Acute Graft-Versus-Host Disease After Humanized Anti-CD19-CAR T Therapy in Relapsed B-ALL Patients After Allogeneic Hematopoietic Stem Cell Transplant

Abstract

We studied the acute graft-versus-host disease (GVHD) after humanized anti-CD19-CAR T therapy in relapsed B-acute lymphoblastic leukemia (ALL) patients after allogeneic hematopoietic stem cell transplant (allo-HSCT). Fifteen B-ALL patients were enrolled in our study. Thirteen patients (86.67%) achieved a complete response (CR) or CR with incomplete count recovery. The donor chimerism of the 13 patients reached 99.86 ± 0.21%. The development of aGVHD was observed in 10 patients (66.67%). Six patients developed grade I-II of aGVHD, while the other four patients developed grade III-IV of aGVHD. The notable adverse events were grade 1-2 cytokine release syndrome (CRS) in 10 patients and grade 3-4 CRS in five patients. Two patients died of infection, while another patient died of sudden cardiac arrest. The anti-CD19-CAR T cells were not eliminated in peripheral blood when the patients developed aGVHD. However, we did not observe their expansion peaks again in the process of aGVHD. During the aGVHD, the peaks of IL-6 and TNF-a were correlated with aGVHD levels. By May 31, 2020, the rates of leukemia-free survival (LFS) and overall survival (OS) at 180 days were 53.846 and 61.638%, respectively. All the patients who survived to date experienced aGVHD after humanized anti-CD19-CAR T cell therapy. Trial registration: The patients were enrolled in clinical trials of ChiCTR-ONN-16009862 and ChiCTR1800019622.

Keywords: acute lymphoblastic leukemia; allogeneic hematopoietic stem cell transplantation; chimeric antigen receptor (CARs); cytokine release syndrome; graft-versus-host disease; relapse.

Figure 1

The secretion levels of IL-6, IL-2R, TNF-α, and IL-8 in the anti-CD19-CAR T-cell therapy. The peaks of the cytokines were on days 4–7 post infusion of anti-CD19-CAR T-cells, and the levels then declined 14 days post infusion. (A) The secretion levels of IL-6 in the anti-CD19-CAR T-cell therapy. (B) The secretion levels of IL-8 in the anti-CD19-CAR T-cell therapy. (C) The secretion levels of IL-2R in the anti-CD19-CAR T-cell therapy. (D) The secretion levels of TNF-a in the anti-CD19-CAR T-cell therapy.

Figure 2

Expansion of anti-CD19-CAR T-cells and anti-CD19-CAR gene. (A) The average expansion peak of anti-CD19-CAR T cells was 32.54 ± 19.94% on days 4–14 (median time was 11.31 ± 3.47 days) after the infusion. The mean level of anti-CD19-CAR T cells was 2.58 ± 1.32% when the patients developed aGVHD. (B) DNA level of anti-CD19-CAR gene showed the same trend.

Figure 3

Correlation analysis between the aGVHD and the cytokine levels or CAR-T cell levels. (A–D) The peaks of the cytokines in the anti-CD19-CAR T-cell therapy were uncorrelated with aGVHD levels. (E,H) The peaks of IL-6 and TNF-a in grade I-II in the aGVHD group were lower than those of the grade III-IV in the aGVHD group during the occurrence of aGVHD. (F,G) The peaks of the IL-2R and IL-8 during the occurrence of aGVHD were uncorrelated with aGVHD levels. (I–L) The peaks of anti-CD19-CAR T cells and anti-CD19-CAR gene were uncorrelated with aGVHD levels during the anti-CD19-CAR T-cell therapy and the occurrence of aGVHD. (N) The CD3+CD8+CD4- percentages in grade I-II in the aGVHD group were lower than that of the grade III-IV in the aGVHD group. (M,O,P) The CD3+ percentage, the CD3+ absolute value and the CD3+CD8+CD4- absolute value were uncorrelated with aGVHD levels during the occurrence of aGVHD.

Figure 4

The follow-up post anti-CD19-CAR-T therapy of the B-ALL patients who relapsed after allo-HSCT. (A,B) The LFS and OS of the 13 patients on 180 days were 53.846 and 61.638%. (C) The LFS, OS, occurrence of aGVHD, cause of death and CD19 expression at the moment of recurrence are listed.