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Umbilical cord blood transplantation (UCBT) has been used to treat malignant and non-malignant diseases. UCBT offers the advantages of easy procurement and acceptable partial HLA mismatches, but also shows delayed hematopoietic and immunological recoveries. We postulated that an intrabone (IB) infusion of cord blood could provide a faster short- and long-term engraftment in a pediatric population with malignant and non-malignant hematologic diseases. We conducted this phase I-II single arm, exploratory clinical trial (NCT01711788) from 2012 to 2016 in a single center. Fifteen patients aged from 1.9 to 16.4 years received an IB UCBT. Median time to neutrophils and platelet recoveries were 18 days (range: 13-36 days) and 42 days (range: 26-107 days), respectively. Rate of severe acute GVH grade was low, with only one patient with grade III aGVH. Relapse occurred in 5 patients (38.5%) and TRM occurred in 1 patient. This leads to 6 years EFS and OS of 66.7% and 80% respectively. In conclusion, IB UCBT is safe and well-tolerated in children and hematological recovery compared similarly to the results obtained with IV UCBT.

Importance Prompt recognition of a child with a cancer predisposition syndrome (CPS) has implications for cancer management, surveillance, genetic counseling, and cascade testing of relatives. Diagnosis of CPS requires practitioner expertise, access to genetic testing, and test result interpretation. This diagnostic process is not accessible in all institutions worldwide, leading to missed CPS diagnoses. Advances in electronic health technology can facilitate CPS risk assessment. Objective To evaluate the diagnostic accuracy of a CPS prediction tool (McGill Interactive Pediatric OncoGenetic Guidelines [MIPOGG]) in identifying children with cancer who have a low or high likelihood of having a CPS. Design, Setting, and Participants In this international, multicenter diagnostic accuracy study, 1071 pediatric (

BACKGROUND Plexiform neurofibromas (PN) are observed in up to 50% of patients with neurofibromatosis type 1 (NF1). Trametinib has been used widely to treat PN but limited data has been reported on its efficacy within a clinical trial. METHODS This ongoing multicenter phase II trial includes patients with pediatric low-grade glioma and PN. Patients received daily oral trametinib (MEK inhibitor) for eighteen 28-day cycles. The volumes of PN were centrally quantified using a new semi-automatic 3D segmentation method. RESULTS As of May 15, 2022, 46 patients with PN were enrolled in the study and the recruitment was completed for this study arm. Thirty-four completed treatment and were available for analysis. For these patients, the median age was 10.5 years (range 0.7-19.8). The median volume of PN at baseline was 51cm3 (range 2.6 to 487.6). Among the 34 patients, 28 (82.4%) completed 18 cycles as planned. Two patients discontinued due to adverse reaction, three patients refused to continue treatment and one patient discontinued treatment based on physician decision. Median duration of treatment was 16.8 months (range 2.8 to 16.8). Median duration of follow-up was 30.4 months (range 8.2 to 42). A total of 38 PN were available for volumetric analysis. Using RECIST evaluation, the overall response rate was 13.1%. Volumetric assessment demonstrated an overall response rate of 64.7% (22/34 patients), and 65.8% (25/38 PN) of PN showed a decrease of more than 20% in volume. Median volume change was -30% (range -93.5 to 14.3). Thirty-one patients (91.1%) had durable response without progression (lasting ≥ 1 year). After discontinuation of treatment, one patient underwent surgery and three patients resumed MEK inhibitor. CONCLUSION We report outcome and volumetric quantification of PN treated with trametinib within a large clinical trial. Based on the current results, trametinib is effective and offers durable response.

Over the past decades, survival of patients with acute lymphoblastic leukemia (ALL) has dramatically improved, but the subgroup of patients with relapsed/refractory ALL still continues to have dismal prognosis. As an emerging therapeutic approach, chimeric antigen receptor-modified T-cells (CAR-T) represent one of the few practice-changing therapies for this subgroup of patients. Originally conceived and built in Philadelphia (University of Pennsylvania), CTL019 or tisagenlecleucel, the first CAR-T approved by the US Food and Drug Administration, showed impressive results in refractory/relapsed ALL since the publication on two pediatric patients in 2013. It is in this context that we provide a review of this product in terms of manufacturing, pharmacology, toxicity, and efficacy studies. Evaluation and management of toxicities, particularly cytokine release syndrome and neurotoxicity, is recognized as an essential part of the patient treatment with broader use of IL-6 receptor inhibitor. An under-assessed aspect, the quality of life of patients entering CAR-T cells treatment, will also be reviewed. By their unique nature, CAR-T cells such as tisagenlecleucel operate in a different way than typical drugs, but also provide unique hope for B-cell malignancies.

BACKGROUND Pediatric low-grade gliomas (PLGG) are the most frequent brain tumors in children. It is known that the majority of PLGG have activation of the MAPK/ERK pathway. METHODS This ongoing multicenter phase II trial includes three progressing/refractory PLGG groups: NF1 patients, KIAA1549-BRAF fusion patients and patients with other activation of the MAPK/ERK pathway (excluding V600E). The primary objective was to evaluate the overall response rate based on RANO criteria after daily oral trametinib administration for 18 cycles, lasting 28 days each. Secondary objectives include the assessment of progression-free survival, tolerability of trametinib, serum levels of trametinib and quality of life evaluation during treatment. RESULTS As of February 12 2021, 50 patients have been enrolled (NF1: n=10; KIAA1549-BRAF fusion: n=31; other: n=9 including 5 patients with FGFR1 alterations). Median age is 8.8 years (range 2.4-25.5). Median follow-up is 17.5 months (range 4.7-28.5). Forty-three patients are evaluable. The overall response includes: 4 partial response (PR) (9%), 18 minor response (MR) (42%), 17 stable disease (40%), 4 progressive disease (9%). Median time to response is 5.5 months (range 2.4-13.8). Median duration of response is 6.1 months (range 0.6-26.5). Progression free survival at 12 months is 79.9% (95% CI 68.5-93.6%) and median progression free survival has not yet been reached. Treatment was discontinued for 30 patients: 16 after completing 18 cycles as planned, 5 for progressive disease, 5 for adverse events, 4 for other reasons. A total of 8 patients progressed after discontinuation of treatment including 6 patients (37.5%) that completed 18 cycles. Five of these patients had achieved minor response prior to discontinuation. CONCLUSION Trametinib is a potentially effective targeted therapy for patients with recurrent/refractory PLGG. Treatment was overall well tolerated. This ongoing trial will continue to gather data on response rate, duration of response and safety of trametinib for PLGG.

Background New rescue regimens are needed for pediatric refractory/recurrent low-grade glioma. Nilotinib is a tyrosine kinase inhibitor that has potential synergistic effects with vinblastine on angiogenesis, tumor cell growth, and immunomodulation. Methods This phase I trial aimed to determine the recommended doses of this combination for phase II trials (RP2D) using the dual-agent Bayesian continual reassessment method. Nilotinib was given orally twice daily (BID) in combination with once-weekly vinblastine injections for a maximum of 12 cycles of 28 days (clinicaltrials.gov, NCT01884922). Results Thirty-five pediatric patients were enrolled across 4 dose levels. The median age was 7 years and 10 had neurofibromatosis type 1. Patients had received a median of 3 prior treatment lines and 25% had received more than 4 previous treatment lines. Dose-limiting toxicity (DLT) during cycle 1 was hematologic, dermatologic, and cardiovascular. The RP2D was identified at 3 mg/m2 weekly for vinblastine with 230 mg/m2 BID for nilotinib (estimated probability of DLT = 18%; 95% credibility interval, 7–29%). Fifteen patients completed the 12 cycles; 2 stopped therapy prematurely due to toxicity and 18 due to disease progression. Three patients achieved a partial response leading to an objective response rate of 8.8% (95% confidence interval [CI], 1.9–23.7), and the disease control rate was 85.3% (95% CI, 68.9–95.1). The 12-month progression-free survival was 37.1% (95% CI, 23.2–53.67). Conclusions Vinblastine and nilotinib combination was mostly limited by myelosuppression and dermatologic toxicity. The efficacy of the combination at the RP2D is currently evaluated in a randomized phase II trial comparing this regimen to vinblastine alone.

Importance Little progress in pediatric cancer treatment has been noted in the past decade, urging the development of novel therapeutic strategies for adolescents and children with hard-to-treat cancers. Use of comprehensive molecular profiling in the clinical management of children and adolescents with cancer appears a suitable approach to improve patient care and outcomes, particularly for hard-to-treat cases. Objective To assess the feasibility of identifying potentially actionable mutations using next-generation sequencing–based assays in a clinically relevant time frame. Design, Setting, and Participants This diagnostic study reports the results of the TRICEPS study, a prospective genome sequencing study conducted in Quebec, Canada. Participants, aged 18 years or younger at diagnosis, with refractory or relapsed childhood and adolescent cancers were enrolled from April 2014 through January 2018. Whole-exome sequencing (WES) of matched tumor normal samples and RNA sequencing of tumor were performed to identify single-nucleotide variants, fusion transcripts, differential gene expression, and copy number alterations. Results reviewed by a team of experts were further annotated, synthesized into a report, and subsequently discussed in a multidisciplinary molecular tumor board. Main Outcomes and Measures Molecular profiling of pediatric patients with hard-to-treat cancer, identification of actionable and targetable alteration needed for the management of these patients, and proposition of targeted and personalized novel therapeutic strategies. Results A total of 84 patients with hard-to-treat cancers were included in the analysis. These patients had a mean (range) age of 10.1 (1-21) years and a similar proportion of male (45 [54%]) and female (39 [46%]). Sixty-two patients (74%) had suitable tissues for multimodal molecular profiling (WES and RNA sequencing). The process from DNA or RNA isolation to genomic sequencing and data analysis steps took a median (range) of 24 (4-41) days. Potentially actionable alterations were identified in 54 of 62 patients (87%). Actions were taken in 22 of 54 patients (41%), and 18 (33%) either were on a second or third line of treatment, were in remission, or had stable disease and thus no actions were taken. Conclusions and Relevance Incorporating genomic sequencing into the management of hard-to-treat childhood and adolescent cancers appeared feasible; molecular profiling may enable the identification of potentially actionable alterations with clinical implications for most patients, including targeted therapy and clinically relevant information of diagnostic, prognostic, and monitoring significance.

Transition from medical school to residency is stressful due to new responsibilities in patient care. OBJECTIVE: To evaluate a new immersion curriculum on the transition from medical school to paediatric residency and its implications for future use in paediatric education. METHODS: In July 2013, a month-rotation offering one-third of time for clinical rounds and two-thirds of time for formal courses was conducted for postgraduate year 1 residents beginning paediatric residency training. Surveys were administered to residents before and after this rotation about their self-confidence in several paediatrics topics and abilities. RESULTS: Eleven junior residents were enrolled (100% participation rate). Among this cohort, pre- and postintervention confidence surveys showed differences for neonatalogy (P

Background: A high rate of prescription errors exists in pediatric teaching hospitals, especially during initial training. Objectives: To determine the effectiveness of a two-hour lecture by a pharmacist on rates of prescription errors and quality of prescriptions. Methods: A two-hour lecture led by a pharmacist was provided to 11 junior pediatric residents (PGY-1) as part of a one-month immersion program. A control group included 15 residents without the intervention. We reviewed charts to analyze the first 50 prescriptions of each resident. Results : Data were collected from 1300 prescriptions involving 451 patients, 550 in the intervention group and 750 in the control group. The rate of prescription errors in the intervention group was 9.6% compared to 11.3% in the control group (p=0.32), affecting 106 patients. Statistically significant differences between both groups were prescriptions with unwritten doses (p=0.01) and errors involving overdosing (p=0.04). We identified many errors as well as issues surrounding quality of prescriptions. Conclusion: We found a 10.6% prescription error rate. This two-hour lecture seems insufficient to reduce prescription errors among junior pediatric residents. This study highlights the most frequent types of errors and prescription quality issues that should be targeted by future educational interventions.

Background Germline pathogenic variants in SDHB/SDHC/SDHD are the most frequent causes of inherited phaeochromocytomas/paragangliomas. Insufficient information regarding penetrance and phenotypic variability hinders optimum management of mutation carriers. We estimate penetrance for symptomatic tumours and elucidate genotype–phenotype correlations in a large cohort of SDHB/SDHC/SDHD mutation carriers. Methods A retrospective survey of 1832 individuals referred for genetic testing due to a personal or family history of phaeochromocytoma/paraganglioma. 876 patients (401 previously reported) had a germline mutation in SDHB/SDHC/SDHD (n=673/43/160). Tumour risks were correlated with in silico structural prediction analyses. Results Tumour risks analysis provided novel penetrance estimates and genotype–phenotype correlations. In addition to tumour type susceptibility differences for individual genes, we confirmed that the SDHD:p.Pro81Leu mutation has a distinct phenotype and identified increased age-related tumour risks with highly destabilising SDHB missense mutations. By Kaplan-Meier analysis, the penetrance (cumulative risk of clinically apparent tumours) in SDHB and (paternally inherited) SDHD mutation-positive non-probands (n=371/67 with detailed clinical information) by age 60 years was 21.8% (95% CI 15.2% to 27.9%) and 43.2% (95% CI 25.4% to 56.7%), respectively. Risk of malignant disease at age 60 years in non-proband SDHB mutation carriers was 4.2%(95% CI 1.1% to 7.2%). With retrospective cohort analysis to adjust for ascertainment, cumulative tumour risks for SDHB mutation carriers at ages 60 years and 80 years were 23.9% (95% CI 20.9% to 27.4%) and 30.6% (95% CI 26.8% to 34.7%). Conclusions Overall risks of clinically apparent tumours for SDHB mutation carriers are substantially lower than initially estimated and will improve counselling of affected families. Specific genotype–tumour risk associations provides a basis for novel investigative strategies into succinate dehydrogenase-related mechanisms of tumourigenesis and the development of personalised management for SDHB/SDHC/SDHD mutation carriers.

Introduction: During recent decades, the prognosis of childhood acute lymphoblastic leukemia (ALL) has improved dramatically, nowadays, reaching a cure rate of almost 90%. These results are due to a better management and combination of old therapies, refined risk-group stratification and emergence of minimal residual disease (MRD) combined with treatment’s intensification for high-risk subgroups. However, the subgroup of patients with refractory/relapsed ALL still presents a dismal prognosis indicating necessity for innovative therapeutic approaches.Areas covered: We performed an exhaustive review of current first-line therapies for childhood ALL in the worldwide main consortia, summarized the major advances for front-line and relapse treatment and highlighted recent and promising innovative therapies with an overview of the most promising ongoing clinical trials.Expert opinion: Two major avenues marked the beginning of 21st century. First, is the introduction of tyrosine-kinase inhibitor coupled ...

Childhood cancer is a group of heterogeneous complex diseases. Although 80% of these children are cured with conventional therapies, it remains the first cause of death among children in Western countries. A significant number of refractory/relapse patients will eventually succumb to their disease and the lack of therapeutic advances for these patients is even more worrisome. Indeed, no significant progress has been noted over the last decade for these patients, urging the need for new and more effective therapeutic approaches. Precision medicine and more effective personalized targeted therapies (PTT) are a major breakthrough leading to increased cure rates and decreased treatment-related morbidity and mortality for the patients with refractory or relapsed tumors. To address this challenge, the TRICEPS study was initiated on April 2014 at the Sainte-Justine UHC (Montreal, Canada) with an overreaching goal to explore the feasibility of performing genomic-driven targeted therapy in pediatric and adolescent (aged 0-21 years) patients with relapsed or refractory childhood cancer. This study offers in-depth genomic and transcriptomic investigation of patient’s tumoral material to identify patient-specific alterations and actionable driver mutation(s) that can be targeted with approved targeted drug and within a reasonable clinically relevant timeframe to assess the feasibility of going from biopsy to a detailed tumor analysis report. Over a period of 30 months, 44 relapsed/refractory cancer patients were recruited. Twenty-two of them underwent extensive genomic investigation (exomic and transcriptomic sequencing) within a median timeframe of 9.7 weeks from patient enrolment to return of results. Patient screen failures occurred due to benign/necrotic tumor biopsies or low tumor purity resulting in suboptimal DNA/RNA quantity or quality for genomic analysis. In all 22 patients, we have identified clinically relevant genomic alterations (SNVs, indels, fusions, CNAs) and relapse-specific mutations influencing patient management and providing options for personalized interventions. We assessed the functional impact of some of these cancer-specific alterations. This was the case of a novel relapse-specific rearrangement, identified on relapsed childhood ETP-ALL, and leading to asparagine synthetase (ASNS) up-regulation through a promoter exchange. The expression of this fusion was associated with reduced apoptosis following l-asparaginase treatment. This study shows that PPT based on next generation sequencing technology is a powerful approach that could be implemented in the clinic within a foreseeable future to guide treatment of hard-to-treat childhood cancers and to further improve patient care and outcomes. Citation Format: Fida Khater, Stephanie Vairy, Sylvie Langlois, Jasmine Healy, Sophie Dumoucel, Mathieu Lajoie, Thomas Sontag, Pascal St-Onge, Henrique Bittencourt, Dorothée Dal Soglio, Anne-Sophie Carret, Sonia Cellot, Josette Champagne, Michel Duval, Maja Krajinovic, Jean-Marie Leclerc, Valerie Larouche, Natalie Patey, Sébastien Perreault, Nelson Piché, Yvan Samson, Pierre Teira, Monia Marzouki, Daniel Sinnett. Identification of actionable targets for refractory/relapsed childhood cancer leading to personalized targeted therapy (TRICEPS Study) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4885. doi:10.1158/1538-7445.AM2017-4885