Abstract: Chimeric antigen receptor (CAR) T-cell therapy targeting CD19 may be associated with long-term adverse effects such as cytopenia and immune deficiency. In order to characterize these late events, we analyzed 31 patients with relapsed or refractory large B-cell lymphoma treated with axicabtagene ciloleucel at our institution on two clinical trials, ZUMA-1 (clinicaltrials gov. Identifier: NCT02348216) and ZUMA-9 (clinicaltrials gov. Identifier: NCT03153462). Complete blood counts, lymphocyte subsets, and immunoglobulin levels were measured serially until month 24 or progression. Fifteen (48%) patients had grade 3-4 cytopenia, including anemia (five, 16%), neutropenia (nine, 29%), or thrombocytopenia (13, 42%) at day 30. Cytopenia at day 30 was not significantly associated with later diagnosis of myelodysplasia. Among patients with ongoing remission, grade 3-4 cytopenia was observed in one of nine (11%) at 2 years. While peripheral CD8+ T cells recovered early, CD4+ T-cell recovery was delayed with a count of 〈 200/mL in three of nine (33%) patients at 1 year and two of seven (29%) at 2 years. Immunoglobulin G levels normalized in five of nine (56%) patients at 2 years. Thirteen (42%) patients developed grade 3-4 infectious complications, including herpes zoster and Pneumocystis jiroveci pneumonia. These results suggest the need for prolonged monitoring and prophylaxis against opportunistic infections in these patients, to improve the longterm safety of axicabtagene ciloleucel therapy.

Abstract: To increase awareness, outline strategies, and offer guidance on the recommended management of immune-related adverse events (irAEs) in patients treated with immune checkpoint inhibitor (ICPi) therapy. METHODS A multidisciplinary panel of medical oncology, dermatology, gastroenterology, rheumatology, pulmonology, endocrinology, neurology, hematology, emergency medicine, nursing, trialists, and advocacy experts was convened to update the guideline. Guideline development involved a systematic literature review and an informal consensus process. The systematic review focused on evidence published from 2017 through 2021. RESULTS A total of 175 studies met the eligibility criteria of the systematic review and were pertinent to the development of the recommendations. Because of the paucity of high-quality evidence, recommendations are based on expert consensus. RECOMMENDATIONS Recommendations for specific organ system–based toxicity diagnosis and management are presented. While management varies according to the organ system affected, in general, ICPi therapy should be continued with close monitoring for grade 1 toxicities, except for some neurologic, hematologic, and cardiac toxicities. ICPi therapy may be suspended for most grade 2 toxicities, with consideration of resuming when symptoms revert ≤ grade 1. Corticosteroids may be administered. Grade 3 toxicities generally warrant suspension of ICPis and the initiation of high-dose corticosteroids. Corticosteroids should be tapered over the course of at least 4-6 weeks. Some refractory cases may require other immunosuppressive therapy. In general, permanent discontinuation of ICPis is recommended with grade 4 toxicities, except for endocrinopathies that have been controlled by hormone replacement. Additional information is available at www.asco.org/supportive-care-guidelines .

Abstract: To increase awareness, outline strategies, and offer guidance on the recommended management of immune-related adverse events (irAEs) in patients treated with chimeric antigen receptor (CAR) T-cell therapy. METHODS A multidisciplinary panel of medical oncology, neurology, hematology, emergency medicine, nursing, trialists, and advocacy experts was convened to develop the guideline. Guideline development involved a systematic literature review and an informal consensus process. The systematic review focused on evidence published from 2017 to 2021. RESULTS The systematic review identified 35 eligible publications. Because of the paucity of high-quality evidence, recommendations are based on expert consensus. RECOMMENDATIONS The multidisciplinary team issued recommendations to aid in the recognition, workup, evaluation, and management of the most common CAR T-cell–related toxicities, including cytokine release syndrome, immune effector cell–associated neurotoxicity syndrome, B-cell aplasia, cytopenias, and infections. Management of short-term toxicities associated with CAR T cells begins with supportive care for most patients, but may require pharmacologic interventions for those without adequate response. Management of patients with prolonged or severe CAR T-cell–associated cytokine release syndrome includes treatment with tocilizumab with or without a corticosteroid. On the basis of the potential for rapid decline, patients with moderate to severe immune effector cell–associated neurotoxicity syndrome should be managed with corticosteroids and supportive care. Additional information is available at www.asco.org/supportive-care-guidelines .

Abstract: Background: To address the current and long-term unmet health needs of the growing population of patients diagnosed with non-Hodgkin lymphoma (NHL) and NHL survivors, we established the Lymphoma Epidemiology of Outcomes (LEO) cohort study (NCT02736357; https://leocohort.org/) with recruitment at eight centers (Cornell University, Emory University, Mayo Clinic, MD Anderson, University of Iowa, University of Miami, University of Rochester, and Washington University). Here we report on the first two years of enrollment. Methods: All patients ≥18 years with NHL (exclusive of chronic lymphocytic leukemia) newly diagnosed within 183 days of enrollment are eligible. LEO reviews all pathology diagnoses; annotates and harmonizes all cases with clinical, epidemiologic, pathology and treatment data; builds a NHL tumor bank that includes an H & E slide, a formalin-fixed, paraffin-embedded tissue sample and extracted tumor DNA and RNA; collects peripheral blood and banks DNA, serum, plasma and buffy coat in a central biorepository; and prospectively follows patients regularly to ascertain disease progression/relapse, retreatment, transformation, second cancers, survival, updated exposures, and patient-reported outcomes. We examined the demographics, clinical characteristics, and NHL subtypes for patients enrolled in the first two years (2015-2017) in LEO Cohort and compared these characteristics to population-based registry data from the United States Surveillance, Epidemiology, and End Results (SEER) Program for 2011-2015. We also examined baseline body mass index (BMI), comorbidities and quality of life (QOL) measured with the Functional Assessment of Cancer Therapy - General (FACT-G) scores (0-100 scale) overall and by NHL subtype that were collected in LEO but not available in SEER or any other large, prospective US NHL cohort. Results: From 2015-2017, LEO enrolled 3244 NHL patients across 47 states (Figure) with a median age at diagnosis of 62 years (range, 18-94 years) and 55.9% male. Based on self-identified race/ethnicity, 85% of the participants were White, 7.4% were Black/African American, 2.6% were Asian, and 3.5% other or more than one race; 9.9% were Hispanic (regardless of race). The most common subtypes were diffuse large B-cell (DLBCL, 33.9%), follicular (FL, 22.2%), mantle cell (MCL, 9.3%), marginal zone (MZL, 8.3%), T-cell (TCL, 10.9%), and all other NHL subtypes (other NHL, 15.3%). These distributions were all within 5% of SEER data, except that 6.8% of participant in LEO were in the age 80+ years group compared to 18.5% in SEER (Table). The overall prevalence of self-reported comorbidities at enrollment was 13.5% for heart disease (range, 12.1% for FL to 16.6% for MCL), 8.8% for diabetes (range, 7.1% for FL to 9.8% for DLBCL), 4.6% for osteoporosis (range, 3.0% for MCL to 6.3% for MZL), and 5.9% for autoimmune disease (range, 2.0% for MCL to 12.6% for MZL). The median BMI was 27.9 kg/m2 (range, 26.7 kg/m2 for TCL to 28.3 kg/m2 for MZL). A total of 2151 participants completed the FACT-G with a median score of 78.7 (range, 75.9 for TCL to 83.3 for MZL). Complete IPI data were available on 2296 participants: 40.4% IPI 0-1, 32.7% IPI 2, 18.3% IPI 3, 8.7% IPI 4-5. Overall, 73.7% of participants were initially treated with systemic therapy (range, 40.0% for MZL and 91.8% for DLBCL); 14.5% were initially managed with observation (range, 1.4% DLBCL and 31.8% for FL); and 2.0% were initially manage with radiotherapy (range, 0.2% for MCL and 3.8% for DLBCL). Outcomes are being prospectively collected. Conclusions: LEO is a large and diverse cohort of newly diagnosed NHL patients and the first two years of enrollment reflects the broader United States NHL population. Enrollment is ongoing. This unique resource will enable examination of the interactions among a broad array of clinical and molecular factors and their impact on multiple outcomes, to improve prognostication, identify new approaches to improve outcomes and survivorship, and facilitate clinical trials using this infrastructure. Disclosures Flowers: Acerta: Research Funding; Pharmacyclics/ Janssen: Consultancy; OptumRx: Consultancy; Janssen Pharmaceutical: Research Funding; V Foundation: Research Funding; Burroughs Wellcome Fund: Research Funding; Spectrum: Consultancy; Eastern Cooperative Oncology Group: Research Funding; Abbvie: Consultancy, Research Funding; Bayer: Consultancy; Millennium/Takeda: Research Funding; Abbvie: Research Funding; Celgene: Research Funding; Gilead: Consultancy; BeiGene: Research Funding; Karyopharm: Consultancy; Denovo Biopharma: Consultancy; Genentech/Roche: Consultancy; Gilead: Research Funding; Genentech/Roche: Research Funding; National Cancer Institute: Research Funding; TG Therapeutics: Research Funding; Pharmacyclics: Research Funding. Nastoupil:TG Therappeutics: Research Funding; Merck: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Janssen: Research Funding; Spectrum: Honoraria; Gilead: Honoraria; Genentech: Honoraria, Research Funding; Karus: Research Funding; Novartis: Honoraria; Juno: Honoraria. Kahl:Acerta: Consultancy; Genentech: Consultancy; Seattle Genetics: Consultancy; Juno: Consultancy; CTI: Consultancy; ADC Therapeutics: Consultancy; Gilead: Consultancy; Celgene: Consultancy; AstraZeneca: Consultancy; Abbvie: Consultancy. Casulo:Celgene: Research Funding; Gilead: Honoraria. Friedberg:Bayer: Honoraria. Lossos:Affimed: Research Funding. Martin:Seattle Genetics: Consultancy; Kite: Consultancy; Janssen: Consultancy; Gilead: Consultancy; Bayer: Consultancy; AstraZeneca: Consultancy. Leonard:Bayer: Consultancy; Celgene: Consultancy; Biotest: Consultancy; United Therapeutics: Consultancy; BMS: Consultancy; MEI Pharma: Consultancy; Juno: Consultancy; Sutro: Consultancy; Karyopharm: Consultancy; ADC Therapeutics: Consultancy; Pfizer: Consultancy; AstraZeneca: Consultancy; Gilead: Consultancy; Genentech/Roche: Consultancy; Novartis: Consultancy. Bernal-Mizrachi:Kodikaz Therapeutic Solutions: Consultancy, Equity Ownership; Takeda Pharmaceutical Company: Research Funding. Maurer:Morphosys: Research Funding; Nanostring: Research Funding; Celgene: Research Funding. Cerhan:Nanostring: Research Funding; Jannsen: Other: Scientific Advisory Board; Celgene: Research Funding.

Abstract: CNS progression or relapse is an uncommon but devastating complication of aggressive B-cell lymphoma. There is no consensus regarding the optimal approach to CNS prophylaxis. This study was designed to determine whether high-dose methotrexate (HD-MTX) is effective at preventing CNS progression in patients at high risk of this complication. PATIENTS AND METHODS Patients age 18-80 years with aggressive B-cell lymphoma and high risk of CNS progression, treated with curative-intent anti–CD20-based chemoimmunotherapy, were included in this international, retrospective, observational study. Cause-specific hazard ratios (HRs) and cumulative risks of CNS progression were calculated according to use of HD-MTX, with time to CNS progression calculated from diagnosis for all patients (all-pts) and from completion of frontline systemic lymphoma induction therapy, for patients in complete response at completion of chemoimmunotherapy (CR-pts). RESULTS Two thousand four hundred eighteen all-pts (HD-MTX; n = 425) and 1,616 CR-pts (HD-MTX; n = 356) were included. CNS International Prognostic Index was 4-6 in 83.4% all-pts. Patients treated with HD-MTX had a lower risk of CNS progression (adjusted HR, 0.59 [95% CI, 0.38 to 0.90]; P = .014), but significance was not retained when confined to CR-pts (adjusted HR, 0.74 [95% CI, 0.42 to 1.30] ; P = .29), with 5-year adjusted risk difference of 1.6% (95% CI, –1.5 to 4.4; all-pts) and 1.4% (95% CI, –1.5 to 4.1; CR-pts). Subgroups were underpowered to draw definitive conclusions regarding the efficacy of HD-MTX in individual high-risk clinical scenarios; however, there was no clear reduction in CNS progression risk with HD-MTX in any high-risk subgroup. CONCLUSION In this large study, high-risk patients receiving HD-MTX had a 7.2% 2-year risk of CNS progression, consistent with the progression risk in previously reported high-risk cohorts. Use of HD-MTX was not associated with a clinically meaningful reduction in risk of CNS progression.

Abstract: 7518 Background: T-cell directed therapies (e.g., CAR-T, blinatumomab) are associated with significant risk of Grade (Gr) ≥3 neurotoxicity and CRS/infusion-related reaction (IRR). Mosunetuzumab is a CD20/CD3 bispecific antibody that directs T-cells to engage and eliminate malignant B-cells. We report safety results from an ongoing phase 1/1b study of mosunetuzumab in patients (pts) with R/R B-cell NHL. Methods: Pts received ascending doses on Day 1, Day 8, and Day 15 of Cycle 1 (step-fractionation), then a fixed dose on Day 1 of every 21-day cycle thereafter, up to a maximum of 17 cycles. Primary outcome measures included safety and efficacy. Results: As of October 23, 2018, 114 pts who received step-fractionated dosing of mosunetuzumab were evaluable for safety (Table). The majority of adverse events (AE) occurred during Cycle 1 and 2. Neurologic AEs (NAE), defined from Nervous System or Psychiatric System Organ Classes, were mostly low grade, transient (median duration 4 days) and reversible; most common ones were headache (14%) and dizziness (8%). Gr ≥3 NAEs occurred in 4 pts (4%) with only 1 treatment-related event (hepatic encephalopathy). CRS/IRR was reported in 25% of pts, with only 1 Gr 3 event. Most common CRS symptoms were pyrexia (86%), chills (38%), and tachycardia and headache (14% each). There were no Gr 5 events related to CRS or NAEs. No apparent dose toxicity relationship was observed with step-fractionation in these pts, despite escalation of the Cycle 1 Day 15 dose to 20 mg, consistent with observed peak IL-6 levels after a low Cycle 1 Day 1 dose. In these pts, objective responses were observed in 24/73 (33%; complete response [CR], 13 [18%] ) aggressive NHL and 17/32 (53%; CR, 10 [31%]) indolent NHL pts. Conclusions: Step-fractionation has enabled continued dose escalation of mosunetuzumab with no apparent increases in toxicity, exhibiting a promising risk-benefit profile. Clinical trial information: NCT02500407; GO29781. [Table: see text]

Abstract: To increase awareness, outline strategies, and offer guidance on the recommended management of immune-related adverse events in patients treated with immune checkpoint inhibitor (ICPi) therapy. Methods A multidisciplinary, multi-organizational panel of experts in medical oncology, dermatology, gastroenterology, rheumatology, pulmonology, endocrinology, urology, neurology, hematology, emergency medicine, nursing, trialist, and advocacy was convened to develop the clinical practice guideline. Guideline development involved a systematic review of the literature and an informal consensus process. The systematic review focused on guidelines, systematic reviews and meta-analyses, randomized controlled trials, and case series published from 2000 through 2017. Results The systematic review identified 204 eligible publications. Much of the evidence consisted of systematic reviews of observational data, consensus guidelines, case series, and case reports. Due to the paucity of high-quality evidence on management of immune-related adverse events, recommendations are based on expert consensus. Recommendations Recommendations for specific organ system–based toxicity diagnosis and management are presented. While management varies according to organ system affected, in general, ICPi therapy should be continued with close monitoring for grade 1 toxicities, with the exception of some neurologic, hematologic, and cardiac toxicities. ICPi therapy may be suspended for most grade 2 toxicities, with consideration of resuming when symptoms revert to grade 1 or less. Corticosteroids may be administered. Grade 3 toxicities generally warrant suspension of ICPis and the initiation of high-dose corticosteroids (prednisone 1 to 2 mg/kg/d or methylprednisolone 1 to 2 mg/kg/d). Corticosteroids should be tapered over the course of at least 4 to 6 weeks. Some refractory cases may require infliximab or other immunosuppressive therapy. In general, permanent discontinuation of ICPis is recommended with grade 4 toxicities, with the exception of endocrinopathies that have been controlled by hormone replacement. Additional information is available at www.asco.org/supportive-care-guidelines and www.asco.org/guidelineswiki .

Abstract: Background: Follicular lymphoma (FL) remains an incurable disease for most patients (pts), characterized by a relapsing and remitting pattern. For pts with relapsed/refractory (r/r) FL, treatment outcomes typically worsen with each subsequent line of therapy, highlighting an unmet need. Tisagenlecleucel (tisa-cel) has demonstrated clinical benefits and manageable safety in pediatric and young adult pts with r/r B-cell acute lymphoblastic leukemia and adult pts with r/r diffuse large B-cell lymphoma. In a prior phase (Ph) 2a study of 14 pts with r/r FL, 71% achieved durable complete remission with tisa-cel (Chong et al. ICML 2019). Here we present a planned interim analysis of ELARA, a Ph 2, international trial of tisa-cel in adults with r/r FL. Methods: Adults with histologically confirmed FL (grades [Gr] 1-3A) being r/r within 6 mo after second-/later-line therapy (including an anti-CD20 monoclonal antibody with an alkylating agent) or relapsed after autologous hematopoietic stem cell transplant (autoHSCT), and with ECOG performance score of 0-1 were eligible. Pts wi th histologic transformation, prior allogeneic HSCT, or active CNS involvement were excluded. All pts received lymphodepleting chemotherapy followed by tisa-cel infusion of 0.6-6×108 CAR-T cells (bridging therapy prior to infusion was permitted). Disease was reassessed prior to infusion for all pts who received bridging therapy to establish a new baseline. After infusion, disease assessments were performed every 3 mo. The primary endpoint was complete response rate (CRR) based on best response by central review (Lugano 2014 criteria). Pts evaluable for efficacy had measurable disease at infusion and ≥6 mo follow-up from infusion or discontinued early. Secondary endpoints included overall response rate (ORR), duration of response (DOR), progression-free survival (PFS), overall survival (OS), and safety. Results: As of May 26, 2020, 122 pts were screened, 98 were enrolled, 97 received tisa-cel (median follow-up, 6.5 mo), and 52 were evaluable for efficacy (median follow-up, 9.9 mo). At study entry, median age among treated pts was 57 y (range, 29-73), 66% of pts were male, 84% had stage III-IV disease, and 60% had a FLIPI score ≥3. The median number of prior lines of therapy was 4 (range, 2-13), including prior autoHSCT in 36%; 77% were refractory to the last prior treatment (75% ≥2 prior regimens), and 60% had disease progression within 2 y of initial anti-CD20-containing treatment. Overall, 43% of pts received bridging therapy; 18% were treated as outpatient. Of the first 52 pts evaluable for efficacy, CRR was 65.4% (34/52; 99.5% CI, 45.1-82.4) in the intent-to-treat (ITT) population and 71.1% (33/46; 99.5% CI, 56.5-84.0) in the per-protocol (PP) population; ORR was 82.7% (43/52; 95% CI, 69.7-91.8) in the ITT population and 84.8% (39/46; 95% CI, 71.1-93.7) in the PP population. In pts with best response of CR, probability of response lasting ≥6 mo was 89.7% (84.4% for all responding pts [CR+PR]). CRR and ORR were consistent across key prognostic subgroups and per investigator assessment. Median DOR, PFS, OS, and time to next antilymphoma treatment were not reached. Of 97 pts evaluable for safety, 69% experienced Gr ≥3 adverse events, most commonly neutropenia (Gr 3, 13%; Gr 4, 15%); 48% of pts had cytokine release syndrome related to tisa-cel (CRS; Gr 1, 29%; Gr 2, 20%; Gr ≥3, 0%; per Lee scale). To treat CRS, 15% of pts required tocilizumab and 3% required steroids. Any grade serious neurologic events (NEs; per CTCAE v4.03) occurred in 10% of pts; 2% had Gr ≥3 and all recovered (1 pt developed Gr 4 immune-effector cell neurotoxicity syndrome related to tisa-cel concomitant with possible HHV6 encephalitis; 1 pt developed Gr 3 delirium unrelated to tisa-cel after progression of disease and start of salvage therapy). Median time to CRS and serious NEs onset were 4 and 8.5 d, respectively, with respective median time to resolution of 4 and 2 d. Three pts died from progressive disease; no deaths were treatment-related. Conclusions: Preliminary data from ELARA suggest that tisa-cel is effective in extensively treated r/r FL, resulting in high CRRs and ORRs, including in high-risk pts. The overall safety profile is favorable, with no severe CRS and very low NE reported, requiring limited anticytokine therapy. Updated safety and efficacy results on 97 pts (including dose and cellular kinetics data) will be presented at the meeting. Disclosures 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. Dickinson:Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Gilead: Consultancy, Honoraria, Research Funding, Speakers Bureau; Merck Sharp & Dohme: Consultancy; Novartis: Consultancy, Honoraria, Research Funding, Speakers Bureau; Janssen: Consultancy, Honoraria, Speakers Bureau. Dreyling:Astra Zeneca: Consultancy; Abbvie: Research Funding; Roche: Consultancy, Research Funding, Speakers Bureau; Celgene: Consultancy, Research Funding, Speakers Bureau; Bayer: Consultancy, Speakers Bureau; Beigene: Consultancy; Gilead: Consultancy, Research Funding, Speakers Bureau; Janssen: Consultancy, Research Funding, Speakers Bureau; Novartis: Consultancy. Martinez-Lopez:Janssen: Consultancy, Honoraria; Novartis: Consultancy; Janssen-cilag: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Consultancy, Research Funding; Incyte: Consultancy, Research Funding. Kolstad:Merck: Research Funding; Nordic Nanovector: Membership on an entity's Board of Directors or advisory committees, Research Funding. Popplewell:Pfizer: Research Funding; Novartis: Research Funding; Roche: Research Funding. Chavez:Genentech: Speakers Bureau; Epizyme: Speakers Bureau; Gilead: Consultancy; Verastem: Consultancy; AbbVie: Consultancy; Karyopharm: Consultancy; BeiGene: Speakers Bureau; Novartis: Consultancy; Kite, a Gilead Company: Consultancy, Speakers Bureau; Pfizer: Consultancy; AstraZeneca: Speakers Bureau; Morphosys: Consultancy, Speakers Bureau; Merck: Research Funding; Bayer: Consultancy; Celgene: Consultancy. Bachy:Beigene: Membership on an entity's Board of Directors or advisory committees; Roche, Celgene, Amgen, Janssen, Gilead, Novartis, Sanofi: Honoraria; Amgen: Research Funding; Roche, Gilead: Consultancy. Kato:AbbVie, AstraZeneca, Celgene, Chugai, Eisai, Janssen, and Novartis: Consultancy; hugai, Takeda, Kyowa-Kirin, Abbvie, Novartis, Eisai, Janssen, Celgene, Ono: Research Funding; Chugai, Takeda, MSD, Kyowa-Kirin, Janssen, Celgene, Ono, Mundi, Dainippon-Sumitomo, Novartis: Honoraria. Harigae:Novartis, Chugai, BMS: Honoraria. Kersten:BMS: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); Celgene: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Research Funding; Amgen: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); Janssen/Cilag: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); Miltenyi Biotech: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); Takeda: Research Funding; Roche: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Research Funding; Kite/Gilead: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); MSD: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); Novartis: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company). Andreadis:Novartis: Research Funding; Gilead/Kite: Consultancy; Merck: Research Funding; Incyte: Consultancy; Karyopharm: Honoraria; Jazz Pharmaceuticals: Honoraria; BMS/Celgene/Juno: Honoraria, Research Funding; Genentech: Consultancy, Current equity holder in publicly-traded company. Riedell:Bayer: Honoraria; Karyopharm Therapeutics: Honoraria; Morphosys: Research Funding; Celgene/Bristol-Myers Squibb Company: Honoraria, Research Funding; Verastem Oncology: Honoraria; Kite Pharmaceuticals/Gilead: Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding. Nastoupil:Karus Therapeutics: Research Funding; Gamida Cell: Honoraria; Gilead/KITE: Honoraria; Novartis: Honoraria, Research Funding; Merck: Research Funding; Celgene: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding; Bayer: Honoraria; Janssen: Honoraria, Research Funding; LAM Therapeutics: Research Funding; TG Therapeutics: Honoraria, Research Funding; Genentech, Inc.: Honoraria, Research Funding. von Tresckow:Takeda: Honoraria, Other: Travel support, Research Funding; Amgen: Honoraria; Pfizer: Honoraria; Kite/Gilead: Honoraria; Roche: Honoraria; MSD Sharp & Dohme: Honoraria, Research Funding; Takeda: Honoraria, Other: Travel support, Research Funding; Novartis: Other: Travel support, Research Funding. Ferreri:Morphosys: Research Funding; Hutchinson: Research Funding; BMS: Research Funding; Gilead: Membership on an entity's Board of Directors or advisory committees, Research Funding. Teshima:Sharp & Dohme Corp: Consultancy, Honoraria; Bristol-Myers Squibb: Honoraria; Pfizer Japan Inc.: Honoraria; Kyowa Kirin Co., Ltd.: Honoraria, Research Funding; TEIJIN PHARMA LIMITED: Honoraria; The Center of Innovation Program from Japan Science and Technology Agency: Other; Fuji Pharma Co., Ltd.: Honoraria; NIPPON SHINYAKU CO., LTD.: Honoraria; Janssen Pharmaceutical K.K.: Other; Japan Society for the Promotion of Science KAKENHI (17H04206): Other; Novartis Pharma K.K.: Consultancy, Other: Manuscript preparation, Research Funding; Takeda Pharmaceutical Company Limited: Consultancy, Honoraria; Chugai Pharmaceutical Co., Ltd.: Research Funding; Astellas Pharma Inc.: Research Funding; Merck: Consultancy, Honoraria; Sanofi K.K.: Research Funding. Patten:Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Astra Zeneca: Honoraria; Gilead: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Consultancy, Honoraria. McGuirk:Novartis: Research Funding; Fresenius Biotech: Research Funding; Astellas: Research Funding; Juno Therapeutics: Consultancy, Honoraria, Research Funding; Allo Vir: Consultancy, Honoraria, Research Funding; Kite Pharmaceuticals: Consultancy, Honoraria, Research Funding, Speakers Bureau; Pluristem Ltd: Research Funding; Gamida Cell: Research Funding; Bellicum Pharmaceutical: Research Funding. Petzer:Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Kite-Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees. Viardot:Amgen: Honoraria, Other: advisory board; Novartis: Honoraria, Other: advisory board; Kite/Gilead: Honoraria, Other: advisory board; Roche: Honoraria, Other: advisory board. Zinzani:ADC Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; MSD: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Immune Design: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Merck: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; EUSA Pharma: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Immune Design: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Incyte: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sanofi: Consultancy, Membership on an entity's Board of Directors or advisory committees; Sandoz: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Portola: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Kyowa Kirin: Consultancy, Speakers Bureau; Eusapharma: Consultancy, Speakers Bureau; Verastem: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Kirin Kyowa: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Servier: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Gilead: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; TG Therapeutics, Inc.: Honoraria, Speakers Bureau; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen-Cilag: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Consultancy, Honoraria, Speakers Bureau; Celltrion: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Malladi:Novartis: Consultancy, Honoraria. Bubuteishvili Pacaud:Novartis: Current Employment. Forcina:Novartis: Current Employment. Zia:Novartis: Current Employment. Schuster:Novartis, Genentech, Inc./ F. Hoffmann-La Roche: Research Funding; AlloGene, AstraZeneca, BeiGene, Genentech, Inc./ F. Hoffmann-La Roche, Juno/Celgene, Loxo Oncology, Nordic Nanovector, Novartis, Tessa Therapeutics: Consultancy, Honoraria. Thieblemont:Cellectis: Speakers Bureau; Roche, Amgen, Kyte Gilead, Celgene, Abbvie, Novartis, Cellectis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel support; Roche, Hospita: Research Funding.

Abstract: Background: Follicular lymphoma (FL) is the most common indolent lymphoma and is generally characterized by prolonged survival with multiple relapses throughout the disease course. There is no standard of care as to the initial choice or sequencing of treatments for relapsed disease. Novel agents approved in the relapsed setting include lenalidomide in combination with rituximab (R2) and PI3K inhibitors (PI3Ki) including idelalisib, duvelisib, and copanlisib. However, there are no prospective data comparing the safety/efficacy of these novel agents to guide treatment selection. We aimed to examine the characteristics and outcomes of patients with relapsed follicular lymphoma treated with these novel agents. Methods: We conducted a retrospective analysis of adult patients with FL treated with commercially-available novel agents at 10 US academic cancer centers. Patients were excluded if they received one of these therapies as first line therapy or for the treatment of transformed disease. Treatment with lenalidomide or PI3Ki was determined by the treating physician, as was the decision to incorporate monoclonal antibody (mAb). For patients who received both classes of novel agent, baseline and treatment characteristics were grouped by first novel class used. The Fisher's Exact test was used to compare categorical variables and the Mann Whitney U test for continuous variables. Progression-free survival (PFS) was defined as time from the initiation of the first novel agent to progression of disease (POD), either FL or transformed disease, or death from any cause. Overall survival (OS) was defined as time from the initiation of the first novel agent to death from any cause. Outcomes were estimated using the Kaplan-Meier method and compared using the log-rank test. Results: 98 patients were included. Available baseline characteristics at diagnosis are described in Table 1. The median time from the end of the last FL treatment to the start of the first novel agent was 12 months (range 0-79). The first novel agent was lenalidomide +/-mAb in 49% (n=48) of the patients and a PI3Ki +/- mAb in 51% (n=50) of patients. Idelalisib was the most commonly used PI3Ki (n=47) followed by copanlisib (n=2) and duvelisib (n=1). The median number of therapies prior to the first novel agent was 2 (range 1-8) and not significantly different between treatment classes. Reason for discontinuation of novel agent was significantly different between groups with greater discontinuations due to toxicity (40% vs 28%) and transformed disease (15% vs. 3%) for the PI3Ki ± mAb group vs. lenalidomide ± mAb group, respectively (p = 0.02). The median PFS and OS for the entire cohort was 10 months (95% CI 7.6-14) and 120 months (95% CI, 49-NA), respectively (Figure A). When comparing outcomes to current FDA approvals-lenalidomide + mAb (n=43) versus PI3Ki monotherapy (PI3Ki, n=38), the median PFS was significantly longer in the lenalidamide + mAb group compared to the PI3Ki group (15 vs. 6 months, p=0.016), as was the OS (120 vs. 37 months, p=0.002, respectively, Figure B). Conclusions: In this multi-center analysis, despite multiple relapses, the median survival for FL patients treated with novel agents was 120 months from the initiation of the first novel therapy. With the caveat of retrospective comparison, lenalidomide + mAb (i.e. R2) appears superior to PI3Ki as first novel agent in the relapsed setting with the recognition that a high proportion of patients discontinued PI3Ki due to toxicity. Because the majority of the patients received idelalisib conclusions cannot be drawn about alternative PI3Ki which may have lower toxicity profiles or intermittent dosing strategies, allowing for safer and more prolonged treatment. Future prospective studies are needed to directly compare these agents and determine optimal sequencing of therapies. Disclosures Landsburg: Takeda: Research Funding; Triphase: Research Funding; Triphase: Research Funding; Takeda: Research Funding; Curis, INC: Consultancy, 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; Celgene: Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Speakers Bureau; Seattle Genetics: Speakers Bureau; Curis, INC: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Kahl:AbbVie Inc, Acerta Pharma - A member of the AstraZeneca Group, AstraZeneca Pharmaceuticals LP, BeiGene, Celgene Corporation, Genentech, Pharmacyclics LLC, an AbbVie Company, Roche Laboratories Inc.: Consultancy. Maddocks:Merck: Research Funding; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Teva: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; BMS: Research Funding; Novartis: Research Funding. Danilov:TG Therapeutics: Consultancy; Bayer Oncology: Consultancy, Research Funding; Celgene: Consultancy; Curis: Consultancy; Seattle Genetics: Consultancy; Aptose Biosciences: Research Funding; Takeda Oncology: Research Funding; Bristol-Meyers Squibb: Research Funding; MEI: Research Funding; Janssen: Consultancy; Abbvie: Consultancy; Pharmacyclics: Consultancy; Gilead Sciences: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; AstraZeneca: Consultancy, Research Funding; Verastem Oncology: Consultancy, Other: Travel Reimbursement , Research Funding. Ujjani:Pharmacyclics: Honoraria; PCYC: Research Funding; Atara: Consultancy; Atara: Consultancy; Genentech: Honoraria; AbbVie: Honoraria, Research Funding; Gilead: Consultancy; Pharmacyclics: Honoraria; PCYC: Research Funding; Astrazeneca: Consultancy; Genentech: Honoraria; AbbVie: Honoraria, Research Funding. Lynch:Juno Therapeutics: Research Funding; Rhizen Pharmaceuticals S.A: Research Funding; T.G. Therapeutics: Research Funding; Incyte Corporation: Research Funding; Takeda Pharmaceuticals: Research Funding; Johnson Graffe Keay Moniz & Wick LLP: Consultancy. Nastoupil:Gilead: Honoraria; Bayer: Honoraria; Celgene: Honoraria, Research Funding; Spectrum: Honoraria; TG Therapeutics: Honoraria, Research Funding; Novartis: Honoraria; Janssen: Honoraria, Research Funding; Genentech, Inc.: Honoraria, Research Funding. Ghosh:Forty Seven Inc: Research Funding; Celgene: Consultancy, Research Funding, Speakers Bureau; Genentech: Research Funding; T G Therapeutics: Consultancy, Research Funding; Gilead/Kite: Consultancy, Speakers Bureau; Pharmacyclics: Consultancy, Research Funding, Speakers Bureau; AbbVie: Consultancy, Speakers Bureau; Seattle Genetics: Consultancy, Speakers Bureau; Spectrum: Consultancy, Speakers Bureau; Astra Zeneca: Speakers Bureau. Stephens:Karyopharm: Research Funding; Gilead: Research Funding; Acerta: Research Funding. Cohen:ASH: Research Funding; Lymphoma Research Foundation: Research Funding; Astra Zeneca: Research Funding; Seattle Genetics, Inc.: Consultancy, Research Funding; Bristol-Meyers Squibb Company: Research Funding; Takeda Pharmaceuticals North America, Inc.: Research Funding; Gilead/Kite: Consultancy; LAM Therapeutics: Research Funding; UNUM: Research Funding; Hutchison: Research Funding; Genentech, Inc.: Consultancy, Research Funding; Janssen Pharmaceuticals: Consultancy. Hill:Gilead: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Research Funding; Takeda: Research Funding; Genentech: Consultancy, Research Funding; Celegene: Consultancy, Honoraria, Research Funding; Seattle Genetics: Consultancy, Honoraria; TG therapeutics: Research Funding; AstraZeneca: Consultancy, Honoraria; Pharmacyclics: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Abbvie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Kite: Consultancy, Honoraria.