scholarly journals Description of neurotoxicity in a series of patients treated with CAR T-cell therapy

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Catherine Belin ◽  
Perrine Devic ◽  
Xavier Ayrignac ◽  
Amélie Dos Santos ◽  
Adrien Paix ◽  
...  
Keyword(s):  
T Cell ◽  
Cell Therapy ◽  
Cognitive Disorders ◽  
Language Disorders ◽  
Motor Disorders ◽  
T Cell Therapy ◽  
Car T Cell ◽  
Car T Cell Therapy ◽  
Car T ◽  
Grade 3

Abstract Chimeric antigen receptor-modified T (CAR T) cell therapy is a highly promising treatment for haematological malignancies but is frequently associated with cytokine release syndrome and neurotoxicity. Between July 2018 and July 2019, all patients treated with CD19-targeted CAR T-cell therapy for relapsing lymphoma were followed-up longitudinally to describe neurological symptoms and their evolution over time. Four different French centres participated and 84 patients (median age 59 years, 31% females) were included. Neurotoxicity, defined as the presence of at least one neurological symptom appearing after treatment infusion, was reported in 43% of the patients. The median time to onset was 7 days after infusion with a median duration of 6 days. More than half of the patients (64%) had grade 1–2 severity and 34% had grade 3–4. CRS was observed in 80% of all patients. The most frequent neurological symptoms were cognitive signs, being severe in 36%, and were equally distributed between language disorders and cognitive disorders without language impairment. Non-pyramidal motor disorders, severe in 11%, were reported in 42% of the patients. Elevation of C-reactive protein (CRP) within 4 days after treatment was significantly correlated with the occurrence of grade 3–4 neurotoxicity. Although sometimes severe, neurotoxicity was almost always reversible. The efficacy of steroids and antiepileptic drugs remains unproven in the management of neurotoxicity. Neurotoxicity associated with CAR T-cell therapies occurs in more than 40% of patients. The clinical pattern is heterogeneous but cognitive disorders (not limited to language disorders) and, to a minor degree, non-pyramidal motor disorders, appeared as a signature of severe neurotoxicity.

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

Blood ◽  
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.

scholarly journals 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 ◽  
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.

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

2020 ◽  
Vol 4 (13) ◽  
pp. 3024-3033 ◽  
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.

scholarly journals Clinical Presentation, Management and Biomarkers of Cytokine Release Syndrome after Anti-CD19 CART-Cell Therapy for r/r ALL

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 5625-5625
Author(s):  
Ping Li ◽  
Lili Zhou ◽  
Shiguang Ye ◽  
Shaoguang Li ◽  
Aibin Liang
Keyword(s):  
T Cell ◽  
Cell Therapy ◽  
Clinical Presentation ◽  
Cytokine Release ◽  
Cytokine Release Syndrome ◽  
T Cell Therapy ◽  
Car T Cell ◽  
Car T Cell Therapy ◽  
Car T ◽  
Grade 3

Chimeric antigen receptor T (CAR-T) cell therapy has emerged as a novel treatment modality for B-cell malignancies. CD19-specific CAR-T cells induce high rates of initial response among patients with relapsed B-cell acute lymphoblastic leukemia (ALL). However, cytokine release syndrome (CRS) is the most common and severe toxicities of CAR T-cell therapy for ALL, and clinical experience is limited. Here, we describe the clinical presentation and management of 30 patients who presented with CRS following CAR-T cell therapy for relapsed/refractory ALL at our hospital. 12 of the 30 patients (40%) developed grade 1-2 CRS, 14 patients (46.7%) presented with grade 3-4 CRS and 2 patients (6.7%) died of grade 5 CRS. Compared with grade 1-2 CRS, grade 3-4 CRS correlated negatively with overall survival and progression-free survival (P =0.02). We found that higher ferritin levels and percentages of CD19 positive cells in blood lymphocytes cells at time of CAR-T cell infusion were associated with more severe CRS. Grade 3-4 neurotoxicity was frequently present in patients with grade ≧3 CRS. We also observed that the organ disfunctions occurred in sequence after fever onset during the period of CRS. Neurotoxicity, cardiovascular disfunction and cytopenia in some patients manifest as biphasic. Compared to use of tocilizumab for CRS ≧ grade 3, early intervention of tocilizumab for hyperpyrexia duration ≧ 6h alleviates the severity of CRS, and no patients died of severe CRS since this management approach was performed. As use of novel CAR-T cell therapy expands, the data from our clinical experience may help others anticipated the clinical course of organ function and manage CRS in CAR-T therapy. Figure Disclosures No relevant conflicts of interest to declare.

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

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 1612-1612 ◽  
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.

scholarly journals Combination of Anti-CD19 and Anti-CD20 Chimeric Antigen Receptor T Cells for Relapsed and Refractory Diffuse Larger B Cell Lymphoma: An Open-Label, Single-Arm, Phase Ⅰ/Ⅱ Trial

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 1590-1590 ◽  
Author(s):  
Wei Sang ◽  
Ming Shi ◽  
Jingjing Yang ◽  
Jiang Cao ◽  
Linyan Xu ◽  
...  
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 ◽  
Anti Cd20

Objective Chimeric antigen receptor T (CAR-T) cells therapy demonstrated remarkable efficiency in refractory and relapsed diffuse large B cell lymphoma (R/R DLBCL). Antigen-loss potentially leads to failure after single-target CAR-T cellss therapy. Aim to evaluate the efficiency and safety of double-target CAR-T cellss therapy, we performed a phase Ⅰ/Ⅱ clinical trial of combination anti-CD19 and anti-CD20 CAR-T cellss therapy for R/R DLBCL. Methods A total of 21 patients were enrolled, and patients were monitored for treatment response, toxicity and persistence. Patients received a conditioning regimen of fludarabine and cyclophosphamide followed by infusion of anti-CD19 and anti-CD20 CAR-T cellss. Results Of the 21 patients, 17 had objective response, and the ORR was 81.0% (95% CI, 58 to 95). 11 had CR, the CR rate was 52.4% (95% CI, 26 to 70). 4 of 9 patients in completed remission at 3 months remain in remission by 6 months, the CR rate was 44.4% (95% CI, 14 to 79). The median OS was 8.1 months (95% CI, 7 to 10) and the median PFS was 5.0 months (95% CI, 2 to 8). The median duration response was 6.8 months (95% CI, 4 to 10). Cytokine release syndrome (CRS) occurred in all patients. Of the 21 patients, 15 (71.4%) had grade 1-2 CRS, 6 (28.5%) had severe (≥grade 3) CRS, and no grade 5 CRS occurred. There were 5 patients with different degrees of neurotoxicity, namely CAR-T associated encephalopathy syndrome (CRES). There were 2 cases with grade 3 or above CRES, 5 of them were self-limited, and none of them died of severe CRS or CRES. There were significant differences in peak levels of IL-6 (P=0.004)、ferritin (P=0.008) and CRP (P=0.000) secretion between CRS 1-2 and CRS 3-4 patients within one month after CAR-T cell infusion. In terms of hematological toxicity, there were 11 cases of neutropenia above grade 3 (52.4%), 6 cases of anemia (28.6%) and 6 cases of thrombocytopenia (28.6%). After 12 patients with response and 1 patient without response received CAR-T cell therapy, CD19 cell subsets all disappeared after 2 weeks. The level of serum immunoglobulin in 14 patients with response decreased progressively after 1 week of treatment with CAR-T cells, and maintained at a relatively low level. Eight patients received intravenous immunoglobulin during CAR-T cell therapy. Conclusion Anti-CD19 combined with anti-CD20 CAR-T cell is effective in the treatment of R/R DLBCL patients.2. Anti-CD19 combined with anti-CD20 CAR-T cell therapy has the occurrence of CRS, CRES and hematological toxicity, and adverse reactions could be controlled. This is the first report to our knowledge of successful treatment of combination of anti-CD19 and anti-CD20 CAR-T cellss in R/R DLBCL. Our results provide strong support for further multiple-target CAR-T cells therapy, which could potentially resolve antigen-loss related failure. Disclosures No relevant conflicts of interest to declare.

scholarly journals Axicabtagene Ciloleucel: Clinical Data for the Use of CAR T-cell Therapy in Relapsed and Refractory Large B-cell Lymphoma

2020 ◽  
pp. 106002802094423
Author(s):  
Zachery Halford ◽  
Mary Kate Anderson ◽  
Lunawati L. Bennett
Keyword(s):  
T Cell ◽  
Cell Therapy ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
T Cell Therapy ◽  
Car T Cell ◽  
Large B Cell Lymphoma ◽  
Car T Cell Therapy ◽  
Car T ◽  
Grade 3

Objective: To evaluate the literature for axicabtagene ciloleucel (axi-cel), a first-in-class chimeric antigen receptor (CAR) T-cell therapy, in the treatment of relapsed/refractory (r/r) large B-cell lymphoma (LBCL). Data Sources: We conducted a PubMed (inception to June 22, 2020) and ClinicalTrials.gov search using the following terms: CD19, chimeric antigen receptor, and lymphoma. Study Selection and Data Extraction: All retrospective and prospective studies evaluating the use of axi-cel in LBCL were reviewed. Data Synthesis: In the pivotal ZUMA-1 trial, axi-cel exhibited unprecedented overall and complete response rates of 83% and 58%, respectively. With a median follow-up of 27.1 months, 39% of patients had ongoing responses. Furthermore, postmarketing retrospective analyses found similar response rates in a more clinically diverse LBCL patient population. Novel CAR T-cell therapy elicits unique and potentially life-threatening toxicities that include cytokine release syndrome (CRS) and immune effector cell–associated neurotoxicity syndrome (ICANS). Studies reported grade ≥3 CRS in 7% to 14% of patients and grade ≥3 ICANS in 31% to 55% of patients. Relevance to Patient Care and Clinical Practice: Axi-cel was the first US Food and Drug Administration–approved genetically engineered autologous CAR T-cell agent in r/r LBCL, representing an important milestone and paradigm shift in cancer treatment. Adoptive T-cell immunotherapy is a breakthrough treatment modality requiring careful patient selection, multidisciplinary collaboration, comprehensive patient counseling, and expert training to ensure optimal treatment. Conclusions: The initial and ongoing results with axi-cel are encouraging, but long-term safety and efficacy data are lacking. Additional studies are required to identify axi-cel’s ideal place in LBCL therapy.

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

Blood ◽  
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.

scholarly journals 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 ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 4190-4190 ◽  
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.

scholarly journals Granulocyte Colony-Stimulating Factor (G-CSF) Interactions with Chimeric Antigen Receptor (CAR) T-Cell Therapy for Diffuse Large B-Cell Lymphoma

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 4109-4109 ◽  
Author(s):  
Daria Gaut ◽  
Kevin Tang ◽  
Myung Sim ◽  
Tuyen Duong ◽  
Joshua Sasine ◽  
...  
Keyword(s):  
T Cell ◽  
Cell Therapy ◽  
B Cell Lymphoma ◽  
T Cell Therapy ◽  
Car T Cell ◽  
Large B Cell Lymphoma ◽  
Car T Cell Therapy ◽  
Car T ◽  
Grade 3 ◽  
Stimulating Factor

Introduction Chimeric Antigen Receptor (CAR) T-cell therapy is an innovative therapy for relapsed or refractory diffuse large B-cell lymphoma (DLBCL). Prior to CAR T-cell infusion, patients receive lymphodepleting chemotherapy and may receive granulocyte colony-stimulating factor (G-CSF) to decrease the duration of neutropenia and risk of infection. However, G-CSF also has the potential to increase the incidence and/or severity of cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) by promoting antigen-presenting cell function (Mehta HM, J Immunol, 2015). More data is required to guide clinicians on the benefits and risks of G-CSF use in CAR T-cell treatment. Methods A retrospective analysis was performed among 22 DLBCL patients who received CAR T-cell therapy with Axicabtagene ciloleucel at the University of California Los Angeles from March 2018 to May 2019. All patients received standard lymphodepleting therapy with fludarabine 30 mg/m2/day and cyclophosphamide 500 mg/m2/day on days -5 through -3, except one patient who received reduced dosages for renal disease. Prophylactic tocilizumab 8 mg/kg was given to all patients at 36 hours after CAR T-cell infusion, with additional doses of tocilizumab and/or steroids given for evidence of CRS/ICANS based on the American Society for Transplantation and Cellular Therapy (ASTCT) consensus grading system. G-CSF was administered by physician discretion following CAR T-cell infusion at a weight-based dosage of either 300 or 480 mcg and cumulative G-CSF dose recorded within the first 30 days. Results Patient and disease characteristics are shown in Table 1. Seven of the 22 patients (31.8%) received G-CSF at a median cumulative dosage of 2880 mcg (IQR 900-8640), with the majority (4 patients, 57.1%) receiving G-CSF in the first 5 days post CAR T-cell infusion (Table 2). The median duration of neutropenia following lymphodepleting therapy was 5 days (IQR 4.5-8.5) for those patients treated with G-CSF compared to 15 days (IQR 8.0-30.0) for those who did not receive G-CSF (p = 0.0157). Seven patients (31.8%) developed infection in the 30 days post CAR T-cell therapy with 4 infections being grade 3 or higher. There was no difference in the incidence and severity of infection between those patients who received G-CSF and those that did not (p = 0.630, p = 0.424, Figure 1). CRS was noted in 14 patients overall (63.6%), 4 of which were grade 3 or higher. ICANS was noted in 11 patients overall (50.0%), 9 of which were grade 3 or higher. Among the 7 patients that received G-CSF, 6 patients (85.7%) and 4 patients (57.1%) had evidence of CRS and ICANS, respectively. Among the 15 patients that did not receive G-CSF, 8 patients (53.3%) and 7 patients (46.7%) had evidence of CRS and ICANS, respectively. There was no significant difference in the incidence of developing CRS (any grade) or ICANS (any grade) between the group of patients that received G-CSF and those that did not (p = 0.193, p = 0.647). However, there was a significant increase in the severity of CRS for patients that received G-CSF compared to those that did not (p = 0.0418, Figure 1), but no increase in the severity of ICANS based on G-CSF use (p = 0.660, Figure 1). Thirteen patients (59.1%) received corticosteroids following CAR T-cell treatment at a median cumulative dosage of 666.7 mg prednisone equivalents (IQR 445.0-933.3), with the majority (9 patients, 69.2%) receiving steroids in the first 5 days post CAR T-cell infusion (Table 2). More than half of the cohort (14 patients, 63.6%) required more than 1 dose of tocilizumab (Table 2). There was no association between G-CSF use and steroid use or administration of more than 1 dose of tocilizumab (p = 0.648, p = 0.074). Conclusions Our data demonstrates a significant increase in severity without an increase in incidence of CRS with G-CSF use within 30 days of Axicabtagene ciloleucel administration for relapsed/refractory DLBCL. There was no association of G-CSF with severity or incidence of ICANS and no difference in infection rates with G-CSF in this setting. *Both Daria Gaut and Kevin Tang contributed equally to this work. Disclosures No relevant conflicts of interest to declare.

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