PHILADELPHIA - In an update to a global clinical trial stretching from Philadelphia to four continents, the chimeric antigen receptor (CAR) T cell therapy Kymriah® (tisagenlecleucel, formerly CTL019) led to long-lasting remissions in patients with relapsed/refractory (r/r) diffuse large B-cell lymphoma (DLBCL). The most recent results from the trial will be presented today at the 60th American Society of Hematology (ASH) Annual Meeting and Exposition in San Diego (Abstract #1684). Stephen J. Schuster, MD, director of the Lymphoma Program at the Abramson Cancer Center of the University of Pennsylvania, was the principal investigator on the trial, which is known as JULIET and has already led to approval by the U.S. Food and Drug Administration as well as by the European Commission, Health Canada, and Swissmedic. Another data set from the JULIET trial with an earlier cut-off date will also be published simultaneously in the New England Journal of Medicine (NEJM).
JULIET included 27 sites in 10 countries across North America, Europe, Australia, and Asia. According to the data presented at ASH, 115 patients with r/r DLBCL received an infusion of CAR T cells. The overall response rate of evaluable patients was 54 percent, with 40 percent achieving a complete response. The median duration of those responses was not reached at a median follow-up of 19 months.
"These findings are consistent with what we've shown in our single-site studies here at Penn, which is that the majority of patients who go into remission stay in remission," said Schuster, who is the senior author on the ASH abstract and is the lead author on the NEJM study. The data will be presented at ASH by Richard T. Maziarz, MD, a professor of Medicine at the Oregon Health and Science Knight Cancer Institute.
Two-thirds of DLBCL cases are successfully treated with frontline chemotherapy. When that fails, a high-dose chemotherapy combined with an autologous stem cell transplant can potentially lead to long-term disease-free survival. However, only half of r/r patients are candidates for this approach, and for those who are, the expected three-year event-free survival rate is just 20 percent.
"CAR T therapy represents a potentially life-saving alternative for these patients, who now have a therapy that can help them achieve durable remissions even after other therapies, including transplant, have failed," Schuster said.
The treatment modifies patients' own immune T cells, which are collected and reprogrammed to potentially seek and destroy the patients' cancer cells. After being infused back into patients' bodies, these CAR-expressing T cells both multiply and attack, targeting cells that express a protein called CD19. Tests reveal that this army of hunter cells can grow to more than 10,000 new cells for each single engineered cell patients receive, producing high remission rates. They can also survive in the body for years.
Grade 3/4 cytokine-release syndrome (CRS), a toxicity associated with CAR T therapy, which includes varying degrees of flu-like symptoms, with high fevers, nausea, and muscle pain, and can require ICU-level care, was reported in 23 percent of patients, 16 percent of whom required treatment with tocilizumab, which is the standard therapy for the toxicity. All patients recovered from their CRS. Other Grade 3/4 toxicities included infections (19 percent of patients), fever resulting from low blood count (15 percent), neurological events (11 percent), and a metabolic abnormality called tumor lysis syndrome (two percent). There were no treatment-related deaths.
In May 2018, Kymriah® was approved by the U.S. Food and Drug Administration for the treatment of adult patients with r/r large B-cell lymphoma after two or more lines of systemic therapy, including DLCBL, high grade B-cell lymphoma, and DLBCL arising from follicular lymphoma. In August 2018, it was approved by the European Commission, making it the first cellular therapy approved for two different cancer indications. The original FDA approval came in August 2017 for the treatment of patients up to 25 years of age with acute lymphoblastic leukemia (ALL) that is refractory or in second or later relapse. Penn and Novartis formed a global research and development collaboration in 2012.
###
The trial was supported by Novartis. Dr. Schuster's work is also supported by a grant from the National Institutes of Health (1R01CA165206), as well as through philanthropic support for the Lymphoma Program at the Abramson Cancer Center of the University of Pennsylvania from James and Frances Maguire and the Frances Maguire Lymphoma Research Fund, Margarita Louis-Dreyfus, and Sharyn Berman and the Richard Berman Family Funds for CLL and Lymphomas.
Editor's Note: The University of Pennsylvania has licensed some technologies involved in these studies to Novartis. Some of the scientists involved in these trials are inventors of these technologies. As a result of the licensing relationship with Novartis, the University of Pennsylvania receives significant financial benefit, and some of these inventors have benefitted financially and/or may benefit financially in the future.
Penn Medicine is one of the world's leading academic medical centers, dedicated to the related missions of medical education, biomedical research, and excellence in patient care. Penn Medicine consists of the Raymond and Ruth Perelman School of Medicine at the University of Pennsylvania (founded in 1765 as the nation's first medical school) and the University of Pennsylvania Health System, which together form a $7.8 billion enterprise.
The Perelman School of Medicine has been ranked among the top medical schools in the United States for more than 20 years, according to U.S. News & World Report's survey of research-oriented medical schools. The School is consistently among the nation's top recipients of funding from the National Institutes of Health, with $405 million awarded in the 2017 fiscal year.
The University of Pennsylvania Health System's patient care facilities include: The Hospital of the University of Pennsylvania and Penn Presbyterian Medical Center -- which are recognized as one of the nation's top "Honor Roll" hospitals by U.S. News & World Report -- Chester County Hospital; Lancaster General Health; Penn Medicine Princeton Health; Penn Wissahickon Hospice; and Pennsylvania Hospital -- the nation's first hospital, founded in 1751. Additional affiliated inpatient care facilities and services throughout the Philadelphia region include Good Shepherd Penn Partners, a partnership between Good Shepherd Rehabilitation Network and Penn Medicine, and Princeton House Behavioral Health, a leading provider of highly skilled and compassionate behavioral healthcare.
Penn Medicine is committed to improving lives and health through a variety of community-based programs and activities. In fiscal year 2017, Penn Medicine provided more than $500 million to benefit our community.
Journal
New England Journal of Medicine