Complete remissions have occurred in 45 of 48 patients treated thus far, including 13 patients with remissions that have persisted for a year or long.
During a median follow-up of 8 months, 15 patients have relapsed, but no relapses occurred more than a month after treatment with chimeric antigen receptor (CAR)-modified T-cells (CTL019), Shannon Maude, MD, PhD, of the University of Pennsylvania in Philadelphia, and colleagues reported at the American Society of Pediatric Hematology/Oncology meeting.
"Single-agent CTL019 can induce potent and durable responses in patients with relapsed and refractory ALL," Maude said. "No unexpected toxicity has been observed."
"Cytokine release syndrome occurs frequently and is related to disease burden at the time of treatment," she explained. "The condition can be reversed with anticytokine therapy, but it can be severe in some cases and require hemodynamic and respiratory support. Severe cases are associated with high disease burden and elevated levels of C-reactive protein."
Emerging over the past several years, CAR immunotherapy has demonstrated activity in multiple studies of hematologic malignancies. As previously described here and elsewhere, CAR immunotherapy involves taking a cancer patient's own T-cells, introducing genetically altered antigen receptors into the cells, and returning the cells to the patients, where the modified T-cells attack cancer cells with newly created potency.
After demonstrating safety and efficacy in adults, CAR-based immunotherapy has begun expanding into pediatric populations. Maude reported data from one of the largest experiences to date in pediatric ALL. The treatment involves introducing anti-CD19, anti-CD3, and anti-CD28 fragments into the T-cells, which become activated and capable of initiating a strong cytotoxic response against tumor cells.
"These T-cells can stick around for quite some time and quite possibly provide long-term disease control," Maude said.
The patients enrolled thus far have progressed/relapsed on two or more prior regimens or had disease that had proven refractory to all therapies. In 33 cases, relapse occurred after stem cell transplantation.
The patients received as many as three infusions of modified T-cells. Most received lymphodepleting chemotherapy a week prior to cell infusion. Within 1 month of treatment, all but three patients had achieved complete remissions, Maude said. All three patients had a high disease burden prior to immunotherapy. In only a handful of cases did the response not meet criteria for minimum residual disease. No patient has developed graft-versus-host disease to date.
Ten of 15 relapses that occurred after modified T-cell therapy were associated with antigen escape, meaning that the patients tested negative for CD19.
Follow-up ranges from 1 to 35 months for all patients. Overall, 18 patients are alive for more than a year after treatment, and 13 of the 18 remain in complete remission, Maude said. Most patients have not received additional therapy after CAR immunotherapy, but five have gone on to stem-cell transplantation.
The treatment has a well recognized toxicity, most commonly in the form of cytokine release syndrome (CRS), which reflects T-cell proliferation. The severity of CRS appears to correlate with disease burden prior to CAR immunotherapy. CRS can be reversed with cytokine blockade with tocilizumab (Actemra).
Tumor lysis syndrome has not been a prominent issue but "is certainly possible," Maude stated. "Most of these patients have fairly low white counts going in, as they do get some chemotherapy prior to infusion."
Neurotoxicity, observed in other studies of CAR T-cell immunotherapy, has occurred in a few patients but has resolved without treatment. Chronic B-cell aplasia (an "on target" toxicity) also has occurred but has responded to immunoglobulin replacement therapy.
The 48 patients have a 6-month overall survival of 81% and 12-month survival of 78%. Maude said 18 patients have survived at least a year with 13 still in complete remission (10 of 13 without additional treatment).
kaynak: http://www.medpagetoday.com/
