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Abstract Purpose: Axicabtagene ciloleucel (axi-cel) is an anti-CD19 chimeric antigen receptor T-cell (CAR-T) therapy utilized for patients with non-Hodgkin lymphoma (NHL) refractory to at least 2 lines of therapy. F-18 fluorodeoxyglucose positron emission tomography/computed tomography (PET/CT) is used to evaluate disease extent prior to CAR-T infusion at two time points: pre-leukapheresis (pre-leuk) approximately 6 weeks prior to CAR-T infusion, and pre-lymphodepletion chemotherapy (pre-LD) approximately 1 week prior to CAR-T infusion. We hypothesized that PET/CT characteristics beyond Lugano criteria, such as metabolic tumor volume (MTV), total lesion glycolysis (TLG), SUV maximum (SUVMax), and changes in these parameters from pre-leuk to pre-LD, may predict for progressive disease (PD), death, and treatment toxicity after CAR-T infusion. Methods: Patients with NHL who received axi-cel on a prospective registry at Mayo Clinic Rochester were included. Lesions on pre-leuk and pre-LD PET/CT scans were segmented with a fixed absolute SUVMax threshold of 2.5 using a semi-automated workflow (LesionID, MIM Software Inc.) with manual modification to exclude physiologic uptake as needed. MTV, TLG, SUVMax, number of lesions, and other lesion characteristics were assessed for each PET/CT, and changes from pre-leuk to pre-LD were calculated. Lesions were categorized as either nodal, spleen, bone, parenchymal (i.e. liver, lung), or soft tissue (i.e. subcutaneous, muscle), and MTV was calculated for each category. Univariate Cox modeling was used to associate relative and directional change in metabolic and volumetric PET/CT characteristics with PD and death, after adjusting for bridging therapy. LASSO method was used for multivariable model selection. Pre-LD PET/CT characteristics were also assessed for association with presence and duration of cytokine release syndrome (CRS), grade 3+ immune effector cell-associated neurotoxicity syndrome (ICANS), tocilizumab (toci) use, and corticosteroid use. Results: From 2018-2020, axi-cel was delivered to 69 patients. Histology included diffuse large B-cell lymphoma (57%), transformed follicular lymphoma (23%), or high-grade lymphoma (19%). Pre-leuk and pre-LD PET/CT scans were performed a median of 46 days and 7 days prior to CAR-T infusion, respectively. Forty patients (58%) received bridging therapy between scans, including 9 (13%) receiving radiotherapy. At a median follow-up of 13 months, 39 (57%) had died and 46 (67%) had PD. Sixty patients (87%) developed CRS following CAR-T infusion for a median duration of 5 days. Presence of pre-LD parenchymal disease was associated with longer duration CRS (p=0.032). Thirty-seven patients (54%) developed ICANS for a median duration of 4.5 days, including 12 (32%) with grade 3+ ICANS. Greater pre-LD total MTV was associated with higher risk of grade 3+ ICANS (p=0.042). Greater pre-LD SUVMax was associated with longer duration ICANS (p=0.032). Nineteen (28%) patients required toci. Greater pre-LD total MTV, SUVMax, TLG, and volume of the largest lesion were associated with increased use of toci (p<0.05 for all). Greater pre-LD total MTV and TLG of the largest lesion were associated with increased use of corticosteroid (p<0.05 for each). While no individual pre-leuk or pre-LD PET/CT characteristics were associated with risk of PD or death, increases from pre-leuk to pre-LD in total MTV, total TLG, parenchymal MTV, and nodal MTV were associated with increased risk of PD (Figure 1). Similarly, increases from pre-leuk to pre-LD in parenchymal MTV, nodal MTV, TLG of the largest lesion, and total number of lesions were associated with increased risk of death (p<0.05 for all). LASSO analysis identified increasing extranodal MTV (≥25% increase) and increasing TLG of the largest lesion (≥10% increase) as strong predictors of death (AUC 0.74, Table 1). Kaplan-Meier plots were generated for overall and progression-free survival using these risk factors (Figure 2). Additional patients and follow-up will be presented. Conclusions: Patients with greater pre-LD MTV had higher risk of grade 3+ ICANS and use of toci or corticosteroids. Increasing metabolic disease burden during CAR-T manufacturing is associated with increased risk of PD and death. A two variable risk score using increasing extranodal disease and increasing TLG of the largest lesion may stratify prognosis prior to CAR-T and inform treatment paradigms. Figure 1 Figure 1. Disclosures Bennani: Verastem: Other: Advisory Board; Purdue Pharma: Other: Advisory Board; Daichii Sankyo Inc: Other: Advisory Board; Kyowa Kirin: Other: Advisory Board; Vividion: Other: Advisory Board; Kymera: Other: Advisory Board. Paludo: Karyopharm: Research Funding. Wang: Genentech: Research Funding; LOXO Oncology: Membership on an entity's Board of Directors or advisory committees, Research Funding; Eli Lilly: Membership on an entity's Board of Directors or advisory committees; Incyte: Membership on an entity's Board of Directors or advisory committees, Research Funding; InnoCare: Research Funding; Novartis: Research Funding; MorphoSys: Research Funding; TG Therapeutics: Membership on an entity's Board of Directors or advisory committees. Ansell: Bristol Myers Squibb, ADC Therapeutics, Seattle Genetics, Regeneron, Affimed, AI Therapeutics, Pfizer, Trillium and Takeda: Research Funding. Lin: Gamida Cell: Consultancy; Janssen: Consultancy, Research Funding; Legend: Consultancy; Novartis: Consultancy; Celgene: Consultancy, Research Funding; Sorrento: Consultancy; Bluebird Bio: Consultancy, Research Funding; Takeda: Research Funding; Kite, a Gilead Company: Consultancy, Research Funding; Merck: Research Funding; Vineti: Consultancy; Juno: Consultancy.

The World Health Organization Classification of Tumours of Haematopoietic and Lymphoid Tissues (WHO 2017) included updated criteria for diagnosis and classification of post-transplant lymphoproliferative disorders (PTLDs). This study evaluated the clinicopathologic spectrum using WHO 2017 criteria and adult PTLD patients’ outcomes over 30 years between 1987 and 2017 at Mayo Clinic (Rochester, MN). Patients were retrospectively reviewed for clinical features, outcomes, and diagnostic pathology material and classified based on WHO 2017 criteria. A total of 227 patients were diagnosed with PTLD, with a median time from transplant to PTLD of 45 months. PTLD occurred >1 year after transplant in 149 (66%) patients. Monomorphic PTLD was the most common subtype (173, 76%), with diffuse large B cell lymphoma as the commonest morphology (n = 137). Epstein-Barr virus was positive in 61% of total cases and 90% of PTLD that developed within 1 year from transplant. The median event-free survival (EFS) and overall survival for the entire cohort were 21 months (95% confidence interval [CI]: 9–35) and 82 months (95% CI: 39–115), respectively. The EFS or overall survival was not impacted by Epstein-Barr virus status but differed based on WHO subtypes and year of diagnosis. Management changed over time with increased use of rituximab or chemotherapy + immunosuppression reduction as initial therapy. When compared to the matched general population and de novo diffuse large B cell lymphoma, patients not achieving EFS 24 status (no progression/treatment or death within 24 mo of diagnosis) had a worse standardized mortality ratio 16.75 (95% CI: 13.91–20) versus SMR 1.72 (95% CI: 1.26–2.28) in those who achieved EFS24. Cause of death was mostly attributed to non-lymphoma–related causes in those achieving EFS 24.

e19556 Background: CD19 chimeric antigen receptor T cell therapy possesses unique side effects including cytokine release syndrome (CRS) and immune effector cell associated neurotoxicity syndrome (ICANS). Age is a major risk factor for ICANS. However, whether ICANS in older patients is different compared to younger patients is unknown. Herein, we report clinical course, outcomes and risk factors for ICANS in older patients with large B cell lymphoma (LBCL) treated with axicabtagene ciloleucel (axi-cel). Methods: We comprehensively reviewed detailed clinical courses of ICANS in 78 adult patients with LBCL treated with axi-cel between June 2016 and October 2020. Incidence, manifestation, risk factors, treatment, and outcomes of ICANS were compared between patients age ≥60 (n=32) and <60 (n=46) years old. Results: Baseline characteristics were comparable between older and younger patients except higher proportion of high international prognostic index and underlying cerebral microvascular disease in older patients. ICANS was observed in 16 patients in the older and 24 patients in the younger age group, with a 30-day incidence of 52% and 50%, respectively. Median time to CRS and ICANS were similar between 2 age groups. The most common initial neurological findings included aphasia, dysgraphia and encephalopathy in both age groups. Table summarizes the characteristics, clinical course and interventions of ICANS in older and younger patients. In Cox regression model, the presence of CRS was the only factor associated with ICANS in both age groups. Age, history of central nervous system involvement and cerebral microvascular disease were not associated with ICANS. Importantly, all patients had complete resolution of ICANS. No elderly patients in our cohort experienced seizure as a manifestation of ICANS. Conclusions: In our study, older age was not a risk factor for ICANS. CRS was the only factor associated with ICANS in both younger and older patients. Incidence, clinical course and neurological outcomes of ICANS in older patients treated with axi-cel were comparable to younger patients. [Table: see text]

e19554 Background: Obesity is associated with a pro-inflammatory state and immune dysregulation. Retrospective studies indicate that obesity could affect toxicities and outcomes after immunotherapies including checkpoint inhibitors and allogeneic stem cell transplant. Currently, there are no data specifically on outcomes for obese patients who receive chimeric antigen receptor T (CAR-T) cells. We described the clinical outcome in obese patients with large B cell lymphoma (LBCL) who received axicabtagene ciloleucel (axi-cel). Methods: We analyzed the effect of body weight (BW) and body mass index (BMI) on toxicities and outcomes of 78 adults with LBCL who received axi-cel between June 2016 and October 2020 at Mayo Clinic. Obesity was defined as having BMI of 30 or higher. Results: Of 78 patients, 22 (28%) and 19 (24%) were classified as overweight (BMI 25-29.99 kg/m2) and obese (BMI ≥30 kg/m2), respectively. Baseline characteristics were not statistically significantly different between non-obese and obese patients. The median delivered dose of fludarabine was similar between non-obese and obese patients (89 [0-105] vs 88 [56-94] mg/m2, P=0.32) whereas the median delivered dose of cyclophosphamide was lower in non-obese patients (1503 [1077-1525] vs 1512 [1021-1660] mg/m2, P=0.01). The 30-days cumulative incidence of CRS and ICANS were similar between non-obese and obese patients. BW and BMI were not associated with CRS or ICANS. The overall response rate was 66% (CR 47%) and 68% (CR 53%) in non-obese and obese group, respectively ( P=0.83). The 1-year event free survival (EFS) and overall survival (OS) was 34.6% and 64.5%, neither were different between non-obese and obese patients (EFS 35.8% vs. 30.7%, P=0.60; OS 59.4% vs. 83.9%, P=0.18). The 1-year cumulative incidence of relapse and non-relapse mortality was comparable (60.8% vs. 69.0%, P=0.40 and 3.4% vs. 0%, P=0.42). In the Cox proportional hazards model, higher dose of fludarabine, but not cyclophosphamide, was associated with better EFS and OS; however, neither obesity nor BW were associated with toxicities and outcomes. Conclusions: In our study, Obesity was not associated with risk of toxicities or adverse survival outcomes. The effect of obesity on the pattern of LD chemotherapy dosing including toxicities and outcomes after CAR-T warrants further exploration. [Table: see text]

Abstract The dilemma of whether to treat elderly patients with diffuse large B-cell lymphoma (DLBCL) with a full or reduced dose intensity (DI) of R-CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisolone+rituximab) is often faced by clinicians. We conducted a systematic review assessing the impact of R-CHOP DI on DLBCL survival outcomes, according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses for Protocols (PRISMA-P) guidelines. We searched MEDLINE, EMBASE, and Cochrane CENTRAL for studies with ≥100 patients treated with R-CHOP/R-CHOP–like therapies published from January 2002 through November 2020. Studies were included if they reported the impact of R-CHOP DI on survival outcomes. We screened records, extracted data, and reviewed all the studies for quality and statistical appraisal. Of 380 screened records, 13 studies including 5188 patients were reviewed. DI was often calculated as the ratio of the cumulative delivered dose of prespecified drug(s) to the cumulative planned dose multiplied by a time-correction factor. Lower DI (intended or relative) was associated with inferior survival in 7 of 9 studies reporting crude survival analyses. Multivariable analysis using DI as a covariate was performed in 10 studies. Six showed an association (P &lt; .05) with adjustment for other covariates, and 4 did not. Most studies and those larger studies of higher quality showed poorer outcomes associated with reduced DI. In subgroups aged ≥80 years, survival was not consistently affected by reduced DI. DI-specific randomized trials are warranted, but these data support full-dose R-CHOP in elderly and fit patients aged &lt;80 years with DLBCL, but not in those aged ≥80 years, where dose-reduced R-CHOP does not appear to compromise survival.

AbstractNeurolymphomatosis (NL) is a rare manifestation of lymphoma, with limited evidence for optimal management. The largest patient series, 50 cases of lymphoma and leukemia, was published in 2010 with limited rituximab exposure. This study aims to evaluate the clinical presentation, diagnostic testing, and outcomes of NL in the rituximab era. Forty biopsy-proven cases of NL, in association with non-Hodgkin lymphoma (NHL), at the Mayo Clinic were retrospectively evaluated. B-cell NHL was associated with 97% of NL cases, of which diffuse large B-cell lymphoma (DLBCL) was the most common (68%). Primary NL, defined as neural involvement present at the time of diagnosis of lymphoma, was noted in 52% cases. Seventy percent of patients presented with sensorimotor weakness and neuropathic pain. Magnetic resonance imaging (MRI) was positive in 100% patients. Overall survival (OS) was significantly better for primary NL and NL associated with indolent lymphomas. Relapses were seen in 60% (24/40) of patients; 75% involved the peripheral or central nervous system at relapse. The use of rituximab in the frontline setting significantly impacted progression-free survival (PFS). Transplant consolidation was noted to be associated with improved OS. This study adds to the available literature on NL in the rituximab era. The overall outcomes have improved in recent years. In our experience, MRI and positron emission tomography/computed tomography may be required for accurate assessment of the extent of disease involvement and identification of an optimal biopsy site. The use of rituximab was associated with improvement in PFS, and autologous stem cell transplant was associated with OS.