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CAR-T Drives Long-Term CRs in Highly Aggressive Pediatric ALL

Carlson, Robert H.

doi: 10.1097/01.COT.0000460532.04720.78
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SAN FRANCISCO—Chimeric antigen receptor T-cell (CAR-T) therapy again generated much excitement here at the American Society of Hematology Annual Meeting, as it did at the 2013 Annual Meeting in New Orleans.

One clinical study of the CAR-T agent CTL019 showed a 92 percent rate of complete remission (CR) in 39 pediatric patients with relapsed/refractory acute lymphoblastic leukemia (ALL). The 36 patients who achieved a CR did so within 28 days after T-cell infusion (Abstract 380).

The investigators also saw persistence of the CAR-T cells of at least six months after treatment. “We are beginning to see a picture of longer-term persistence in ALL and longer-term disease control,” said Stephan Grupp, MD, PhD, Professor of Pediatrics at the Perelman School of Medicine at the University of Pennsylvania and Director of Translational Research at Children's Hospital of Philadelphia, speaking in a news conference devoted to novel strategies that direct the immune system to attack recurrent, difficult-to-treat hematologic cancers.

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Longer Follow-Up

“With this longer follow-up, we now have children who remain in remission a year or more after treatment, solely because of this T-cell therapy,” he said. “Our next step is to conduct a Phase II, multi-site trial to assess the safety and efficacy of this treatment in multiple centers and to further evaluate its long-term potential to become a replacement for stem cell transplant for children with relapsed, treatment-resistant disease.”

The therapy has already received Breakthrough Therapy designation from the FDA in both pediatric and adult ALL.

The overall survival rate was 75 percent at one year—in most cases without further therapy, he said. CAR T-cells have the ability to target a cancer cell based on an antigen expressed on the cell surface—in this case CD19.

This is very much an individualized therapy, he said, as T-cells are collected by apheresis from each patient.

Grupp said there have been 10 relapses, five of which are related to the disappearance of T-cells. Those five patients had a CD19-positive relapse, and the other five relapses were related to antigen escape—that is, a CD19-negative relapse.

Fifteen patients remain in remission a year or more after treatment—the first patient for 31 months. “We have not seen events in patients who remain in remission after 12 months,” Grupp said.

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Not Considered ‘Bridge to Transplant’

He pointed out that this treatment is not being considered as a “bridge to stem cell transplant,” and only three patients treated have gone on to transplant.

A key point in the results is that the response rates are independent of the disease burden—there was an 88 percent response rate in patients with five percent blasts, but a very similar 82 percent response in patients with 50 percent or more blasts.

Patients do get ill, he said, and if they come into the study with a high burden of disease they can experience cytokine release syndrome.

Patients who have less than 50 percent bone marrow blasts do not have a significant degree of cytokine release syndrome, Grupp said, while those with more than 50 percent have a high risk of the syndrome.

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Cautions about Toxicity

The moderator of the news conference, Catherine Bollard, MD, Senior Scientist in the Center for Cancer and Immunology Research at Children's Research Institute in Washington, D.C., and Adjunct Professor of Pediatrics at George Washington University, commented in an interview afterwards about how “amazingly potent” the CTL019 appeared to be.

STEPHAN GRUPP, MD, PHD

STEPHAN GRUPP, MD, PHD

“But it does still have significant toxicities,” she cautioned, “and in many cases these patients are sicker than you see with the average allogeneic transplant patients.”

Grupp said that ultimately CAR-T could replace allogeneic transplant as a way to treat those primary refractory relapsed patients with ALL, both adults and children.

“We still don't understand why some patients who relapsed after CAR-T treatment relapsed with CD19-negative disease, and most of those had had blinatumomab [another anti-CD19 agent] previously,” Bollard said. “So the concern is whether the use of blinatumomab increases the risk of these patients relapsing from CD19-negative disease after they get CAR-T cells.”

What can be said for CAR-T therapy is that it is “unbelievably impressive in ALL, but for other cancers we don't know yet,” she said.

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Comments from ASH President

ASH President Linda J. Burns, MD, Professor of Medicine in the Division of Hematology, Oncology, and Transplantation at the University of Minnesota, discussed the study in a teleconference briefing for reporters before the meeting.

She said it was remarkable that the researchers were able to detect the engineered T cells up to two years following initial treatment in patients who had responses to therapy.

“It is encouraging that many of these children had relapsed after the most aggressive attempt to cure, an allogeneic transplant,” Burns said. “This suggests that the therapy is very effective even when the most aggressive therapies have failed.

“This also tells us something about the biology of the disease and those children whose disease unfortunately comes back. Of those children whose disease relapsed, half of them no longer had the presence of the antigen to CD19 on the leukemia cells—that is, they no longer expressed the target. That helps us understand better why that drug is no longer effective and may help the investigators identify ways to overcome that.”

She said it was also interesting that the researchers were able to detect the CAR-T cells in the central nervous system—“and it actually got rid of spinal fluid disease in two patients.

“ALL is one of those diseases that has a high risk of disease in the spinal fluid. This therapy helped clear leukemia there—that's really exciting and encouraging.”

Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
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