Survival outcomes of children with relapsed or refractory myeloid leukemia associated with Down syndrome.

Children with Down syndrome (DS) are at a significantly higher risk of developing acute myeloid leukemia, also termed myeloid leukemia associated with DS (ML-DS). In contrast to the highly favorable prognosis of primary ML-DS, the limited data that are available for children who relapse or who have refractory ML-DS (r/r ML-DS) suggest a dismal prognosis. There are few clinical trials and no standardized treatment approach for this population.

SAMHD1 single nucleotide polymorphisms impact outcome in children with newly diagnosed acute myeloid leukemia.

Cytarabine arabinoside (Ara-C) has been the cornerstone of acute myeloid leukemia (AML) chemotherapy for decades. After cellular uptake, it is phosphorylated into its active triphosphate form (Ara-CTP), which primarily exerts its cytotoxic effects by inhibiting DNA synthesis in proliferating cells. Interpatient variation in the enzymes involved in the Ara-C metabolic pathway has been shown to affect intracellular abundance of Ara-CTP and, thus, its therapeutic benefit.

Integrated stem cell signature and cytomolecular risk determination in pediatric acute myeloid leukemia.

Relapsed or refractory pediatric acute myeloid leukemia (AML) is associated with poor outcomes and relapse risk prediction approaches have not changed significantly in decades. To build a robust transcriptional risk prediction model for pediatric AML, we perform RNA-sequencing on 1503 primary diagnostic samples. While a 17 gene leukemia stem cell signature (LSC17) is predictive in our aggregated pediatric study population, LSC17 is no longer predictive within established cytogenetic and molecular (cytomolecular) risk groups.

Chronic conditions, late mortality, and health status after childhood AML: a Childhood Cancer Survivor Study report.

Five-year survival following childhood acute myeloid leukemia (AML) has increased following improvements in treatment and supportive care. Long-term health outcomes are unknown. To address this, cumulative incidence of late mortality and grades 3 to 5 chronic health condition (CHC) were estimated among 5-year AML survivors diagnosed between 1970 and 1999.

The two-hit hypothesis in practice: Monozygotic twins with simultaneous hyperdiploid acute lymphoblastic leukemia.

Approximately 25% of B-cell acute lymphoblastic leukemia (B-ALL) cases are defined by hyperdiploidy, with RAS mutations occurring in 30% of hyperdiploid B-ALL patients. It is believed that hyperdiploidy is an in utero event with RAS mutations occurring postnatally, but clinical evidence of this is based on relatively few patients. We present a case of monozygotic, monochorionic twins who developed concordant hyperdiploid B-ALL with identical chromosomal gains but different RAS mutations, adding further evidence that hyperdiploidy is occurring prenatally, with RAS mutations developing postnatally.

Hematopoietic Cell Transplantation in the Treatment of Pediatric Acute Myelogenous Leukemia and Myelodysplastic Syndromes: Guidelines from the American Society of Transplantation and Cellular Therapy.

The role of allogeneic hematopoietic stem cell transplantation (HCT) in the treatment of acute myelogenous leukemia (AML) in children is reviewed and critically evaluated in this evidence-based review. Specific criteria were used for searching the published literature, grading the quality and strength of evidence, and assigning the strength of treatment recommendations. Genomic characterization and response to therapy have been critical in the risk stratification of pediatric AML.

Newly Diagnosed Children with Cancer Have Lower 25-Vitamin D Levels than Their Cancer-Free Peers: A Comparison across Age, Race, and Sex.

Children with cancer have a greater risk for vitamin D concerns because of compromised health before diagnosis, the disease itself, and treatments for the cancer. This IRB-approved retrospective, matched case−control study of children with and without cancer included three race categories: black, other, and Caucasian. This is the first study to directly compare serum 25-hydroxy vitamin D (25(OH)D) levels and status in newly diagnosed pediatric cancer patients with age-, sex-, and race-matched cancer-free children from the same geographic region of the US, all of whom are free from other conditions that negatively impact 25(OH)D levels.

A clinician's guide to HLA matching in allogeneic hematopoietic stem cell transplant.

Human leukocyte antigen (HLA) matching is an essential component of allogeneic hematopoietic stem cell transplant (HSCT). However, for some clinicians the biology underpinning HLA structure and function may be but a distant memory from lectures many years past, and, understanding the complexities of HLA matching can be challenging for clinicians new to the field, particularly as there have been several important advances in the field this past decade. In this review, we provide an up to date resource to educate and remind clinicians of: 1) Why HLA matching matters, including reviewing the role HLA molecules play in the adaptive immune system and the consequences of HLA mismatch.

Efficacy of Flotetuzumab in Combination with Cytarabine in Patient-Derived Xenograft Models of Pediatric Acute Myeloid Leukemia.

Children with acute myeloid leukemia (AML) have a poor prognosis despite the intensification of chemotherapy. Future efforts to improve outcomes should focus on more precise targeting of leukemia cells. CD123, or IL3RA, is expressed on the surface of nearly all pediatric AML samples and is a high-priority target for immunotherapy.

Blood Count Recovery Following Induction Therapy for Acute Myeloid Leukemia in Children Does Not Predict Survival.

International Working Group (IWG) and European LeukemiaNet (ELN) response definitions are utilized to evaluate the efficacy of new agents for childhood acute myeloid leukemia (AML) for regulatory purposes. However, these criteria are not consistent with definitions used in pediatric AML trials or with standard pediatric practice to proceed with subsequent therapy cycles prior to IWG/ELN-defined count recovery. We retrospectively analyzed data from the two most recent Phase 3 pediatric AML clinical trials conducted by the Children's Oncology Group (COG) to assess the incidence, timing, and prognostic significance of count recovery following induction chemotherapy.

Targeted inhibitors and antibody immunotherapies: Novel therapies for paediatric leukaemia and lymphoma.

Despite improved outcomes achieved in the last decades for children with newly diagnosed leukaemia and lymphoma, treatment of patients with refractory/relapsed disease remains a challenge. The cure rate is still unsatisfactory and often achieved at the cost of significant morbidity. Exploring treatment with novel agents should offer less toxic therapeutic options, without compromising efficacy.

Attitudes and Practices of Pediatric Oncologists Regarding Palliative Care Consultation for Pediatric Oncology Patients.

Objective: We sought to describe palliative care services available to children with cancer along with pediatric oncologists' current and ideal practices of palliative care involvement in children with cancer.

Design: A novel survey tool was administered via REDCap to attending pediatric oncologists in the United States. The survey remained open from June to September 2020.

Clinical relevance of proteomic profiling in pediatric acute myeloid leukemia: a Children's Oncology Group study.

Pediatric acute myeloid leukemia (AML) remains a fatal disease for at least 30% of patients, stressing the need for improved therapies and better risk stratification. As proteins are the unifying feature of (epi)genetic and environmental alterations, and are often targeted by novel chemotherapeutic agents, we studied the proteomic landscape of pediatric AML. Protein expression and activation levels were measured in 500 bulk leukemic patients' samples and 30 control CD34+ cell samples, using reverse phase protein arrays with 296 strictly validated antibodies.

Physician risk perceptions and surveillance practices for tyrosine kinase inhibitor long-term effects in pediatric CML.

Chronic myeloid leukemia (CML) is effectively treated with long-term tyrosine kinase inhibitor (TKI) therapy, yet little is known about risks of prolonged TKI exposure in young patients, and long-term effect monitoring is not standardized. We surveyed North American pediatric oncologists (n = 119) to evaluate perceived risk of and surveillance practices for potential toxicities associated with prolonged TKI exposure in children and adolescents/young adults (AYAs) with CML. Survey domains included general and specific risk perceptions and surveillance practices for asymptomatic patients on chronic TKI therapy.

Bortezomib is significantly beneficial for de novo pediatric AML patients with low phosphorylation of the NF-κB subunit RelA.

Purpose: The addition of the proteasome inhibitor (PI) bortezomib to standard chemotherapy (ADE: cytarabine [Ara-C], daunorubicin, and etoposide) did not improve overall outcome of pediatric AML patients in the Children's Oncology Group AAML1031 phase 3 randomized clinical trial (AAML1031) . Bortezomib prevents protein degradation, including RelA via the intracellular NF-kB pathway. In this study, we hypothesized that subgroups of pediatric AML patients benefitting from standard therapy plus bortezomib (ADEB) could be identified based on pre-treatment RelA expression and phosphorylation status.

Pediatric Cancer Data Commons: Federating and Democratizing Data for Childhood Cancer Research.

The international pediatric oncology community has a long history of research collaboration. In the United States, the 2019 launch of the Children's Cancer Data Initiative puts the focus on developing a rich and robust data ecosystem for pediatric oncology. In this spirit, we present here our experience in constructing the Pediatric Cancer Data Commons (PCDC) to highlight the significance of this effort in fighting pediatric cancer and improving outcomes and to provide essential information to those creating resources in other disease areas.

The menin-MLL1 interaction is a molecular dependency in NUP98-rearranged AML.

Translocations involving the NUP98 gene produce NUP98-fusion proteins and are associated with a poor prognosis in acute myeloid leukemia (AML). MLL1 is a molecular dependency in NUP98-fusion leukemia, and therefore we investigated the efficacy of therapeutic blockade of the menin-MLL1 interaction in NUP98-fusion leukemia models. Using mouse leukemia cell lines driven by NUP98-HOXA9 and NUP98-JARID1A fusion oncoproteins, we demonstrate that NUP98-fusion-driven leukemia is sensitive to the menin-MLL1 inhibitor VTP50469, with an IC50 similar to what we have previously reported for MLL-rearranged and NPM1c leukemia cells.

Online patient portal use by caregivers in pediatric oncology: Are we widening sociodemographic disparities?

Background: Financial and regulatory incentives have encouraged and increased the availability of online patient portals that provide caregivers access to their child's electronic health records (EHR). Such access is believed to promote better engagement and outcomes of care. Little is known about the use of portals by caregivers of children with cancer.

CBFB-MYH11 fusion transcripts distinguish acute myeloid leukemias with distinct molecular landscapes and outcomes.

transcripts and mutations predict relapse in AML. High-risk transcripts are associated with distinct transcriptional landscapes and upregulation of early hematopoiesis genes.

Facilitators and barriers to clinical practice guideline-consistent supportive care at pediatric oncology institutions: a Children's Oncology Group study.

Background: Clinical practice guideline (CPG)-consistent care improves patient outcomes, but CPG implementation is poor. Little is known about CPG implementation in pediatric oncology. This study aimed to understand supportive care CPG implementation facilitators and barriers at pediatric oncology National Cancer Institute (NCI) Community Oncology Research Program (NCORP) institutions.

Results of a phase 2, multicenter, single-arm, open-label study of lenalidomide in pediatric patients with relapsed or refractory acute myeloid leukemia.

Background: Outcomes after relapse remain poor in pediatric patients with acute myeloid leukemia (AML), and new therapeutic approaches are needed. Lenalidomide has demonstrated activity in adults with lower risk myelodysplastic syndromes and older adults with relapsed or refractory (R/R) AML.

Methods: In this phase 2 study (NCT02538965), pediatric patients with R/R AML who received two or more prior therapies were treated with lenalidomide (starting dose 2 mg/kg/day on days 1-21 of each 28-day cycle) for a maximum of 12 cycles.

Molecular and phenotypic diversity of CBL-mutated juvenile myelomonocytic leukemia.

Mutations in the gene CBL were first identified in adults with various myeloid malignancies. Some patients with juvenile myelomonocytic leukemia (JMML) were also noted to harbor mutations in CBL, but were found to have generally less aggressive disease courses compared to other forms of Ras pathway-mutant JMML. Importantly, and in contrast to most reports in adults, the majority of CBL mutations in JMML patients are germline with acquired uniparental disomy occurring in affected marrow cells.

Implementation of a learning healthcare system for sickle cell disease.

Objective: Using sickle cell disease (SCD) as a model, the objective of this study was to create a comprehensive learning healthcare system to support disease management and research. A multidisciplinary team developed a SCD clinical data dictionary to standardize bedside data entry and inform a scalable environment capable of converting complex electronic healthcare records (EHRs) into knowledge accessible in real time.

Materials And Methods: Clinicians expert in SCD care developed a data dictionary to describe important SCD-associated health maintenance and adverse events.

A Complicated Case of Vaccine Refusal.

Parents in the United States have a legal right to refuse vaccination for their children. There are, however, special circumstances under which the state may compel vaccination against parental wishes. In this Ethics Rounds article, we present the case of a young boy with sickle cell disease who was partially vaccinated against encapsulated bacteria and the ethics of whether to compel complete vaccination before splenectomy.