T-Cell Therapy Produces High Remission Rates in ALL

Ninety percent of patients with relapsed or refractory acute lymphoblastic leukemia (ALL) achieved complete remission after treatment with autologous T cells transduced with a CD19-directed chimeric antigen receptor (CTL019) lentiviral vector, according to the results of a small study published in the New England Journal of Medicine.

“With a follow-up period of 2 to 24 months, sustained remissions were observed in 19 patients (15 of whom received no further therapy) and were associated with the persistence of CTL019 and B-cell aplasia that continued beyond 2 to 3 months, suggesting continued effector function,” wrote Shannon L. Maude, MD, PhD, of the Children’s Hospital of Philadelphia, and colleagues.

According to the study, relapsed and refractory ALL is associated with extremely poor prognosis in adults and is a leading cause of death in pediatric cancers. Prior studies examined the effect of targeting CD19 in chronic lymphocytic leukemia and B-cell ALL; however, this is the first study to look at remission rates and durability of response when using chimeric antigen receptor–modified T cells in a larger cohort of patients with ALL.

“Chimeric antigen receptors are genetically engineered receptors that couple an anti-CD19 single-chain Fv domain to intracellular T-cell signaling domains of the T-cell receptor, thereby redirecting cytotoxic T lymphocytes to cells expressing this antigen,” the researchers wrote.

In this study, Maude and colleagues infused autologous T cells transduced with CTL019 lentiviral vector in 30 adults and children at doses of 0.76×10⁶ to 20.6×10⁶ CTL019 cells per kilogram of body weight.

Of the 30 patients in the study, 27 (90%) achieved complete remission, including two patients who had blinatumomab-refractory disease and 15 who had undergone prior stem-cell transplantation. The researchers were able to detect the CTL019 cells in the blood, bone marrow, and cerebrospinal fluid of patients who responded to treatment.

Durable response to the treatment was observed. The 6-month event-free survival was 67% and the overall survival was 78%. No significant differences in event-free or overall survival were observed between the patients who had relapsed disease after allogeneic stem-cell transplantation and those who had not had prior transplantation. In addition, at 6 months, the probability of a patient having persistence of CTL019 was 68%.

“CTL019 sequences remained detectable by means of quantitative polymerase-chain-reaction assay in patients with sustained remissions until 2 years,” the researchers wrote.

All patients experienced cytokine-release syndrome, a systemic inflammatory response that is produced by elevated levels of cytokines. Severe cytokine-release syndrome occurred in 27% of patients and was associated with a higher disease burden before CTL019 infusion.

“Tocilizumab, an interleukin-6 receptor–blocking antibody, produced a rapid and profound improvement in severe manifestations of the cytokine-release syndrome without an apparent impact of the efficacy of CTL019,” the researchers wrote. Based on this result, tocilizumab has been included as a first-line treatment for the management of this adverse effect of CTL019 treatment.