Children's Oncology Group's 2023 blueprint for research: Neuroblastoma

Abstract

Neuroblastoma is the most common extra-cranial solid tumor in children and is known for its clinical heterogeneity. A greater understanding of the biology of this disease has led to both improved risk stratification and new approaches to therapy. Outcomes for children with low and intermediate risk disease are excellent overall, and efforts to decrease therapy for such patients have been largely successful. Although survival has improved over time for patients with high-risk disease and treatments evaluated in the relapse setting are now being moved into earlier phases of treatment, much work remains to improve survival and decrease therapy-related toxicities. Studies of highly annotated biobanked samples continue to lead to important insights regarding neuroblastoma biology. Such studies, along with correlative biology studies incorporated into therapeutic trials, are expected to continue to provide insights that lead to new and more effective therapies. A focus on translational science is accompanied by an emphasis on new agent development, optimized risk stratification, and international collaboration to address questions relevant to molecularly defined subsets of patients. In addition, the COG Neuroblastoma Committee is committed to addressing the patient/family experience, mitigating late effects of therapy, and studying social determinants of health in patients with neuroblastoma.

Keywords: ALL neuroblastoma; neuroblastoma; neuroblastoma biology.

Figure 1 –. Survival among North American patients with high-risk neuroblastoma based on year of diagnosis.

Kaplan-Meier curves of EFS and OS for patients diagnosed with high-risk neuroblastoma and enrolled on Children’s Oncology Group ANBL00B1 (2001 and thereafter) and predecessor cooperative group biology studies (prior to 2001) between 1990 and 2019 shown in 5-year intervals. A. Event-free survival; B. Overall survival. Data are courtesy of Arlene Naranjo, Children’s Oncology Group Statistics and Data Center.

Figure 2 –. Clinical trial schema for Children’s Oncology Group study ANBL1531, A Phase 3 Study of ¹³¹I-Metaiodobenzylguanidine (¹³¹I-MIBG) or Lorlatinib Added to Intensive Therapy for Children with Newly Diagnosed High-Risk Neuroblastoma.

Enrolled patients receive an initial cycle of Induction therapy while tumors are tested for ALK status and central review of diagnostic MIBG scans is performed. Patients with tumors harboring an activating mutation in or amplification of the ALK gene are assigned to receive intensive, multi-modality therapy along with the ALK inhibitor lorlatinib (Arm E). Patients with ALK wild type, MIBG non-avid disease receive COG standard therapy (Arm D). Patients with ALK wild type, MIBG avid disease are randomized to receive standard therapy with (Arm B) or without (Arm A) the addition of ¹³¹I-MIBG during Induction. Patients on Arms A, B, D and E undergo tandem cycles of high dose chemotherapy during consolidation before proceeding to radiation therapy and immunotherapy. Patients on Arm E continue therapy with single agent lorlatinib for one year after completion of post-Consolidation immunotherapy. Randomized trial Arm C includes ¹³¹I-MIBG therapy during Induction followed by a Consolidation containing a single cycle of high dose chemotherapy with autologous stem cell rescue, radiation and immunotherapy.

Figure 3 –. Overall Strategy of the COG Neuroblastoma Committee.

The mission of the COG Neuroblastoma Committee is to conduct practice-change research aimed to improve outcomes for children with neuroblastoma. The committee emphasizes translational research and the development and implementation of clinical trials while working to improve risk classification and new agent development. In addition, the committee emphasizes international collaboration to address key questions in the field as well as research that addresses the patient/family experience in the context of a neuroblastoma diagnosis. Research related to social determinants of health and survivorship are also being prioritized.