Hematopoietic recovery and immune reconstitution after axicabtagene ciloleucel in patients with large B-cell lymphoma

Abstract

Chimeric antigen receptor (CAR) T-cell therapy targeting CD19 may be associated with long-term adverse effects such as cytopenia and immune deficiency. In order to characterize these late events, we analyzed 31 patients with relapsed or refractory large B-cell lymphoma treated with axicabtagene ciloleucel at our institution on two clinical trials, ZUMA-1 (clinicaltrials gov. Identifier: NCT02348216) and ZUMA-9 (clinicaltrials gov. Identifier: NCT03153462). Complete blood counts, lymphocyte subsets, and immunoglobulin levels were measured serially until month 24 or progression. Fifteen (48%) patients had grade 3-4 cytopenia, including anemia (five, 16%), neutropenia (nine, 29%), or thrombocytopenia (13, 42%) at day 30. Cytopenia at day 30 was not significantly associated with later diagnosis of myelodysplasia. Among patients with ongoing remission, grade 3-4 cytopenia was observed in one of nine (11%) at 2 years. While peripheral CD8+ T cells recovered early, CD4+ T-cell recovery was delayed with a count of <200/mL in three of nine (33%) patients at 1 year and two of seven (29%) at 2 years. Immunoglobulin G levels normalized in five of nine (56%) patients at 2 years. Thirteen (42%) patients developed grade 3-4 infectious complications, including herpes zoster and Pneumocystis jiroveci pneumonia. These results suggest the need for prolonged monitoring and prophylaxis against opportunistic infections in these patients, to improve the longterm safety of axicabtagene ciloleucel therapy.

Hematologic Rescue of CAR T-cell–mediated Prolonged Pancytopenia Using Autologous Peripheral Blood Hematopoietic Stem Cells in a Lymphoma Patient

“…Prolonged cytopenia is a common finding in CD19 -targeting CART therapy 2 , 3 with up to 29% and 42% of 31 lymphoma patients experiencing grade 3-4 neutropenia and thrombocytopenia after axicabtagene ciloleucel, 4 which is consistent with data from the pivotal ZUMA-1 (17% ≥3 cytopenias at 3 mo) 5 and JULIET (24% ≥3 cytopenias at 28 d) 6 trials. In our own cohort of patients treated with commercially available CD19 -directed chimeric antigen receptor (CAR) T-cells, 9/35 patients (26%) experienced prolonged neutropenia.…”

“…The underlying mechanisms remain poorly understood. Higher grade CRS with or without neurotoxicity 2 , 4 , 7 consistently correlated with prolonged cytopenias. In a cohort of 41 patients suffering from lymphoma, leukemia, and myeloma, correlation of CRS and high inflammatory parameters still remained significant after adjustment for other factors that cause prolonged cytopenia (ie, baseline cytopenia, CAR construct).…”

Reactions Related to CAR-T Cell Therapy

“…It has been shown that cytopenias developing after CAR-T cell therapy may last for a long time, exceeding 30 days (10,13,15,138,139). This phenomenon is termed as prolonged hematologic toxicity (PHT), and it is characterized with ≥ grade 3 neutropenia or thrombocytopenia following CAR-T cells infusion(exceeding 30 days) (15).…”

CAR T-Cell Therapy: An Update for Radiologists

“…Currently approved CAR T-cell therapies target antigens found on B-cells such as CD19, resulting in B-cell aplasia and hypogammaglobulinemia that can last from months to years [48].…”