Targeted therapy for children with high-risk Hodgkin’s lymphoma (HL) has been shown to significantly reduce relapse rates in a large, multicenter clinical trial conducted by the Children’s Oncology Group (COG) and led by pediatric oncologists from Roswell Park Comprehensive Cancer Center, Children’s Healthcare of Atlanta and Emory University’s Winship Cancer Institute. When combining the antibody-targeted drug conjugate (ADC) brentuximab vedotin (BV) with the standard chemotherapy regimen, children were 10% less likely to relapse. The results were published today in the New England Journal of Medicine (NEJM).
We found a 10% improvement in event-free survival; a real breakthrough. This is quite a significant gain, especially in this area. We expect this treatment regimen will soon become the standard of care for pediatric patients with high-risk Hodgkin’s lymphoma.”
Kara Kelly, MD, lead study author
Kara Kelly, MD, is chair of the Roswell Park Oishei Children’s Cancer and Blood Disorders Program and Waldemar J. Kaminski Chair of Pediatrics at Roswell Park and also Division Chief of Hematology/Oncology in the Department of Pediatrics at Jacobs School of Medicine and Biomedical Sciences at the University at Buffalo
The clinical trial, AHOD1331 (NCT02166463), was funded by the National Cancer Institute (NCI) of the National Institutes of Health and conducted at 153 COG sites. The study was also supported by Seagen, formerly known as Seattle Genetics, and the St. Baldrick’s Foundation. The study was sponsored by the Division of Cancer Treatment and Diagnosis, NCI, and brentuximab vedotin was provided by Seagen under a cooperative research and development agreement with NCI.
“This trial reflects a paradigm shift for advanced stage Hodgkin’s lymphoma in children, and an introduction of the first targeted approach for the initial treatment of pediatric Hodgkin’s lymphoma and the first new treatment regimen in two decades,” says the first author. of the study, Sharon Castellino, MD, MSc, director of the leukemia and lymphoma program at the Aflac Cancer and Blood Disorders Center of Children’s Healthcare in Atlanta, professor of pediatrics at Emory University School of Medicine and research fellow at Emory University’s Winship Cancer Institute. Dr. Castellino succeeded Dr. Kelly this year as chairman of the COG Hodgkin Committee. “We are optimistic that this trial will pave the way for FDA approval of this targeted antibody-drug conjugate for children and adolescents.”
Study vice-chair and co-author Frank Keller, MD, pediatric hematologist/oncologist at the Aflac Cancer and Blood Disorders Center of Children’s Healthcare in Atlanta and professor of pediatrics at Emory University School of Medicine, adds: “Demonstration of the efficacy of a highly targeted therapy directed against the malignant cell population in newly diagnosed pediatric and young adult patients with high-risk Hodgkin’s lymphoma is a significant step forward in improving cure rate and can do so without adding significant long-term toxicity for this young population with many years of life remaining.”
HL is the most common cancer in patients aged 12 to 29. Although it has a high five-year survival rate -; 97% of under-19s are alive five years after diagnosis -; about a third of survivors are classified as high risk; of these, about 15-20% will relapse.
The COG study -; the largest and only randomized Phase 3 trial with ADC targeting CD-30 ever conducted in pediatric patients newly diagnosed with high-risk HL; involved 587 patients aged 2 to 21 years with previously untreated disease.
Patients were randomized to one of two arms, with both arms receiving treatment over five 21-day cycles. Those in the control group received the standard pediatric chemotherapy regimen.
The second group received the standard pediatric chemotherapy regimen plus brentuximab vedotin. Brentuximab vedotin (BV) is an antibody-drug conjugate that specifically targets the CD30 protein on the surface of HL cancer cells, killing them while primarily sparing healthy cells.
Both groups received radiation therapy to the site based on responses assessed after two cycles of treatment.
Follow-up at approximately three and a half years after treatment showed an event-free survival of 92.1% in the brentuximab vedotin group, compared to 82.5% for the control group -; an overall reduction in the risk of 59% of relapse, death or a second malignancy.
A lower risk of relapse could possibly eliminate the need for retreatment with additional toxic therapies. Long-term treatment toxicity puts HL survivors at very high risk for breast cancer, stroke, myocardial infarction, restrictive lung disease, infertility and shortened life expectancy. .
“Brentuximab vedotin is not expected to have long-term toxicity,” says Dr. Kelly, noting that during the treatment phase of the clinical trial, less than 10% of patients who received it needed a dose reduction. “Because the drug could be delivered more consistently, its effectiveness improved without an increase in neuropathy or severe infection.”
Dr. Kelly, Dr. Castellino and their colleagues will build on these findings in a new clinical trial expected to open in early 2023 with support from the National Cancer Institute. The randomized phase 3 study will enroll approximately 1,900 children and adults aged 5 to 60 years with medium- and low-risk HL. The objective: to determine whether the combination of the ADC brentuximab vedotin and the immunotherapy agent nivolumab can prolong progression-free survival and further reduce patient exposure to standard chemotherapy and radiation therapy. Patients will be followed for 12 years to monitor their progress and assess outcomes.
Allison Brashear, MD, vice president of health sciences at the University at Buffalo and dean of the Jacobs School of Medicine and Biomedical Sciences, says the study results “mean greatly improved quality of life for patients.” the most vulnerable and brave -; children with cancer.
“As one of the greatest demonstrations of a successful immuno-oncology approach in children with cancer,” notes Dr. Brashear, “it is a powerful example of what happens when extraordinary institutions decide that collaboration is the key to their success”.
Lucky Jain, MD, MBA, chief pediatrician for Atlanta Children’s Health Care and chair of the Department of Pediatrics at Emory University School of Medicine, says, “A 10% reduction in relapses in children with high-risk Hodgkin’s lymphoma is an important milestone for the field of pediatric cancer. Children’s Healthcare of Atlanta and Emory University are proud of this incredible leap forward led by our physicians, Dr. Sharon Castellino and the Dr. Frank Keller, along with their collaborators and the Children’s Oncology Group.
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