Prospective longitudinal evaluation of treatment-related toxicity and health-related quality of life during the first year of treatment for pediatric acute lymphoblastic leukemia.

BACKGROUND: Pediatric acute lymphoblastic leukemia (ALL) therapy is accompanied by treatment-related toxicities (TRTs) and impaired quality of life. In Australia and New Zealand, children with ALL are treated with either Children's Oncology Group (COG) or international Berlin-Frankfurt-Munster (iBFM) Study Group-based therapy. We conducted a prospective registry study to document symptomatic TRTs (venous thrombosis, neurotoxicity, pancreatitis and bone toxicity), compare TRT outcomes to retrospective TRT data, and measure the impact of TRTs on children's general and cancer-related health-related quality of life (HRQoL) and parents' emotional well-being. METHODS: Parents of children with newly diagnosed ALL were invited to participate in the ASSET (Acute Lymphoblastic Leukaemia Subtypes and Side Effects from Treatment) study and a prospective, longitudinal HRQoL study. TRTs were reported prospectively and families completed questionnaires for general (Healthy Utility Index Mark 3) and cancer specific (Pediatric Quality of Life Inventory (PedsQL)-Cancer Module) health related quality of life as well the Emotion Thermometer to assess emotional well-being. RESULTS: Beginning in 2016, 260 pediatric patients with ALL were enrolled on the TRT registry with a median age at diagnosis of 59 months (range 1-213 months), 144 males (55.4%), majority with Pre-B cell immunophenotype, n = 226 (86.9%), 173 patients (66.5%) treated according to COG platform with relatively equal distribution across risk classification sub-groups. From 2018, 79 families participated in the HRQoL study through the first year of treatment. There were 74 TRT recorded, reflecting a 28.5% risk of developing a TRT. Individual TRT incidence was consistent with previous studies, being 7.7% for symptomatic VTE, 11.9% neurotoxicity, 5.4% bone toxicity and 5.0% pancreatitis. Children's HRQoL was significantly lower than population norms throughout the first year of treatment. An improvement in general HRQoL, measured by the HUI3, contrasted with the lack of improvement in cancer-related HRQoL measured by the PedsQL Cancer Module over the first 12 months. There were no persisting differences in the HRQoL impact of COG compared to iBFM therapy. CONCLUSIONS: It is feasible to prospectively monitor TRT incidence and longitudinal HRQoL impacts during ALL therapy. Early phases of ALL therapy, regardless of treatment platform, result in prolonged reductions in cancer-related HRQoL.

Measurable residual disease analysis in paediatric acute lymphoblastic leukaemia patients with ABL-class fusions.

BACKGROUND: ABL-class fusions including NUP214-ABL1 and EBF1-PDGFRB occur in high risk acute lymphoblastic leukaemia (ALL) with gene expression patterns similar to BCR-ABL-positive ALL. Our aim was to evaluate new DNA-based measurable residual disease (MRD) tests detecting these fusions and IKZF1-deletions in comparison with conventional immunoglobulin/T-cell receptor (Ig/TCR) markers. METHODS: Precise genomic breakpoints were defined from targeted or whole genome next generation sequencing for ABL-fusions and BCR-ABL1. Quantitative PCR assays were designed and used to re-measure MRD in remission bone marrow samples previously tested using Ig/TCR markers. All MRD testing complied with EuroMRD guidelines. RESULTS: ABL-class patients had 46% 5year event-free survival and 79% 5year overall survival. All had sensitive fusion tests giving high concordance between Ig/TCR and ABL-class fusion results (21 patients, n = 257 samples, r2 = 0.9786, P < 0.0001) and Ig/TCR and IKZF1-deletion results (9 patients, n = 143 samples, r2 = 0.9661, P < 0.0001). In contrast, in BCR-ABL1 patients, Ig/TCR and BCR-ABL1 tests were discordant in 32% (40 patients, n = 346 samples, r2 = 0.4703, P < 0.0001) and IKZF1-deletion results were closer to Ig/TCR (25 patients, n = 176, r2 = 0.8631, P < 0.0001). CONCLUSIONS: MRD monitoring based on patient-specific assays detecting gene fusions or recurrent assays for IKZF1-deletions is feasible and provides good alternatives to Ig/TCR tests to monitor MRD in ABL-class ALL.

Malignant Melanoma in Children and Adolescents Treated in Pediatric Oncology Centers: An Australian and New Zealand Children's Oncology Group (ANZCHOG) Study.

OBJECTIVES: Unlike adults, malignant melanoma in children and adolescents is rare. In adult melanoma, significant progress in understanding tumor biology and new treatments, including targeted therapies and immunotherapy have markedly improved overall survival. In sharp contrast, there is a paucity of data on the biology and clinical behavior of pediatric melanoma. We report a national case series of all pediatric and adolescent malignant melanoma presenting to ANZCHOG Childhood Cancer Centers in Australia and New Zealand. METHODS: A retrospective, descriptive, multi-center study was undertaken to identify patients less than 18 years of age treated for cutaneous malignant melanoma over a twenty-year period (1994 to 2014). Data on clinical characteristics, histopathology, and extent of disease, treatment and follow-up are described. RESULTS: A total of 37 cases of malignant melanoma were identified from all of the Australasian tertiary Childhood Cancer Centers. The median age was 10 years (range 1 month - 17 years). Clinically, the most common type of lesion was pigmented, occurring in sixteen (57%) patients, whilst amelanotic was seen in 7 patients (25%). In 11 (27.9%) the Breslow thickness was greater than 4mm. A total of 11 (29.7%) patients relapsed and 90% of these died of disease. Five-year event free survival (EFS) and overall survival were 63.2 (95% CI: 40.6 - 79.1) and 67.7% (95% CI: 45.1 - 82.6) respectively. CONCLUSION: Our data confirms that melanoma is a rare presentation of cancer to tertiary Australasian Childhood Cancer Centers with only 37 cases identified over two decades. Notably, melanoma managed in Childhood Cancer Centers is frequently at an advanced stage, with a high percentage of patients relapsing and the majority of these patients who relapsed died of disease. This study confirms previous clinical and prognostic information to support the early multidisciplinary management in Childhood Cancer Centers, in conjunction with expert adult melanoma centers, of this rare and challenging patient group.

Outcomes for Australian children with relapsed/refractory acute lymphoblastic leukaemia treated with blinatumomab.

We report on the Australian experience of blinatumomab for treatment of 24 children with relapsed/refractory precursor B-cell acute lymphoblastic leukaemia (B-ALL) and high-risk genetics, resulting in a minimal residual disease (MRD) response rate of 58%, 2-year progression-free survival (PFS) of 39% and 2-year overall survival of 63%. In total, 83% (n = 20/24) proceeded to haematopoietic stem cell transplant, directly after blinatumomab (n = 12) or following additional salvage therapy (n = 8). Four patients successfully received CD19-directed chimeric antigen receptor T-cell therapy despite prior blinatumomab exposure. Inferior 2-year PFS was associated with MRD positivity (20%, n = 15) and in KMT2A-rearranged infants (15%, n = 9). Our findings highlight that not all children with relapsed/refractory B-ALL respond to blinatumomab and factors such as blast genotype may affect prognosis.

Childhood cancer registration in New Zealand: A registry collaboration to assess and improve data quality.

AIM: To evaluate the completeness and accuracy of child cancer registration in New Zealand. METHODS: Registrations for children aged 0-14 diagnosed between 1/1/2010 and 31/12/2014 were obtained from the New Zealand Cancer Registry (NZCR) and the New Zealand Children's Cancer Registry (NZCCR). Six key data fields were matched using National Health Index numbers in order to identify and resolve registration discrepancies. Capture-recapture methods were used to assess the completeness of cancer registration. RESULTS: 794 unique cases were reported; 718 from the NZCR, 721 from the NZCCR and 643 from both registries. 27 invalid cancer registrations were identified, including 19 residents of the Pacific Islands who had travelled to New Zealand for treatment. The NZCCR provided 55 non-malignant central nervous system tumour and 16 Langerhans cell histiocytosis cases which were not registered by the NZCR. The NZCR alerted the NZCCR to 18 cases missed due to human error and 23 cases that had not been referred to the specialist paediatric oncology centres. 762 cases were verified as true incident cases, an incidence rate of 166.8 per million. Registration accuracy for six key data fields was 98.6%. According to their respective inclusion criteria case completeness was 99.3% for the NZCR and 94.4% for the NZCCR. For childhood malignancies covered by both registries, capture-recapture methods estimated case ascertainment at greater than 99.9%. CONCLUSION: With two national registries covering childhood cancers, New Zealand is uniquely positioned to undertake regular cooperative activities to ensure high quality data is available for research and patient care.

Enrollment in clinical cancer trials: how are we doing and what are the obstacles to improving enrollment rates? A 2-year retrospective review of pediatric cancer trial enrollment in New Zealand.

Clinical trials contribute to the establishment of the best therapy for children with cancer. This study looks at rates of enrollment in therapeutic clinical trials over a 2-year period in New Zealand and examines the reasons for nonenrollment. All new diagnoses of cancer in children aged 16 or younger over the period of 1 January, 2009 to 31 December, 2010 were identified through the New Zealand Child Cancer Registry. Clinical trial enrollment status was identified from the medical records. For those not enrolled, the reason for nonenrollment was ascertained. A total of 28% of children diagnosed with cancer who received chemotherapy with curative intent in this time period were enrolled on clinical trials. The 2 most common reasons for nonenrollment in this study were that no study was open locally in which to enroll children (27%) or that previously open-clinical trials were closed to accrual at the time of the child's diagnosis (20%). In New Zealand, enrollment rates on clinical trials for children with cancer are lower than expected.

18F-FDG PET/CT compared to conventional imaging modalities in pediatric primary bone tumors.

BACKGROUND: F-Fluoro-2-deoxy-D: -glucose (FDG) positron emission tomography (PET) is useful in adults with primary bone tumors. Limited published data exist in children. OBJECTIVE: To compare hybrid FDG positron emission tomography/computed tomography (PET/CT) with conventional imaging (CI) modalities in detecting malignant lesions, predicting response to chemotherapy and diagnosing physeal involvement in pediatric primary bone tumors. MATERIALS AND METHODS: Retrospective analysis of PET/CT and CI reports with histopathology or follow-up > 6 months as reference standard. Response parameters and physeal involvement at diagnosis were compared to histopathology. RESULTS: A total of 314 lesions were detected in 86 scans. Excluding lung lesions, PET/CT had higher sensitivity and specificity than CI (83%, 98% and 78%, 97%, respectively). In lung lesions, PET/CT had higher specificity than CI (96% compared to 87%) but lower sensitivity (80% compared to 93%). Higher initial SUV(max) and greater SUV(max) reduction on PET/CT after chemotherapy predicted a good response. Change in tumor size on MRI did not predict response. Both PET/CT and MRI were very sensitive but of low specificity in predicting physeal tumor involvement. CONCLUSION: PET/CT appears more accurate than CI in detecting malignant lesions in childhood primary bone tumors, excluding lung lesions. It seems better than MRI at predicting tumor response to chemotherapy.

18F-FDG PET/CT in paediatric lymphoma: comparison with conventional imaging.

PURPOSE: In children with Hodgkin's disease and non-Hodgkin's lymphoma, the ability of (18)F-fluoro-2-deoxy-D-glucose PET/CT and conventional imaging (CI) to detect malignant lesions and predict poor lesion response to therapy was assessed and compared. METHODS: A retrospective review of findings reported on PET/CT and CI was performed using a lesion-based analysis of 16 lymph node and 8 extra-nodal regions. Lesions were defined by histopathological findings or follow-up > 6 months. RESULTS: The study included 209 PET/CT scans with a valid CI comparator. A total of 5,014 regions (3,342 lymph node, 1,672 extra-nodal) were analysed. PET/CT performed significantly better than CI in the detection of malignant lesions with sensitivity and specificity of 95.9 and 99.7% compared to 70.1 and 99.0%, respectively. For predicting poor lesion response to therapy, PET/CT had fewer false-positive lesions than CI. The specificity for predicting poor lesion response to treatment for PET/CT was 99.2% compared to 96.9% for CI. PET/CT was the correct modality in 86% of lesions with discordant findings. CONCLUSION: PET/CT is more accurate than CI in detecting malignant lesions in childhood lymphoma and in predicting poor lesion response to treatment. In lesions with discordant findings, PET/CT results are more likely to be correct.

Familial pleuropulmonary blastoma in Australia.

We present three cases of pleuropulmonary blastoma (PPB) in Australian children. Each had a family history of childhood tumors which collectively included PPB, infant lung cyst, cystic nephroma, medullo-epithelioma and a Sertoli-Leydig ovarian tumor. Two of the patients also had additional malignancies: a concurrent bladder rhabdomyosarcoma and a post therapy non-PPB malignant lung tumor. In two cases, the family histories were elicited years after the PPB diagnosis. Archived pathology material allowed revision of pathologic diagnoses from decades earlier. These cases illustrate the importance of detailed inquiry into family medical history and the pleiotropy of the PPB-related familial cancer predisposition syndrome, which appears to result from heterozygous DICER1 mutations.

Hypercalcemia and osteoblastic lesions induced by 13-Cis-retinoic acid mimicking relapsed neuroblastoma.

A 6-year-old male diagnosed with extensive neuroblastoma was treated with chemotherapy, surgery, autotransplantation, and radiotherapy. He was then enrolled on a study to assess the monoclonal antibody Ch14.18 (anti-GD2) with 13 cis-retinoic acid. 13-cis-retinoic acid therapy caused severe bone pain and hypercalcemia. Bone scans showed multiple osteoblastic lesions suggesting recurrent disease however MIBG scans were negative. Serum markers of bone turnover were increased and the patient required pamidronate therapy to treat persistent hypercalcemia. Retinoic acid toxicity needs to be considered in the differential of painful osteoblastic lesions and/or hypercalcemia. MIBG scans can assist in differentiating from recurrent disease.