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.
No relevant conflicts of interest to declare.
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