The Prognostic Value of Eight Immunohistochemical Markers Expressed in the Tumor Microenvironment and on Hodgkin Reed-Sternberg Cells in Pediatric Patients With Classical Hodgkin Lymphoma

Immunohistochemical markers are associated with treatment outcome in adults with classical Hodgkin Lymphoma (cHL). Studies in children are scarce and inconsistent. We investigated in 67 children with cHL, whether the expression of CD15, CD30, PAX5, PD-1, PD-L1, CD68, CD163 and TARC at diagnosis is associated with disease free survival (DFS) and with interim remission status. Low CD15 and low TARC expression were associated with relapsed disease. Low expression of PD-L1 was associated with complete remission at interim PET-scan. Our data suggest a difference between pediatric and adult cHL. This underlines the importance of future research into specific prognostic factors in pediatric cHL, indispensable for improvement of treatment in this population

Machine Learning Logistic Regression Model for Early Decision Making in Referral of Children with Cervical Lymphadenopathy Suspected of Lymphoma

While cervical lymphadenopathy is common in children, a decision model for detecting high-grade lymphoma is lacking. Previously reported individual lymphoma-predicting factors and multivariate models were not sufficiently discriminative for clinical application. To develop a diagnostic scoring tool, we collected data from all children with cervical lymphadenopathy referred to our national pediatric oncology center within 30 months (n = 182). Thirty-nine putative lymphoma-predictive factors were investigated. The outcome groups were classical Hodgkin lymphoma (cHL), nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL), non-Hodgkin lymphoma (NHL), other malignancies, and a benign group. We integrated the best univariate predicting factors into a multivariate, machine learning model. Logistic regression allocated each variable a weighing factor. The model was tested in a different patient cohort (n = 60). We report a 12-factor diagnostic model with a sensitivity of 95% (95% CI 89–98%) and a specificity of 88% (95% CI 77–94%) for detecting cHL and NHL. Our 12-factor diagnostic scoring model is highly sensitive and specific in detecting high-grade lymphomas in children with cervical lymphadenopathy. It may enable fast referral to a pediatric oncologist in patients with high-grade lymphoma and may reduce the number of referrals and unnecessary invasive procedures in children with benign lymphadenopathy.</p

Acute Activation of Metabolic Syndrome Components in Pediatric Acute Lymphoblastic Leukemia Patients Treated with Dexamethasone

Although dexamethasone is highly effective in the treatment of pediatric acute lymphoblastic leukemia (ALL), it can cause serious metabolic side effects. Because studies regarding the effects of dexamethasone are limited by their small scale, we prospectively studied the direct effects of treating pediatric ALL with dexamethasone administration with respect to activation of components of metabolic syndrome (MetS); in addition, we investigated whether these side effects were correlated with the level of dexamethasone. Fifty pediatric patients (3-16 years of age) with ALL were studied during a 5-day dexamethasone course during the maintenance phase of the Dutch Childhood Oncology Group ALL-10 and ALL-11 protocols. Fasting insulin, glucose, total cholesterol, HDL, LDL, and triglycerides levels were measured at baseline (before the start of dexamethasone; T1) and on the fifth day of treatment (T2). Dexamethasone trough levels were measured at T2. We found that dexamethasone treatment significantly increased the following fasting serum levels (P3.4) from 8% to 85%(P</p

Allogeneic Hematopoietic Stem Cell Transplantation (alloHSCT) Following Blinatumomab-Induced Remission in Pediatric Patients with Relapsed/Refractory (r/r) B-Precursor Acute Lymphoblastic Leukemia (ALL): Preliminary Results from a Phase I/II Stud

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Machine Learning Logistic Regression Model for Early Decision Making in Referral of Children with Cervical Lymphadenopathy Suspected of Lymphoma

While cervical lymphadenopathy is common in children, a decision model for detecting high-grade lymphoma is lacking. Previously reported individual lymphoma-predicting factors and multivariate models were not sufficiently discriminative for clinical application. To develop a diagnostic scoring tool, we collected data from all children with cervical lymphadenopathy referred to our national pediatric oncology center within 30 months (n = 182). Thirty-nine putative lymphoma-predictive factors were investigated. The outcome groups were classical Hodgkin lymphoma (cHL), nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL), non-Hodgkin lymphoma (NHL), other malignancies, and a benign group. We integrated the best univariate predicting factors into a multivariate, machine learning model. Logistic regression allocated each variable a weighing factor. The model was tested in a different patient cohort (n = 60). We report a 12-factor diagnostic model with a sensitivity of 95% (95% CI 89–98%) and a specificity of 88% (95% CI 77–94%) for detecting cHL and NHL. Our 12-factor diagnostic scoring model is highly sensitive and specific in detecting high-grade lymphomas in children with cervical lymphadenopathy. It may enable fast referral to a pediatric oncologist in patients with high-grade lymphoma and may reduce the number of referrals and unnecessary invasive procedures in children with benign lymphadenopathy

High-Throughput Drug Library Screening in Primary KMT2A-Rearranged Infant ALL Cells Favors the Identification of Drug Candidates That Activate P53 Signaling

KMT2A-rearranged acute lymphoblastic leukemia (ALL) in infants (<1 year of age) represents an aggressive type of childhood leukemia characterized by a poor clinical outcome with a survival chance of <50%. Implementing novel therapeutic approaches for these patients is a slow-paced and costly process. Here, we utilized a drug-repurposing strategy to identify potent drugs that could expeditiously be translated into clinical applications. We performed high-throughput screens of various drug libraries, comprising 4191 different (mostly FDA-approved) compounds in primary KMT2A-rearranged infant ALL patient samples (n = 2). The most effective drugs were then tested on non-leukemic whole bone marrow samples (n = 2) to select drugs with a favorable therapeutic index for bone marrow toxicity. The identified agents frequently belonged to several recurrent drug classes, including BCL-2, histone deacetylase, topoisomerase, microtubule, and MDM2/p53 inhibitors, as well as cardiac glycosides and corticosteroids. The in vitro efficacy of these drug classes was successfully validated in additional primary KMT2A-rearranged infant ALL samples (n = 7) and KMT2A-rearranged ALL cell line models (n = 5). Based on literature studies, most of the identified drugs remarkably appeared to lead to activation of p53 signaling. In line with this notion, subsequent experiments showed that forced expression of wild-type p53 in KMT2A-rearranged ALL cells rapidly led to apoptosis induction. We conclude that KMT2A-rearranged infant ALL cells are vulnerable to p53 activation, and that drug-induced p53 activation may represent an essential condition for successful treatment results. Moreover, the present study provides an attractive collection of approved drugs that are highly effective against KMT2A-rearranged infant ALL cells while showing far less toxicity towards non-leukemic bone marrow, urging further (pre)clinical testing

High-Throughput Drug Library Screening in Primary KMT2A-Rearranged Infant ALL Cells Favors the Identification of Drug Candidates That Activate P53 Signaling

KMT2A-rearranged acute lymphoblastic leukemia (ALL) in infants (<1 year of age) represents an aggressive type of childhood leukemia characterized by a poor clinical outcome with a survival chance of <50%. Implementing novel therapeutic approaches for these patients is a slow-paced and costly process. Here, we utilized a drug-repurposing strategy to identify potent drugs that could expeditiously be translated into clinical applications. We performed high-throughput screens of various drug libraries, comprising 4191 different (mostly FDA-approved) compounds in primary KMT2A-rearranged infant ALL patient samples (n = 2). The most effective drugs were then tested on non-leukemic whole bone marrow samples (n = 2) to select drugs with a favorable therapeutic index for bone marrow toxicity. The identified agents frequently belonged to several recurrent drug classes, including BCL-2, histone deacetylase, topoisomerase, microtubule, and MDM2/p53 inhibitors, as well as cardiac glycosides and corticosteroids. The in vitro efficacy of these drug classes was successfully validated in additional primary KMT2A-rearranged infant ALL samples (n = 7) and KMT2A-rearranged ALL cell line models (n = 5). Based on literature studies, most of the identified drugs remarkably appeared to lead to activation of p53 signaling. In line with this notion, subsequent experiments showed that forced expression of wild-type p53 in KMT2A-rearranged ALL cells rapidly led to apoptosis induction. We conclude that KMT2A-rearranged infant ALL cells are vulnerable to p53 activation, and that drug-induced p53 activation may represent an essential condition for successful treatment results. Moreover, the present study provides an attractive collection of approved drugs that are highly effective against KMT2A-rearranged infant ALL cells while showing far less toxicity towards non-leukemic bone marrow, urging further (pre)clinical testing

Is pharmacokinetic-guided dosing of desmopressin and von Willebrand factor-containing concentrates in individuals with von Willebrand disease or low von Willebrand factor reliable and feasible? A protocol for a multicentre, non-randomised, open label cohort trial, the OPTI-CLOT: To WiN study

Introduction Von Willebrand disease (VWD) is a bleeding disorder, caused by a deficiency or defect of von Willebrand factor (VWF). In case of medical procedures or bleeding, patients are treated with desmopressin and/or VWF-containing concentrates to increase plasma VWF and factor VIII (FVIII). However, in many cases these factor levels are outside the targeted range. Therefore, population pharmacokinetic (PK) models have been developed, which aim to quantify and explain intraindividual and interindividual differences in treatment response. These models enable calculation of individual PK parameters by Bayesian analysis, based on an individual desmopressin test or PK profile with a VWF-containing concentrate. Subsequently, the dose necessary for an individual to achieve coagulation factor target levels can be calculated. Methods and analysis Primary aim of this study is to assess the predictive performance (the difference between predicted and measured von VWF activity and FVIII levels) of Bayesian forecasting using the developed population PK models in four different situations: (A) desmopressin testing (n≥30); (B) medical procedures (n=70; 30 receiving desmopressin, 30 receiving VWF-containing concentrate and 10 receiving a combination of both); (C) bleeding episodes (n=20; 10 receiving desmopressin and 10 receiving VWF-containing concentrate) and (D) prophylaxis with a VWF-containing concentrate (n=3 to 5). Individuals with all types of VWD and individuals with low VWF (VWF 0.30-0.60 IU/mL) will be included. Reliability and feasibility of PK-guided dosing will be tested by assessing predictive performance, treatment duration, haemostasis, patient satisfaction and physician satisfaction. Ethics and dissemination The OPTI-CLOT:to WiN study was approved by the medical ethics committee of the Erasmus MC, University Medical Centre Rotterdam, the Netherlands. Results of the study will be communicated through publication in international scientific journals and presentation at (inter)national conferences. Trial registration number NL7212 (NTR7411); Pre-results, EudraCT 2018-001631-46

Bosutinib in Resistant and Intolerant Pediatric Patients With Chronic Phase Chronic Myeloid Leukemia:Results From the Phase I Part of Study ITCC054/COG AAML1921

PURPOSE Bosutinib is approved for adults with chronic myeloid leukemia (CML): 400 mg once daily in newly diagnosed (ND); 500 mg once daily in resistant/intolerant (R/I) patients. Bosutinib has a different tolerability profile than other tyrosine kinase inhibitors (TKIs) and potentially less impact on growth (preclinical data). The primary objective of this first-in-child trial was to determine the recommended phase II dose (RP2D) for pediatric R/I and ND patients. PATIENTS AND METHODS In the phase I part of this international, open-label trial (ClinicalTrials.gov identifier: NCT04258943), children age 1-18 years with R/I (per European LeukemiaNet 2013) Ph+ CML were enrolled using a 6 + 4 design, testing 300, 350, and 400 mg/m2 once daily with food. The RP2D was the dose resulting in 0/6 or 1/10 dose-limiting toxicities (DLTs) during the first cycle and achieving adult target AUC levels for the respective indication. As ND participants were only enrolled in phase II, the ND RP2D was selected based on data from R/I patients. Results Thirty patients were enrolled; 27 were evaluable for DLT: six at 300 mg/m2, 11 at 350 mg/m2 (one DLT), and 10 at 400 mg/m2 (one DLT). The mean AUCs at 300 mg/m2, 350 mg/m2, and 400 mg/m2 were 2.20 g h/mL, 2.52 g h/mL, and 2.66 g h/mL, respectively. The most common adverse event was diarrhea (93%; ≥grade 3: 11%). Seven patients stopped because of intolerance and eight because of insufficient response. Complete cytogenetic and major molecular response to bosutinib appeared comparable with other published phase I/II trials with second-generation TKIs in children. CONCLUSION Bosutinib was safe and effective. The pediatric RP2D was 400 mg/m2 once daily (max 600 mg/d) with food in R/I patients and 300 mg/m2 once daily (max 500 mg/d) with food in ND patients, which achieved targeted exposures as per adult experience.</p