ABSTRACT
Recent research showed that precision medicine can identify new treatment strategies for patients with childhood cancers. However, it is unclear which patients will benefit most from precision-guided treatment (PGT). Here we report consecutive data from 384 patients with high-risk pediatric cancer (with an expected cure rate of less than 30%) who had at least 18 months of follow-up on the ZERO Childhood Cancer Precision Medicine Program PRecISion Medicine for Children with Cancer (PRISM) trial. A total of 256 (67%) patients received PGT recommendations and 110 (29%) received a recommended treatment. PGT resulted in a 36% objective response rate and improved 2-year progression-free survival compared with standard of care (26% versus 12%; P = 0.049) or targeted agents not guided by molecular findings (26% versus 5.2%; P = 0.003). PGT based on tier 1 evidence, PGT targeting fusions or commenced before disease progression had the greatest clinical benefit. Our data show that PGT informed by comprehensive molecular profiling significantly improves outcomes for children with high-risk cancers. ClinicalTrials.gov registration: NCT03336931.
Subject(s)
Neoplasms , Precision Medicine , Humans , Precision Medicine/methods , Child , Neoplasms/genetics , Neoplasms/therapy , Neoplasms/drug therapy , Female , Male , Adolescent , Child, Preschool , Infant , Progression-Free Survival , Treatment OutcomeABSTRACT
Ataxia-telangiectasia (A-T) is an autosomal-recessive disorder caused by pathogenic variants (PVs) of the ATM gene. Children with A-T are predisposed to hematological malignancies. We aimed to investigate their characteristics and outcomes in order to generate data-based treatment recommendations. In this multinational, observational study we report 202 patients aged ≤25 years with A-T and hematological malignancies from 25 countries. Ninety-one patients (45%) presented with mature B-cell lymphomas, 82 (41%) with acute lymphoblastic leukemia/lymphoma, 21(10%) with Hodgkin lymphoma and eight (4%) with other hematological malignancies. Four-year overall survival and event-free survival (EFS) were 50.8% (95% CI 43.6-59.1) and 47.9% (95% CI 40.8-56.2), respectively. Cure rates have not significantly improved over the last four decades (p=.76). The major cause of treatment failure was treatment-related mortality (TRM) with a four-year cumulative incidence of 25.9% (95% CI 19.5-32.4). Germline ATM PVs were categorized as null or hypomorphic and patients with available genetic data (n=110) were classified as having absent (n=81) or residual (n=29) ATM kinase activity. Four-year EFS was 39.4% (95% CI 29-53.3) vs 78.7% (95% CI 63.7-97.2), (p<.001), and TRM rates were 37.6% (95% CI 26.4-48.7) vs 4.0% (95% CI 0-11.8), (p=.017), for those with absent and residual ATM kinase activity, respectively. Absence of ATM kinase activity was independently associated with decreased EFS (HR=0.362, 95% CI 0.16-0.82; p=.009) and increased TRM (HR=14.11, 95% CI 1.36-146.31; p=.029). Patients with A-T and leukemia/lymphoma may benefit from de-escalated therapy for patients with absent ATM kinase activity and near-standard therapy regimens for those with residual kinase activity.
ABSTRACT
AIMS: The potential harm associated with medication errors is widely reported, but data on actual harm are limited. When actual harm has been measured, assessment processes are often poorly described, limiting their ability to be reproduced by other studies. Our aim was to design and implement a new process to assess actual harm resulting from medication errors in paediatric inpatient care. METHODS: Prescribing errors were identified through retrospective medical record reviews (n = 26 369 orders) and medication administration errors through direct observation (n = 5137 administrations) in a tertiary paediatric hospital. All errors were assigned potential harm severity ratings on a 5-point scale. Multidisciplinary panels reviewed case studies for patients assigned the highest three potential severity ratings and determined the following: actual harm occurrence and severity level, plausibility of a link between the error(s) and identified harm(s) and a confidence rating if no harm had occurred. RESULTS: Multidisciplinary harm panels (n = 28) reviewed 566 case studies (173 prescribing related and 393 administration related) and found evidence of actual harm in 89 (prescribing = 22, administration = 67). Eight cases of serious harm cases were found (prescribing = 1, administration = 7) and no cases of severe harm. The panels were very confident in 65% of cases (n = 302) where no harm was found. Potential and actual harm ratings varied. CONCLUSIONS: This harm assessment process provides a systematic method for determining actual harm from medication errors. The multidisciplinary nature of the panels was critical in evaluating specific clinical, therapeutic and contextual considerations including care delivery pathways, therapeutic dose ranges and drug-drug and drug-disease interactions.
Subject(s)
Hospitals, Pediatric , Medication Errors , Humans , Medication Errors/statistics & numerical data , Medication Errors/prevention & control , Child , Retrospective Studies , Hospitals, Pediatric/standards , Inpatients , Child, Preschool , InfantABSTRACT
PURPOSE: The AIEOP-BFM ALL 2009 protocol included, at the end of the induction phase, a randomized study of patients with high-risk (HR) ALL to investigate if an intensive exposure to pegylated L-asparaginase (PEG-ASNASE, 2,500 IU/sqm once a week × 4) on top of BFM consolidation phase IB allowed us to decrease minimal residual disease (MRD) and improve outcome. PATIENTS AND METHODS: A total of 1,097 patients presented, from June 2010 to February 2017, with one or more of the following HR criteria: KMT2A::AFF1 rearrangement, hypodiploidy, prednisone poor response, poor bone marrow response at day 15 (Flow MRD ≥10%), or no complete remission (CR) at the end of induction. Of them, 809 (85.1%) were randomly assigned to receive (404) or not receive (405) four weekly doses of PEG-ASNASE. RESULTS: By intention to treat (ITT) analysis, there was no significant difference in the proportion of patients with polimerase chain reaction MRD ≥5 × 10-4 at the end of phase IB in the experimental versus control arm (13.9% v 17.0%, P = .25). The 5-year event-free survival (median follow-up 6.3 years) by ITT in the experimental and control arms was 70.4% (2.3) versus 75.0% (2.2; P = .18), and the 5-year overall survival was 81.5% (2.0) versus 84.0% (1.9; P = .25), respectively. The corresponding 5-year cumulative incidence of death in CR was 9.5% (1.5) versus 5.7% (1.2; P = .08), and that of relapse was 17.7% (1.9) versus 17.2% (1.9), respectively (P = .94). Adverse reactions in phase IB occurred in 22.2% and 8.9% of patients in the experimental and control arm, respectively (P < .001). CONCLUSION: Additional PEG-ASNASE in phase IB did not translate into a benefit for decreasing relapse incidence but was associated with higher toxicity. Further improvements with conventional chemotherapy might be difficult in the context of intensive treatment protocols.
Subject(s)
Asparaginase , Precursor Cell Lymphoblastic Leukemia-Lymphoma , Humans , Infant , Prednisone/adverse effects , Treatment Outcome , Disease-Free Survival , Neoplasm Recurrence, Local/drug therapy , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Polyethylene Glycols , Recurrence , Randomized Controlled Trials as TopicABSTRACT
B-cell acute lymphoblastic leukaemia (B-ALL) is characterised by diverse genomic alterations, the most frequent being gene fusions detected via transcriptomic analysis (mRNA-seq). Due to its hypervariable nature, gene fusions involving the Immunoglobulin Heavy Chain (IGH) locus can be difficult to detect with standard gene fusion calling algorithms and significant computational resources and analysis times are required. We aimed to optimize a gene fusion calling workflow to achieve best-case sensitivity for IGH gene fusion detection. Using Nextflow, we developed a simplified workflow containing the algorithms FusionCatcher, Arriba, and STAR-Fusion. We analysed samples from 35 patients harbouring IGH fusions (IGH::CRLF2 n = 17, IGH::DUX4 n = 15, IGH::EPOR n = 3) and assessed the detection rates for each caller, before optimizing the parameters to enhance sensitivity for IGH fusions. Initial results showed that FusionCatcher and Arriba outperformed STAR-Fusion (85-89% vs. 29% of IGH fusions reported). We found that extensive filtering in STAR-Fusion hindered IGH reporting. By adjusting specific filtering steps (e.g., read support, fusion fragments per million total reads), we achieved a 94% reporting rate for IGH fusions with STAR-Fusion. This analysis highlights the importance of filtering optimization for IGH gene fusion events, offering alternative workflows for difficult-to-detect high-risk B-ALL subtypes.
Subject(s)
Antineoplastic Agents , Precursor Cell Lymphoblastic Leukemia-Lymphoma , Child , Humans , Pregnancy , Female , Asparaginase/adverse effects , Precursor Cell Lymphoblastic Leukemia-Lymphoma/diagnosis , Precursor Cell Lymphoblastic Leukemia-Lymphoma/drug therapy , Polyethylene Glycols/adverse effects , Antineoplastic Agents/therapeutic useABSTRACT
INTRODUCTION: Identifying an underlying germline cancer predisposition (CP) in a child with cancer has potentially significant implications for both the child and biological relatives. Cohort studies indicate that 10%-15% of paediatric cancer patients carry germline pathogenic or likely pathogenic variants in cancer predisposition genes, but many of these patients do not meet current clinical criteria for genetic testing. This suggests broad tumour agnostic germline testing may benefit paediatric cancer patients. However, the utility and psychosocial impact of this approach remain unknown. We hypothesise that an approach involving trio whole-genome germline sequencing (trio WGS) will identify children and families with an underlying CP in a timely fashion, that the trio design will streamline cancer risk counselling to at-risk relatives if CP was inherited, and that trio testing will not have a negative psychosocial impact on families. METHOD AND ANALYSIS: To test this, we present the Cancer PREDisposition In Childhood by Trio sequencing study (PREDICT). This study will assess the clinical utility of trio WGS to identify CP in unselected patients with cancer 21 years or younger in New South Wales, Australia. PREDICT will perform analysis of biological parents to determine heritability and will examine the psychosocial impact of this trio sequencing approach. PREDICT also includes a broad genomics research programme to identify new candidate genes associated with childhood cancer risk. ETHICS AND DISSEMINATION: By evaluating the feasibility, utility and psychosocial impact of trio WGS to identify CP in paediatric cancer, PREDICT will inform how such comprehensive testing can be incorporated into a standard of care at diagnosis for all childhood cancer patients. TRIAL REGISTRATION NUMBER: NCT04903782.
Subject(s)
Neoplasms , Adolescent , Child , Humans , Cohort Studies , Disease Susceptibility , Genetic Predisposition to Disease , Neoplasms/diagnosis , Neoplasms/genetics , Prospective Studies , Whole Genome Sequencing/methodsABSTRACT
Although initial central nervous system (CNS) involvement is rarely detected in childhood acute lymphoblastic leukemia (ALL), risk-adapted CNS-directed therapy is essential for all patients. Treatment intensity depends on the initial CNS status. In the AIEOP-BFM ALL 2009 trial, patients with cytomorphologic detection of leukemic blasts in initial cerebrospinal fluid were classified as CNS2 or CNS3 and received five intrathecal doses of methotrexate (MTX) in induction therapy compared to patients with CNS1 status (no blasts detected) who received three doses. The impact of additional intrathecal (IT) MTX on systemic toxicity in induction therapy is unknown. Between June 1st 2010 and February 28th 2017, a total of 6,136 ALL patients aged 1-17 years were enrolled onto the AIEOP-BFM ALL 2009 trial. The effect of three versus five doses of IT MTX during induction therapy on the incidence of severe infectious complications was analyzed. Among 4,706 patients treated with three IT MTX doses, 77 (1.6%) had a life-threatening infection during induction as compared to 59 of 1,350 (4.4%) patients treated with five doses (P<0.001; Odds Ratio 2.86 [95% Confidence Interval 1.99-4.13]). In a multivariate regression model, treatment with additional IT MTX proved to be the strongest risk factor for life-threatening infections (Odds Ratio 2.85 [1.96-4.14]). Fatal infections occurred in 16 (0.3%) and 38 (1.6%) patients treated with three or five IT MTX doses, respectively (P<0.001). As the relevance of additional intrathecal MTX in induction for relapse prevention in CNS2 patients is unclear, doses of intrathecal therapy have been reduced for these patients. (Clinicaltrials.gov identifiers: NCT01117441 and NCT00613457).
Subject(s)
Methotrexate , Precursor Cell Lymphoblastic Leukemia-Lymphoma , Child , Humans , Methotrexate/therapeutic use , Induction Chemotherapy/adverse effects , Precursor Cell Lymphoblastic Leukemia-Lymphoma/complications , Precursor Cell Lymphoblastic Leukemia-Lymphoma/drug therapy , Combined Modality Therapy , Antineoplastic Combined Chemotherapy Protocols/adverse effectsABSTRACT
Aneurysmal bone cysts (ABC) are rare osteolytic, benign but often locally aggressive tumours of the long bones or vertebrae. For spinal ABC, surgical management, embolisation or sclerotherapy alone often carry high morbidity and/or high recurrence rates. Interruption of receptor activator of nuclear factor-kappa B ligand (RANKL) signalling holds promise as an effective therapeutic strategy for these tumours. We aimed to review the approach to surgical management and evaluate the efficacy and safety of denosumab for ABC of the spine in children. Retrospective review of 7 patients treated with denosumab using a standardised protocol for ABC of the spine in a tertiary paediatric centre. Surgical intervention was only conducted if there was spinal instability or significant neurological impairment. Denosumab 70 mg/m2 was given 4-weekly for at least 6 months, followed by 2 doses of zoledronate 0.025 mg/kg, aiming to prevent rebound hypercalcaemia. All patients achieved stability of the spine and resolution of neurological impairment, if present. Six patients achieved metabolic remission and have ceased denosumab without recurrence to date; the other showed clinical and radiological improvement without complete metabolic remission. Three patients developed symptomatic hypercalcaemia 5-7 months after cessation of denosumab, requiring additional bisphosphonate treatment. We present our algorithm for the surgical and medical management of paediatric spinal ABC. Denosumab produced a radiological and metabolic response in all patients, with complete remission in most. Follow-up time was not long enough to evaluate the endurance of response after cessation in some patients. Incidence of rebound hypercalcaemia in this paediatric cohort was high, prompting a change to our protocol.
Subject(s)
Bone Cysts, Aneurysmal , Bone Density Conservation Agents , Hypercalcemia , Humans , Child , Denosumab/therapeutic use , Bone Cysts, Aneurysmal/drug therapy , Bone Cysts, Aneurysmal/surgery , Hypercalcemia/drug therapy , Australia , Bone Density Conservation Agents/therapeutic use , Spine/pathologyABSTRACT
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.
Subject(s)
Pancreatitis , Precursor Cell Lymphoblastic Leukemia-Lymphoma , Acute Disease , Child , Humans , Male , Precursor Cell Lymphoblastic Leukemia-Lymphoma/drug therapy , Quality of Life , Retrospective Studies , Surveys and QuestionnairesABSTRACT
PURPOSE: The aim of this study is to report two cases of paediatric Yolk sac tumours (YST) of the orbit and sinonasal tract, with a major review on the subject. METHODS: Two case reports along with a comprehensive retrospective literature review of all English language publications between 1974 and 2021 is presented. Literature review examined the demographics, clinical presentation and diagnostic and prognostic factors of extragonadal YSTs of the orbit and sinonasal tract. RESULTS: Orbit and sinuses are rare sites for YST, with only 25 paediatric cases reported in the literature. Extragonadal yolk sac tumours carry a significantly worse outcome than those localised to the gonads, with the 5-year survival of 66% and 81-89%, respectively. Our review found the median age of presentation to be 18 months (18 months for males and 24 months for females), and females are more commonly affected. The most common presentations were proptosis, facial swelling and ophthalmoplegia. Treatments and therefore outcomes varied in the cases due to the large time period. Of the cases reported in the last 10 years, all patients with data provided were alive and disease-free at follow-up. CONCLUSION: Sino-orbital yolk sac tumours are rare and have variable presentations, dependent on the extent of local invasion. Early diagnosis and treatment with multimodal therapy are paramount in having improved overall survival.
Subject(s)
Endodermal Sinus Tumor , Exophthalmos , Paranasal Sinuses , Male , Female , Humans , Child , Infant , Endodermal Sinus Tumor/diagnosis , Endodermal Sinus Tumor/therapy , Endodermal Sinus Tumor/pathology , Retrospective Studies , Combined Modality Therapy , Paranasal Sinuses/pathologyABSTRACT
Children with relapse of T-cell acute lymphoblastic leukemia (T-ALL) or lymphoblastic lymphoma (T-LBL) have a dismal prognosis, largely due to difficulty attaining second remission. We hypothesized that adding etoposide and cyclophosphamide to the nucleoside analog nelarabine could improve response rates over single-agent nelarabine for relapsed T-ALL and T-LBL. This phase I dose-escalation trial's primary objective was to evaluate the dose and safety of nelarabine given in combination with etoposide at 100 mg/m2 /day and cyclophosphamide at 330-400 mg/m2 /day, each for 5 consecutive days in children with either T-ALL (13 patients) or T-LBL (10 patients). Twenty-three patients were treated at three dose levels; 21 were evaluable for dose-limiting toxicities (DLT) and response. The recommended phase II doses (RP2D) for this regimen, when given daily ×5 every 3 weeks, were nelarabine 650 mg/m2 /day, etoposide 100 mg/m2 /day, and cyclophosphamide 400 mg/m2 /day. DLTs included peripheral motor and sensory neuropathies. An expansion cohort to evaluate responses at the RP2D was terminated early due to slow accrual. The overall best response rate was 38% (8/21), with 33% (4/12) responses in the T-ALL cohort and 44% (4/9) responses in the T-LBL cohort. These response rates are comparable to those seen with single-agent nelarabine in this setting. These data suggest that the addition of cyclophosphamide and etoposide to nelarabine does not increase the incidence of neurologic toxicities or the response rate beyond that obtained with single-agent nelarabine in children with first relapse of T-ALL and T-LBL.
Subject(s)
Lymphoma, Non-Hodgkin , Precursor Cell Lymphoblastic Leukemia-Lymphoma , Precursor T-Cell Lymphoblastic Leukemia-Lymphoma , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Arabinonucleosides/adverse effects , Child , Cyclophosphamide/adverse effects , Etoposide/adverse effects , Humans , Lymphoma, Non-Hodgkin/drug therapy , Nucleosides/therapeutic use , Plant Nectar , Precursor Cell Lymphoblastic Leukemia-Lymphoma/drug therapy , Precursor Cell Lymphoblastic Leukemia-Lymphoma/etiology , Precursor T-Cell Lymphoblastic Leukemia-Lymphoma/pathology , RecurrenceABSTRACT
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.
Subject(s)
Fusion Proteins, bcr-abl , Precursor Cell Lymphoblastic Leukemia-Lymphoma , Child , Fusion Proteins, bcr-abl/genetics , Humans , Immunoglobulins , Neoplasm, Residual/genetics , Precursor Cell Lymphoblastic Leukemia-Lymphoma/genetics , Receptors, Antigen, T-Cell/geneticsABSTRACT
PCR is widely used to measure minimal residual disease (MRD) in lymphoid neoplasms, but its sensitivity is limited. High Adenine/Thymine PCR and High Annealing Temperature PCR (HAT-PCR) is a modified PCR designed to minimize nonspecificity and hence increase sensitivity. It was evaluated in the laboratory and the clinic, using samples from 58 patients. Of these patients, 57 were adolescents or young adults who were participating in the Australasian Leukemia and Lymphoma Group ALL06 trial in which MRD was measured in blood principally by HAT-PCR and in marrow by conventional PCR. HAT-PCR produced significantly less nonspecificity than conventional PCR, and its limit of detection was <10-6 in 90% of patients. In 196 samples, an excellent correlation was found between blood and marrow MRD. Variable partitioning of leukemic cells between blood and marrow was observed. Measurement of MRD in blood by HAT-PCR was noninferior to measurement of MRD in marrow by conventional PCR, in terms of both detecting disease and predicting clinical outcome. At a median follow-up of 3 years and for MRD levels in blood at the end of consolidation treatment, an MRD level of >10-4 cells/L significantly predicted relapse and mortality, whereas undetectable MRD significantly predicted relapse-free survival and overall survival. HAT-PCR is a simple, quick, cheap and sensitive method for measurement of MRD, and its adoption for MRD in blood may be clinically useful.
Subject(s)
Bone Marrow , Adolescent , Bone Marrow/pathology , Humans , Neoplasm, Residual/diagnosis , Neoplasm, Residual/genetics , Polymerase Chain Reaction , Recurrence , Young AdultABSTRACT
BACKGROUND: Central giant cell granulomas (CGCG) are rare osteolytic, benign but often locally aggressive tumours of bone. Surgical curettage may not be possible in extensive lesions and resection carries high morbidity, especially in growing children, and previous medical therapies have had variable efficacy and high recurrence rates. Interruption of receptor activator of nuclear factor-kappa B ligand (RANKL) signalling holds promise as an effective therapeutic strategy for these tumours. AIMS: To evaluate the efficacy and safety of our protocol for denosumab treatment of CGCG in children. METHODS: Retrospective review of 4 patients treated with denosumab using a standardised protocol for CGCG in a tertiary paediatric centre. Denosumab 70 mg/m2 was given 4-weekly, followed by 2 doses of zoledronate 0.025 mg/kg, aimed at preventing rebound hypercalcaemia. RESULTS: Treatment of CGCG resulted in metabolic remission in all patients, but recurrence, detected by positron emission tomography (PET), occurred at 6 months in three patients and 12 months in one patient. Three patients developed symptomatic hypercalcaemia 4-5 months and one patient asymptomatic hypercalcaemia 7 months after cessation of denosumab, with 3 requiring additional bisphosphonate treatment. CONCLUSIONS: Denosumab produced a radiological and metabolic response in our patients, but metabolic recurrence occurred in all patients. PET imaging was effective for monitoring treatment response and early detection of recurrence. Incidence of rebound hypercalcaemia in this paediatric cohort was high. We present proposed changes to our protocol with the aim of producing sustained remission and preventing rebound hypercalcaemia.
Subject(s)
Bone Density Conservation Agents , Bone Neoplasms , Giant Cell Tumor of Bone , Granuloma, Giant Cell , Hypercalcemia , Australia , Bone Density Conservation Agents/adverse effects , Bone Neoplasms/drug therapy , Child , Denosumab/therapeutic use , Giant Cell Tumor of Bone/pathology , Granuloma, Giant Cell/chemically induced , Granuloma, Giant Cell/diagnostic imaging , Granuloma, Giant Cell/drug therapy , Humans , Hypercalcemia/drug therapyABSTRACT
INTRODUCTION: The Australian Technical Advisory Group on Immunisation and New Zealand Ministry of Health recommend all children aged ≥ 5 years receive either of the two mRNA COVID-19 vaccines: Comirnaty (Pfizer), available in both Australia and New Zealand, or Spikevax (Moderna), available in Australia only. Both vaccines are efficacious and safe in the general population, including children. Children and adolescents undergoing treatment for cancer and immunosuppressive therapy for non-malignant haematological conditions are particularly vulnerable, with an increased risk of severe or fatal COVID-19. There remains a paucity of data regarding the immune response to COVID-19 vaccines in immunosuppressed paediatric populations, with data suggestive of reduced immunogenicity of the vaccine in immunocompromised adults. RECOMMENDATIONS: Considering the safety profile of mRNA COVID-19 vaccines and the increased risk of severe COVID-19 in immunocompromised children and adolescents, COVID-19 vaccination is strongly recommended for this at-risk population. We provide a number of recommendations regarding COVID-19 vaccination in this population where immunosuppressive, chemotherapeutic and/or targeted biological agents are used. These include the timing of vaccination in patients undergoing active treatment, management of specific situations where vaccination is contraindicated or recommended under special precautions, and additional vaccination recommendations for severely immunocompromised patients. Finally, we stress the importance of upcoming clinical trials to identify the safest and most efficacious vaccination regimen for this population. CHANGES IN MANAGEMENT AS A RESULT OF THIS STATEMENT: This consensus statement provides recommendations for COVID-19 vaccination in children and adolescents aged ≥ 5 years with cancer and immunocompromising non-malignant haematological conditions, based on evidence, national and international guidelines and expert opinion. ENDORSED BY: The Australian and New Zealand Children's Haematology/Oncology Group.
Subject(s)
COVID-19 , Hematology , Neoplasms , Adolescent , Australia/epidemiology , COVID-19/prevention & control , COVID-19 Vaccines , Child , Child, Preschool , Humans , Neoplasms/therapy , New Zealand/epidemiology , VaccinationABSTRACT
Biomarkers which better match anticancer drugs with cancer driver genes hold the promise of improved clinical responses and cure rates. We developed a precision medicine platform of rapid high-throughput drug screening (HTS) and patient-derived xenografting (PDX) of primary tumor tissue, and evaluated its potential for treatment identification among 56 consecutively enrolled high-risk pediatric cancer patients, compared with conventional molecular genomics and transcriptomics. Drug hits were seen in the majority of HTS and PDX screens, which identified therapeutic options for 10 patients for whom no targetable molecular lesions could be found. Screens also provided orthogonal proof of drug efficacy suggested by molecular analyses and negative results for some molecular findings. We identified treatment options across the whole testing platform for 70% of patients. Only molecular therapeutic recommendations were provided to treating oncologists and led to a change in therapy in 53% of patients, of whom 29% had clinical benefit. These data indicate that in vitro and in vivo drug screening of tumor cells could increase therapeutic options and improve clinical outcomes for high-risk pediatric cancer patients.
Subject(s)
Antineoplastic Agents , Neoplasms , Animals , Antineoplastic Agents/pharmacology , Antineoplastic Agents/therapeutic use , Child , Disease Models, Animal , Genomics/methods , Humans , Neoplasms/pathology , Precision Medicine/methods , Xenograft Model Antitumor AssaysABSTRACT
Identification of cancer-predisposing germline variants in childhood cancer patients is important for therapeutic decisions, disease surveillance and risk assessment for patients, and potentially, also for family members. We investigated the spectrum and prevalence of pathogenic germline variants in selected childhood cancer patients with features suggestive of genetic predisposition to cancer. Germline DNA was subjected to exome sequencing to filter variants in 1048 genes of interest including 176 known cancer predisposition genes (CPGs). An enrichment burden analysis compared rare deleterious germline CPG variants in the patient cohort with those in a healthy aged control population. A subset of predicted deleterious variants in novel candidate CPGs was investigated further by examining matched tumor samples, and the functional impact of AXIN1 variants was analyzed in cultured cells. Twenty-two pathogenic/likely pathogenic (P/LP) germline variants detected in 13 CPGs were identified in 19 of 76 patients (25.0%). Unclear association with the diagnosed cancer types was observed in 11 of 19 patients carrying P/LP CPG variants. The burden of rare deleterious germline variants in autosomal dominant CPGs was significantly higher in study patients versus healthy aged controls. A novel AXIN1 frameshift variant (Ser321fs) may impact the regulation of ß-catenin levels. Selection of childhood cancer patients for germline testing based on features suggestive of an underlying genetic predisposition could help to identify carriers of clinically relevant germline CPG variants, and streamline the integration of germline genomic testing in the pediatric oncology clinic.
Subject(s)
Genetic Predisposition to Disease , Germ-Line Mutation/genetics , Neoplasms , Adolescent , Aged , Child , Child, Preschool , Cohort Studies , Genetic Predisposition to Disease/epidemiology , Genetic Predisposition to Disease/genetics , Humans , Infant , Infant, Newborn , Neoplasms/epidemiology , Neoplasms/genetics , Exome SequencingABSTRACT
Symptomatic methotrexate-related central neurotoxicity (MTX neurotoxicity) is a severe toxicity experienced during acute lymphoblastic leukemia (ALL) therapy with potential long-term neurologic complications. Risk factors and long-term outcomes require further study. We conducted a systematic, retrospective review of 1,251 consecutive Australian children enrolled on Berlin-Frankfurt-Münster or Children's Oncology Group-based protocols between 1998-2013. Clinical risk predictors for MTX neurotoxicity were analyzed using regression. A genome-wide association study (GWAS) was performed on 48 cases and 537 controls. The incidence of MTX neurotoxicity was 7.6% (n=95 of 1,251), at a median of 4 months from ALL diagnosis and 8 days after intravenous or intrathecal MTX. Grade 3 elevation of serum aspartate aminotransferase (P=0.005, odds ratio 2.31 [range, 1.28-4.16]) in induction/consolidation was associated with MTX neurotoxicity, after accounting for the only established risk factor, age ≥10 years. Cumulative incidence of CNS relapse was increased in children where intrathecal MTX was omitted following symptomatic MTX neurotoxicity (n=48) compared to where intrathecal MTX was continued throughout therapy (n=1,174) (P=0.047). Five-year central nervous system relapse-free survival was 89.2 4.6% when intrathecal MTX was ceased compared to 95.4 0.6% when intrathecal MTX was continued. Recurrence of MTX neurotoxicity was low (12.9%) for patients whose intrathecal MTX was continued after their first episode. The GWAS identified single-nucletide polymorphism associated with MTX neurotoxicity near genes regulating neuronal growth, neuronal differentiation and cytoskeletal organization (P<1x10-6). In conclusion, increased serum aspartate aminotransferase and age ≥10 years at diagnosis were independent risk factors for MTX neurotoxicity. Our data do not support cessation of intrathecal MTX after a first MTX neurotoxicity event.
Subject(s)
Genome-Wide Association Study , Precursor Cell Lymphoblastic Leukemia-Lymphoma , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Australia , Child , Humans , Injections, Spinal , Methotrexate/therapeutic use , Precursor Cell Lymphoblastic Leukemia-Lymphoma/drug therapy , Precursor Cell Lymphoblastic Leukemia-Lymphoma/genetics , Risk FactorsABSTRACT
We conducted a three-armed trial to assess Cascade, a four-module group videoconferencing cognitive behavior therapy (CBT) intervention for parents of childhood cancer survivors currently aged <18 years. We allocated parents to Cascade, an attention control (peer-support group), or a waitlist. The primary outcome was parents' health-related quality of life (PedsQL-Family Impact/EQ-5D-5L) six months post-intervention. Parents also reported their anxiety/depression, parenting self-agency, fear of recurrence, health service and psychotropic medication use, engagement in productive activities, confidence to use, and actual use of, CBT skills, and their child's quality of life. Seventy-six parents opted in; 56 commenced the trial. Cascade achieved good parent engagement and most Cascade parents were satisfied and reported benefits. Some parents expressed concerns about the time burden and the group format. Most outcomes did not differ across trial arms. Cascade parents felt more confident to use more CBT skills than peer-support and waitlisted parents, but this did not lead to more use of CBT. Cascade parents reported lower psychosocial health scores for their child than waitlisted parents. Cascade parents' health service use, psychotropic medication use, and days engaged in productive activities did not improve, despite some improvements in waitlisted parents. Our trial was difficult to implement, but participants were largely satisfied. Cascade did not improve most outcomes, possibly because many parents were functioning well pre-enrolment. We used these findings to improve Cascade and will trial the new version in future.