Background CD19-directed Chimeric Antigen Receptor T-Cell (CAR-T) therapy has emerged as a promising and novel treatment for relapsed and refractory (r/r) B-cell malignancies. Efforts are directed towards increasing persistence of CAR-T cells, which is known to lead to durable responses. Repeat CAR-T infusions have been explored in clinical trials.1-14 Here, we report a second CD19-directed CAR-T treatment in a patient with diffuse large B-cell lymphoma (DLBCL).
Methods A 60-year old man diagnosed with r/r DLBCL received a CAR-T infusion with tisagenlecleucel having a cell viability of 75%, not meeting FDA specifications of ≥80%. After relapse, the same patient received a second CAR-T with axicabtagene ciloleucel (axi-cel). For both infusions, the patient received appropriate lymphodepletion. Throughout and following both infusions, the patient was monitored for cytokine release syndrome (CRS) or immune effector associated neurotoxicity syndrome (ICANS). mEASIX scores (figure 1) were calculated to evaluate association with developing CRS/ICANS and disease response. Appropriate imaging and additional follow-up of response was completed.
Results Following the patient’s first CAR-T, he had no CRS or ICANS. He was discharged on day +9, then presented on day +84 with cough and dyspnea. Imaging showed an increase in lung lesion and pleural effusion. Biopsy of the lesion confirmed active lymphoma. Due to progression following CAR-T, he received two cycles of polatuzumab vedotin and rituximab for salvage. He then received his second CAR-T cell with axi-cel. On day +4, he developed grade 1 CRS, consisting of fever. CRS symptoms resolved on day +5 and he was discharged on day +12 without complications. Positron Emission Tomography (PET) scans on day +30, 3 and 6-months showed complete metabolic response (CMR), with persistently avid lesion at the L1 spine. This was biopsied showing no active lymphoma. Nine-month PET and 12-month CT showed no new findings to suggest active lymphoma and the patient remains in remission.
Conclusions Here, we present a case of a patient with r/r DLBCL who received two infusions of CAR-T cells. A second CAR-T treatment with a different product was used to treat relapse after first CAR-T in order to harness potential benefit from inherent differences between the 2 available commercial products, achieve adequate CAR-T cell dose, and avoid the higher-risk associated with the alternative treatment of allogeneic hematopoietic stem cell transplantation. As of 1-year post-second CAR-T the patient remains in a remission. This report reflects the benefit of a second infusion of CAR-T therapy in certain cases.
June CH and Sadelain, M. Chimeric Antigen Receptor Therapy. N Engl J Med 2018; 379:64-73. Doi: 10.1056/NEJMra1706169
Oluwole OO, Bishop MR, Gisselbrecht, C, et al. A phase 3 randomized trial of axicabtagene ciloleucel versus standard-of-care therapy in patients with relapsed/refractory diffuse large B cell lymphoma. Journal of Clinical Oncology 36, no. 15_suppl. Doi: 10.1200/JCO.2018; 36.15_suppl.TPS7585.
Neelapu SS, Locke FL, Bartlett NL, et al. Axicabtagene Ciloleucel CAR T-Cell Therapy in Refractory Large B-Cell Lymphoma. N Engl J Med 2017; 377:2531-2544. Doi: 10.1056/NEJMoa1707447
Schuster SJ, Bishop MR, Tam CS, et al. Tisagenlecleucel in Adult Relapsed or Refractory Diffuse Large B-Cell Lymphoma. N Engl J Med 2019; 380:45-56. Doi: 10.1056/NEJMoa1804980
Abramson JS, Palomba ML, Gordon LI, et al. Lisocabtagene maraleucel for patients with relapsed or refractory large B-cell lymphomas. Lancet. 2020; Sep 19;396(10254):839-852. Doi: 10.1016/S0140-6736(20)31366-0.
Joseph Melenhorst J, Chen GM, Wang M, et al. Decade-long leukaemia remissions with persistence of CD4+ CAR T cells. Nature. 2022; Feb;602(7897):503-509. Doi: 10.1038/s41586-021-04390-6.
Zhao S, Wang C, Lu P, et al. Switch receptor T3/28 improves long-term persistence and antitumor efficacy of CAR-T cells. J Immunother Cancer. 2021; Nov;9(12):e003176. Doi: 10.1136/jitc-2021-003176.
Casucci M and Ciceri F. A second CD19 CAR T-cell infusion: yes or no? Blood (2021); 137 (3): 284-286. Doi: 10.1182/blood.2020009206
Gauthier J, Bezerra ED, Hirayama AV, et al. Factors associated with outcomes after a second CD19-targeted CAR T-cell infusion for refractory B-cell malignancies. Blood (2021); 137 (3): 323-335. Doi: 10.1182/blood.2020006770
Xu X, Sun Q, Liang X, et al. Mechanisms of relapse after CD19 CAR T-cell therapy for acute lymphoblastic leukemia and its prevention and treatment strategies. Front Immunol. 2019; 10:2664.
Yu H, Sotillo E, Harrington C, et al. Repeated loss of target surface antigen after immunotherapy in primary mediastinal B cell lymphoma. Am J Hematol.2017; 92(1):E11-E13.
Pennisi M, Sanchez-Escamilla M, Flynn JR, et al. Modified EASIX predicts severe cytokine release syndrome and neurotoxicity after chimeric antigen receptor T cells. Blood Adv. 2021; 5(17):3397-3406.
Sarkar RR, Gloude NJ, Schiff D, et al. Cost-effectiveness of chimeric antigen receptor T-cell therapy in pediatric relapsed/refractory B-cell acute lymphoblastic leukemia. J Natl Cancer Inst. 2019; 111(7):719-726.
Baumgardner JR, Brauer MS, Zhang J, et al. CAR-T therapy and historical trends in effectiveness and cost-effectiveness of oncology treatments. J Comp Eff Res. 2020; 9(5):327-340.
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