Neuroblastoma is the most common tumour during the first 5 years of life. It is a heterogeneous group of tumours that can affect different body compartments. The incidence of neuroblastoma is approximately one case per 70,000 live newborns, which in Spain amounts to some 100 cases a year. The disease behaves in many different ways: it can be benign and require no treatment (50%-60% of cases), or be aggressive, requiring multimodal treatment (45%-55%).
High-risk neuroblastoma, the type treated mainly at the á SJD Barcelona Children's Hospital, is difficult to treat and has a survival rate of 55% at the best centres. The treatment of children with high-risk neuroblastoma is a complex process that calls for the involvement of numerous experts in fields such as molecular biology, molecular pathology, radiobiology, nuclear medicine, oncological surgery, oncological neurosurgery, radiation therapy and paediatric oncology. Few hospitals in the world have the necessary range of experience and technology to offer the best option to patients with high-risk neuroblastoma.
The treatment of high risk neuroblastoma continues to be one of the greatest challenges facing paediatric oncology professionals. The development of latest-generation anti-GD2 immunotherapy has yielded impossible-to-imagine long-term survival results in relapsing patients or in those with refractory disease.
Researchers from SJD Barcelona Children's Hospital and the Institut de Recerca Sant Joan de Déu have published the results of the treatment with the anti-GD2 humanised antibody naxitamab (DanyelzaⓇ) combined with the granulocyte-macrophage colony-stimulating factor (GM-CSF; LeukineⓇ) in patients with high-risk neuroblastoma in complete remission following induction treatment (with chemotherapy and surgery), demonstrating an overall survival rate of more than 90% in three years without the need for high-dose chemotherapy or autologous transplantation.
Immunotherapy with anti-GD2 antibodies manages to “train” the patient's immune system to recognise and eliminate the neuroblastoma cells, which are major experts in evading the immune surveillance system.
Overall survival rate at 3 years in high-risk NB
Number of patients with high-risk NB
What can we offer for the diagnosis and treatment of high-risk neuroblastoma
The Paediatric Oncology Laboratory team of SJD Barcelona Children's Hospital works with techniques that make it possible to ascertain what type of neuroblastoma each patient has thanks to molecular tumour testing. A precise diagnosis makes for a better prognosis, since it makes it possible to ascertain the lesion's degree of malignancy and to work with treatments specifically targeting each type of tumour, with personalised treatments.
A surgery-only treatment is offered to patients with low-risk neuroblastoma. The overall survival rate of this group is 98% in the long term.
For high-risk patients, SJD Barcelona Children's Hospital has developed its own adaptation of the N7 protocol of the Memorial Sloan Kettering Center in New York (MSKCC), mN7 with early surgery as induction standard. Patients in complete remission after induction follow the consolidation protocol with radiation therapy and immunotherapy with naxitamab. The entire treatment takes 12 months. Patients in continuous first complete remission have an estimated overall survival rate of above 90% after 3 years.
SJD Barcelona Children's Hospital is one of the few centres that currently offers anti-GD2 immunotherapy with the Hu3F8 antibody (naxitamab). Naxitamab (DanyelzaⓇ, USA) is FDA-approved (Food and Drug Administration) for patients with high-risk neuroblastoma with refractory or relapsing disease exclusively in the osteomedullary compartment (bone marrow and/or bone).
Naxitamab is given in combination with other drugs, in this case combined stimulation factors (GM-CSF or AMB) to activate the patient's immune system. Immunotherapy is offered on an outpatient basis, avoiding the need for hospitalisation, in turn making for shorter hospital stays of these patients, who undergo the tests and the follow-up needed to monitor their evolution and response to treatment. The overall survival after 3 years in patients with high-risk neuroblastoma in first or second complete remission treated with naxitamab and GM-CSF is 82.4%.
Naxitamab is still in clinical development for approval by the regulatory agencies in different parts of the world (China, Japan, Australia, European Medicines Agency (EMA), Argentina, Mexico, Russia). Our centre currently provides assessment to the regulatory agencies to expedite the approval and use of naxitamab in other centres all over the world.
Ours was the first centre in the world to give naxitamab on June 12, 2017. The 201 clinical trial by the Y-mAbs Therapeutics company commenced in March 2018. This trial enabled the FDA to approve its indication on 20 November 2020. The FDA required that the clinical trial continued until a total of 85 patients had been recruited. Currently (July 2021), 65 patients have been enrolled in the trial at 8 sites in America and Europe. Our centre recruited 32 patients, more than twice that of any other study site.
The combined treatment called HITS is the first chemo-immunotherapy regimen given simultaneously and developed initially at the Memorial Sloan Kettering Cancer Center and given at our centre since 2018. Experience with HITS shows that complete remission is achieved in 40% of patients.
The current chemo-immunotherapy protocol developed at our centre, NICE, includes HITS cycles and NICE (naxitamab + ICE chemotherapy) cycles. The NICE protocol is indicated in patients with a very poor prognosis with neuroblastoma resistant to treatment with naxitamab or with surgically unresectable refractory disease of the soft tissues.
The increase in the survival rate of patients with high-risk neuroblastoma thanks to the new treatments has led to an increase in central nervous system (SNC) relapses. Our centre offers rescue treatment with radioimmunotherapy with the 8H9 monoclonal antibody (Omburtamab) within the YmAbs 101 clinical trial. The MSKCC's experience demonstrates that up to 50% of patients with SNC relapse treated with regimens including Omburtamab can recover.
The SJD Barcelona Children's Hospital achieved a 90% overall survival rate after three years in patients with high-risk neuroblastoma in first complete remission after induction treatment and without the need for high-dose chemotherapy and autologous transplantation. The overall survival after 3 years in patients with high-risk neuroblastoma in first or second complete remission treated with naxitamab and GM-CSF is 82.4%.
- Mora J, Castañeda A, Gorostegui M, Santa-María V, Garraus M, Muñoz JP, Varo A, Perez-Jaume S, Mañe S. Naxitamab combined with granulocyte-macrophage colony-stimulating factor as consolidation for high-risk neuroblastoma patients in complete remission. Pediatr Blood Cancer. 2021 May 22:e29121. doi: 10.1002/pbc.29121. Epub ahead of print. PMID: 34022112.
- Mora J, Castañeda A, Colombo MC, Gorostegui M, Gomez F, Mañe S, Santa-Maria V, Garraus M, Macias N, Perez-Jaume S, Muñoz O, Muñoz JP, Barber I, Suñol M. Clinical and Pathological Evidence of Anti-GD2 Immunotherapy Induced Differentiation in Relapsed/Refractory High-Risk Neuroblastoma. Cancers (Basel). 2021 Mar 12;13(6):1264. doi: 10.3390/cancers13061264. PMID: 33809255; PMCID: PMC7998131.
- Mora J, Castañeda A, Flores MA, Santa-María V, Garraus M, Gorostegui M, Simao M, Perez-Jaume S, Mañe S. The Role of Autologous Stem-Cell Transplantation in High-Risk Neuroblastoma Consolidated by anti-GD2 Immunotherapy. Results of Two Consecutive Studies. Front Pharmacol. 2020 Oct 30;11:575009. doi: 10.3389/fphar.2020.575009. PMID: 33324208; PMCID: PMC7723438.
Links of interest
The SJD Barcelona Children's Hospital's Oncology Department
The SJD Barcelona Children's Hospital's Oncology and Haematology Department is the national reference centre of for the treatment of developmental cancer and an international reference centre for determined types of tumours.