Chimeric antigen receptor (CAR) T-cell therapy is a type of cancer immunotherapy where patients’ T-cells are collected and genetically modified to produce chimeric antigen receptors that recognize specific targets on cancer cells, allowing these T-cells to locate and destroy the cancer cells. CAR T-cell therapy shows promising results in treating relapsing or refractory B-cell lymphomas. To explore the risks associated with CAR T-cell therapy, researchers from Juntendo University, Japan, including Professor Jun Ando, Professor Miki Ando, and Dr. Erina Hosoya, published a study in Haematologica on October 17, 2024.
Elaborating about this study further, Dr. Hosoya, the study's lead author, says, “We conducted a single-center, retrospective analysis of 59 patients with relapsed/refractory B-cell lymphoma enrolled for CAR T-cell therapy with tisagenlecleucel (tisa-cel) between September 2020 and September 2023. Forty-one study patients (38 with diffuse large B-cell lymphoma (DLBCL) and three with follicular lymphoma (FL)) received an infusion of tisa-cel. Response assessments were completed in 37 patients with DLBCL and one with FL.” The team tracked overall survival (OS) and progress-free survival (PFS) over 12 months, finding OS at 73.8% and PFS at 49.6%. Safety monitoring showed that 30 out of 41 patients who received tisa-cel developed cytokine release syndrome (CRS), an inflammatory side effect. Of these, 14 patients had more severe CRS (grade 3 or higher) and also tended to receive higher doses of CAR-positive cells, leading to earlier fevers compared to those with milder (grade 1 or 2) CRS.
The researchers identified 11 laryngeal edemas in patients as a serious and previously unrecognized side effect of CAR T-cell therapy. Initially thought to affect only those with neck tumors, it was found in all patients, regardless of tumor location. Intensive care and airway management were provided due to the obstruction caused by the edema. This condition typically developed within 3.4 days post-infusion and resolved within 14 days for all patients.
Explaining these results, Dr. Hosoya says, “Although a few case reports of laryngeal edema with tisa-cel treatment for B-cell lymphoma have appeared, the mechanism of this phenomenon is still unknown and no established management guidelines exist despite the major risk of life-threatening airway obstruction. We, therefore, assessed risk factors for the occurrence of laryngeal edema and the influence of steroid treatment on both CAR T-cell expansion and clinical outcome.” The research team identified a key risk factor for laryngeal edema—patients who experienced this condition had a significantly higher number of CAR-positive cells infused (4.0 x 108 vs 3.3 x 108). They found that infusions with more than 3.4 x 108 CAR-positive cells could predict the risk of laryngeal edema. Additionally, the CAR T-cells from patients with laryngeal edema contained a higher proportion of effector T-cells compared to those without edema. Sharing another interesting observation from the study, Dr. Hosoya says, “Our impression clinically was that the frequency of laryngeal edema after tisa-cel infusion rose in the summer of 2022. So, we attempted to coordinate the date of tisa-cel manufacture with the occurrence of laryngeal edema.” This observation was a result of the high numbers of CAR-positive cells in products manufactured after June 2022 than in those manufactured before June 2022.
Based on these observations from the study, the team of researchers concludes that using steroids, such as dexamethasone, could prove effective for early management of laryngeal edema. They found that administering steroids provided relief to patients without reducing the effectiveness of CAR T-cell therapy.
In summary, these findings highlight the serious adverse effects of tisa-cel therapy, its associated risk factors, and management strategies for improving patient safety and treatment experiences. Concluding optimistically, Dr. Hosoya says, “We believe that our analyses encompass both efficacy and safety with tisa-cel therapy in real-world settings.”
Reference
Authors
Erina Hosoya1, Jun Ando1,2, Shintaro Kinoshita1, Yoshiki Furukawa1, Yuko Toyoshima1,2, Yoko Azusawa2, Toru Mitsumori3, Eriko Sato4, Hina Takano5, Yutaka Tsukune1, Naoki Watanabe1, Tomoiku Takaku1, Hajime Yasuda1, Yasuharu Hamano1, Makoto Sasaki1, Shuko Nojiri6 , Midori Ishii1, and Miki Ando1
Title of original paper
Eleven Cases of Laryngeal Edema After Tisagenlecleucel Infusion: A 3-year Single Center Retrospective Study of CD19-directed Chimeric Antigen Receptor T-cell Therapy for Relapsed and Refractory B-cell Lymphomas
Journal
Haematologica
DOI
10.3324/haematol.2024.286169
Affiliations
1Department of Hematology, Juntendo University School of Medicine
2Division of Cell Therapy & Blood Transfusion Medicine, Juntendo University School of Medicine
3Department of Hematology, Juntendo University Urayasu Hospital
4Department of Hematology, Juntendo University Nerima Hospital
5Department of Hematology, Juntendo University Shizuoka Hospital
6Medical Technology Innovation Center, Juntendo University, Japan
About Dr. Erina Hosoya
Dr. Erina Hosoya is a graduate student at the Department of Hematology at the Juntendo University School of Medicine, Tokyo, Japan, and works with Professor Miki Ando and Professor Jun Ando. Dr. Hosoya’s main research interests are in the fields of Clinical Genetics, Clinical Oncology, Cancer Immunotherapy, Stem Cell Transplantation Studies, and Hematology. She has been a part of three research papers this year with her team at the Department of Hematology, Juntendo University, and has won the Excellent Poster Award at the 16th Kanto-Koshinetsu Regional Conference by the Japanese Society of Hematology.
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