Comparative Analysis of Immune Effector Cell-Associated Hematotoxicity (ICAHT) and Infection Incidence Following CD19-Targeted CAR-T Therapy Versus CD7-Targeted CAR-T Therapy

Introduction

CD19 CAR-T cell therapy has been revolutionizing the treatment of refractory /relapsed (R/R) B-cell acute lymphoblastic leukemia (B-ALL) over the past decade. While CD7 CAR-T therapy, an innovative approach, has only recently been applied over the last three years in our center to treat R/R T-cell acute lymphoblastic leukemia (T-ALL) and T-cell lymphoblastic lymphoma (T-LBL). While there are studies and guidelines from EBMT addressing hematologic toxicity, specifically Immune Effector Cell-Associated Hematotoxicity (ICAHT), following CD19 CAR-T treatment, the literature is still scarce on ICAHT occurrence post-CD7 CAR-T therapy. Here we conducted a retrospective study aiming at comparing ICAHT and infection incidences following the two distinct CAR-T therapies.

Methods

Data were extracted from two separate clinical trials. The CD19 CAR is structured with CD19 scFv, CD28-hinge, 4-1BB costimulatory region, and CD3ζ activation domains. T cells were activated by CD3/CD28 microbead 2 days before CD19-CAR lentivirus infection. “Naturally selected” anti-CD7 CAR-T cells (NS7CAR) were transduced an anti-CD7 CAR into bulk peripheral T lymphocytes via a lentivirus vector. NS7CAR is a 2nd generation murine-based CAR-T containing 4-1BB and CD3ζ co-stimulatory domains. All patients received lymphodepletion regimens of fludarabine (30 mg/m ²/d) and cyclophosphamide (300 mg/m ²/d) from Day -5 to Day -3 before CAR-T infusion. A single infusion of either CD19 CAR-T or CD7 CAR-T cells was administrated at a medium dose of 1×10 ⁶/kg. Fitted patients undergo consolidation allogeneic hematopoietic stem cell transplantation (Allo-HSCT) within 1-3 months after CAR-T cell infusion. The hematology toxicity and infection were analyzed during the period from CD19 CAR-T or CD7 CAR-T cell infusion to Allo-HSCT. Hematology toxicity is graded according to “ICAHT: EHA/EBMT Consumption Grading and Best Practice Recommendations” (Table 1). Infection diagnosis includes both etiological diagnosis and imaging diagnosis.

Results

Between June 1, 2019, and September 22, 2022, 60 patients with R/R B-ALL patients received CD19 CAR-T therapy (https://clinicaltrials.gov NCT04546893, and NCT04792593). Meanwhile, between December 1, 2020, and July 16, 2022, 60 patients with R/R T-ALL/LBL received CD7 CAR-T therapy (NCT04572308, NCT04916860). The CD19 CART group had 19 patients ≤ 14 years old, with a male/female gender ratio of 33:27. The CD7 CART group had 20 patients ≤ 14 years old, with a gender ratio of 49:11.

The incidence of severe early ICAHT (Grade III+IV, day 0-30) from CD19 CAR-T cells infusion to allo-HSCT was observed to be 18.3%, which was lower than the incidence of the early ICAHT post CD7 CAR-T therapy at 33.3%, p =0.035. However, the incidence of severe late ICAHT (after day+30) following CD19 CAR-T and the CD7 CAR-T therapy was similar: 27.8% vs. 28.6%, with no statistical difference( p=0.57).

There was no statistical difference between CD19 CAR-T and CD7 CAR-T therapy groups in the infection rates with 28.3%vs. 36.7%, p=0.33. In the CD19 CAR-T group, bacterial infections were noted in 10 patients: 6 with Gram-positive bacteria (1 Enterococcus, 1 Streptococcus agalactis, and 4 Staphylococcus), and 4 with Gram-negative bacteria (1 Pseudomonas aeruginosa, 2 Acinetobacter baumannii, and 1 Klebsiella pneumoniae). Viral infections were observed in 7 patients (EBV 2, CMV 2, BKV 3), and 1 had fungal infection. Infection sites included pulmonary infections (7 cases), sepsis (10 cases), and other areas (4 cases). Post-CD7-CAR-T, bacterial infections were observed in 9 cases, 7 with Gram-positive bacteria (6 Staphylococcus, and 1 Streptococcus bradycardia) and 2 with Gram-negative bacteria (1 Pseudomonas aeruginosa, and 1 Klebsiella pneumoniae). Six cases had viral infections (EBV 2, CMV 2, HHV1 type 1, parainfluenza virus 1), and 6 with fungal infections. Infection sites included pulmonary infection (12 cases), sepsis (10 cases), and other areas (5 cases).

Conclusions

Our study noted a slightly higher incidence of ICAHT within 30 days following CD7 CAR-T infusion compared to CD19 CAR-T therapy. However, there was no statistical difference in the incidence of ICAHT beyond the 30-day. There was no statistical difference for infection rate after CD19 CAR-T and CD7 CAR-T. In both groups, Gram-positive bacteria were primary responsible for bacterial infections.