Phase I/II study assesses infections in patients receiving CD19-targeted CAR-T treatment

Chimeric antigen receptor-modified T-cell (CAR-T) therapy is being tested in an increasing number of clinical trials showing high response rates and durable remissions. Two CD19-targeted CAR-T therapies were approved by the US Food and Drug Administration (FDA) in 2017, Yescarta® and Kymriah®, and will be used commercially in hospitals in the US. It is therefore necessary to have a better understanding of the potential complications of this relatively new treatment.

CAR-T therapy can cause potentially serious acute toxicities such as cytokine release syndrome (CRS) that require quick and effective management to avoid complications. Patients receiving CAR-T may already be immunocompromised due to previous treatments thus increasing their risk of infections. A phase I/II study published in Blood on 4^th January 2018, by Joshua Hill from the Department of Medicine at the University of Washington, Seattle, and colleagues, aimed to assess infections arising in patients receiving CD19-targeted CAR-T immunotherapy (NCT01865617). Patients included in the study had a confirmed diagnosis of a B-cell malignancy including acute lymphoblastic leukemia (ALL), chronic lymphocytic leukemia (CLL) and non-Hodgkin lymphoma (NHL).

Study Overview

• 133 patients were enrolled in the study with a median age of 54 years who had relapsed or refractory (R/R) CD19-positive ALL (n = 47), CLL (n = 24) and NHL (n = 62)
• Patients were treated with lymphodepletion chemotherapy and then with a CAR T-cell infusion with a range of dose levels: 2 x 10⁵, 2 x 10⁶ or 2 x10⁷ per kg
• Patient records were used to collect information on reported infections from Day 0 (day of infusion) to Day 90
• It was noted that in the study population, patients had a median of 4 prior treatments, which meant that this group were generally immunodeficient
• Patients were assessed for the occurrence of bacterial, fungal and viral infections 

Key Findings

• The first infection occurred at a median of 6 days (1­–27) in patients after infusion
• The majority of infections (80%) occurred within the first 10 days of infusion
• In the first 28 days of CAR-T therapy it was found that there were 1.19 infections per 100 days at risk (total number of patient-days at risk = 3615), with a total of 30 patients reporting infections (23%)
  • Bacterial infections occurred the most frequently with a cumulative incidence of 17%, followed by viral infections 9% and fungal infection 4%
  • ALL had the highest infection density of any type of infection
  • CRS was reported in 28 patients accompanied with infection. CRS occurred in a median of 2 days before infection and 3 patients reported CRS after infection
  • Median time to CRS onset was 1.9 days and median time to first infection was 6 days (P = 0.002)
• In days 29-90 after CAR-T therapy, 119 patients were evaluated. It was found that there were 0.67 infections per 100 days at risk (total number of patient-days at risk = 3431), with a total of 17 patients reporting infections (14%)
  • Viral infections occurred most frequently (9%), followed by bacterial (6%) and fungal (2%)
  • Infection density was significantly lower in days 29–90 than 0–28 (relative risk (RR), 0.56; 95% CI, 0.33–0.93; P = 0.02)
• 19 patients experienced severe infections and 3 patients experienced life-threatening infections
  • One death occurred in a CLL patient due to acute pulmonary hemorrhage because of infection with Aspergillus ustus tracheobronchitis. Another death occurred in an ALL patient with fatal CRS with severe clostridium difficile pseudomembranous colitis
• The baseline patient characteristics that were statistically significantly associated with higher infection density included:
  • ≥4 vs >4 prior regimens = 3.53 (1.76-7.10) adjusted ratio 95% CI P = <0.001
  • Absolute neutrophil count <500 cells / mm³ pre-CAR-T = 2.02 (1.08–3.78) P = 0.024
  • Higher CAR T-cell dose of 2 x 10⁷ P < 0.001
  • Additionally, patients were more likely to report infections if they had higher grade CRS and neurotoxicity, treatment with tocilizumab and/or corticosteroids and ICU admissions 

This study showed that a higher number of infection-related complications occurred earlier on in treatment with CAR-T (Day 0–28). It also identified patients who may be at higher risk of infection before, during and after CAR-T therapy. The authors highlighted that the most severe infections were rare in patients with optimized lymphodepletion and CAR T-cell dosing regimens. Finally, they hope that their findings will help to improve prophylaxis and infection management protocols for CAR-T treatment.