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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 4th 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.

References
  1. Hill JA. Et al. Infectious complications of CD19-targeted chimeric antigen receptor-modified T-cell immunotherapy. Blood. 2018 Jan 4;131(1):121-130. DOI: 10.1182/blood-2017-07-793760. Epub 2017 Oct 16.