Factors Associated with Impaired Hematopoietic Recovery after CD19-Targeted CAR-T Cell Therapy

Abstract

<h3>Introduction</h3> Despite promising results in patients with relapsed/refractory B cell malignancies, CD19 CAR-T cell therapy can be associated with significant toxicities. Specifically, impaired hematopoietic recovery can be observed in a subset of patients. <h3>Objectives</h3> We aimed to describe hematopoietic recovery following CD19 CAR-T cell therapy, and to identify factors independently associated with this complication using multivariable modeling. <h3>Methods</h3> We retrospectively analyzed 125 adult patients with R/R acute lymphoblastic leukemia (ALL), non-Hodgkin lymphoma (NHL), and chronic lymphocytic leukemia (CLL), treated with CD19 CAR-T cells on a phase 1/2 clinical trial (characteristics summarized in Table 1). Criteria for neutropenia, thrombocytopenia, and recovery were defined as per the CIBMTR reporting guidelines. For competing risk analysis, an event was defined as ANC or platelet (Plt) recovery, with death, new cytotoxic therapy, relapse with marrow involvement in the absence of ANC or platelet recovery considered as competing events. Patient, disease, and CAR-T cell therapy-related variables were included in multivariable analyses. <h3>Results</h3> ANC and Plt recovery after CD19 CAR-T cell therapy were observed in 91% (ALL, 86%; CLL, 92%; NHL, 95%) and 86% (ALL, 86%; CLL, 86%; NHL, 84%) of patients, respectively. Median time to ANC recovery was 9 days and the probability of ANC recovery at day 28, 60, and 90 was 80% (95%CI, 73-87), 86% (95%CI, 80-92) and 89% (95%CI, 83-94), respectively. The probability of platelet recovery on the day of CAR-T cell infusion was 55% (95%CI, 46-64); rising to 74% (95%CI, 67-82), 83% (95%CI, 76-90), and 84% (95%CI, 77-90) on days 28, 60, and 90, respectively. A competing event was always observed in patients without ANC or Plt recovery. In multivariable analysis (Table 2), higher pre-lymphodepletion (LD) Plt count and higher peak CD8+ CAR-T cells in blood were associated with faster ANC recovery. A diagnosis of ALL was associated with slower ANC recovery. (CLL vs ALL, HR=1.60, p=0.02; NHL vs ALL, HR=2.07, p=0.007). Higher CRS grade was also associated with slower Plt recovery (HR=0.67 per grade increase, p<0.001). Higher pre-LD Plt count (HR=1.08 per 25 × 10⁹/L increase, p=0.001) and higher peak CD8+ CAR-T cell in blood (HR=1.41 per log₁₀ cells/µL increase, p<0.001) were associated with faster Plt recovery. Figure 1 shows cumulative incidence of ANC and Plt recovery by CRS grade. <h3>Conclusion</h3> We observed impaired ANC and Plt recovery in a significant fraction of patients undergoing CD19 CAR-T cell therapy. Moreover, we identified factors independently associated with impaired hematopoietic recovery: disease type, prelymphodepletion Plt count, in vivo CAR-T cell expansion, and CRS grade. In addition to providing a benchmark for future CAR-T cell research, our findings suggest CRS prevention might improve hematopoietic recovery after CD19 CAR-T cell therapy.