Management of Patients with Aggressive B Cell Non-Hodgkin Lymphoma after Relapse from Axicabtagene Ciloleucel: Single Center Real-World Experience

Background: Chimeric Antigen Receptor (CAR) T-cell therapy has changed the treatment landscape for patients with Non-Hodgkin Lymphoma (NHL). Despite the excellent responses in relapsed or refractory (R/R) aggressive NHL (aNHL), the outcome of patients (pts) that fail CAR T-cell therapy remains poor, and there is not a clear path for management of their disease. Methods: We conducted a retrospective analysis of aNHL pts treated with axicabtagene ciloleucel (axi-cel) at the Mayo Clinic campuses in Arizona and Florida between June 2018 and August 2020. We evaluated the predisposing factors, management, toxicities, and response after CAR T-cell therapy failure. Statistical calculations using parametric tests were performed, and survival curves were estimated using the Kaplan-Meier method and compared statistically using the log-rank test and Pearson's correlation. Results: Thirty-four pts with aNHL received axi-cel. The median age was 53 years [IQR 42-63], and 62% were male. All pts received inpatient axi-cel infusions and the median length of hospital stay was 14 days (IQR: 11-17). Cytokine Release Syndrome (CRS) was observed in 91% of pts (3% grade ≥3), while Immune Effector Cell Associated Neurotoxicity Syndrome (ICANS) was observed in 41% (24% grade ≥3). At day 30 response assessment, 16 pts (47%) had complete responses (CR), 9 (26%) had a partial response (PR), 4 (12%) had stable disease (SD), 4 (12%) showed progression with primary refractory disease (PD) and 1 (3%) died before assessment due to grade 5 ICANS (Table 1). After a median follow-up of 178 days, we observed PD in 12 (35%) pts. The median time-to-progression was 72 days (IQR 58-93) and most of the pts (83%) progressed during the first 3 months. None of the patients with more than 5 months of sustained response developed progression of disease. The likelihood of progression during the first 6 months after axi-cel infusion was 19%, 57%, 50% for pts that initially achieved a CR, PR, SD, respectively. Expression of CD19 was observed in 66% (4/6) of pts with available biopsies after axi-cel suggesting a failure mechanism other than antigen escape. The mortality rate of the R/R aNHL group was 58% with a median survival time of 83 days (IQR: 50-109). There was no association between age, stage, number of previous therapies, time from previous therapy to axi-cel infusion, time from apheresis to infusion, use of tocilizumab, or steroids with progression of disease. Of note, no correlation between CRS or ICANS with progression of disease was found (2-way ANOVA test F (1, 4) = 3.802, p=0.1230). Maintaining a response to axi-cel treatment (CR, PR, or SD) for ≥ 3 months was a strong predictor of durable response with an HR of 0.05 (p= <0.0001). Eleven R/R pts received subsequent therapies with a median time to retreatment of 76 days. Those treatments included: Radiotherapy (n=7), pembrolizumab (n=3), polatuzumab-rituximab with (n=3) and without (n=1) bendamustine, obinutuzumab with (n=1) or without (n=1) lenalidomide, Hyper-CVAD (n=2), R-GemOx (n=1), rituximab with lenalidomide (n=1) and intrathecal methotrexate (n=1). Only 2 (17%) patients have responded to salvage therapy achieving PR (one patient treated with radiotherapy and the other with rituximab-lenalidomide after two other salvage therapies). Conclusion: Our experience demonstrates the majority of aNHL patients respond to axi-cel. If patients maintain their response for more than 3 months, the likelihood of progression is very low - 15%. Similar to what has been previously reported in the literature, our series showed that 35% of patients progressed after axi-cel, and subsequently have a poor prognosis with median survival after a relapse of only 83 days (IQR: 50-109). Therapy options following axi-cel were limited due to severe cytopenias, only 2 of 11 patients have responded to salvage therapy, suggesting that conventional treatments are probably not effective/safe in this high-risk group of patients. Interestingly, the majority of R/R pts with available biopsies showed persistent CD19 expression suggesting that CAR T-cell exhaustion, poor in vivo expansion, and inhibitory signals of the tumor microenvironment may contribute to resistance. Additional strategies for monitoring of axi-cel persistence and its immunophenotypic profile could be helpful for prognosis and management of CAR T-cell pts receiving axi-cel. Disclosures Kharfan-Dabaja: Daiichi Sankyo: Consultancy; Pharmacyclics: Consultancy. Castro:Fate Therapeutics: Research Funding; Kite Pharma: Research Funding; Pharmacyclics: Research Funding.

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Fever Characteristics Associated with Toxicity and Outcome after Anti-CD19 CAR T-Cell Therapy for Aggressive Lymphoma

Blood ◽

10.1182/blood-2019-126148 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 1612-1612 ◽

Cited By ~ 1

Author(s):

Hamza Hashmi ◽

Alicia Darwin ◽

Christina A Bachmeier ◽

Julio Chavez ◽

Bijal Shah ◽

...

Keyword(s):

T Cell ◽

Cell Therapy ◽

Board Of Directors ◽

Research Funding ◽

Advisory Committees ◽

T Cell Therapy ◽

Car T Cell ◽

Car T Cell Therapy ◽

Car T ◽

Grade 3

Background: Fever is a cardinal symptom of cytokine release syndrome (CRS) after CAR T-cell therapy with 84% of patients experiencing fever on the ZUMA-1 trial of axicabtagene ciloleucel (axi-cel). Knowledge of the patterns of fever and associated symptoms may inform the clinical management of these patients. Methods: We performed a single center retrospective study in 78 patients receiving axi-cel for large B cell lymphoma (LBCL) as of 12/31/2018. We evaluated all the patients who developed fever during lymphodepleting chemotherapy with fludarabine (Flu) and cyclophosphamide (Cy), after CAR T-cell infusion, and after administration of tocilizumab (toci); and analyzed the association of fever with toxicity rates (grade 3+ CRS and neurotoxicity) and efficacy [overall response rates (ORR) and complete response (CR) rate 6 months post CAR T-cell infusion]. Fever was defined per the Lee criteria [equal to or greater than 38 °C], CRS used the modified Lee criteria and neurotoxicity used the CARTOX grading system. Results: Fever occurred in 71/78 (91%) of patients. Rates of grade 3+ CRS and neurotoxicity were 9% (7/78) and 26% (20/78) respectively. The CR rate at 6 months was 41% (32/78). Toxicities and outcomes in patients with the described fever characteristics are shown in the Table. During lymphodepletion with Flu/Cy, fever was observed in 11% (9/78) of patients. Fever occurred within 24 hours of axi-cel infusion in 47% (37/78) and within 72 hours of axi-cel infusion in 71% (55/78) of the patients. In total, 41% (32/78) of patients were treated with anti-IL6R therapy (tocilizumab; toci) for CAR T toxicity. After the first dose of toci, fever recurred in 69% of patients (22/32), of which 34% (11/32) experienced fever recurrence within 24 hours of toci infusion. Conclusions: This is the first study to our knowledge that describes in detail the characteristics of fever after CAR T-cell therapy with axi-cel. Fever was common and occurred in 71% of the patients within 72 hours of axi-cel infusion. When toci was used, fever recurred in a majority of patients (69%) and in 1/3 of patients the fever recurred within 24 hours of toci infusion. These descriptive data may be used by clinicians to inform their expectations of fever occurring after treatment with axi-cel and/or toci. Table Disclosures Bachmeier: Kite/Gilead: Speakers Bureau. Chavez:Genentech: Speakers Bureau; Kite Pharmaceuticals, Inc.: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Janssen Pharmaceuticals, Inc.: Speakers Bureau. Shah:AstraZeneca: Honoraria; Novartis: Honoraria; Spectrum/Astrotech: Honoraria; Adaptive Biotechnologies: Honoraria; Pharmacyclics: Honoraria; Jazz Pharmaceuticals: Research Funding; Incyte: Research Funding; Kite/Gilead: Honoraria; Celgene/Juno: Honoraria. Pinilla Ibarz:Novartis: Consultancy; Bristol-Myers Squibb: Consultancy; Sanofi: Speakers Bureau; Takeda: Consultancy, Speakers Bureau; Bayer: Speakers Bureau; TG Therapeutics: Consultancy; Teva: Consultancy; Janssen: Consultancy, Speakers Bureau; Abbvie: Consultancy, Speakers Bureau. Nishihori:Novartis: Research Funding; Karyopharm: Research Funding. Lazaryan:Kadmon: Consultancy. Davila:Bellicum: Consultancy; Anixa: Consultancy; GlaxoSmithKline: Consultancy; Precision Biosciences: Consultancy; Novartis: Research Funding; Adaptive: Consultancy; Celgene: Research Funding; Atara: Research Funding. Locke:Cellular BioMedicine Group Inc.: Consultancy; Kite: Other: Scientific Advisor; Novartis: Other: Scientific Advisor. Jain:Kite/Gilead: Consultancy.

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Neurotoxicity of Axicabtagene Ciloleucel and Long-Term Outcomes - in a Minority Rich, Ethnically Diverse Real World Cohort

Blood ◽

10.1182/blood-2021-153917 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 4842-4842

Author(s):

Ryann Quinn ◽

Astha Thakkar ◽

Sumaira Zareef ◽

Richard Elkind ◽

Karen Wright ◽

...

Keyword(s):

T Cell ◽

Cell Therapy ◽

Research Funding ◽

T Cell Therapy ◽

Car T Cell ◽

Car T Cell Therapy ◽

Car T ◽

Grade 3

Abstract Introduction Chimeric antigen receptor (CAR) T-cell therapy has revolutionized the treatment of B- cell malignancies leading to durable responses in patients with relapsed/refractory disease. 1,2 One of the most severe toxicities associated with this treatment is immune effector cell-associated neurotoxicity syndrome (ICANS), which was seen in 65-75% of patients treated with axicabtagene ciloleucel (axi-cel) in initial clinical trials. ICANS can range from mild headache to coma, and can occur with or without cytokine release syndrome (CRS). Due to the recent development of CAR T-cell therapy, the long-term effects of ICANS are unknown. This study sought to determine the long-term outcomes in patients with neurotoxicity from axi-cel. Methods We conducted a retrospective chart review of patients who received CAR T-cell therapy with axi-cel between June 2018 and June 2021. Neurotoxicity was graded according to the American Society for Transplantation and Cellular Therapy (ASTCT) ICANS grading system. 3 The primary outcome was percentage of patients who had neurotoxicity defined as ICANS grade ≥ 1 as well as the percentage of patients with neurotoxicity lasting ≥ 1 month. We captured descriptive data such as age, sex, ethnicity, comorbidities, IPI score, stage, baseline neurologic dysfunction, performance status, and number of prior treatments. Secondary outcomes included progression free survival (PFS) and overall survival (OS). Results Thirty-four patients received axi-cel between June 2018 and June 2021 at our institution. Median age of patients was 65. Twenty patients (59%) were male and 14 (41%) were female. The majority of patients received axi-cel for diffuse large B-cell lymphoma (97%). Study population was predominantly hispanic (35%), white (32%), African american (29%) and asian (3%). (Sixteen patients (47%) developed neurotoxicity of any grade, with 7 patients (21%) ≥ grade 3. Of note, 4 patients (12%) died during admission for CAR T-cell therapy and 3/4 deaths were in patients with ICANS ≥ grade 3. Median follow up time was 8 months. Of the 12 patients with neurotoxicity who survived initial admission for CAR-T, 9 (75%) patients recovered from neurotoxicity and mental status was at baseline at discharge without recurrence during follow up. Three (25%) of patients had prolonged neurotoxicity lasting > 1 month. Long-term neurotoxicity included confusion, disorientation, and mild cognitive impairment in the three patients. One patient recovered 15 months after CAR T-cell infusion. 2 patients had prolonged neurotoxicity resulting in deterioration of functional status and death in 1 patient, and 1 patient transitioning to hospice and being lost to follow up. Conclusions Neurotoxicity from axicabtagene ciloleucel is a common adverse event, with half of patients in our cohort having neurotoxicity of some degree, and 20% ≥ grade 3. Twenty-five percent of patients that developed neurotoxicity had long-term effects lasting > 1 month, which resulted in deterioration of functional status in 2 patients. Long-term neurotoxicity included disorientation, confusion, and memory impairment. Our study is limited by a small sample size. Larger studies with longer follow-up times are needed to further characterize the long-term outcomes of neurotoxicity associated with CAR T-cell therapy. Neurotoxicity can be confounded by other causes of neurological dysfunction in these patients such as hospital delirium, chemotherapy toxicity, encephalopathy from infection, and subtle baseline neurologic dysfunction that may not be apparent at presentation. Next steps include prospective evaluation of patients with formal neurology evaluation prior to CAR T-cell therapy and periodically after treatment, in order to objectively monitor late neurologic effects of CAR T-cell therapy. 1. Fl, L. et al. Long-term safety and activity of axicabtagene ciloleucel in refractory large B-cell lymphoma (ZUMA-1): a single-arm, multicentre, phase 1-2 trial. Lancet Oncol. 20, (2019). 2. Jacobson, C. Primary Analysis of Zuma-5: A Phase 2 Study of Axicabtagene Ciloleucel (Axi-Cel) in Patients with Relapsed/Refractory (R/R) Indolent Non-Hodgkin Lymphoma (iNHL). in (ASH, 2020). 3. Dw, L. et al. ASTCT Consensus Grading for Cytokine Release Syndrome and Neurologic Toxicity Associated with Immune Effector Cells. Biol. Blood Marrow Transplant. J. Am. Soc. Blood Marrow Transplant. 25, (2019). Disclosures Gritsman: iOnctura: Research Funding. Shastri: Onclive: Honoraria; Guidepoint: Consultancy; GLC: Consultancy; Kymera Therapeutics: Research Funding. Verma: Celgene: Consultancy; BMS: Research Funding; Stelexis: Current equity holder in publicly-traded company; Curis: Research Funding; Eli Lilly: Research Funding; Medpacto: Research Funding; Novartis: Consultancy; Acceleron: Consultancy; Stelexis: Consultancy, Current equity holder in publicly-traded company; Incyte: Research Funding; GSK: Research Funding; Throws Exception: Current equity holder in publicly-traded company.

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Consensus Grading of Cytokine Release Syndrome (CRS) in Adult Patients with Relapsed or Refractory Diffuse Large B-Cell Lymphoma (r/r DLBCL) Treated with Tisagenlecleucel on the JULIET Study

Blood ◽

10.1182/blood-2018-99-113052 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 4190-4190 ◽

Cited By ~ 6

Author(s):

Stephen J. Schuster ◽

Richard T. Maziarz ◽

Solveig G. Ericson ◽

Elisha S. Rusch ◽

James Signorovitch ◽

...

Keyword(s):

T Cell ◽

Cell Therapy ◽

Board Of Directors ◽

Research Funding ◽

Advisory Committees ◽

T Cell Therapy ◽

Car T Cell ◽

Car T Cell Therapy ◽

Car T ◽

Grade 3

Abstract Introduction: Autologous anti-CD19 chimeric antigen receptor (CAR) T-cell therapy achieves rapid and durable responses in patients with r/r DLBCL, although unique potential toxicities require specialized management. Cytokine release syndrome (CRS) is the most commonly observed adverse event of special interest associated with CAR T-cell therapy. Two CRS grading scales have been used in different clinical trials of CAR T-cell therapy: the Penn scale (Porter, Sci Transl Med, 2015; Porter, J Hematol & Oncol, 2018) and the Lee scale (Lee, Blood, 2014; Neelapu, Nat Rev Clin Oncol, 2017). To better inform management of CRS and develop best practices, we assessed concordance and differences between the two scales by using the Lee scale to regrade observed CRS events in r/r DLBCL patients treated with tisagenlecleucel, who were previously graded per protocol using the Penn scale. Methods: Individual patient level data from the JULIET trial, a single-arm, open-label, multicenter, global phase 2 trial of tisagenlecleucel in adult patients with r/r DLBCL (NCT02445248), were used in this study. Four medical experts who had managed DLBCL patients using different CAR T-cell therapy protocols and products independently reviewed the data, while blinded to the original Penn grading, and re-graded CRS for JULIET patients using the Lee scale. Re-grading assessments and disagreements in the assigned Lee grade were discussed and reconciled among reviewers during a live meeting. As per the investigational charter, the most conservative final assessment of any expert reviewer determined the final grading for any individual case. For example, if an event was graded as 2, 3, 3 and 4, then grade 4 would be the final grading. Results: As of December. 8, 2017, 111 patients with r/r DLBCL were infused with tisagenlecleucel in the JULIET trial. Sixty-four (58%) patients had CRS graded according to the Penn scale and each case was re-graded using the Lee scale based on JULIET data collected prospectively (e.g., CRS-related symptoms, oxygen supplementation, intervention for hypotension, and organ toxicities). Using the Lee scale, 63 (57%) patients were considered to have any grade CRS by investigators, including grade 1 events in 26 (23%), grade 2 in 18 (16%), grade 3 in 10 (9%), and grade 4 in 9 (8%) (Figure 1). One patient with grade 1 per Penn scale was re-graded to grade 0 due to absence of documented fever or symptoms requiring intervention. Compared to Penn grades, the Lee scale provided the same grade for 39 patients, a lower grade for 20 patients, and a higher grade for 5 patients. Among 64 patients re-graded, 59 (92%) had fever, 27 (42%) had oxygen supplementation (3 with grade 1, 6 grade 2, 9 grade 3, and 9 grade 4 per Lee scale) and 7 (11%) had concurrent infections. Of 29 (45%) patients requiring intervention for hypotension (13 with grade 2, 7 grade 3, and 9 grade 4 per Lee scale), 28 had fluid resuscitation and 10 received high dose/combination vasopressors. In addition, 8 of 9 patients re-graded as Lee grade 4 were intubated. As for anti-cytokine therapy, only 17 patients received tocilizumab (1 for grade 1, 2 for grade 2, 5 for grade 3, and 9 for grade 4 CRS per Lee scale) and 12 patients received corticosteroids (2 for grade 2, 1 for grade 3, and 9 for grade 4 CRS per Lee scale). Conclusions: Different CAR-T studies in DLBCL patients have used different approaches (Lee and Penn scales) for grading CRS and had different thresholds for tocilizumab treatment of CRS. Harmonization of grading CRS between studies permits a more accurate comparison of observations and outcomes. In this analysis, patients with r/r DLBCL receiving tisagenlecleucel in the JULIET trial, which used the Penn scale to grade CRS, were re-graded by expert consensus using the Lee scale. Using the Lee scale, more patients were categorized as grade 1 (Lee vs. Penn: 26 vs. 17), fewer patients as grades 2 and 3 (18 vs. 23, and 10 vs. 15, respectively), and the same number of patients as grade 4 (9 vs. 9) compared to the Penn scale. The re-grading of the JULIET CRS data using the Lee scale makes it possible to perform comparative analyses of CRS outcomes from clinical trials using different CAR-T products and could be used to develop best practice guidelines. Disclosures Schuster: Pfizer: Membership on an entity's Board of Directors or advisory committees; Nordic Nanovector: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Dava Oncology: Consultancy, Honoraria; Merck: Consultancy, Honoraria, Research Funding; OncLive: Honoraria; Genentech: Honoraria, Research Funding; Gilead: Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Physician's Education Source, LLC: Honoraria; Novartis Pharmaceuticals Corporation: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Maziarz:Athersys, Inc.: Patents & Royalties; Kite Therapeutics: Honoraria; Juno Therapeutics: Consultancy, Honoraria; Incyte: Consultancy, Honoraria; Novartis Pharmaceuticals Corporation: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Ericson:Novartis Pharmaceuticals Corporation: Employment. Rusch:Novartis Pharmaceuticals Corporation: Employment. Romanov:Novartis Pharmaceuticals Corporation: Employment. Locke:Cellular BioMedicine Group Inc.: Consultancy; Novartis Pharmaceuticals: Other: Scientific Advisor; Kite Pharma: Other: Scientific Advisor. Maloney:Janssen Scientific Affairs: Honoraria; Roche/Genentech: Honoraria; Seattle Genetics: Honoraria; GlaxoSmithKline: Research Funding; Juno Therapeutics: Research Funding.

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Association of Bridging Therapy Utilization with Clinical Outcomes in Patients Receiving Chimeric Antigen Receptor (CAR) T-Cell Therapy

Blood ◽

10.1182/blood-2021-152479 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 4100-4100

Author(s):

P. Connor Johnson ◽

Caron Jacobson ◽

Alisha Yi ◽

Areej El-Jawahri ◽

Matthew J. Frigault

Keyword(s):

T Cell ◽

Cell Therapy ◽

Hospital Readmission ◽

Research Funding ◽

Bridging Therapy ◽

T Cell Therapy ◽

Car T Cell ◽

Car T Cell Therapy ◽

Car T ◽

Grade 3

Abstract Background: CAR T-cell therapy has altered the landscape of treatment options for patients with hematologic malignancies. Because CAR T-cell therapy involves manufacturing an autologous cellular product over a period of weeks, patients can receive bridging therapy while awaiting CAR T-cells. Currently there is no standard of care for use of bridging therapy. Moreover, data are lacking regarding the impact of bridging therapy use on clinical outcomes. Methods: We conducted a retrospective analysis of 236 patients who received CAR-T cell therapy at two tertiary care centers from 2/2016-12/2019. We abstracted clinical outcomes from review of the Electronic Health Record (EHR) including 1) overall response rate (ORR); 2) complete response (CR) rate; 3) progression-free survival (PFS); 4) overall survival (OS); 5) health care utilization (length of stay [LOS], intensive care unit [ICU] admission during admission for CAR T-cell therapy, and hospital readmission within 3 months of CAR T-cell infusion); and 6) rates of cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) [all grades and grade 3+]. We assessed the association of bridging therapy use with ORR, CR rate, rates of ICU admission and hospital readmission, and rates of CRS (any grade) and ICANS (any grade and grade 3+) using the chi square test. We assessed the association of bridging therapy use with LOS using the Wilcoxon-Mann-Whitney test given the distribution of LOS and with grade 3+ CRS using Fisher's Exact Test given the sample size of this outcome. To assess the association of bridging therapy use with PFS and OS, we used Cox multivariable regression analyses adjusting for age, sex, marital status, Charlson comorbidity index, lymphoma diagnosis, number of prior therapies, history of autologous stem cell transplant, time from relapse to CAR T-cell therapy, vein to vein time, Eastern Cooperative Oncology Group performance status (closest to day 0), LDH (> 500 vs <=500), CRP, ferritin, and platelet count (< 100 vs >=100) prior to CAR T-cell infusion, CAR T-cell product, total dose of steroids received (days 0-31), and receipt of tocilizumab. Results: Patients had a median age of 62.8 years (range: 19-82) and the majority were male (145/236, 61.4%). The most common diagnosis was de novo diffuse large B cell lymphoma (DLBCL) (101/236, 42.8%) and most patients received axicabtagene ciloleucel (axi-cel) (192/236, 81.4%). All patients received lymphodepletion with cyclophosphamide and fludarabine. Overall, 39.4% (93/236) received bridging therapy. Regimens utilized for bridging therapy included systemic chemotherapy (48/236, 20.3%), corticosteroids (25/236, 10.6%), radiation (10/236, 4.2%), and other systemic therapies (10/236, 4.2%). Among the entire cohort, ORR and CR rate were 85.2% (201/236) and 64.8% (153/236), respectively, and bridging therapy use was not associated with ORR (80.0% with bridging therapy vs. 88.8% without bridging therapy; χ 2=3.81; p=0.051) or CR rate (63.4% with bridging therapy vs. 65.7% without bridging therapy; χ 2=0.13; p=0.718). In univariate Cox regression analyses, bridging therapy was associated with worse PFS (HR=1.47; p=0.049) and worse OS (HR=1.85; p=0.006). In multivariable Cox regression models adjusting for covariates (Tables 1 and 2), bridging therapy use was not associated with PFS (HR=1.43; p=0.163) but was associated with worse OS (HR=2.23; p=0.006). Bridging therapy use was not associated with LOS (p=0.451), ICU admission (χ 2=0.22; p=0.638), hospital readmission (χ 2=0.95; p=0.329), CRS (all grades: χ 2=0.46; p=0.500; grades 3+: p=0.574), or ICANS (all grades: χ 2=0.13; p=0.719; grades 3+: χ 2=0.23; p=0.632). Conclusions: We identified that bridging therapy use is not associated with differences in response rates, PFS, health care utilization, or rates of CRS or ICANS but is associated with worse OS in patients receiving CAR T-cell therapy. These findings underscore the need for novel bridging therapy regimens to optimize outcomes in this patient population. Figure 1 Figure 1. Disclosures Jacobson: Celgene: Consultancy, Honoraria, Other: Travel support; Axis: Speakers Bureau; Humanigen: Consultancy, Honoraria, Other: Travel support; Pfizer: Consultancy, Honoraria, Other: Travel support, Research Funding; Novartis Pharmaceuticals Corporation: Consultancy, Honoraria, Other: Travel support; AbbVie: Consultancy, Honoraria; Nkarta: Consultancy, Honoraria; Kite, a Gilead Company: Consultancy, Honoraria, Other: Travel support; Lonza: Consultancy, Honoraria, Other: Travel support; Precision Biosciences: Consultancy, Honoraria, Other: Travel support; Clinical Care Options: Speakers Bureau. Frigault: Novartis: Consultancy, Research Funding; Kite: Consultancy, Research Funding; Arcellx: Consultancy; Iovance: Consultancy; Takeda: Consultancy; Editas: Consultancy; BMS: Consultancy.

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KTE-X19 anti-CD19 CAR T-cell therapy in adult relapsed/refractory acute lymphoblastic leukemia: ZUMA-3 phase 1 results

Blood ◽

10.1182/blood.2020009098 ◽

2021 ◽

Author(s):

Bijal D Shah ◽

Michael R. Bishop ◽

Olalekan O Oluwole ◽

Aaron C Logan ◽

Maria R. Baer ◽

...

Keyword(s):

T Cell ◽

Cell Therapy ◽

Remission Rate ◽

Lymphoblastic Leukemia ◽

Phase 1 ◽

T Cell Therapy ◽

Car T Cell ◽

Car T Cell Therapy ◽

Car T ◽

Grade 3

ZUMA-3 is a phase 1/2 study evaluating KTE-X19, an autologous anti-CD19 chimeric antigen receptor (CAR) T-cell therapy, in adult relapsed/refractory (R/R) B-ALL. We report the phase 1 results. Following fludarabine/cyclophosphamide lymphodepletion, patients received a single infusion of KTE-X19 at 2, 1, or 0.5×106 cells/kg. The rate of dose-limiting toxicities (DLTs) within 28 days following KTE-X19 infusion was the primary endpoint. KTE-X19 was manufactured for 54 enrolled patients and administered to 45 (median age: 46 years [range, 18-77]). No DLTs occurred in the DLT-evaluable cohort. Grade ≥3 cytokine release syndrome (CRS) and neurologic events (NE) occurred in 31% and 38% of patients, respectively. To optimize the benefit-risk ratio, revised adverse event (AE) management for CRS and NE (earlier steroid use for NE and tocilizumab only for CRS) was evaluated at 1×106 cells/kg KTE-X19. In the 9 patients treated under revised AE management, 33% had grade 3 CRS and 11% had grade 3 NE, with no grade 4/5 NE. The overall complete remission rate correlated with CAR T-cell expansion and was 83% in patients treated with 1×106 cells/kg and 69% in all patients. Minimal residual disease was undetectable in all responding patients. At 22.1 months (range, 7.1-36.1) median follow-up, the median duration of remission was 17.6 months (95% CI, 5.8-17.6) in patients treated with 1×106 cells/kg and 14.5 months (95% CI, 5.8-18.1) in all patients. KTE-X19 treatment provided a high response rate and tolerable safety in adults with R/R B-ALL. Phase 2 is ongoing at 1×106 cells/kg with revised AE management.

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Feasibility, and Efficacy of Donor-Derived cd19-Targeted Car t-Cell Therapy in Refractory/Relapsed(r/r)b-Cell Acute Lymphoblastic Leukemia (b-all) Patients

Blood ◽

10.1182/blood-2020-137299 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 4-6

Author(s):

Xian Zhang ◽

Junfang Yang ◽

Wenqian Li ◽

Gailing Zhang ◽

Yunchao Su ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Cell Therapy ◽

T Cell Therapy ◽

Car T Cells ◽

Car T Cell ◽

Car T Cell Therapy ◽

Car T ◽

Grade 3

Backgrounds As CAR T-cell therapy is a highly personalized therapy, process of generating autologous CAR-T cells for each patient is complex and can still be problematic, particularly for heavily pre-treated patients and patients with significant leukemia burden. Here, we analyzed the feasibility and efficacy in 37 patients with refractory/relapsed (R/R) B-ALL who received CAR T-cells derived from related donors. Patients and Methods From April 2017 to May 2020, 37 R/R B-ALL patients with a median age of 19 years (3-61 years), were treated with second-generation CD19 CAR-T cells derived from donors. The data was aggregated from three clinical trials (www.clinicaltrials.gov NCT03173417; NCT02546739; and www.chictr.org.cn ChiCTR-ONC-17012829). Of the 37 patients, 28 were relapsed following allogenic hematopoietic stem cell transplant (allo-HSCT) and whose lymphocytes were collected from their transplant donors (3 HLA matched sibling and 25 haploidentical). For the remaining 9 patients without prior transplant, the lymphocytes were collected from HLA identical sibling donors (n=5) or haploidentical donors (n=4) because CAR-T cells manufacture from patient samples either failed (n=5) or blasts in peripheral blood were too high (>40%) to collect quality T-cells. The median CAR-T cell dose infused was 3×105/kg (1-30×105/kg). Results For the 28 patients who relapsed after prior allo-HSCT, 27 (96.4%) achieved CR within 30 days post CAR T-cell infusion, of which 25 (89.3%) were minimal residual disease (MRD) negative. Within one month following CAR T-cell therapy, graft-versus-host disease (GVHD) occurred in 3 patients including 1 with rash and 2 with diarrhea. A total of 19 of the 28 (67.9%) patients had cytokine release syndrome (CRS), including two patients (7.1%) with Grade 3-4 CRS. Four patients had CAR T-cell related neurotoxicity including 3 with Grade 3-4 events. With a medium follow up of 103 days (1-669days), the median overall survival (OS) was 169 days (1-668 days), and the median leukemia-free survival (LFS) was 158 days (1-438 days). After CAR T-cell therapy, 15 patients bridged into a second allo-HSCT and one of 15 patients (6.7%) relapsed following transplant, and two died from infection. There were 11 patients that did not receive a second transplantation, of which three patients (27.3%) relapsed, and four parents died (one due to relapse, one from arrhythmia and two from GVHD/infection). Two patients were lost to follow-up. The remaining nine patients had no prior transplantation. At the time of T-cell collection, the median bone marrow blasts were 90% (range: 18.5%-98.5%), and the median peripheral blood blasts were 10% (range: 0-70%). CR rate within 30 days post CAR-T was 44.4% (4/9 cases). Six patients developed CRS, including four with Grade 3 CRS. Only one patient had Grade 3 neurotoxicity. No GVHD occurred following CAR T-cell therapy. Among the nine patients, five were treated with CAR T-cells derived from HLA-identical sibling donors and three of those five patients achieved CR. One patient who achieved a CR died from disseminated intravascular coagulation (DIC) on day 16. Two patients who achieved a CR bridged into allo-HSCT, including one patient who relapsed and died. One of two patients who did not response to CAR T-cell therapy died from leukemia. Four of the nine patients were treated with CAR T-cells derived from haploidentical related donors. One of the four cases achieved a CR but died from infection on day 90. The other three patients who had no response to CAR T-cell therapy died from disease progression within 3 months (7-90 days). Altogether, seven of the nine patients died with a median time of 19 days (7-505 days). Conclusions We find that manufacturing CD19+ CAR-T cells derived from donors is feasible. For patients who relapse following allo-HSCT, the transplant donor derived CAR-T cells are safe and effective with a CR rate as high as 96.4%. If a patient did not have GVHD prior to CAR T-cell therapy, the incidence of GVHD following CAR T-cell was low. Among patients without a history of transplantation, an inability to collect autologous lymphocytes signaled that the patient's condition had already reached a very advanced stage. However, CAR T-cells derived from HLA identical siblings can still be considered in our experience, no GVHD occurred in these patients. But the efficacy of CAR T-cells from haploidentical donors was very poor. Disclosures No relevant conflicts of interest to declare.

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Costs of Postinfusion Monitoring By Site of Care for Patients with Relapsed/Refractory (R/R) Large B-Cell Lymphoma (LBCL) Who Received Third-Line or Later Treatment with Lisocabtagene Maraleucel (liso-cel) in the Transcend NHL 001 and Outreach Trials

Blood ◽

10.1182/blood-2020-141415 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 16-17

Author(s):

M. Lia Palomba ◽

Monika P. Jun ◽

Jacob Garcia ◽

James Lymp ◽

November McGarvey ◽

...

Keyword(s):

T Cell ◽

Cell Therapy ◽

Research Funding ◽

Cost Ratio ◽

Publicly Traded ◽

T Cell Therapy ◽

Car T Cell ◽

Car T Cell Therapy ◽

Car T ◽

Third Line

Background: Chimeric antigen receptor (CAR) T cell therapy is generally limited to inpatient settings; yet, exploration of outpatient infusion and monitoring is ongoing. Information on health care resource utilization (HCRU) and costs associated with CAR T cell therapy administration is limited and may differ by postinfusion monitoring site. Liso-cel is an investigational, CD19-directed, defined composition, 4-1BB CAR T cell product administered at equal target doses of CD8+ and CD4+ CAR+ T cells. An interim analysis from the OUTREACH study (NCT03744676) observed lower HCRU with outpatient vs inpatient administration (Bachier et al. J Clin Oncol 2020;38:8037). The patient journey after CAR T cell therapy administration may differ for patients with outpatient vs inpatient monitoring and may result in varying costs of care. This study estimated the cost of postinfusion monitoring by site of care for patients with R/R LBCL who received third-line or later treatment with liso-cel in the TRANSCEND NHL 001 (TRANSCEND; NCT02631044) and OUTREACH clinical trials. Methods: This retrospective study analyzed HCRU reported in clinical trial databases from TRANSCEND and OUTREACH. A 2-step microcosting method was used to identify key HCRU and to estimate postinfusion costs: (1) HCRU was analyzed from the index date (day of liso-cel infusion) through the 6-month follow-up; and (2) costs were applied to each HCRU. HCRU included standard inpatient and intensive care unit (ICU) length of stay (LOS), diagnostics (laboratory work and imaging), procedures (dialysis and intubation), and medications (supportive care, prophylactic treatment, and adverse event management). Unit costs were obtained from the health care system (provider) perspective and adjusted to 2020 US dollars. Cost per standard inpatient day ($2,542) was estimated from Healthcare Cost and Utilization Project databases, and cost per ICU day ($7,556) was sourced from Dasta et al (Crit Care Med. 2005;33:1266-77). All medication costs were obtained from REDBOOK (IBM Micromedex) using wholesale acquisition costs. Diagnostic and procedure costs were obtained from the Centers for Medicare & Medicaid Services laboratory fee schedule, physician fee schedule, or outpatient prospective payment system. A payment-to-cost ratio was applied to Medicare payment rates to estimate unit costs. Costs were adjusted to reflect the site of care where the HCRU occurred. A cost ratio was applied to adjust costs from the physician's office/community oncology clinic to the hospital outpatient department (Winfield, Muhlestein, Leavitt Partners; 2017) and from outpatient to inpatient (Meisenberg et al. Bone Marrow Transplant. 1998;21:927-32). Costs were aggregated by HCRU category, specifically medications, diagnostics, procedures, and facility costs. An average total cost by post-liso-cel infusion month was calculated for patients with ongoing status in that month (patients censored due to data cutoff were not included). Analyses were stratified by site of postinfusion monitoring (inpatients vs outpatients). Results: A total of 303 patients with R/R LBCL across the 2 trials received liso-cel and postinfusion monitoring (inpatients, n = 256; outpatients, n = 47). HCRU and LOS, including standard inpatient and ICU days, are shown in the Table. Inpatients had higher rates of inpatient stays (<100% vs 62%) and tocilizumab use (for CRS and/or NE; 20% vs 9%) than outpatients, respectively. Rates of ICU admission, corticosteroid use, vasopressor use, dialysis, and intubation were similar between groups. Median and average LOS in standard inpatient and ICU settings were higher among inpatients. Median (range) total LOS for inpatients and outpatients was 15 (0-88) and 4 (0-77) days, respectively. The estimated mean postinfusion cost of care was $89,535 for inpatients and $36,702 for outpatients. Over 6 months, most costs were incurred in the first month after infusion ($50,369 [56%] for inpatients and $19,837 [54%] for outpatients). Costs were largely driven by facility costs, namely standard inpatient and ICU stays (Figure). Conclusions: Lower overall HCRU was observed with outpatient liso-cel postinfusion monitoring, primarily due to hospitalizations, which resulted in a mean 6-month cost savings of $52,833 (59%) compared with inpatient monitoring. These results are based on national average costs and may not be generalizable to specific institutions. Disclosures Palomba: Regeneron: Research Funding; Juno Therapeutics, a Bristol-Meyers Squibb Company: Honoraria, Research Funding; Genentech: Research Funding; Merck: Honoraria; Novartis: Honoraria; Celgene: Honoraria; Pharmacyclics: Honoraria. Jun:Bristol-Myers Squibb Company: Current Employment, Current equity holder in publicly-traded company. Garcia:Bristol-Myers Squibb Company: Current equity holder in publicly-traded company; Juno Therapeutics, a Bristol-Myers Squibb Company: Current Employment. Lymp:Bristol-Myers Squibb Company: Current equity holder in publicly-traded company; Juno Therapeutics, a Bristol-Myers Squibb Company: Current Employment. McGarvey:Pfizer, Inc.: Ended employment in the past 24 months; BluePath Solutions: Current Employment. Gitlin:BMS: Research Funding. Pelletier:BMS: Current Employment, Current equity holder in publicly-traded company. Nguyen:BluePath Solutions: Current Employment.

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Qualitative Analysis of the Treatment Experience and Well-Being of Patients with Relapsed/Refractory (R/R) Large B-Cell Lymphoma (LBCL) Enrolled in 2 Trials of Lisocabtagene Maraleucel (liso-cel) during the Initial Stages of Therapy

Blood ◽

10.1182/blood-2020-137656 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 22-23

Author(s):

Tanya Siddiqi ◽

Ulrich Jaeger ◽

Olga Moshkovich ◽

Jennifer Devlen ◽

Matthew Miera ◽

...

Keyword(s):

Clinical Trials ◽

T Cell ◽

Cell Therapy ◽

Research Funding ◽

Well Being ◽

Publicly Traded ◽

T Cell Therapy ◽

Car T Cell ◽

Car T Cell Therapy ◽

Car T

Background: Chimeric antigen receptor (CAR) T cell therapy is a novel treatment modality for patients with R/R LBCL. Limited information exists regarding patients' views of CAR T cell therapy. Our research aimed to better understand patients' needs by capturing their expectations/concerns, current well-being, and treatment experiences during the beginning stages of CAR T cell therapy in the clinical trial setting. Methods: Patients with R/R LBCL from 2 ongoing trials of the investigational, CD19-directed CAR T cell therapy liso-cel (TRANSCEND WORLD [NCT03484702] or PLATFORM [NCT03310619]) were invited to participate in an optional interview component. Semistructured interviews were conducted to gain insight about patients' experience with CAR T cell therapy in the clinical trials. Interviews of ≤1 hour (in-person or over the phone) were conducted in parallel with screening procedures (interview 1), after leukapheresis (interview 2), and up to 3 days after liso-cel infusion (interview 3). Interviews were audio recorded and transcribed. MAXQDA (VERBI GmbH, Berlin, Germany) qualitative analysis software was used to manage and thematically organize interview transcript data to identify key concepts related to each research objective. Previously reported results of interview 1 showed a high perception of unmet needs, lack of alternative options, and expectations for positive outcomes. The analysis presented here primarily focused on interviews 2 and 3. Denominators shown in the Results vary by question as some patients skipped questions. Results: A total of 75 interviews were analyzed, including 35, 24, and 16 patients at interviews 1, 2, and 3, respectively, across sites in the US (n = 14), Europe (n = 26), and Japan (n = 2). Among 42 patients who completed ≥1 interview, the mean age was 62 years and 69% were male. Treatment Experience: Of 24 patients who completed interview 2, 22 (92%) reported positive experiences during leukapheresis and 16 (67%) reported the procedure was as expected. Patients thought the most difficult part of leukapheresis was the length of the procedure (n = 8/21 [38%]). Of 15 patients who provided feedback on lymphodepleting chemotherapy, a majority reported that it was as expected (n = 8 [53%]) or easier than expected (n = 3 [20%]); when asked about the most difficult part, many patients (n = 7/17 [41%]) discussed side effects (eg, nausea, fatigue, and lack of appetite). Of patients who described liso-cel infusion as different than expected, differences included easier (n = 12/13 [92%]) or quicker (n = 3/12 [25%]) than expected, and 5/12 (42%) reported few/no side effects within 3 days post-infusion. Over half of patients (n = 8/14 [57%]) reported that the infusion, as a whole, was not difficult. Changes over Time: At interviews 1, 2, and 3, respectively, 47% (n = 14/30), 47% (n = 9/19), and 69% (n = 9/13) of patients reported hoping for successful treatment. Similarly, patients generally had fewer concerns later in the process, with 21 (64%) and 11 (33%) of 33 patients reporting side-effect and treatment efficacy concerns, respectively, during interview 1 vs 5 (33%) and 3 (20%) of 15 patients, respectively, during interview 3. At time of enrollment, most patients (n = 21/34 [62%]) were able to function normally or with minimal impact from their lymphoma, although most reported some symptoms like fatigue, pain, or stomach problems. At interview 1, 14 (40%) of 35 patients were employed; most patients reported no changes in their work life at interviews 2 (n = 19/20 [95%]) and 3 (n = 11/12 [92%]). From enrollment to immediately post-infusion, the physical health of most patients remained stable (n = 4/16 [25%]) or deteriorated (n = 9/16 [56%]). However, most patients (n = 14/15 [93%]) reported feeling positive at interview 3. Conclusions: This study provided the unique opportunity to gather feedback directly from patients participating in clinical trials of liso-cel therapy, specifically during the initial treatment stages. The overall impression of the treatment was positive, with most patients reporting that study procedures were easier than expected. The results of this qualitative research provide useful insight into the motivations, expectations, and experiences of patients with R/R LBCL receiving liso-cel therapy, which can inform the design of health care support systems and future clinical trials to better meet patients' needs. Disclosures Siddiqi: AstraZeneca: Consultancy, Research Funding, Speakers Bureau; Pharmacyclics: Consultancy, Research Funding, Speakers Bureau; Celgene: Consultancy, Research Funding; Juno: Consultancy, Research Funding; Kite, a Gilead Company: Consultancy, Research Funding; BeiGene: Consultancy, Research Funding; Oncternal: Research Funding; TG Therapeutics: Research Funding; Janssen: Speakers Bureau; Seattle Genetics: Speakers Bureau. Jaeger:F. Hoffmann-La Roche: Honoraria, Research Funding; AbbVie: Honoraria; Novartis: Consultancy, Honoraria, Research Funding; Gilead: Honoraria, Research Funding; BMS/Celgene: Consultancy, Honoraria, Research Funding; Karyopharm: Honoraria; CDR Life AG: Consultancy, Research Funding; Miltenyi: Consultancy, Honoraria. Moshkovich:Icon Plc: Current Employment. Devlen:Icon Plc: Current Employment, Current equity holder in publicly-traded company. Miera:Icon Plc: Current Employment. Williams:Icon Plc: Current Employment. Hasskarl:Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company. Liu:Bristol-Myers Squibb: Current Employment, Current equity holder in publicly-traded company. Braverman:Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company. Salles:MorphoSys: Consultancy, Honoraria, Other; Kite: Consultancy, Honoraria, Other; Debiopharm: Consultancy; Novartis: Consultancy, Honoraria, Other; Janssen: Consultancy, Honoraria, Other: Participation in educational events; Gilead: Consultancy, Honoraria, Other: Participation in educational events; F. Hoffman-La Roche Ltd: Consultancy, Honoraria, Other; Epizyme: Consultancy; Takeda: Consultancy, Honoraria, Other; Bristol Myers Squibb: Consultancy, Other; Karyopharm: Consultancy; Amgen: Honoraria, Other: Participation in educational events; Celgene: Consultancy, Honoraria, Other: Participation in educational events; Abbvie: Consultancy, Honoraria, Other: Participation in educational events; Autolus: Consultancy; Genmab: Consultancy.

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Evaluation of Eligibility for CAR-T Cell Therapy in a Population-Based Cohort of 3550 Patients with Incident Diffuse Large B-Cell Lymphoma (DLBCL) in Sweden

Blood ◽

10.1182/blood-2020-138737 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 38-39

Author(s):

Karin Ekstroem Smedby ◽

Sara Harrysson ◽

Sara Ekberg ◽

Mats Jerkeman ◽

Per-Ola Andersson ◽

...

Keyword(s):

T Cell ◽

Cell Therapy ◽

Research Funding ◽

Eligibility Criteria ◽

T Cell Therapy ◽

Car T Cell ◽

Line Therapy ◽

Car T Cell Therapy ◽

Car T ◽

First Relapse

Background Today, even though most patients with diffuse large B-cell lymphoma (DLBCL) can be cured with standard immunochemotherapy, 20-30% are refractory to primary therapy or relapse during follow-up with a drastic worsening of the prognosis. In recent years, new promising treatment options including CAR-T cell therapy are becoming available for relapsed/refractory (R/R) DLBCL patients although so far with logistic challenges including disease control and toxicities, and a considerable cost. In view of these challenges, we aimed to estimate the proportion of patients with R/R DLBCL that are likely to be eligible for CAR-T cell therapy in clinical routine, and their expected outcome in the pre-CAR-T era. Methods All patients with DLBCL starting primary therapy with curative intent were identified in the Swedish Lymphoma Register for the period 2007-2014 (N=3550). Primary CNS and primary mediastinal B-cell lymphomas were excluded. Data regarding primary treatment response and relapse was validated through medical chart review in the entire cohort during follow-up until Dec 31st 2017, and information about additional treatment lines including disease characteristics, blood test results, and relapse treatment response was collected. Eligibility for CAR-T cell therapy was estimated retrospectively based on eligibility criteria specified in clinical trials, both at first relapse by applying similar criteria as in the ongoing TRANSFORM, ZUMA-7 or PILOT studies (hereafter termed "CAR-T-2ndline"), and at second relapse applying criteria similar to those specified in the JULIET trial (hereafter termed "CAR-T-3rdline"). Administration of second- and third-line therapies and corresponding response rates were considered as proxies for eligibility and response to bridging therapies. Criteria applied for "CAR-T-2ndline" included R/R DLBCL within 12 months of evaluation date of primary treatment, age 18-75 years, ECOG 0-1, and additional criteria as specified in the TRANSFORM trial (see figure footnote). Criteria applied for "CAR-T-3rdline" included relapse following second-line therapy, age 18-76 years, ECOG 0-1, and additional criteria as in the JULIET trial (see figure footnote). Individuals with missing data on performance status were assumed ineligible. We lacked information about other malignancies in the disease history. Overall survival probabilities were estimated with the Kaplan-Meier method among all R/R DLBCL patients in the trial-specified age intervals and separately among those fulfilling all trial criteria. Results In the cohort of 3550 curatively treated DLBCL patients, 847 (cumulative incidence 23%) experienced R/R disease during a median follow-up of 4.3 years. Median age at first relapse was 71 years (range 18-95 years). Overall, 308 patients ≤75 years experienced progression/relapse within 12 months and were able to start second-line therapy. Of these, 148 patients (17% of all R/R DLBCL patients) fulfilled trial eligibility criteria for "CAR-T-2ndline", of whom 60 responded with at least partial remission (overall response rate, ORR, 41%). At second relapse, 370 patients 76 years or younger received third-line therapy, of whom 55 (6.5% of all R/R DLBCL patients) were deemed eligible for "Car-T-3rdline", and 13 responded (ORR 24%, another 5 patients had SD). Two-year overall survival (OS) among all R/R DLBCL patients ≤75 years receiving second-line therapy was 20% (95% confidence interval, CI, 16-25%) (Fig 1). Among those eligible for "CAR-T-2ndline", 2-year OS was 24% (95% CI 17-31%). Among patients ≤76 years at second relapse, 2-year OS was 18% (95% CI 13-24%), and among those eligible for "CAR-T-3rdline", 21% (95% CI 11-32%). Conclusion In the population-based setting, one in six patients (17%) with R/R DLBCL fitted trial eligibility criteria for CAR-T-cell therapy at first relapse and only one in fifteen patients (6.5%) fitted trial criteria at second relapse at retrospective evaluation. Figures were reduced when adding requirement of response to relapse/bridging therapy. These estimates illustrate to what extent current CAR-T cell therapies may be applied in a routine setting when based on trial criteria, and the need for development of modified and additional therapies in this group. Outcome estimation confirmed a poor outcome in these groups and did not indicate that fulfillment of trial criteria led to selection bias in terms of survival. Disclosures Ekstroem Smedby: Janssen Cilag: Research Funding; Celgene: Other: Advisory Board; Takeda: Research Funding. Harrysson:Janssen Cilag: Research Funding. Jerkeman:Janssen: Research Funding; Roche: Research Funding; Celgene: Research Funding; Abbvie: Research Funding; Gilead: Research Funding. Eloranta:Janssen Cilag: Research Funding.

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DLBCL patients treated with CD19 CAR T cells experience a high burden of organ toxicities but low nonrelapse mortality

Blood Advances ◽

10.1182/bloodadvances.2020001972 ◽

2020 ◽

Vol 4 (13) ◽

pp. 3024-3033 ◽

Cited By ~ 3

Author(s):

Kitsada Wudhikarn ◽

Martina Pennisi ◽

Marta Garcia-Recio ◽

Jessica R. Flynn ◽

Aishat Afuye ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Cell Therapy ◽

B Cell Lymphoma ◽

T Cell Therapy ◽

Car T Cells ◽

Car T Cell ◽

Car T Cell Therapy ◽

Car T ◽

Grade 3

Abstract Cytokine release syndrome (CRS) immune effector cell–associated neurotoxicity syndrome are the most notable toxicities of CD19 chimeric antigen receptor (CAR) T-cell therapy. In addition, CAR T-cell–mediated toxicities can involve any organ system, with varied impacts on outcomes, depending on patient factors and involved organs. We performed detailed analysis of organ-specific toxicities and their association with outcomes in 60 patients with diffuse large B-cell lymphoma (DLBCL) treated with CD19 CAR T cells by assessing all toxicities in organ-based groups during the first year posttreatment. We observed 539 grade ≥2 and 289 grade ≥3 toxicities. Common grade ≥3 toxicities included hematological, metabolic, infectious, and neurological complications, with corresponding 1-year cumulative incidence of 57.7%, 54.8%, 35.4%, and 18.3%, respectively. Patients with impaired performance status had a higher risk of grade ≥3 metabolic complications, whereas elevated lactate dehydrogenase was associated with higher risks of grade ≥3 neurological and pulmonary toxicities. CRS was associated with higher incidence of grade ≥3 metabolic, pulmonary, and neurologic complications. The 1-year nonrelapse mortality and overall survival were 1.7% and 69%, respectively. Only grade ≥3 pulmonary toxicities were associated with an increased mortality risk. In summary, toxicity burdens after CD19 CAR T-cell therapy were high and varied by organ systems. Most toxicities were manageable and were rarely associated with mortality. Our study emphasizes the importance of toxicity assessment, which could serve as a benchmark for further research to reduce symptom burdens and improve tolerability in patients treated with CAR T cells.

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