Researchers at Children's Hospital of Philadelphia (CHOP) have demonstrated remarkable success using anaplastic lymphoma kinase (ALK) inhibitors to treat hereditary neuroblastoma, potentially establishing a new standard of care for families affected by this rare genetic form of childhood cancer. The findings, published in JCO Precision Oncology on April 28, 2025, could significantly improve outcomes for patients with inherited ALK mutations.
High-risk neuroblastoma continues to have a poor prognosis, with five-year survival rates below 50% despite advances in treatment. However, the CHOP team's case report offers new hope for the subset of patients with hereditary forms of the disease.
"Our research marks a major advancement in precision medicine for patients predisposed to hereditary neuroblastoma," said Dr. Yael P. Mossé, senior study author and Professor of Pediatrics in CHOP's Cancer Center. "With these findings, we can offer new hope for affected families and pave the way for more personalized, less invasive treatment strategies in pediatric oncology."
Mother-Daughter Case Demonstrates Treatment Efficacy
The study focused on a mother and daughter who both carried the ALK R1275Q mutation and were diagnosed with neuroblastoma. The daughter was diagnosed at six months of age and initially received standard chemotherapy and surgery, which proved ineffective. When her cancer recurred, she was treated with the ALK inhibitor crizotinib and showed a dramatic response.
Five years later, the previously asymptomatic mother was diagnosed with bilateral adrenal tumors at age 36 during pregnancy. After delivering a healthy baby, she began treatment with crizotinib but later switched to alectinib, another ALK inhibitor, due to side effects. Following surgical removal of the tumors and continued alectinib treatment, she has maintained remission for several years.
Both patients now undergo semiannual surveillance with whole-body MRI and circulating tumor DNA (ctDNA) testing, with no evidence of disease recurrence.
Implications for Treatment Protocols
The researchers recommend ALK inhibitors as frontline therapy for patients with inherited ALK mutations, potentially reducing or eliminating the need for intensive chemotherapy and extensive surgery. This approach represents a significant shift toward precision medicine in pediatric oncology.
"These findings could fundamentally change our approach to hereditary neuroblastoma linked to ALK mutations," Dr. Mossé explained. "By targeting the specific genetic driver of the disease, we can potentially achieve better outcomes with fewer side effects."
Challenging Current Surveillance Guidelines
The study also challenges existing guidelines that typically end surveillance for neuroblastoma in childhood. The mother's diagnosis at age 36 highlights the importance of lifelong monitoring for individuals with hereditary predisposition.
The researchers recommend implementing semiannual whole-body MRI and ctDNA testing throughout patients' lives, which could lead to earlier detection and intervention for asymptomatic individuals carrying ALK mutations.
Future Research Directions
The CHOP team plans to investigate whether patients with hereditary ALK mutations have a lower risk of developing drug resistance compared to those with non-inherited mutations. This could have important implications for long-term treatment strategies and outcomes.
The research was supported by Alex's Lemonade Stand Foundation, the Patricia Brophy Endowed Chair in Neuroblastoma Research, and the National Cancer Institute (NCI) grant R35 CA220500.
Clinical Significance
Neuroblastoma is the most common extracranial solid tumor in children, accounting for approximately 7-10% of all pediatric cancers. While most cases are sporadic, about 1-2% are hereditary, with ALK mutations identified as the primary genetic driver in familial cases.
The successful implementation of ALK inhibitors in this case report demonstrates how precision medicine approaches can transform treatment paradigms for genetically defined cancer subtypes. For families affected by hereditary neuroblastoma, these findings offer not only improved treatment options but also the potential for preventive strategies through genetic testing and early intervention.
