Background: The prognosis of patients with diffuse large B-cell lymphoma refractory to first-line or subsequent salvage therapy is extremely poor, with a median overall survival of 6.3months. Anti-CD19 chimeric antigen receptor (CAR) T-cell therapy is a promising approach with 35~39% patients achieving durable remission after CAR T cells infusion. Whether autologous hematopoietic stem cell transplantation (HSCT) consolidation after CAR T therapy would reduce relapse is controversial, considering that myeloablative conditioning might eliminate residual CAR T cells and be adverse to immunological surveillance from CAR T cells. We hypothesized that, following HSCT, the immunosuppressive microenvironment would be diminished and the tumor burden would be decreased as a result of myeloablative conditioning, and that administering CAR T cells during hematopoietic reconstitution could eradicate posttransplant residual disease, leading to lower rate of relapse. We therefore conducted a single-arm, single-center study to assess the safety and efficacy of anti-CD19 CAR T therapy following autologous HSCT in patients with refractory large B-cell lymphoma. This trial was approved by Blood Diseases Hospital Internal Review Board.
Methods: Patients with large B-cell lymphoma refractory to primary or salvage therapy were eligible for this study. Autologous stem cell reinfusion was performed after conditioning of GBC (Gemcitabine 600mg/m2/h, infused for 3 hours with loading bolus of 75mg/m2, day -7, -3, busulfan 105mg/m2 day -7 until -5, cyclophosphamide 45mg/kg day -3, -2), and second-generation anti-CD19 CAR T cells bearing 4-1BB costimulatory domain were administered 2~4 days after stem cell infusion.
Results: Between January 2018 and May 2019, 6 patients were enrolled, with median age of 47 years (range, 29~55 years). 5 patients had a diagnosis of DLBCL and 1 patient had a diagnosis of high grade B-cell lymphoma (HGBL) with MYC, BCL2 and BCL6 rearrangement. 2/3 patients had P53 deletion detected by FISH. The median number of prior therapy was 3 (range, 2~4). ALL patients received R-DA-EDOCH (administered in 4 patients) or R-CHOP (administered in 2 patients) as their first-line therapy. 4 patients had received lenalidomide and 1 patient had received ibrutinib before transplantation. At baseline (prior to conditioning), 4 patients had progressive disease, the other two patients had progressive disease after induction therapy, but achieved partial response or complete response before conditioning. All patients received autologous HSCT followed by CD19 CAR T cells infusion. The median dose of infused stem cell was 2.44×106 per kilogram of body weight (range, 1.77~8.7×106) and the median dose of infused anti-CD19 CAR T-cell was 2×106 per kilogram of body weight (range, 1.7~4×106). After CAR T cells infusion, all patients experienced grade 1 cytokine release syndrome (CRS), 3 patients received tocilizumab and no patient received corticosteroids for management of CRS. Only 1 patient experienced CAR-T-cell-related encephalopathy syndrome (CRES), manifesting as generalized seizures, which was classified as grade 4. He was managed with corticosteroids and seizures was resolved in one day. The median time to neutrophil and platelet engraftment were 10.5 days and 12.5 days, respectively, with 1 patient had a delayed platelet engraftment (at 57 days after stem cell infusion). 5/6(83%) participants achieved complete response, 1 patient had stable disease at 1 month, progressive disease at 2 months and died from progression at 3 months after transplantation. With median follow-up of 5.5 months (range, 3~18 months), 3/6(50%) patients were in continuing complete remission, with 1 patient had been in complete remission for 18 months.
Conclusion: CD19 CAR T therapy following autologous HSCT exhibited a higher rate of complete remission in patients with refractory large B-cell lymphoma compared to that of CAR T therapy alone. No grade 2 or higher CRS occurred. Data from this pilot trial supports the safety and feasibility of administering CAR T cells following autologous HSCT in patients with refractory large B-cell lymphoma.
No relevant conflicts of interest to declare.
