Teaching pack: Neuroblastoma (paediatric)

Neuroblastoma arises from developing sympathetic nerve cells, usually in the adrenal gland or along the spine, and is the most common cancer of infants and the most common extracranial solid tumour of childhood. It spans the widest clinical range in oncology: some infant tumours (stage MS) regress without treatment, while high-risk disease (about half of patients, defined by INRG stage, age over 18 months, MYCN amplification and other genomic features) kills roughly 40-50% despite the most intensive therapy given to children. ALK mutations (~10%) are the main druggable driver; MYCN, though not directly druggable, points to polyamine and ALK biology.

High-risk therapy is a year-long sequence: five to six cycles of induction chemotherapy, surgery, myeloablative chemotherapy with autologous stem-cell rescue (tandem transplant in North America after ANBL0532; busulfan-melphalan single transplant in Europe after HR-NBL1), radiotherapy to the primary site, then anti-GD2 immunotherapy (dinutuximab or dinutuximab beta with GM-CSF; IL-2 abandoned after HR-NBL1) and isotretinoin. Anti-GD2 antibody raised survival by about 20 points (ANBL0032). Since December 2023, two years of oral eflornithine (DFMO) is approved as maintenance on the strength of an externally controlled study; naxitamab and irinotecan-temozolomide-dinutuximab treat relapse; lorlatinib is being added for ALK-aberrant tumours and 131I-MIBG tested in induction (ANBL1531).

• Anti-GD2 raised high-risk survival to ~60%.
• GD2 CAR-T responses.
• Anti-GD2 immunotherapy after transplant is standard worldwide (ANBL0032), with IL-2 removed after HR-NBL1 showed no benefit.
• Tandem transplant (North America) and busulfan-melphalan (Europe) are the two evidence-based consolidation standards.
• Eflornithine is the first oral maintenance therapy approved (December 2023), on an externally controlled study.
• GD2 CAR-T produced durable complete remissions in relapsed neuroblastoma, the first such result in a childhood solid tumour.

1. 1910James Homer Wright describes neuroblastoma and its rosettes
2. 1971Spontaneous regression of stage IV-S (now MS) disease recognised (Evans staging)
3. 1983MYCN amplification linked to aggressive disease (Brodeur, Schwab)
4. 1985131I-MIBG therapy first used in relapsed neuroblastoma
5. 1999CCG-3891: myeloablative therapy with autologous rescue and isotretinoin improve survival
6. 2008ALK mutations identified as a hereditary and somatic driver
7. 2009INRG classification unifies international risk grouping
8. 2010Anti-GD2 (ch14.18) improves EFS
9. 2010ANBL0032: anti-GD2 immunotherapy raises survival ~20 points (NEJM)
10. 2015Dinutuximab approved (US); dinutuximab beta in EU 2017

• Armoured, logic-gated & next-gen CARs (technology)
• COG ANBL1531 (trial)
• 131I-MIBG (iobenguane I-131) therapy (product)
• Lorlatinib (product)
• GD2-CART01 (Bambino Gesù phase 1/2) (trial)
• GD2 CAR-T as consolidation in high-risk neuroblastoma (idea)
• 18F-MFBG PET replacing 123I-MIBG scintigraphy (idea)
• MIBG imaging and 131I-MIBG therapy (technology)
• Eflornithine (DFMO) (product)
• Naxitamab (product)
• Anti-GD2 antibody + irinotecan-temozolomide (chemoimmunotherapy) (pairing)
• Tandem autologous transplant (technology)

• COG ANBL0032 (phase 3, n=226): Event-free survival at 2 years: 66% vs 46%
• COG ANBL0532 (phase 3, n=652): Event-free survival at 3 years: 61.6% vs 48.4%
• SIOPEN HR-NBL1 (phase 3, n=3,700): Event-free survival at 3 years (R1 conditioning): 50% vs 38%
• NMTRC003/003B (DFMO maintenance) (phase 2, n=105): Event-free survival: pending
• Naxitamab Study 201 (phase 2, n=74): Objective response rate: 50%
• GD2-CART01 (Bambino Gesù phase 1/2) (phase 1/2, n=27): Objective response rate: 63%

• Relapsed high-risk disease.
• Long-term toxicity of intensive therapy.
• Relapsed high-risk neuroblastoma is rarely curable; MYCN-amplified relapse worst of all.
• Anti-GD2 therapy causes severe neuropathic pain; less painful antibody formats (e.g., humanised, Fc-engineered) and CAR-T are needed.
• Long-term toxicity of tandem transplant, cisplatin (hearing loss), and radiation in children who will live 70 years.
• Eflornithine's approval rests on an external control; a randomised trial is unlikely, so uncertainty persists.

1. Which biomarkers must be tested at diagnosis of advanced non-small-cell lung cancer?
   Answer

   EGFR, ALK, ROS1, BRAF V600E, MET exon 14/amplification, RET, NTRK, KRAS G12C, HER2 mutations, and PD-L1 TPS.
2. What is the longest progression-free survival ever reported for a targeted pill in metastatic lung cancer?
   Answer

   Lorlatinib in ALK-positive NSCLC (CROWN): five-year PFS about 60% versus 8% for crizotinib.

• Wikipedia: https://en.wikipedia.org/wiki/Neuroblastoma
• Guideline: https://www.cancer.gov/types/neuroblastoma/hp/neuroblastoma-treatment-pdq