CAR T-Cell Therapy Elicits High Response Rate in Pediatric ALL

The CAR T-cell therapy CTL019 demonstrated an impressive complete response rate in pediatric patients with relapsed/refractory acute lymphoblastic leukemia.

Results of small and early studies involving CAR T-cell therapy has shown promising results, attracting the attention of patients and the public. At this year's annual meeting of the American Society of Hematology results were announced that showed the anti-CD19 chimeric antigen receptor (CAR)-modified T-cell therapy called CTL019 demonstrated an impressive 92 percent complete response (CR) rate in pediatric patients with relapsed/refractory acute lymphoblastic leukemia (ALL).

“What we really have now that we didn’t have before is longer follow-up. A lot of kids are now a year out. We’re seeing the possibility of longer term disease control without further treatment, especially without bone marrow transplant, so I am very excited about that,” said lead author Stephan Grupp, who is director of translational research for the Center for Childhood Cancer Research at The Children’s Hospital of Philadelphia, in an interview with OncLive. “I am excited about the prospect of having a pediatric multisite trial to see how well these cells are going to work in broader application.”

CTL019 is an autologous T-cell therapy engineered to express a CD19-specific CAR. Once infused into the patient, CTL019 continues to undergo robust in vivo expansion that can persist for longer than two years in some patients.

In July 2014, CTL019 received a breakthrough therapy designation from the Food and Drug Administration for its potential as a treatment for pediatric and adult patients with relapsed/refractory ALL.

In the updated findings from the phase 1 study, 39 patients with CD19-positive ALL received treatment with CTL019. One week prior to treatment with CTL019, 87 percent of patients received lympho-depleting chemotherapy. The day prior to the infusion of CTL019, five patients tested negative for minimal residual disease (MRD). Of the 36 patients who achieved a CR, 85 percent tested MRD-negative. The event-free survival was 70 percent and overall survival was 75 percent.

At a median follow-up of six months, 76 percent of patients continued to respond to therapy. “Although the median follow-up is six months, there are patients who are out a year and even as far as 31 months. Fifteen patients are out a year or more,” Grupp said. In patients with a large burden of disease, with more than 50 percent blasts by MRD, the overall response rate (ORR) was 82 percent. In patients with blasts greater than 5 percent, the ORR was 88 percent.

Patients with low levels of disease experienced an ORR of 100 percent. Flow cytometry analysis within the study revealed that CTL019 cells are persistent over time. Additionally, further study showed that CTL019 cells were found in the cerebrospinal fluid of 90 percent of patients, with two patients with central nervous system involvement experiencing a CR.

“Persistence of the cells is a key point here. Once we give these cells, they stick around for many months for many patients,” Grupp said. “About two-thirds of patients retain their T cells for six months or longer, which is a key point for maintaining remission in these patients.” There were ten relapses in the study, half of which occurred following a loss of CD19 expression. At the time of the analysis, few patients had required subsequent therapy, with three going on to receive a stem cell transplant. Forty percent of patients who relapsed with CD19-negative disease after achieving a CR were also refractory to prior treatment with Blincyto (blinatumomab).

“Some of the patients that we have treated have relapsed. If you go into remission, the likelihood that you'll remain in remission six months later is 76 percent. That’s pretty good,” said Grupp.

“Some of those patients recur because their leukemia cells learn how to hide the target and then the T cells can’t see the leukemia anymore. In that situation, the T cells aren’t going to work.”

All patients enrolled in the study experienced cytokine release syndrome (CRS), at the point of peak T-cell expansion. In 37 percent of patients, CRS was rapidly reversed using the interleukin-6 inhibitor Actemra (tocilizumab), a treatment that is currently approved for patients with rheumatoid arthritis.

The incidence of severe CRS was found to correlate with disease burden, suggesting this side effect could effectively be predicted and prevented. Overall, patients with a high disease burden prior to treatment with CTL019 were significantly more likely to experience CRS.

“You can control cytokine release syndrome with tocilizumab, which targets IL-6," said Grupp. “In the patients who have enough T-cell proliferation to require this drug, they have a 100 percent likelihood of going into clinical response. I think if we try to control the T cells using steroids, we’d start to see limitations in efficacy.”

Overall, 21 patients had relapsed on an allogeneic stem cell transplant prior to entering the study. As a result, cells collected to manufacture CTL019 were 100 percent of donor origin. Despite this, graft-versus-host disease was not apparent in the trial. Other side effects with CTL019 include B cell aplasia, macrophage activation syndromes and neurotoxicity.