ALBERT

Description: Introduction. Cytokine release syndrome (CRS) and neurotoxicity (NT)(also known as immune effector cell-associated neurotoxicity syndrome or ICANS) are commonly observed after chimeric antigen receptor (CAR) T-cell therapy. While the clinical features of CRS have been extensively described, limited data exists for NT. Here, we report clinical and radiological features of NT after standard of care (SOC) axicabtagene ciloleucel (axi-cel) in patients (pts) with relapsed or refractory (r/r) large B-cell lymphoma (LBCL). Methods. Pts with r/r LBCL treated with SOC axi-cel at MD Anderson Cancer Center between 01/2018 and 04/2019 were included in the study. All pts received anti-seizure prophylaxis with levetiracetam starting on the day of axi-cel infusion for 30 days. CRS and NT were prospectively graded according to CARTOX criteria (Neelapu et al, Nat Rev Clin Oncol, 2018). Association between continuous variables were assessed using the bivariate Pearson correlation. Results. Ninety-five pts were included in the study, 72 (76%) with diffuse LBCL, 17 (18%) with transformed follicular lymphoma, and 6 (6%) with primary mediastinal LBCL. Median age was 60 (range, 18-85), 71 (75%) were male. Median number of previous therapies was 4 (range, 2-15), 26 (27%) had a previous autologous stem cell transplant (SCT), and 1 (1%) a previous allogeneic SCT. Eight (8%) pts had prior central nervous system lymphomatous involvement (parenchymal in 5), and 39 (41%) had prior neurological and/or psychiatric medical history. After axi-cel infusion, NT of any grade was observed in 65 (68%) pts, grade ³3 in 46 (48%)(Table). No significant association was observed between above outlined baseline characteristics and development of NT. Median time from axi-cel infusion to NT onset was 5 days (range, 0-25 days) and median duration was 6 days (range, 1-52 days); no new onset/recurrent NT was observed beyond day 30. Among the 65 pts who developed NT, a CT head without contrast was performed in 48, and was not evaluable in 2 because of motion artifacts. Among the 46 evaluable scans, 1 (4%) was abnormal as compared to baseline, and showed new onset cortical edema (non-diffuse but symmetrical). An MRI brain with contrast was performed in 36 pts, but was not evaluable in 10 because of lack of baseline, motion artifacts or differences in imaging sequences. Among the 26 evaluable scans, 15 (58%) showed abnormal findings, including autoimmune encephalitis-like, characterized by symmetric white matter changes of the pons and hippocampus (6; Fig. A), stroke-like (4; Fig. B), LMD-like (3; Fig. C) and PRES-like (2; Fig. D), with concomitant cortical edema in 5. EEGs were performed in 52 pts (〉1/pt, for a total of 116 EEGs) and were abnormal in 47 (90%). Focal and/or diffuse slowing was the most common abnormality (isolated finding in 35 [73%] pts), while epileptiform discharges and/or non-convulsive status epilepticus (NCSE) were observed 12 (27%) pts. A lumbar puncture was performed in 12 pts: median white blood cell count was 2 cells/µL (range, 0-6), median protein 47 mg/dL (range, 13-600), median glucose 69 mg/dL (range, 30-111), and cytology was positive for malignant cells in 2 (7%) pts. Convulsive seizure was observed in 4 (6%) pts and 10 (15%) received additional anti-seizure therapy for convulsive or non-convulsive seizures. Among the 65 pts with NT, dexamethasone up to 20 mg IV Q6H was given to 42 (65%) pts, methylprednisolone 1000 mg IV daily to 12 (18%), and tocilizumab to 64 (98%; during CRS or CRS with concurrent NT). Overall, 93 (98%) pts developed CRS, grade 〉3 in 27 (28%). A significantly higher rate of NT of any grade (96% vs 57%, p3 (81% vs 35%, p3 CRS. After a median follow-up of 4 months, 6-month progression-free (PFS) and overall survival (OS) rates were 60% and 65%, respectively. Significantly shorter 6-month PFS (46% vs 80%, p=0.02) and OS rates (56% vs 83%, p=0.01) were observed among pts developing NT of any grade. Conclusions. Our results suggest that multiple radiological patterns of NT after axi-cel are possible in r/r LBCL pts, MRI being more sensitive than CT scan for their detection. NCSE is a common event, supporting the use of seizure prophylaxis and EEGs for evaluation of these pts. Pts with NT experience a worse outcome, and additional clinical and biological predictors of NT will be analyzed and presented at the meeting. Figure Disclosures Nastoupil: Spectrum: Honoraria; Janssen: Honoraria, Research Funding; Bayer: Honoraria; Celgene: Honoraria, Research Funding; Genentech, Inc.: Honoraria, Research Funding; Gilead: Honoraria; TG Therapeutics: Honoraria, Research Funding; Novartis: Honoraria. Westin:47 Inc: Research Funding; Novartis: Other: Advisory Board, Research Funding; Juno: Other: Advisory Board; MorphoSys: Other: Advisory Board; Unum: Research Funding; Curis: Other: Advisory Board, Research Funding; Genentech: Other: Advisory Board, Research Funding; Celgene: Other: Advisory Board, Research Funding; Kite: Other: Advisory Board, Research Funding; Janssen: Other: Advisory Board, Research Funding. Fowler:Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Abbvie: Membership on an entity's Board of Directors or advisory committees, Research Funding; TG Therapeutics: Membership on an entity's Board of Directors or advisory committees, Research Funding. Lee:Seattle Genetics, Inc.: Research Funding. Parmar:Cellenkos Inc.: Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Research Funding. Wang:Guidepoint Global: Consultancy; BioInvent: Consultancy, Research Funding; Janssen: Consultancy, Honoraria, Research Funding, Speakers Bureau; Pharmacyclics: Honoraria, Research Funding; AstraZeneca: Consultancy, Honoraria, Research Funding, Speakers Bureau; MoreHealth: Consultancy, Equity Ownership; Acerta Pharma: Consultancy, Research Funding; Kite Pharma: Consultancy, Research Funding; VelosBio: Research Funding; Loxo Oncology: Research Funding; Celgene: Honoraria, Research Funding; Juno Therapeutics: Research Funding; Aviara: Research Funding; Dava Oncology: Honoraria. Pinnix:Merck: Research Funding. Hawkins:Novartis Pharmaceuticals: Other: advisory panels. Neelapu:Precision Biosciences: Consultancy; Novartis: Consultancy; Allogene: Consultancy; Incyte: Consultancy; BMS: Research Funding; Cellectis: Research Funding; Poseida: Research Funding; Karus: Research Funding; Acerta: Research Funding; Celgene: Consultancy, Research Funding; Kite, a Gilead Company: Consultancy, Research Funding; Merck: Consultancy, Research Funding; Cell Medica: Consultancy; Unum Therapeutics: Consultancy, Research Funding; Pfizer: Consultancy. Chi:Kite, A Gilead Company: Consultancy, Honoraria, Other: Kite Patient Management Advisory Board.

Description: Introduction. Cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) are common adverse effects of chimeric antigen receptor (CAR) T-cell therapy. Elevated biomarkers, such as ferritin and LDH, have been shown to correlate with more severe toxicity. The endothelial activation and stress index (EASIX) is a surrogate of endothelial activation, and correlates to other biomarkers of endothelial dysfunction. In allogeneic hematopoietic cell transplantation (HCT), it is predictive of toxicity such as fluid overload, which is correlative with endothelial dysfunction, as well as sinusoidal obstruction syndrome, non relapse mortality and overall survival (Luft et al, BMT 2019, Varma et al, BBMT, 2020, Jiang et al, Haematologica, 2020). In this study we describe the correlation of EASIX to CAR T cell related CRS and ICANS. Methods. Retrospective data from consecutive patients treated with standard of care axi-cel for non-Hodgkin's lymphoma at MD Anderson Cancer Center between January 2018 and April 2020 were included in the study. CRS and ICANS were graded according to CARTOX criteria (Neelapu et al, Nat Rev Clin Oncol, 2018), and after 5/2019, according to the ASTCT criteria (Lee et al, BBMT, 2019). EASIX parameters were recorded prior to lymphodepletion (the latest value on days -12 to -6) and were available for all 171 patients. The score was defined as lactate dehydrogenase (U/L) × creatinine (mg/dL)/ thrombocytes (10^9 cells per L), with LDH adjusted to the upper limit of normal. Predictors of toxicity were evaluated using Fine and Grey regression analysis considering death before grade 2-4 toxicity as a competing risk. Results. 171 consecutive patients treated with commercial axi-cel for diffuse large B cell lymphoma (n=133), transformed follicular lymphoma (n=28) and primary mediastinal lymphoma (n=10) were included in the study. Median age was 59 years (range, 18-85), and 120 (70%) were male. 151 patients had an ECOG performance status ≤1, 45 patients (26%) had a previous autologous HCT, and 3 (1.8%) had a previous allogeneic HCT. Prior to lymphodepletion, 96 (56%) patients had a high IPI score (≥3) and 134 (78%) were refractory to the previous line of treatment. With a median follow-up of 259 days (range: 25-800) since infusion, ICANS of any grade was noted in 109 (64%) patients, with 84 (49%) having grades 2-4. CRS of any grade was observed in 160 (93%) patients, with 81 (47%) having grades 2-4 CRS. A total of 56 (33%) patients were diagnosed with grade 2-4 ICANS and CRS. The median EASIX score for the entire cohort was 2.1 (range: 0.3-283; inter-quartiles: 1.1 and 4.6). On univariate analysis, EASIX levels above the median were associated with higher cumulative incidence (CI) of grade 2-4 ICANS (% CI: 61 vs 31%; HR=2.4, p