A non-inferiority study of MRI versus CT for staging and image-defined risk factor assessment in the preoperative work-up of abdominopelvic neuroblastoma.

BACKGROUND: Neuroblastoma accounts for 15 % of cancer deaths in children. Complete surgical resection is associated with a higher overall survival rate but also a higher morbidity rate. An international group of experts has defined a nomenclature of image-defined risk factors (IDRFs) for the determination of operability and the anticipation of reasonably foreseeable complications of surgery. However, there is no consensus on the optimal imaging modality (CT or MRI) for the assessment of IDRFs. The objective of the present study was to determine the non-inferiority of MRI vs. CT in the preoperative assessment of abdominopelvic neuroblastoma. The secondary objective was to assess the contribution of gadolinium contrast enhancement. METHODS: All children diagnosed with abdominopelvic neuroblastoma and whose preoperative work-up included a contrast-enhanced CT or MRI scan of the abdomen and pelvis between January 2014 and January 2023 were included. To evaluate the IDRFs, all the images were reviewed in three steps: (i) non-contrast MRI scans, (ii) both non-contrast and contrast-enhanced MRI scans, and (iii) contrast-enhanced CT scans. RESULTS: Twenty-five patients were found to be eligible, and fifteen were included. The mean time interval between MRI and preoperative CT was 23 days. In all patients, the identified IDRFs were similar for all three imaging modalities. Fourteen patients underwent full resection of the tumour. The surgical reports were fully consistent with the IDRFs described on CT and/or MRI. CONCLUSION: A high-resolution three-dimensional T2 MRI sequence agreed fully with contrast-enhanced CT for the detection of IDRFs. Contrast-enhanced MRI did not add value. However, surgeons will need time to adapt to this MRI-based approach and learn how to interpret the results with confidence.

Sequential Analysis of cfDNA Reveals Clonal Evolution in Patients with Neuroblastoma Receiving ALK-Targeted Therapy.

PURPOSE: The study of cell-free DNA (cfDNA) enables sequential analysis of tumor cell-specific genetic alterations in patients with neuroblastoma. EXPERIMENTAL DESIGN: Eighteen patients with relapsing neuroblastoma having received lorlatinib, a third-generation ALK inhibitor, were identified (SACHA national registry and/or in the institution). cfDNA was analyzed at relapse for nine patients and sequentially for five patients (blood/bone marrow plasma) by performing whole-genome sequencing library construction followed by ALK-targeted ddPCR of the hotspot mutations [F1174L, R1275Q, and I1170N; variant allele fraction (VAF) detection limit 0.1%] and whole-exome sequencing (WES) to evaluate disease burden and clonal evolution, following comparison with tumor/germline WES. RESULTS: Overall response rate to lorlatinib was 33% (CI, 13%-59%), with response observed in 6/10 cases without versus 0/8 cases with MYCN amplification (MNA). ALK VAFs correlated with the overall clinical disease status, with a VAF < 0.1% in clinical remission, versus higher VAFs (>30%) at progression. Importantly, sequential ALK ddPCR detected relapse earlier than clinical imaging. cfDNA WES revealed new SNVs, not seen in the primary tumor, in all instances of disease progression after lorlatinib treatment, indicating clonal evolution, including alterations in genes linked to tumor aggressivity (TP53) or novel targets (EGFR). Gene pathway analysis revealed an enrichment for genes targeting cell differentiation in emerging clones, and cell adhesion in persistent clones. Evidence of clonal hematopoiesis could be observed in follow-up samples. CONCLUSIONS: We demonstrate the clinical utility of combining ALK cfDNA ddPCR for disease monitoring and cfDNA WES for the study of clonal evolution and resistance mechanisms in patients with neuroblastoma receiving ALK-targeted therapy.

Chemo-immunotherapy with dinutuximab beta in patients with relapsed/progressive high-risk neuroblastoma: does chemotherapy backbone matter?

BACKGROUND: Addition of anti-GD2 antibodies to temozolomide-based chemotherapy has demonstrated increased antitumor activity and progression-free survival in patients with relapsed/progressive high-risk neuroblastoma. However, chemo-immunotherapy is not yet approved for this indication. This study presents the chemo-immunotherapy experience in patients with relapsed/progressive high-risk neuroblastoma treated within the off-label use program of the Neuroblastoma Committee of the French Society of Pediatric Oncology (SFCE). METHODS: Dinutuximab beta (dB) was administered alongside temozolomide-topotecan (TOTEM) or temozolomide-irinotecan (TEMIRI) at first disease relapse/progression or topotecan-cyclophosphamide (TopoCyclo) at further relapse/progression. Real-world data on demographics, treatment, antitumor activity and safety was collected from all patients after inclusion in SACHA-France (NCT04477681), a prospective national registry, which documents safety and efficacy data on innovative anticancer therapies prescribed to patients ≤ 25 years old as compassionate or off-label use. RESULTS: Between February 2021 and July 2023, 39 patients with confirmed relapsed/progressive high-risk neuroblastoma (median age 6 years, range 1-24) were treated with dB+TopoCyclo (n = 24) or dB+TOTEM/TEMIRI (n = 15) across 17 centers. In total, 163 chemo-immunotherapy cycles were administered, main toxicities were mild or moderate, with higher incidence of hematological adverse drug reactions with dB+TopoCyclo than dB+TOTEM/TEMIRI. Objective response rate was 42% for dB+TopoCyclo (CI95% 22-63%) and 40% for dB+TOTEM/TEMIRI (CI95% 16-68%). CONCLUSION: Similar objective response rates for dB+TopoCyclo and dB+TOTEM/TEMIRI in patients with relapsed/progressive high-risk neuroblastoma emphasize the importance of chemo-immunotherapy, irrespective of the chemotherapy backbone.