Villejuif, June 4th 2020
A new immunotherapeutic agent for children and adolescents with advanced lymphoma
The excellent results of the phase III international paediatric study, Inter-B-NHL ritux 2010, have been published today in the New England Journal of Medicine. This academic trial involved two international cooperative groups — the European Intergroup for Childhood Non-Hodgkin Lymphoma (EICNHL) and the Children’s Oncology Group (COG). The trial sponsors were Gustave Roussy (for countries in Europe and Asia) and COG (for Australia, Canadaand the United States) and included a partnership with Roche. It establishes a new standard treatment with an improved cure rate for children with advanced non-Hodgkin lymphoma, mainly Burkitt lymphoma. It supports the value of an immunotherapeutic agent, which was authorised in March 2020 by the European Commission for the treatment of a rare childhood cancer.
“With a three-year survival rate exceeding 95%, these results are outstanding. This study changes the international treatment bench-mark in young patients with advanced B-cell non-Hodgkin lymphoma”, declared Dr. Véronique Minard-Colin, paediatrician at the Gustave Roussy Department of Child and Adolescent Oncology in France who coordinated this major international trial with Dr. Thomas G Gross currently at Children’s Hospital Colorado in the United States.
The management of children with Burkitt lymphoma has improved considerably over recent decades. Cure rates have risen from 30% in the 1980s to higher than 85% with chemotherapy alone (LMB protocol) with no major late sequelae associated with the medication or the disease. This conventional LMB treatment was established more than 30 years ago by Dr. Catherine Patte, paediatric oncologist at Gustave Roussy and her French collaborators. However, despite this advance, about 15% of children continued to die of this condition.
Rituximab is a monoclonal anti-CD20 antibody directed against lymphoma cells. This immunotherapeutic agent, developed by Roche is indicated in combination with chemotherapy as a treatment for adults with malignant non-Hodgkin lymphoma. The international Inter-B-NHL-ritux 2010 clinical trial evaluated rituximab in children and adolescents by means of a Paediatric Investigation Plan in the context of European Paediatric Regulation.
As Burkitt lymphoma is a rare disease (~1000/1200 new cases/year in Europe and in the US), 12 countries collaborated to address the question as to whether rituximab would increase survival of children and young adults. The Inter-B-NHL ritux 2010 phase III randomised trial was conducted between December 2011 and November 2015 and involved 328 patients age 2-18 years, treated in 176 centres distributed over four continents (Europe, North America, Australia and Asia). It assessed the effects of addition of rituximab to standard LMB chemotherapy in high-risk B-cell non-Hodgkin lymphoma (the majority with Burkitt lymphoma).
When rituximab is administered with chemotherapy, more than 95% of children and adolescents with advanced Burkitt lymphoma remain alive and disease-free after more than three years of follow-up. This new combined therapy increases overall survival by around 10% and reduces the rate of occurrence of an event (death, relapse, tumour progression, second cancer, etc.) by 70%.
Aggressive B-cell non-Hodgkin lymphoma is a cancer which develops in the lymphatic system, carrier of immune cells throughout the body. It can develop in any part of the body. It is most frequently seen in the abdomen and neck, areas which harbour many lymph nodes. It is one of the most aggressive cancers and grows very rapidly although it is rare and affects both children and adults. It is the most common lymphoma in children, accounting for more than 60% of paediatric non-Hodgkin lymphoma.
Cancers are fortunately rare in childhood, but this means that the development of new drugs to treat them must be conducted internationally. The Inter-B-NHL ritux 2010 trial is an excellent example of an international cooperation of academic clinical research in childhood cancer and of the importance of public-private collaborations with the pharmaceutical industry, so that positive findings result in marketing authorisation. The trial was run as part of a Paediatric Investigation Plan. Rituximab (MabThera®) has been authorised in Europe since March 2020 for the treatment of children with high-risk B-cell non-Hodgkin lymphoma. It will be available for all children and costs will be reimbursed through the health systems of member states and beyond.
This international trial was sponsored by Gustave Roussy and financed by a hospital clinical research programme of the French Ministry of Health (PHRC2010), Cancer Research UK, the National Institute for Health Research Clinical Research network, Children’s Cancer Foundation Hong Kong, US National Cancer Institute, St. Baldrick’s Foundation, and Roche.
Véronique Minard-Colin, MD PhD1*, Anne Aupérin, MD PhD2*, Marta Pillon M, MD PhD3, G.A. Amos Burke, MB ChB PhD 4, Donald A. Barkauskas, PhD5, Keith Wheatley, PhD6, Rafael F Delgado, MD PhD7, Sarah Alexander, MD8, Anne Uyttebroeck, MD PhD9, Catherine M. Bollard, MBChB MD10, József Zsiros, MD PhD11, Monika Csoka, MD PhD12, Bernarda Kazanowska, MD PhD13, Alan K. Chiang, MD PhD14, Rodney R. Miles, MD PhD15, Andrew Wotherspoon, MD PhD16, Peter C. Adamson, MD PhD17, Gilles Vassal, MD PhD18, Catherine Patte, MD1** and Thomas G. Gross, MD PhD19** on behalf of the European Intergroup for Childhood Non-Hodgkin lymphoma (EICNHL) and the Children’s Oncology Group (COG)
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- Department of Pediatric and Adolescent Oncology, Gustave Roussy, Université Paris-Saclay, INSERM 1015, Villejuif, France
- Unit of Biostatistics and Epidemiology, Gustave Roussy, Université Paris-Saclay, INSERM 1018, Villejuif, France
- Pediatric Hematology and Oncology, University of Padova, Italy
- Department of Paediatric Haematology, Oncology and Palliative Care, Cambridge University Hospitals NHS Foundation Trust, Addenbrooke’s Hospital, Cambridge, UK
- Department of Preventive Medicine, Keck School of Medicine of the University of Southern California, Los Angeles, CA, USA
- Cancer Research UK Clinical Trials Unit, Institute of Cancer and Genomic Sciences, College of Medical and Dental Sciences, University of Birmingham, Birmingham, UK
- Pediatric Hematology and Oncology, University of Valencia, Valencia, Spain
- Division of Haematology/Oncology, Hospital for Sick Children, Toronto, ON, Canada
- Department of Pediatric Hematology and Oncology, University Hospitals Leuven, Leuven, Belgium
- Center for Cancer and Immunology Research, Children's National Health System and The George Washington University, Washington, DC, USA
- Princess Máxima Center for Pediatric Oncology, Utrecht, Netherlands
- Pediatric Hematology and Oncology, Semmelweis University, Budapest, Hungary.
- Department of Pediatric Bone Marrow Transplantation, Oncology, and Hematology, Wroclaw Medical University, Wroclaw, Poland
- Department of Paediatrics and Adolescent Medicine, Li Ka Shing Faculty of Medicine, Queen Mary Hospital, The University of Hong Kong, Hong Kong
- Department of Pathology and ARUP Laboratories and Huntsman Cancer Institute, Salt Lake City, Utah, USA
- Department of Histopathology, Royal Marsden NHS Foundation Trust, London, UK
- Children's Hospital of Philadelphia, PA, USA
- Department of Clinical Research, Gustave Roussy, Université Paris-Saclay, Villejuif, France
- National Cancer Institute, Center for Global Health, Rockville, MD, USA