Paediatric strategy forum for medicinal product development of PI3-K, mTOR, AKT and GSK3ß inhibitors in children and adolescents with cancer.

Phosphatidylinositol 3-kinase (PI3-K) signalling pathway is a crucial path in cancer for cell survival and thus represents an intriguing target for new paediatric anti-cancer drugs. However, the unique clinical toxicities of targeting this pathway (resulting in hyperglycaemia) difficulties combining with chemotherapy, rarity of mutations in childhood tumours and concomitant mutations have resulted in major barriers to clinical translation of these inhibitors in treating both adults and children. Mutations in PIK3CA predict response to PI3-K inhibitors in adult cancers. The same mutations occur in children as in adults, but they are significantly less frequent in paediatrics. In children, high-grade gliomas, especially diffuse midline gliomas (DMG), have the highest incidence of PIK3CA mutations. New mutation-specific PI3-K inhibitors reduce toxicity from on-target PI3-Kα wild-type activity. The mTOR inhibitor everolimus is approved for subependymal giant cell astrocytomas. In paediatric cancers, mTOR inhibitors have been predominantly evaluated by academia, without an overall strategy, in empiric, mutation-agnostic clinical trials with very low response rates to monotherapy. Therefore, future trials of single agent or combination strategies of mTOR inhibitors in childhood cancer should be supported by very strong biological rationale and preclinical data. Further preclinical evaluation of glycogen synthase kinase-3 beta inhibitors is required. Similarly, even where there is an AKT mutation (∼0.1 %), the role of AKT inhibitors in paediatric cancers remains unclear. Patient advocates strongly urged analysing and conserving data from every child participating in a clinical trial. A priority is to evaluate mutation-specific, central nervous system-penetrant PI3-K inhibitors in children with DMG in a rational biological combination. The choice of combination, should be based on the genomic landscape e.g. PTEN loss and resistance mechanisms supported by preclinical data. However, in view of the very rare populations involved, innovative regulatory approaches are needed to generate data for an indication.

Standard Venipuncture vs a Capillary Blood Collection Device for the Prospective Determination of Abnormal Liver Chemistry.

BACKGROUND: Abnormal liver function is a common manifestation of human disease and may also occur in approved and investigational medications as drug-induced liver injury (DILI). Capillary blood collection devices may allow for more frequent and convenient measurement outside of the clinic. Validation of such approaches is lacking. METHODS: This prospective, biospecimens collection study evaluated the Tasso+ in patients with abnormal liver tests (NCT05259618). The primary objective was to define the concordance of alanine aminotransferase (ALT) obtained via Tasso+ compared to standard venipuncture. Secondary objectives included measurement of 14 other analytes and patient surveys. At the time of venipuncture, 2 Tasso+ samples were collected: one was centrifuged and shipped, and the other was refrigerated and shipped as whole blood. RESULTS: Thirty-six patients with elevated ALT values were enrolled. In total, 100 venipuncture, 50 Tasso+ centrifuged, and 48 Tasso+ whole blood samples were obtained. Tasso+ centrifuged samples demonstrated concordance correlation coefficients (CCC) of >0.99 for ALT, alkaline phosphatase (ALP), aspartate aminotransferase (AST), and total bilirubin and CCC >0.95 for albumin, chloride, enzymatic creatinine, serum glucose, magnesium, and phosphorus. Tasso+ whole blood showed CCC of >0.99 for AST, bilirubin total, and enzymatic creatinine and CCC >0.95 for ALT, ALP, albumin, magnesium, and phosphorus. Hemolysis was comparable across the 3 sample types, but its impact was reflected in the Tasso+ potassium data. Patient feedback indicated a very favorable patient experience. CONCLUSIONS: The capillary blood collection device, Tasso+, showed substantial to almost perfect concordance to standard venipuncture for measurement of abnormal liver function. Studies are ongoing to validate longitudinal sampling outside of the clinic. Clinicaltrials.gov Registration Number: NCT05259618.

Toward a Treatment Sequencing Strategy: A Systematic Review of Treatment Regimens in Advanced Gastric Cancer/Gastroesophageal Junction Adenocarcinoma.

BACKGROUND: Platinum and fluoropyrimidine combinations typically comprise first-line (1L) therapy in advanced gastric cancer or gastroesophageal junction adenocarcinoma (G/GEA), although controversy exists regarding the use of 5doublet versus triplet cytotoxic regimens. Historically, second-line (2L) and third-line or later (3L+) therapy has been fragmented. Recent trials have increased the need for optimal treatment sequencing in advanced G/GEA. MATERIALS AND METHODS: We conducted a systematic search of peer-reviewed manuscripts of randomized clinical trials examining 1L, 2L, and 3L+ therapy for advanced G/GEA published from 2009 through November 19, 2019. When available, overall survival, progression-free survival, time to progression, overall response rate, and toxicity were extracted from each and compared descriptively. RESULTS: In 1L therapy, chemotherapy triplets demonstrated variable efficacy improvements with invariable increased toxicity compared with platinum/fluoropyrimidine doublets. Currently, the only published report of positive outcomes using biologics in 1L describes adding trastuzumab in HER2-overexpressing advanced G/GEA. In 2L, doublet chemotherapy regimens are not uniformly more efficacious than single-agent taxanes or irinotecan, and ramucirumab has demonstrated improved outcomes both as monotherapy and in combination. CONCLUSION: For advanced G/GEA, review of trial results from 2009-2019 support 1L therapy with platinum and fluoropyrimidine and sequencing with taxanes or irinotecan in combination with biologics as effective 2L options. Escalating to a triplet may add some efficacy at the expense of added toxicity. IMPLICATIONS FOR PRACTICE: The rapidly changing treatment landscape for advanced gastric cancer includes increasing options for refractory disease. With multiple first-line platinum-based regimens, identification of those with the best benefit-to-risk ratio may provide guidance on treatment sequencing strategies. This article presents findings from the published literature of randomized controlled trials that included a first-line platinum/fluoropyrimidine combination and, for second-line trials, patients with platinum/fluoropyrimidine-refractory disease. This guiding summary could be a tool for clinicians to identify the optimal first-line regimen(s) followed by a strategy for subsequent regimens.

Early Weight Loss as a Prognostic Factor in Patients with Advanced Gastric Cancer: Analyses from REGARD, RAINBOW, and RAINFALL Phase III Studies.

BACKGROUND: Weight loss is common in advanced gastric and gastroesophageal junction adenocarcinoma (G/GEA); however, the prognostic implications of weight loss during the first cycle (C1) of chemotherapy remain poorly characterized. In this study, we investigated the impact of early weight loss during systemic treatment as a potential prognostic factor for overall survival (OS) in patients with advanced G/GEA. MATERIALS AND METHODS: We performed a post hoc analysis of three phase III studies of ramucirumab. Patients were categorized into two groups: weight loss of ≥3% and <3% based on weight change during C1 (3-4 weeks) of treatment. OS by weight groups was assessed for each study and as a pooled meta-analysis. The effect of C1 weight change on patient survival was evaluated using univariate and multivariate Cox models. RESULTS: A total of 1,464 patients with weight data at the end of C1 were analyzed: REGARD (n = 311), RAINBOW (n = 591), and RAINFALL (n = 562). For all three studies, there were fewer patients in the weight loss ≥3% than <3% group. OS was numerically shorter for patients with weight loss of ≥3% than for patients with weight loss of <3% during C1 irrespective of treatment arm. Similar treatment independent effects of early weight loss on OS were observed in the meta-analysis. Overall, early weight loss ≥3% was associated with shorter survival in patients receiving active drug as well as placebo/best supportive care. CONCLUSION: This large post hoc analysis demonstrated that weight loss of ≥3% during C1 was a negative prognostic factor for OS in patients with advanced G/GEA. IMPLICATIONS FOR PRACTICE: This comprehensive analysis examining early weight loss during systemic treatment as a predictor of survival outcomes in patients with advanced gastric and gastroesophageal junction adenocarcinoma (G/GEA) includes a large sample size, reliable on-treatment data reported in well-conducted phase III clinical trials, and global representation of cancer patients with advanced G/GEA. Understanding the impact of on-treatment weight loss is clinically relevant and may represent an opportunity for targeted interventions.

Characterization of Dronabinol Usage in a Pediatric Oncology Population.

OBJECTIVES: Chemotherapy-induced nausea and vomiting (CINV) remains an important side effect associated with administration of chemotherapy in pediatrics. The aim of this study was to retrospectively review dronabinol use in a pediatric cancer center, with the intent of characterizing its use and identifying trends such as age, sex, diagnosis, and chemotherapy that describe where dronabinol is best used as an adjuvant antiemetic. METHODS: Patients receiving dronabinol at Riley Hospital for Children between 2000 and 2010 were identified. Patients eligible for inclusion were those with malignancy ≤18 years old, who received at least 1 dose of dronabinol for CINV during admission. RESULTS: Ninety-five percent of patients received moderate or highly emetogenic chemotherapy. When dronabinol doses were analyzed, 95% of patients received doses that were lower than reference guidelines, 55% received dronabinol as a scheduled medication, and 19% received dronabinol 1 to 3 hours before chemotherapy. Overall, 60% of patients had a defined positive response to dronabinol. Sixty-five percent of patients received repeat courses of dronabinol, and 62% received outpatient prescriptions for dronabinol. CONCLUSIONS: Dronabinol appears to be a viable option as an adjuvant antiemetic in pediatric CINV, but a prospective trial using patients as their own controls is necessary to truly define dronabinol's place in therapy.

Clinical course of postthrombotic syndrome in children with history of venous thromboembolism.

Postthrombotic syndrome (PTS) is a chronic morbidity of venous thromboembolism (VTE) in children. Information about the evolution of PTS is lacking in children. Present study was aimed to evaluate the time-course of extremity PTS in children who were serially followed in a hematology clinic. This retrospective cohort study included 69 consecutive children with documented VTEs that presented with symptoms of extremity VTE: 67 extremity VTEs with or without extension to vena cava, 2 inferior vena cava VTEs. Severity of PTS was assessed using modified Villalta scale. Median age of the cohort was 12.6 years (interquartile range 1.6-15 years) while median follow-up was 28.7 months (interquartile range 13.3-33.4 months. PTS prevalence was 46.8% [95% confidence interval (CI) 37.9-57.7%]. Lower extremity VTE was associated with development of PTS compared to upper extremity VTE regardless of catheter use (P = 0.002). The time-course of PTS fluctuated in 11 of 33 children (33%; 95% CI 20-47%) at a median interval of 12 months from diagnosis of VTE (range 4-14 months): three progressed from mild/moderate to severe, one improved from moderate to mild, seven fluctuated between mild and moderate. Recurrence and incomplete resolution of VTE were associated with variability in PTS severity (P < 0.05). In summary, this study suggested that almost 50% of study cohort developed PTS, and the time-course of PTS was not static in one third of children. Future research should focus on identifying the predictors contributing to the worsening of PTS and developing risk-stratified treatment interventions so as to improve the outcome of children with VTE.

Hyperphosphatemia in pediatric oncology patients receiving liposomal amphotericin B.

OBJECTIVE: After transitioning our front-line amphotericin product to the liposomal formulation, we observed an increased incidence of hyperphosphatemia. We aimed to determine the incidence of hyperphosphatemia in children with oncologic disorders receiving an amphotericin B product and to establish whether the incidence varies depending on amphotericin formulation. METHODS: This retrospective review of the medical record was conducted at a tertiary, free standing children's hospital. Pharmacy data revealed 159 patients receiving an amphotericin product between November 2006 and December 2008. Doses of amphotericin, serum phosphorous, calcium and creatinine concentrations were recorded at daily time points during the 10 days following both initiation and discontinuation of amphotericin. Administration of phosphate binders and total parenteral nutrition was noted. The incidence of hyperphosphatemia, defined as a serum value greater than the age-adjusted upper limit of normal, was compared among the amphotericin groups. RESULTS: One hundred thirty-nine amphotericin recipients had a serum phosphorus measurement during amphotericin therapy. Final analysis included 117 children, of which 64 (55%) were oncology patients. Deoxycholate (mean maximum dose 1 mg/kg), lipid complex (mean maximum dose 4.8 mg/kg) and liposomal amphotericin (mean maximum dose 4.9 mg/kg) were used in 24 (20.5%), 37 (31.6%) and 56 (47.9%) of all patients, respectively. Hyperphosphatemia developed in 27% (32/117) of all patients, and in 33% (21/64) of oncology patients. Similar to within all recipients, among oncology patients, 45% (n=18) of liposomal recipients demonstrated hyperphosphatemia compared to 13% of those receiving lipid complex (n=3, p=0.007). No oncology patient received deoxycholate. CONCLUSION: Nearly 45% of children with oncologic disorders receiving liposomal amphotericin developed hyperphosphatemia. The incidence is significantly greater for the liposomal formulation than either of the other amphotericin formulations.

Central nervous system involvement at the time of presentation in acute promyelocytic leukemia.

Central nervous system (CNS) involvement is rarely observed in acute promyelocytic leukemia (APML). Most cases of CNS involvement occur at relapse rather than at presentation. Because of the extremely low incidence of CNS disease, diagnostic lumbar puncture is not routinely required and prophylactic intrathecal chemotherapy is not routinely administered. Here, we describe a teenage patient with newly diagnosed APML, chloromas, and symptomatic CNS involvement confirmed by MRI and cerebrospinal fluid (CSF) findings.

Inclusion of parents in pediatric subspecialty team rounds: attitudes of the family and medical team.

The importance of the family's involvement in caring for children with cancer is as tremendous as the need to successfully educate our medical students and residents about the value of effective communication and family-centered care. This article presents a model of change undertaken by one large pediatric cancer center to improve family-centered care. The author describes how the inclusion of families in sit-down medical team rounds influenced family, medical trainee, and attending physician satisfaction. Despite initial reluctance from the medical team and early challenges, this model was found to be successful and to have improved the standard of care.Each morning, patients' families were given the opportunity to sign up to attend sit-down team rounds while their child's case was discussed. Participation was voluntary, and parents could ask questions and offer input. Together, the student, resident, fellow, family member, and attending formulated the treatment plan for that day.Family and trainee participants were surveyed for their opinions of the new style of rounds. Family satisfaction was unanimously improved. Medical trainees reported mixed opinions. Families reported increased feelings of inclusion, respect, and having a better understanding of their child's care. Trainees recognized the value in patient care and family satisfaction, but some doubted the benefit to their own training. Details of this change, including challenges faced, as well as the descriptive survey results of both the families and medical trainees, are discussed.

Recombinant Factor VIIa for Bleeding in Non-hemophiliac Pediatric Patients.

OBJECTIVE: To evaluate the use of recombinant factor VIIa (rFVIIa) for the treatment of bleeding in nonhemophiliac children. METHODS: This was a retrospective chart review of all patients < 18 years of age who received rFVIIa over a 2 year period. RESULTS: Twenty-four pediatric patients received a total of 240 doses of rFVIIa for treatment of bleeding. Recombinant factor VIIa was effective in achieving bleeding resolution in 54% of patients. The mean age of patients in the bleeding non-resolution versus resolution group was 50% younger (5.5 vs. 10.3 years, P = 0.104). CONCLUSIONS: Bleeding resolution can be achieved with recombinant factor VIIa using similar doses to those recommended for children with hemophilia. Widespread use of rFVIIa for bleeding in children without hemophilia is not warranted given this efficacy data. Further safety studies are needed with rFVIIa in this population to clarify thrombotic risks.

Predicting asparaginase-associated pancreatitis.

BACKGROUND: Pancreatitis is a well-known, but little-understood complication of asparaginase. There is no predictor of who will develop asparaginase-associated pancreatitis (AAP). To better define this population, we present a retrospective analysis regarding AAP and provide a review of the relevant literature. METHODS: We systematically reviewed medical records of 254 asparaginase recipients during a 5-year period. Pancreatitis was defined and graded according to CTCAE v3.0. RESULTS: Pancreatitis was diagnosed in 48 (19%) patients. Thirty-three (13%) patients were identified as having AAP. Twelve cases occurred after Escherichia coli asparaginase and 20 followed PEG-asparaginase. Pancreatitis was independent of the individual or cumulative asparaginase dose. The interval to pancreatitis diagnosis was longer for PEG-asparaginase than E. coli asparaginase (P = 0.02). AAP was seen more frequently in patients receiving prednisone (P = 0.02) and daunomycin (P = 0.006) while less frequent with dexamethasone (P = 0.04). Other chemotherapy agents appeared to have no association with AAP. As observed by others, those with pancreatitis were older (P = 0.001), but the significance of this remains uncertain. CONCLUSIONS: This study emphasizes our inability to predict who will develop pancreatic toxicity from asparaginase and suggests that those at risk might have an unidentified genetic predisposition.

Lepirudin anticoagulation for heparin-induced thrombocytopenia after cardiac surgery in a pediatric patient.

A 21-month-old boy received anticoagulation with lepirudin for heparin-induced thrombocytopenia (HIT) after undergoing cardiac surgery and receiving extracorporeal membrane oxygenation (ECMO). This report illustrates the significance of HIT in pediatric patients after cardiac surgery and the successful administration of lepirudin in this setting. To our knowledge, this is the first published report of lepirudin administered to treat HIT in a child after cardiac surgery and ECMO. Although guidelines exist that suggest the potential administration of lepirudin as treatment for children with HIT, further studies are needed to determine the safest yet most effective dosage for this population.