Recording diagnostic conversations for communication research purposes in pediatric leukemia.

Recordings of patient-doctor interactions is a recommended method in communication research. However, concerns are expressed regarding audio-recording of conversations with vulnerable patients. Our study examined experiences of children, parents, and oncologists with recording diagnostic conversations in the pediatric acute leukemia setting.

Mutational mechanisms in multiply relapsed pediatric acute lymphoblastic leukemia.

Pediatric acute lymphoblastic leukemia (ALL) is marked by low mutational load at initial diagnosis, which increases at relapse. To determine which processes are active in (relapsed) ALL and how they behave during disease progression before and after therapy, we performed whole genome sequencing on 97 tumor samples of 29 multiply relapsed ALL patients. Mutational load increased upon relapse in 28 patients and upon every subsequent relapse in 22 patients.

Increased risk of subsequent neoplasm after hematopoietic stem cell transplantation in 5-year survivors of childhood acute lymphoblastic leukemia.

Acute lymphoblastic leukemia (ALL) survivors are at risk for developing subsequent neoplasms, but there is limited information on long-term risks and risk factors for both subsequent malignant neoplasms (SMNs) and subsequent non-malignant neoplasms (SNMNs). We analyzed long-term risk and risk factors for SMNs and SNMNs among 3291 5-year ALL survivors from the Dutch Childhood Cancer Survivor Study-LATER cohort (1963-2014). We calculated standardized incidence ratios (SIRs) and cumulative incidences and used multivariable Cox proportional hazard regression analyses for analyzing risk factors.

gene deletions drive resistance to cytarabine in B-cell precursor acute lymphoblastic leukemia.

IKZF1 deletions occur in 10-15% of patients with B-cell precursor acute lymphoblastic leukemia (BCP-ALL) and predict a poor outcome. However, the impact of IKZF1 loss on sensitivity to drugs used in contemporary treatment protocols has remained underexplored. Here we show in experimental models and in patients that loss of IKZF1 promotes resistance to cytarabine (AraC), a key component of both upfront and relapsed treatment protocols.

Continuous PEGasparaginase Dosing Reduces Hypersensitivity Reactions in Pediatric ALL: A Dutch Childhood Oncology Group ALL11 Randomized Trial.

Purpose: The primary objective of this randomized study was to determine whether a continuous dosing schedule (without the asparaginase-free interval) would result in less hypersensitivity reactions to PEGasparaginase (PEGasp) compared with the standard noncontinuous dosing schedule.

Methods: Eight hundred eighteen patients (age 1-18 years) with ALL were enrolled in the Dutch Childhood Oncology Group-ALL11 protocol and received PEGasp. Three hundred twelve patients stratified in the medium-risk arm were randomly assigned to receive 14 individualized PEGasp doses once every two weeks in either a noncontinuous or continuous schedule after the first three doses in induction (EudraCT: 2012-000067-25).

Improved Outcome for ALL by Prolonging Therapy for Deletion and Decreasing Therapy for Other Risk Groups.

Purpose: The ALL10 protocol improved outcomes for children with ALL by stratifying and adapting therapy into three minimal residual disease-defined risk groups: standard risk, medium risk (MR), and high risk. -deleted (del) ALL in the largest MR group still showed poor outcome, in line with protocols worldwide, accounting for a high number of overall relapses. ALL10 showed high toxicity in Down syndrome (DS) and excellent outcome in ALL.

Immune Response following BNT162b2 mRNA COVID-19 Vaccination in Pediatric Cancer Patients.

COVID-19 vaccinations are recommended for children with cancer but data on their vaccination response is scarce. This study assesses the antibody and T-cell response following a 2- or 3-dose vaccination with BNT162b2 mRNA COVID-19 vaccine in children (5-17 years) with cancer. For the antibody response, participants with a serum concentration of anti-SARS-CoV-2 spike 1 antibodies of >300 binding antibody units per milliliter were classified as good responders.

The Prognostic Effect of Deletions in :: and High Hyperdiploid Childhood Acute Lymphoblastic Leukemia.

deletions are an established prognostic factor in childhood acute lymphoblastic leukemia (ALL). However, their relevance in patients with good risk genetics, namely :: and high hyperdiploid (HeH), ALL remains unclear. We assessed the prognostic impact of deletions in 939 :: and 968 HeH ALL patients by evaluating data from 16 trials from 9 study groups.

Fludarabine exposure predicts outcome after CD19 CAR T-cell therapy in children and young adults with acute leukemia.

The addition of fludarabine to cyclophosphamide as a lymphodepleting regimen prior to CD19 chimeric antigen receptor (CAR) T-cell therapy significantly improved outcomes in patients with relapsed/refractory (r/r) B-cell acute lymphoblastic leukemia (B-ALL). Fludarabine exposure, previously shown to be highly variable when dosing is based on body surface area (BSA), is a predictor for survival in allogeneic hematopoietic cell transplantation (allo-HCT). Hence, we hypothesized that an optimal exposure of fludarabine might be of clinical importance in CD19 CAR T-cell treatment.

Clonal dynamics in pediatric B-cell precursor acute lymphoblastic leukemia with very early relapse.

Introduction: One-quarter of the relapses in children with B-cell precursor acute lymphoblastic leukemia (BCP-ALL) occur very early (within 18 months, before completion of treatment), and prognosis in these patients is worse compared to cases that relapse after treatment has ended.

Methods: In this study, we performed a genomic analysis of diagnosis-relapse pairs of 12 children who relapsed very early, followed by a deep-sequencing validation of all identified mutations. In addition, we included one case with a good initial treatment response and on-treatment relapse at the end of upfront therapy.

Unravelling the Sequential Interplay of Mutational Mechanisms during Clonal Evolution in Relapsed Pediatric Acute Lymphoblastic Leukemia.

Pediatric acute lymphoblastic leukemia (ALL) is the most common pediatric malignancy and is characterized by clonal heterogeneity. Genomic mutations can increase proliferative potential of leukemic cells and cause treatment resistance. However, mechanisms driving mutagenesis and clonal diversification in ALL are not fully understood.

Anti-GD2 antibody and Vorinostat immunocombination therapy is highly effective in an aggressive orthotopic neuroblastoma model.

Neuroblastoma is a childhood malignancy and in the majority of patients, the primary tumor arises in one of the adrenal glands. Neuroblastoma cells highly express the disialoganglioside GD2, which is the primary target for the development of neuroblastoma immunotherapy. Anti-GD2 mAbs have shown clinical efficacy and are integrated into standard treatment for high-risk neuroblastoma patients.

Multiclonal complexity of pediatric acute lymphoblastic leukemia and the prognostic relevance of subclonal mutations.

Genomic studies of pediatric acute lymphoblastic leukemia (ALL) have shown remarkable heterogeneity in initial diagnosis, with multiple (sub)clones harboring lesions in relapse-associated genes. However, the clinical relevance of these subclonal alterations remains unclear. We assessed the clinical relevance and prognostic value of subclonal alterations in the relapse-associated genes IKZF1, CREBBP, KRAS, NRAS, PTPN11, TP53, NT5C2, and WHSC1 in 503 ALL cases.

Examining the Potential Relationship Between Multidisciplinary Team Meetings and Patient Survival in Pediatric Oncology Settings: A Systematic Review.

The organization of multidisciplinary team meetings (MTMs) has become standard practice in pediatric oncology and is widely felt to improve communication, knowledge, and patient care. Although the impact of MTMs on survival in adult oncology has been extensively researched, the potential benefits of survival for pediatric cancer patients are still unclear. This systematic review aimed to examine the impact of MTMs on survival in pediatric oncology settings.

Use of quality indicators in neuroblastoma treatment: A feasibility assessment.

Background: Quality indicators (QIs) may be used to monitor the quality of neuroblastoma (NBL) care during treatment, in addition to survival and treatment toxicity, which can only be evaluated in the years after treatment. The present study aimed to assess the feasibility of a new set of indicators for the quality of NBL therapy.

Procedure: Seven QIs have been proposed based on literature and consensus of experts: (a) duration of complete diagnostic work-up, (b) prescription of thyroid prophylaxis before metaiodobenzylguanidine imaging, (c) treatment intensity, (d) use of tumor board meetings, (e) number of outpatient visits and sedation procedures during follow-up, (f) protocolled follow-up, and (g) required apheresis sessions.

Cost-effectiveness of Anti-CD19 chimeric antigen receptor T-Cell therapy in pediatric relapsed/refractory B-cell acute lymphoblastic leukemia. A societal view.

Introduction: In several studies, the chimeric antigen receptor T-cell therapy tisagenlecleucel demonstrated encouraging rates of remission and lasting survival benefits in pediatric patients with relapsed/refractory (r/r) acute lymphoblastic leukemia (ALL). We assessed the cost-effectiveness of tisagenlecleucel (list price: 320 000 EUR) among these patients when compared to clofarabine monotherapy (Clo-M), clofarabine combination therapy (Clo-C), and blinatumomab (Blina) from both a healthcare and a societal perspective. We also assessed future medical and future non-medical consumption costs.

Upfront Treatment Influences the Composition of Genetic Alterations in Relapsed Pediatric B-Cell Precursor Acute Lymphoblastic Leukemia.

Genomic alterations in relapsed B-cell precursor acute lymphoblastic leukemia (BCP-ALL) may provide insight into the role of specific genomic events in relapse development. Along this line, comparisons between the spectrum of alterations in relapses that arise in different upfront treatment protocols may provide valuable information on the association between the tumor genome, protocol components and outcome. Here, we performed a comprehensive characterization of relapsed BCP-ALL cases that developed in the context of 3 completed Dutch upfront studies, ALL8, ALL9, and ALL10.

Combined sialic acid and histone deacetylase (HDAC) inhibitor treatment up-regulates the neuroblastoma antigen GD2.

Neuroblastoma cells highly express the disialoganglioside GD2, a tumor-associated carbohydrate antigen, which is only sparsely expressed on healthy tissue. GD2 is a primary target for the development of immunotherapy for neuroblastoma. Immunotherapy with monoclonal anti-GD2 antibodies has proven safety and efficacy in clinical trials and is included in the standard treatment for children with high-risk neuroblastoma.

Tumor suppressor BTG1 limits activation of BCL6 expression downstream of ETV6-RUNX1.

Translocation t(12;21) (p13;q22), giving rise to the ETV6-RUNX1 fusion gene, is the most common genetic abnormality in childhood B-cell precursor acute lymphoblastic leukemia (BCP-ALL). This translocation usually arises in utero, but its expression is insufficient to induce leukemia and requires other cooperating genetic lesions for BCP-ALL to develop. Deletions affecting the transcriptional coregulator BTG1 are frequently observed in ETV6-RUNX1-positive leukemia.

High Yield of Pathogenic Germline Mutations Causative or Likely Causative of the Cancer Phenotype in Selected Children with Cancer.

In many children with cancer and characteristics suggestive of a genetic predisposition syndrome, the genetic cause is still unknown. We studied the yield of pathogenic mutations by applying whole-exome sequencing on a selected cohort of children with cancer. To identify mutations in known and novel cancer-predisposing genes, we performed trio-based whole-exome sequencing on germline DNA of 40 selected children and their parents.

Tumor suppressors BTG1 and IKZF1 cooperate during mouse leukemia development and increase relapse risk in B-cell precursor acute lymphoblastic leukemia patients.

Deletions and mutations affecting lymphoid transcription factor IKZF1 (IKAROS) are associated with an increased relapse risk and poor outcome in B-cell precursor acute lymphoblastic leukemia. However, additional genetic events may either enhance or negate the effects of deletions on prognosis. In a large discovery cohort of 533 childhood B-cell precursor acute lymphoblastic leukemia patients, we observed that single-copy losses of were significantly enriched in -deleted B-cell precursor acute lymphoblastic leukemia (=0.