharma: Consultancy, Honoraria, Research Funding. Samaniego: Arog: Research Funding; Imbrium: Membership on an entity's Board of Directors or advisory committees. Fowler: BostonGene, Corp: Current Employment, Current holder of stock options in a privately-held company; Bristol Myers Squibb, F. Hoffmann-La Roche Ltd, TG Therapeutics and Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding. Flowers: Karyopharm: Consultancy; SeaGen: Consultancy; Genentech/Roche: Consultancy, Research Funding; AbbVie: Consultancy, Research Funding; Acerta: Research Funding; Biopharma: Consultancy; Genmab: Consultancy; 4D: Research Funding; Denovo: Consultancy; Spectrum: Consultancy; BeiGene: Consultancy; Celgene: Consultancy, Research Funding; Pharmacyclics/Janssen: Consultancy; Epizyme, Inc.: Consultancy; Bayer: Consultancy, Research Funding; Gilead: Consultancy, Research Funding; Adaptimmune: Research Funding; Allogene: Research Funding; Amgen: Research Funding; Cellectis: Research Funding; EMD: Research Funding; Guardant: Research Funding; Iovance: Research Funding; Janssen: Research Funding; Kite: Research Funding; Morphosys: Research Funding; Nektar: Research Funding; Novartis: Research Funding; Pfizer: Research Funding; Sanofi: Research Funding; Takeda: Research Funding; TG Therapeutics: Research Funding; Xencor: Research Funding; Ziopharm: Research Funding; Burroughs Wellcome Fund: Research Funding; Eastern Cooperative Oncology Group: Research Funding; National Cancer Institute: Research Funding; Cancer Prevention and Research Institute of Texas: CPRIT Scholar in Cancer Research: Research Funding; Pharmacyclics: Research Funding.