Nick Mulcahy

December 18, 2014

SAN FRANCISCO — More and longer-term data on chimeric antigen receptor (CAR) T-cell engineering for the treatment of pediatric leukemia were presented here at the American Society of Hematology (ASH) 56th Annual Meeting.

As the results continue to shine, words like "seismic shift" and "sea change" were bandied about at the meeting as potentially applying to the experimental technology and its impact on practice.

But researcher Stephan Grupp, MD, PhD, from the Children's Hospital of Philadelphia (CHOP) and the University of Pennsylvania, was much more understated. He told Medscape Medical News that his "fondest hope" is that the new treatment approach will replace stem cell transplantation in this population.

Dr Grupp presented results on the use of CAR T-cells in 39 children and young adults with relapsed and refractory acute lymphoblastic leukemia (ALL).

The information is an update and expansion of data presented at the ASH meeting last year, which was then revised and published in the New England Journal of Medicine in April.


Dr Stephan Grupp


According to the latest findings, 36 of 39 patients (92%) achieved an initial complete response after experimental CAR T-cell treatment.

"We see very high rates of remission induction," Dr Grupp reported during a meeting press briefing.

Six months after treatment, 70% of children enrolled in the study remained cancer free, and 75% have survived.

Only five children have received subsequent treatment, three of whom underwent stem cell transplantation.

The median follow-up is 6 months (range, 1.5 - 31 months), he said.

Fifteen of the patients have been treated and followed for at least a year. There have been no relapses in the patients who have been in remission for a year or more.

"The duration of response has been very favorable," he said.

Disease Burden: Important and Not Important

A picture is emerging of how the novel treatment plays out over time in the clinic, Dr Grupp explained.

One of the characteristics of CAR T-cell therapy so far is that response is independent of disease burden, which is a "key point," he noted.

For example,   82% of the study patients with a disease burden of more than 50% bone marrow blast cells had a complete response, as did 88% with less than 5% blasts.  In other words, despite the wide range in the disease burden in these two groups, there was only a negligible difference in the rate of response.

However, high disease burdens do influence outcomes in terms of toxicity, he explained.

"Patients do get ill if they come into the study with a high disease burden," said Dr Grupp, referring to an increase in the likelihood of cytokine-release syndrome, an inflammatory process characterized by high temperatures and myalgia.

Patients with a bone marrow blast level below 50% "essentially do not have significant degrees of cytokine-release syndrome," he said. But patients with a blast level above 50% have a "high likelihood" of the syndrome.

In severe cytokine-release syndrome, hypotension and renal insufficiency can require treatment in an intensive care unit. Several of the study patients experienced neurologic toxicities (including encephalopathy), but these "fully resolved without further intervention or apparent long-term implications," according to a Novartis press release, as reported by Medscape Medical News.

Researchers have successfully used tocilizumab, an interleukin-6 receptor blocking antibody, to treat the syndrome, Dr Grupp and colleagues report.

There are other toxicities associated with the therapy, including B-cell aplasia, which has been observed in all responding patients and is managed with intravenous immunoglobulin replacement therapy, Dr Grupp explained. There have also been cases of macrophage-activation syndrome. However, these adverse effects are less of a concern. "The significant risk is really cytokine-release syndrome," he said.

During the press briefing, Dr Grupp also discussed the importance of the persistence of the investigational CAR therapy, known as CTL019 (Novartis), in a patient's blood.

"We see amazing growth of these cells, which I think is really correlated to the response," he said. "We see [CTL019] persistence, which I think is the key to patients remaining in remission. I think that is extraordinarily important."

Dr Grupp and his colleagues are "beginning to see the picture of longer-term persistence that may allow longer-term disease control," he said.

Growing Enthusiasm

The longer-term data have inspired some hematologists to use far-reaching words. The "accumulating data" in chronic lymphocytic leukemia and ALL "highlight what might become the next sea change in the care of all types of hematologic malignancies," Laura Michaelis, MD, from the Medical College of Wisconsin in Milwaukee, wrote in the daily ASH meeting newspaper.

Such big change is rare but does happen, said Dr Michaelis, who cited stem cell transplantation, imatinib (Gleevec, Novartis), and all-trans retinoic acid (ATRA) as "disruptive technologies" that result in "seismic shifts" in treatment and allow "patient care to accelerate along a totally new trajectory." CAR T-cell therapy has that potential, she suggested.

The technology also has deep-pocketed and committed backers, another expert pointed out.

"One of the exciting things about the CAR T-cell field is that there has been so much interest from pharma," said Catherine M. Bollard, MD, MBChB, from the Children's National Health System and the George Washington University in Washington, DC, who moderated the press briefing.

"I think we will start seeing these more centralized manufacturing models, where they centrally manufacture the product and ship it out to the various centers," she explained.

She cited the ongoing phase 2 multicenter pediatric study in ALL that is designed "to show that the model is totally feasible."

Dr Grupp addressed the issue of logistics and the reproducibility of the results at other centers.

"Are we actually going to be able to develop these personalized products for every patient?" he asked rhetorically.

The logistics feasibility has already been demonstrated to some extent at CHOP, he said, "because Penn has made our cells."  However, the two institutions are just blocks apart.

A bigger challenge is underway with the aforementioned phase 2 study, which involves centers across the United States.

The study is facilitated and funded by Novartis, which has licensed the CAR T-cell therapy and built a cell manufacturing facility.

CTL019 has been granted breakthrough status by the US Food and Drug Administration.

Dr Grupp reports financial ties with Novartis. Dr Bollard reports receiving honoraria from Cell Medica.

American Society of Hematology (ASH) 56th Annual Meeting: Abstract 380. Presented December 8, 2014.


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