Background and Aims

According to the Surveillance, Epidemiology, and End Results (SEER) Program, the incidence for neuroblastoma (NB) in the USA is 10.5/ million children. The reported South African incidence (2015) is 2.7/ million children, based on the South African Children’s Tumour Registry (SACTR), a clinical data-based registry. We determined the true incidence of NB in South Africa using multiple data sources.

Methods

We conducted a probabilistic record linkage using data from three sources: NB cases from nine paediatric oncology units in SA, the South African National Cancer Registry (a national pathology-based cancer registry) and the SACTR. For the purpose of record linkage, the cases from the nine oncology units were merged with the SACTR. We included patients diagnosed between 2000 and 2016.

Results

There were 463 cases from hospital-based records, 312 and 603 cases from the South African National Cancer Registry (SA-NCR) and SACTR respectively. After excluding duplicates (n=148) and patients with insufficient data (n=14), 824 cases were included for linkage. Only 329 records (39.9%) matched between these respective registries. The SA-NCR and SACTR reported between 23 – 51 cases per annum and 18 – 57 cases per annum respectively. The SA-NCR incidence for children under 15-years varied between 1.5-2.8/ million children and between 1.74-2.6 /million children in the SACTR. A probabilistic record linkage from all the sourced data resulted in a combined incidence of 2.9 cases/ million children.

Conclusions

South Africa still reported a lower incidence of NB than the SEER Program. The reasons for a lower incidence are not clear, but might be due to a true lower incidence, underdiagnoses or under-reporting of NB cases. Underdiagnoses may be due to spontaneous regression of tumours, death before the diagnosis of NB was made or misdiagnosis as other diseases.

Background and Aims

More than half of neuroblastoma (NB) patients’ present with bone marrow (BM) infiltration at diagnosis. Cytomorphology (CM) is the gold standard to detect BM disease, however qRT-PCR using an mRNA marker panel containing adrenergic (ADRN) and mesenchymal (MES) neuroblastoma markers, as well as automatic immunofluorescence plus FISH (AIPF), have been demonstrated to be feasible, more sensitive, and clinically relevant. In this study we compare BM disease detection by cytomorphological examination of BM smears, AIPF, and qPCR.

Methods

312 BM samples from 124 Austrian and Dutch non-high-risk- and high-risk NB patients, taken at diagnosis and during treatment (HR-NBL-1/SIOPEN and NBL2009), were prospectively obtained. AIPF for GD2/CD56/DAPI was performed at the CCRI (A) and qRT-PCR at Sanquin (NL) using the ADRN mRNA panel: ß-glucuronidase (GUSB), paired-like homeobox 2b (PHOX2B), tyrosine hydroxylase (TH), cholinergic receptor alpha 3 (CHRNA3), and growth-associated protein 43 (GAP43). CM was performed independently at local sites.

Results

In total 308 samples were analysed by all techniques, 172 (= 55.8 %) were positive for one or more techniques. Both AIPF and qRT-PCR detected BM disease more frequent than CM, with qRT-PCR to a greater extent (168 qRT-PCR vs. 94 AIPF vs. 46 CM positive samples). AIPF and qRT-PCR double positive samples (n=90) show a high correlation of calculated infiltration levels. All three techniques were able to detect high level tumour cell infiltration. At very low levels, n=4 samples were positive by AIPF only (range 2.1e-5 – 1.0e-4%) and n=37 by PHOX2B qRT-PCR only (range 6.9e-6 – 0.5%). Interestingly, in the course of treatment a fraction of patients with negative samples showed positivity in subsequent samples.

Conclusions

Our findings demonstrate feasibility of cross-border prospective analysis and the sensitivity for the detection of BM disease in NB patients through the validation of AIPF and qPCR.

Background and Aims

Radiotherapy to primary site is part of high-risk neuroblastoma (HRNB) treatment paradigms in US and Europe. Dose of 21.6 Gray (Gy) has been utilized within the Children’s Oncology Group (COG) since benefit of 22Gy vs 10Gy shown in CCG3891 (Haas-Kogan, 2003). Dose escalation to 36Gy for residual disease was introduced on ANBL0532 and accepted as standard until 4/2019; historical comparison then demonstrated no benefit. The study below was carried out to evaluate impact of this change on practice patterns within the US proton therapy community.

Methods

Patients treated for HRNB with proton therapy to the primary site between 2014-2019 were enrolled on the PPCR. Kaplan-Meier method was used to evaluate DFS and OS. Relationship between maximal surgical resection and radiation dose was compared using Chi-square.

Results

Proton therapy delivered to 147 patients with HRNB at 13 US centers; 86 (59%) male and 101 (70%) white. All were treated according to standard chemotherapy protocols, 22% enrolled on clinical trial. OS at 5y was 68% (95% CI 52%-79%) and DFS 52% (95% CI 36%-67%). Median radiation dose was 27.3Gy (range 15-39.6Gy, mean 30.9Gy); 48% of pts received <24Gy and 44% ≥36Gy. Maximum surgical resection was reported as biopsy (Bx)/subtotal (STR) (n=60, 51.7%), near total (NTR) (n=9; 7.8%), or gross total resection (n=47, 40.5%). Most patients (85%) were treated before 4/2019. In this group, 49% of patients received ≥36Gy after Bx/STR/NTR compared with 28% after GTR (p = 0.063). For patients treated after 4/2019, 20% received ≥36Gy after Bx/STR/NTR compared with 0 after GTR (p = NS).

Conclusions

Our data suggest that findings from COG resulted in major shift in practice patterns, resulting in many fewer patients receiving dose escalation (including those not enrolled on trial). Future analysis will allow further understanding of impact of radiation dose on late-effects/ disease-related outcomes in the setting of HRNB.

Background and Aims

High-risk neuroblastoma represents a treatment challenge; frequently metastatic at presentation and residual disease in bone or bone marrow (BM) increases the risk of relapse. Naxitamab was recently approved in the US in combination with GM-CSF for the treatment of R/R HR NB in the bone or BM in patients ≥1 year of age who demonstrated a partial response, minor response, or stable disease to prior therapy. Here we present updated interim subgroup analyses from the pivotal study supporting this accelerated approval.

Methods

Study 201 (NCT03363373) is an international multicenter phase II study of naxitamab in patients with R/R HB NB with disease in bone/BM. Naxitamab was administered over ≥30 min in the outpatient setting on Days 1, 3 and 5 at 3 mg/kg/infusion in combination with GM-CSF at 250 µg/m²/day on Days -4 to 0 and at 500 µg/m²/day on days 1 to 5. Subgroups assessed include refractory vs relapsed disease and disease by compartment (bone/BM).

Results

The safety population comprised 48 patients, the efficacy population 36 patients. The overall response rate (ORR) was 58% (21/36) with a complete response rate (CR) of 44% (16/36) and a partial response rate of 14% (5/36) as per independent review. The ORR was 47% (CR 29%) for relapsed disease and 68% (CR 58%) for refractory disease. Compartmental responses were 68% (CR 47%) in bone and 75% (CR 75%) in BM. The safety profile was manageable, similar to previously reported interim results.

Conclusions

Naxitamab provided a clinically meaningful response in patients with R/R HR NB with bone/BM disease, regardless of disease status and compartment. The safety profile was manageable in the outpatient setting. Considering current treatment options and unmet medical need, naxitamab presents a unique treatment option for these patients.

Background and Aims

There is no established standard chemotherapy for recurrent pediatric solid tumors. Since some of these tumor cells show dysfunctions in homologous recombination repair, the goal is to conduct a phase I study of olaparib, a poly(ADP-ribose) polymerase (PARP) inhibitor. In this clinical trial, the aims are to evaluate the safety, tolerability, and efficacy of olaparib in pediatric patients with refractory solid tumors and to recommend a dose for phase II trials.

Methods

This phase I trial assessed the PARP inhibitor olaparib (AZD-2281) as monotherapy. In this open-label, multicenter study, olaparib tablets (62.5, 125, and 187.5 mg/m² b.i.d.) will be administered orally every day (1 cycle 28 days) in a standard 3 + 3 dose-escalation design. Patients aged 3 to 18 years with recurrent pediatric solid tumors are eligible. Pharmacokinetic and pharmacodynamic analyses will also be performed.

Results

Fifteen patients were enrolled; 15 received olaparib monotherapy, which was safe and well-tolerated. The recommended phase II dose (RP2D) for everyday administration was 187.5 mg/m² b.i.d. Among 13 evaluable cases, two patients achieved RECISTv1.1 partial response. A patient with metastatic Wilms harboring ATM mutation and loss of heterozygosity and A patient with neuroblastoma. Pharmacokinetics were dose-proportional and by comparison with previously published adult data, the value of Cmax in 187.5 mg/m² bid in the child was similar to the data of the 200 mg bid cohort in adults. In terms of AUC_0-12, the value of 187.5 mg/m² bid in the child was similar to the 200 mg bid cohort but lower than the 300 mg bid cohort in adults. Pharmacodynamic studies demonstrated substantial inhibition of PARP activity.

Conclusions

This is the first report of a PARP inhibitor as monotherapy in children. Olaparib was well tolerated, with preliminary antitumor responses with DNA damage response defective pediatric tumor observed.

Background and Aims

ch14.18/SP2/0 treatment significantly improves prognosis in high-risk neuroblastoma (HR-NB) patients. Studies assessing long-term outcome, impact on long-term sequalae and quality-of-life are lacking.

Methods

Between 1992 and 2003 a cohort of 63 children (aged 0.4-17.6 years, median 3.1 years) received ch14.18 for primary HR-NB (INSS-stage 4 in 59 patients (93,6%), 4 (6,4%) stage 3 with MYCN-amplification). All patients received induction-chemotherapy according to German NB90/NB97-protocol, all but 7 received HD-chemotherapy+autologous stem cell transplantation (ASCT). Four to eleven cycles of ch14.18 were administered, 100mg/m²/cycle.

We evaluated overall- and event-free-survival, risk-factors and conducted a questionnaire-based survey in long-term survivors to determine the proportion with severe toxicity and impact on quality-of-life (EORTC-QLQ-C30).

Results

Overall-survival and event-free-survival 25 years after initial diagnosis were 54.2% and 46.0%, 27 patients died, causes were progression/relapse (n=22), secondary neoplasm (MDS=4, Adenocarinoma=1); Lost to follow-up: 5 patients.

Thirty-one long-term survivors were identified with median follow-up of 24.6 years (15.5-32.2 years).

Long-term survivors underwent ASCT (n=24), tandem-transplant (n=1), allogenic SCT (n=1). Additionally, radiotherapy (n=15) and/or mIBG-therapy (n=17).

Twenty patients were evaluated for QoL and long-term effects. In all survivors long-term sequelae occurred: Ototoxicity in 15/20 (75%), cardiac toxicity in 3/20 (15%), pulmonary toxicity in 1/20 (5%), nonreproductive endocrine toxicity in 17/20 (85%), renal toxicity 3/20 (15%). Height/weight z-scores were less than -1.7 in 2/20 (10%).

3/31 (9.4%) developed secondary malignancies: MPNST(1), colon carcinoma(1), basalioma (1), all within radiation-field.

All QoL-scores were comparable to those of general population, with women showing slightly lower functioning and higher symptom-levels. All patients attained secondary education, 8 graduated from university. Two female patients have children of their own.

Conclusions

Immunotherapy with ch14.18 can induce long-term survival in HR-NB patients. The high incidence of long-term sequalae underlines the importance of careful follow-up. EORTC-QLQ-C30 scales were comparable to general population. With the limitation of non-randomization, no ch14.18-specific long-term sequelae could be identified.