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Global Trial of CTL019, Gene Therapy for Hemophilia, Child Abuse Within Military, New Radiologist-in-Chief, ADHD in Preschool

Published on December 16, 2016 in Cornerstone Blog · Last updated 4 months ago


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Your holiday season has been hectic, no doubt. Catch up with an early gift from us: Our biweekly roundup of research news from Children’s Hospital of Philadelphia comes with all the trimmings!

This installment shares the latest findings reported by CHOP researchers at The American Society of Hematology (ASH) annual meeting on advances in immunotherapy for acute lymphoblastic leukemia (ALL) and gene therapy for hemophilia. Find out about new PolicyLab research that raises concerns about Army-reported rates of child abuse. Meet CHOP’s new Radiologist in Chief. And see coverage by The New York Times on a study of guidelines that included a new category for preschool attention-deficit hyperactivity disorder (ADHD).

Results From First Global, Multicenter Trial of CTL019 Advance Research

CHOP pediatric oncologist Stephan Grupp, MD, director of CHOP’s Cancer Immunotherapy Frontier Program, co-moderated a session at the ASH annual meeting held in San Diego on advances in immunotherapy for relapsed or refractory ALL. At this session, Dr. Grupp reported results from the first global, multicenter trial (ELIANA) of chimeric antigen receptor (CAR) T cells, called CTL019 cells, of which he is the lead investigator. This investigational immunotherapy modifies a patient’s own immune T cells, extracted and engineered to potentially seek and destroy the patient’s leukemia cells.

ELIANA, sponsored by Novartis, is a global registration trial that has enrolled 81 patients at 25 centers in the U.S., Canada, Europe, Japan, and Australia. Among the 50 patients who have received a single dose of the T cells, 41 patients (82 percent) had a complete response (that is, no detectable leukemia cells) within one to three months after treatment.

“Our results in this first international clinical trial are similar to what we saw in our single-center trials — in both the safety profile and high levels of effectiveness,” Dr. Grupp said.

As in previous, single-center trials, the immunotherapy stimulated a sometimes severe side effect called cytokine release syndrome (CRS), a known complication of the investigational therapy that may occur when the engineered cells become activated in the patient's body. The researchers followed an existing protocol to successfully managed CRS, which can present as a flu-like illness with high fever and muscle aches, and can extend to requiring ICU-level care.

Novartis aims to apply for U.S. Food and Drug Administration approval in 2017. The research reflects an ongoing collaboration between Dr. Grupp, his colleagues in the Perelman School of Medicine at the University of Pennsylvania led by Carl H. June, MD, a co-author of the current study, and Novartis.

During the same ASH session, CHOP pediatric oncologist Shannon Maude, MD, presented findings from a pilot phase 1 study of “humanized” CAR T cells, called CTL119 cells, in 36 children and young adults with relapsed and refractory ALL. In this study, researchers modified CAR T cells to carry a CAR protein more similar to human protein than is the murine (mouse) protein used in CTL019 and other CD19-targeted CAR T cell treatments.

“These CTL119 results are consistent with the high remission rates we have seen with CTL019,” Dr. Maude said. “It is also encouraging that patients previously treated with CD19 CAR T cells could respond to humanized CTL119.”

Read more in the CHOP press release and Novartis press release.

Results From Hemophilia Gene Therapy Trial Show Reduction in Bleeding Events

After receiving a single dose of an experimental gene therapy in a phase 1/2 clinical trial sponsored by Spark Therapeutics Inc. and Pfizer Inc., patients with hemophilia produced near-normal levels of clotting factor IX, allowing them to stop clotting factor infusions and to pursue normal activities of daily life without disabling bleeding episodes. Lindsey A. George, MD, a hematologist at CHOP and the study’s lead investigator, presented these results at ASH.

The clinical trial of nine adult hemophilia B patients, aged 18 to 52 years, used a single dose of a gene therapy product engineered to enter patients’ liver cells and direct the production of the blood clotting factor that they lack. The patients maintained factor levels of approximately 30 percent, which is near-normal. Patients would be expected to experience bleeding only in the event of major trauma or surgery.

“At these new levels, hemophilia patients do not typically need to self-treat with factor to avoid bleeding events,” Dr. George said. “This represents a potential dramatic improvement in their quality of life and a shift in the way we think about treating hemophilia.”

Dr. George acknowledged that this trial is a small study, with a short follow-up period as yet. However, as the researchers continue to monitor patients in the current trial, next steps will be to discuss with the FDA the outlines of a larger, phase 3 clinical trial. No gene therapies for any genetic diseases have yet been approved for clinical use in the U.S.

Spark Therapeutics was spun off from CHOP in 2013, and CHOP maintains a financial interest in the company.

Read more in the press release and in a article.

Low Child Abuse Reporting Rates by Army Raise Concerns

A new study by CHOP’s PolicyLab raises questions and concerns about possible under-reporting of U.S. Army-reported rates of child abuse cases compared to those reported by civilian Child Protective Services (CPS).

PolicyLab Director David Rubin, MD, and his fellow researchers found that only 20 percent of child abuse cases in U.S. Army dependent children had a substantiated report with the Army’s Family Advocacy Program (FAP), the agency responsible for investigating and treating child abuse. This rate represents less than half of the child abuse cases substantiated by CPS during the same time period from 2004 to 2007. The study, published by Child Abuse & Neglect, raises questions about the Army-reported rates of child abuse, and suggests under-reporting of abuse cases by medical providers and/or a breakdown in communication between civilian CPS and established military services.

Responding to the study results, Dr. Rubin noted for a number of years the U.S. Army reported child abuse rates well below that of the civilian population. He acknowledged, however, that the Army can only report cases they know about and said the study points to the fact that they may not be aware of the majority of the cases.

“What this study tells us is that we have an incomplete picture of what is happening to a large population of children in this country who might need our help,” said Dr. Rubin, who is a presidential appointee to the federal Commission to Eliminate Child Abuse & Neglect Fatalities. PolicyLab partnered with U.S. Army FAP on this research. Read more about the study in the PolicyLab press release.

New Radiologist-in-Chief Named

Kassa Darge, MD, PhD, DTM&P, FSAR, FESUR the new Chair of the department of Radiology and Radiologist-in-Chief at CHOP, has an extensive research portfolio encompassing 28 years with more than 200 publications and multiple grants. His research focus is on innovative and advanced body imaging methods, particularly in magnetic resonance and ultrasound modalities.

Dr. Darge has served as Chief of the division of Body Imaging in the department of Radiology at CHOP and a professor of Radiology at Penn since 2006. He currently holds the John W. Hope Endowed Chair for Radiology Faculty Development at CHOP. He is also an honorary professor of Radiology in the department of Radiology at Addis Ababa University in Ethiopia.

“We are delighted to have Dr. Darge serve as our Radiologist-in-Chief,” said Chad Hough, senior vice president, Support Services at CHOP. “Dr. Darge is a highly accomplished researcher, educator, and scholar in radiology who will help lead CHOP’s strategy and future as we continue to find better ways to provide exceptional care and research discoveries for children.”

Read more in a press release.

News Coverage on Study of ADHD Guidelines in Preschoolers

The New York Times reported on a study published by CHOP pediatrician Alexander G. Fiks, MD, MSCE, and coauthors in the journal Pediatrics that found including preschoolers in the guidelines for how pediatricians manage ADHD — which covered only school-age children before 2011 — did not increase diagnoses and prescriptions of stimulant medications.

In 2011, the American Academy of Pediatrics (AAP) issued new guidelines for diagnosing preschool-age children with ADHD and for using stimulant medications, which were not recommended as a first-line treatment at this age. The rate of ADHD diagnoses among 4- and 5-year-olds was then rising, but after the AAP guidelines, the rates have remained steady.

“There was no difference seen for stimulant medication prescribing before and after, it was absolutely flat,” Dr. Fiks said in The New York Times interview. Dr. Fiks is director of the Pediatric Research in Office Settings Network at the AAP, which coordinated the study.

Dr. Fiks encouraged parents of preschoolers who are struggling with behavior problems to speak with their pediatricians, and together they can consider if a child should be carefully evaluated for ADHD or other social, medical, developmental, or psychological problems.


In case you missed it, this week on Cornerstone researchers from the Center for Autism Research at CHOP discuss in a Q&A the phenomenon of “instantly diagnosable” children on the autism spectrum.

Our Dec. 2 In the News post highlighted an important update for clinicians to recognize that hypertension risk may be underdiagnosed in children; research on the ongoing needs of childhood cancer survivors; findings about what it takes for working mothers to continue breastfeeding their babies successfully; a new study getting underway in an effort to reduce children’s exposure to antibiotic side effects while also reducing resistant bacteria; and a national update on the state of knowledge about food allergy prevalence.

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