CT-329 CD19-Directed Chimeric Antigen Receptor T Cell Therapy in Waldenström Macroglobulinemia: Initial Experience in Two Clinical Trials

Abstract

Waldenström macroglobulinemia (WM) is a treatable but incurable disease that can cause significant morbidity or mortality when refractory to available therapies. Chimeric antigen receptor (CAR) T cell therapy directed against the CD19 antigen has demonstrated efficacy in relapsed or refractory B lymphoid malignancies but has not been evaluated in WM. We included patients with relapsed/refractory (R/R) WM in two clinical trials evaluating the safety and activity of autologous CD19-directed CAR T therapy for lymphoid malignancies. Trial NCT00466531 evaluated a 19-28ζ CAR T product similar to that seen in axicabtagene ciloleucel. Trial NCT03085173 evaluated CD19-targeted 19-28ζ 'armored' CAR T cells engineered to co-express 4-1BBL, another co-stimulatory signal. Two patients were treated on protocol NCT00466531 and one on NCT03085173. All were female, 65-74 years of age. All had received at least 5 prior lines of therapy, including anti-CD20-containing chemoimmunotherapy, ibrutinib, and bortezomib. All 3 patients had grade 1-2 cytokine release syndrome (CRS), with no grade ≥3 CRS. One patient had grade 2 neurotoxicity, which resolved in 24 hours with steroids; no other neurotoxicity and no grade ≥3 treatment-related adverse events were observed. All patients attained a clinical response to treatment, including one with an MRD-negative complete response lasting 26 months. All three eventually had disease progression 3-26 months after initial treatment; CD19 expression remained detectable in each instance, though a quantitative decrease in CD19 expression was observed in one relapse. Two patients died, one from influenza A and pseudomonas infection 4 months after treatment and one from WM progression 12.4 months after treatment. In the first series of patients with heavily pretreated R/R WM treated with CD19-directed CAR T therapy, toxicity was similar to that seen with CAR T therapy in other lymphoid malignancies, and all patients had a clinical response to treatment. However, subsequent disease progression was seen in all cases. CAR T therapy represents a possible treatment option in patients with R/R WM. Larger studies evaluating CAR T activity in WM are needed, along with further evaluation into mechanisms of CAR T resistance.