ASH 2014: CD19-Directed CAR T-Cell Therapy Yields High Rate of Durable Remissions in Pediatric Acute Lymphoblastic Leukemia
As more experience is gained with the use of genetically engineered chimeric antigen receptor (CAR) T cells in pediatric patients with relapsed/refractory acute lymphoblastic leukemia (ALL), the data continue to be highly encouraging.
To date, 36 of 39 pediatric ALL patients (92%) treated with this novel therapy using a compound called CTL019 have experienced complete remissions, and responses are durable. At a median follow-up of 6 months, sustained remissions were achieved of up to 1 year or more, with a 6-month event-free survival of 70% and overall survival of 75%, in most cases with no further therapy.
“We are seeing pediatric patients who have not responded to other therapies achieve complete remission as a result of treatment with CTL019,” said lead author Stephan Grupp, MD, of Perelman School of Medicine at the University of Pennsylvania, speaking at a press conference during the 56th American Society of Hematology (ASH) Annual Meeting and Exposition (Abstract 380).
Other important findings are that after the genetically engineered T cells are reinfused into the patient, they continue to proliferate in vivo to an “extraordinary” level, up to 31 months in ongoing responders. Expansion and proliferation is accompanied by B-cell aplasia, a pharmacodynamic marker of CTL019 persistence and function, considered a toxicity and managed with intravenous immunoglobulin replacement therapy.
Cytokine-Release Syndrome
The major toxicity of concern is cytokine-release syndrome, which was seen in all responding patients at peak T-cell expansion. Symptoms of cytokine-release syndrome include varying degrees of flu-like symptoms with high fevers, nausea, muscle pain, and in some cases low blood pressure and respiratory distress. Treatment of severe cytokine-release syndrome was required in 33% of the pediatric patients. Fortunately, this syndrome resolves within a day or two with use of tocilizumab (Actemra), an IL-6 receptor antagonist, Dr. Grupp told listeners.
The severity of cytokine-release syndrome appears to be related to disease burden at the time of infusion; patients with higher disease burden are more likely to develop severe cytokine-release syndrome, Dr. Grupp said.
Other toxicities include macrophage activation syndrome and neurotoxicity in a small number of patients after the occurrence of cytokine-release syndrome.
CAR T-Cell Therapy
Manufacturing CTL019 is labor-intensive and involves extracting the patient’s own T cells and genetically engineering them to target the CD19 surface antigen on tumor cells. The T cells are then reinfused into the patient, unleashing cytotoxicity against tumor cells in an antigen-dependent manner. Dr. Grupp said that ongoing research is being devoted to expediting the manufacturing process so that the CAR T cells can become more widely available.
This novel therapy made national headlines when the first pediatric and adult patients treated with this therapy showed complete remission of leukemia after having exhausted all other options.
CTL019 was developed at the University of Pennsylvania with the financial support of Novartis. Overall, more than 130 patients with ALL, chronic lymphocytic leukemia, and non-Hodgkin lymphoma have been treated with CTL019.
Other institutions studying CAR T cells in hematologic malignancies include Memorial Sloan Kettering Cancer Center, Fred Hutchinson Cancer Research Center, and the National Cancer Institute.
Dr. Grupp reported research funding from and consultancy with Novartis. For full disclosures of the study authors, view the study abstract.
The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.
