A phase 1 trial of CD123-directed chimeric antigen receptor T-cell therapy in adults with relapsed/refractory acute myeloid leukemia or blastic plasmacytoid dendritic cell neoplasm.

Patients with relapsed acute myeloid leukemia (AML), particularly following allogeneic stem cell transplant (alloHCT), have extremely limited therapeutic options. CD123 is an AML-associated antigen and represents an attractive target for immunotherapy. We report outcomes of a phase 1 trial evaluating CD123-targeting chimeric antigen receptor (CAR) T cells in patients with relapsed/refractory (r/r) AML or blastic plasmacytoid dendritic cell neoplasm (BPDCN). This was a single center, open-label, phase 1 dose escalation study enrolling patients with either CD123-positive r/r AML (Arm 1) or BPDCN (Arm 2). Patients received autologous or donor-derived allogeneic CD123 CAR T cells following lymphodepletion. The co-primary objectives were to examine safety and anti-tumor activity using an activity-constrained for toxicity design and to determine the recommended phase 2 dose. Secondary objectives included assessments of progression-free and overall survival. We enrolled 41 patients, of whom 21 patients (n = 19 on Arm 1 and n = 2 on Arm 2) received CD123 CAR T-cell infusion. The median age of treated AML patients was 45 years (range: 20-71); the two BPDCN patients were aged 24 and 75 years. Among AML patients, 17 (89%) had undergone prior alloHCT. AML patients received 50 × 106 (n = 2), 200 × 106 (n = 6), or 500 × 106 (n = 11) CAR T cells; BPDCN patients received 100 × 106 CAR T cells. There was no dose-limiting toxicity, prolonged myelosuppression, or graft-versus-host disease. Fourteen (74%) AML patients developed grade ≤ 3 cytokine release syndrome (CRS) and 11 (58%) experienced grade ≤ 2 neurotoxicity. Fifteen of 19 treated AML patients were evaluable for disease response for overall best response, of whom 4 (26.7%) had best response of complete remission, including 2 with incomplete count recovery. Neither patient with BPDCN developed CRS but both experienced grade 1 neurotoxicity. One of 2 BPDCN patients achieved CR and relapsed at 3 months. CAR T cell expansion was dose-dependent, but persistence was limited. CD123-directed CAR T-cell therapy is feasible and demonstrates a favorable safety profile in patients with r/r AML and BPDCN, including those with prior alloHCT. Although the estimated overall complete remission rate was modest, these findings provide a foundation for further optimization of CD123 CAR T-cell design, patient selection, and combination strategies. This trial was registered at ClinicalTrials.gov as NCT02159495.