Aflac (United States)

Pediatric acute myeloid leukemia (pAML) is a heterogeneous malignancy driven by diverse cytogenetic mutations. While identification of cytogenetic lesions improved risk stratification, prognostication remains inadequate with 30% of standard-risk patients experiencing relapse within 5 years. To deeply characterize pAML heterogeneity and identify poor outcome-associated blast cell profiles, we performed an analysis on 708,285 cells from 164 bone marrow biopsies of 95 patients and 11 healthy controls. The longitudinal analysis on cell abundances at the time of disease diagnosis, end of induction, and relapse identified treatment resistant stem-like blast cells specific to RUNX1::RUNX1T1, FLT3-ITD, and CBFB::MYH11 patients that are associated with poor outcomes. Treatment resistant blast cells from RUNX1::RUNX1T1 were found to associate with T cell exhaustion, while those from FLT-ITD utilized enriched antioxidant metabolism to persist through treatment. Interestingly, the analysis also identified novel mast cell-like pAML associated with treatment resistance and poor outcomes. Deconvolution of ex vivo treatment data and subsequent in vitro validation identified bortezomib (RUNX1), ponatinib, and venetoclax (FLT3) as specifically potent against treatment resistant blasts from the respective cytogenetic groups. Our findings indicate immature and mature pAML subtypes are promising biomarkers for enhanced patient risk stratification and identifies targeted agents to increase their clearance after treatment.

The investigational agent osivelotor, a small molecule hemoglobin (Hb) modifier in development for the treatment of sickle cell disease (SCD), acts by increasing Hb‐oxygen affinity and inhibiting the polymerization of sickle Hb. We report safety, pharmacokinetic (PK), and pharmacodynamic (PD) data from the first two phase 1 clinical trials of osivelotor in healthy participants and participants with SCD. Healthy participants (N = 129) were randomized to receive either osivelotor or placebo in single‐ascending doses (50–3,000 mg) or multiple‐ascending doses (loading doses, then 15–100 mg once‐daily maintenance doses through 14 days). A population PK‐based adaptive design was used to inform loading‐ and maintenance‐dose regimens from emerging data. Osivelotor was generally well tolerated, demonstrated dose‐dependent PK exposure increase, and had a terminal elimination half‐life of 19.9 to 30.7 days, with high partitioning into the red blood cell (RBC) compartment in healthy participants. In participants with SCD (N = 6), osivelotor treatment for up to 6 weeks was generally well tolerated; no participants discontinued due to treatment‐emergent adverse events. Disease‐dependent PK was observed in participants with SCD; notably, the terminal elimination half‐life was shorter (~10 days) than in healthy participants. The percentage of Hb bound by osivelotor (%Hb occupancy) increased in a dose‐dependent fashion, and improvements in Hb concentration and markers of hemolysis appeared related to osivelotor concentration. Furthermore, Hb‐oxygen affinity and RBC deformability improved, whereas dense RBCs and circulating sickled cells decreased. In conclusion, once‐daily osivelotor was generally well tolerated at exposures associated with meaningful PD activity, supporting the ongoing clinical investigation.

The pathogenesis of immune thrombocytopenia (ITP) is complex and incompletely understood. Multiple cell types have been implicated, and their respective contribution is unclear. A recent genome-wide association study identified single-nucleotide polymorphisms (SNPs) associated with pediatric ITP within or near 5 genes in the canonical Wnt signaling pathway. To investigate whether this pathway was dysregulated in ITP and identify which cell types were involved, we leveraged extensive functional genomics and single-cell RNA sequencing (scRNA-seq) data. By linking the identified SNPs to likely regulated genes, we showed an enrichment in the Wnt pathway and identified 2 additional genes in this pathway involved in ITP. The SNPs affected regulation of the Wnt pathway genes in multiple cell types. Indeed, scRNA-seq showed some of these genes were expressed in lymphocytes, whereas others were expressed in platelets or megakaryocytes. By comparing the cell-specific expression of these genes between individuals with ITP and healthy controls, we demonstrated that several genes in the Wnt pathway were differentially expressed between these 2 groups. Some genes were upregulated, whereas other were downregulated in ITP. In sum, the Wnt signaling pathway is broadly dysregulated in ITP, with a complex pattern that varies across genes and cell types.

CHIPS (Childhood Hodgkin International Prognostic Score), a predictive score for event-free-survival (EFS), was originally developed using factors presenting at diagnosis in patients with intermediate-risk Hodgkin lymphoma (HL). Prospective validation of CHIPS in patients was a pre-specified aim of AHOD1331, a trial comparing brentuximab-vedotin, doxorubicin, vincristine, etoposide, prednisone, and cyclophosphamide (Bv-AVEPC) to standard ABVE-PC (and response-adapted radiation) in children with high-risk HL. AHOD1331 was a multicenter randomized phase 3 study. Patients were aged 2-21years with untreated stages IIB+bulk, IIIB, IV HL. CHIPS was determined by assigning one point each for: Stage IV disease, large mediastinal adenopathy (greater than one-third thoracic diameter), albumin (<3.5g/dL), and fever (T≥38°C). Associations between CHIPS, baseline patient, and disease characteristics were tested. The validity of CHIPS to predict EFS was evaluated by both overall and within pre-specified subgroups defined by treatment arm, PET2 response, and disease stage. The four CHIPS components were analyzable in 576 of the 587 eligible patients. Distribution of CHIPS did not differ by study treatment arm (p = 0.158). CHIPS was significantly prognostic for EFS in this high-risk cohort (p = 0.008) and was independently predictive of EFS regardless of treatment arm, PET2 response, or stage. In subset analyses, CHIPS remained independently prognostic among patients with PET2 rapid responding lesions (RRL; p = 0.021) or Stage IVB disease (p = 0.047). CHIPS were predictive of EFS in patients with high-risk HL treated on AHOD1331. CHIPS may aid in the allocation of patients to risk-based treatment algorithms, and can serve as an effective, inexpensive, and feasible proxy for more biologically based factors.

Patients with sickle cell disease (SCD) experience painful vaso-occlusive episodes that increase with age; a subset develops chronic pain (CP). CP is usually managed with acute pain management guidelines despite evidence of ineffectiveness. Buprenorphine (BUP), a partial opioid agonist, is a potent analgesic with less euphoric effect and a respiratory "ceiling effect." BUP therefore provides an alternative "harm reduction" approach for CP management in pediatric SCD patients. This single urban center retrospective study assessed the feasibility of inpatient transition to BUP-containing analgesics in adolescents with SCD and CP. Patients aged 12-20years who transitioned from full opioid agonists (FOA) to BUP between December 2020 and September 2022 were included. Acute care utilization, hospital length of stay, and FOA use in both inpatient and outpatient settings were compared pre- and post-BUP induction for up to a year. Fourteen adolescents with SCD underwent inpatient BUP induction and maintenance therapy. Inpatient transition using a micro-induction approach was feasible and well tolerated in this population. There were low rates of adverse events, such as opioid withdrawal signs. Maintenance on BUP products was sustainable over the 1-year post-induction period. Three patients (21%) discontinued BUP during maintenance therapy. There was a significant reduction (p<0.05) in acute care utilization, length of stay, and FOA use (both inpatient and outpatient). Inpatient micro-induction to BUP from FOA in adolescent SCD patients with CP is feasible with minimal signs of opioid withdrawal. This study suggests decreased acute care utilization with BUP.

Wilms tumor (WT) is the most common pediatric renal tumor, and with multidisciplinary treatment overall outcomes are excellent. However, a small subset of patients with WT will relapse. The ideal treatment of relapsed WT is yet to be defined. Ongoing studies through the Children's Oncology Group Renal Tumors Committee (COG-RTC) and the International Society of Paediatric Oncology Renal Tumor Study Group (SIOP-RTSG) aim to improve risk stratification and treatment strategies. Members met at the SIOP 55th Annual Congress 2023 to outline available data and knowledge gaps and develop future research priorities.

Measurement of transfused red blood cell (RBC) survival is relevant to the effective management of sickle cell disease (SCD). Following amustaline/glutathione pathogen-reduced (PR) RBC transfusion, small quantities of PR-RBC surface-bound acridine are detectable by flow cytometry. Concurrent biotin labeling was used to validate the acridine marker and track transfused PR-RBCs in SCD. SCD patients (n = 6) on chronic transfusion therapy received three aliquots of different (2 μg/mL, 6 μg/mL, and 18 μg/mL) biotin-dose labeled RBCs during one transfusion episode. Aliquots were from one unit labeled before (Pre-PR) and after PR treatment (PR-RBC) and from a conventional RBC unit. The full RBC units (PR and conventional) were transfused, followed by the labeled aliquots from those units. Serial flow cytometry analyses for acridine- and biotin-labeled RBCs were performed on 10 occasions over 16 weeks. Acridine surface density was quantitated using calibrated beads. Mean acridine surface density was 5062 molecules/PR-RBC at 1-4 h post-transfusion and declined 84.5% within 7 days, remaining detectable (180 molecules/PR-RBC) at 16 weeks. The biotin-labeled PR-RBC aliquots (initial enrichment 0.6%-1.4%) demonstrated near-identical survival kinetics as the entire acridine-labeled PR-RBC units (initial enrichment 7.5%-13.7%). Pre-PR, PR, and Conventional RBCs revealed non-linear RBC survival kinetics, with similar 24-h post-transfusion recoveries (PTR24) and half-lives (T50), but PR-RBC mean predicted lifespan (mean [SD] 104.4 [4.7] days) was decreased by 9.3% (Pre-PR-RBCs 115.1 [7.2] days, p = 0.006). Survival of amustaline/glutathione PR-RBCs can be tracked in vivo by flow cytometry for RBC surface acridine with similar sensitivity as biotin, without additional processing or radiolabeling.

Hematopoietic stem cell transplantation (HCT) is potentially curative for numerous malignant and non-malignant diseases but can lead to lung injury due to chemoradiation toxicity, infection, and immune dysregulation. Bronchoalveolar lavage (BAL) is the most commonly used procedure for diagnostic sampling of the lung but is invasive, cannot be performed in medically fragile patients, and is challenging to perform serially. We previously showed that BAL transcriptomes representing pulmonary inflammation and cellular injury can phenotype post-HCT lung injury and predict mortality outcomes. However, whether peripheral blood testing is a suitable minimally-invasive surrogate for pulmonary sampling in the HCT population remains unknown. To address this question, we compared 210 paired BAL and peripheral blood transcriptomes obtained from 166 pediatric HCT patients at 27 children's hospitals. BAL and blood mRNA abundance showed minimal overall correlation at the level of individual genes, gene set enrichment scores, imputed cell fractions, and T- and B-cell receptor clonotypes. Instead, we identified significant site-specific transcriptional programs. In BAL, expression of innate and adaptive immune pathways was tightly co-regulated with expression of epithelial mesenchymal transition and hypoxia pathways, and these signatures were associated with mortality. In contrast, in blood, expression of endothelial injury, DNA repair, and cellular metabolism pathways was associated with mortality. Integration of paired BAL and blood transcriptomes dichotomized patients into two groups, of which one group showed twice the rate of hypoxia and significantly worse outcomes within 7 days of enrollment. These findings reveal a compartmentalized injury response, where BAL and peripheral blood transcriptomes provide distinct but complementary insights into local and systemic mechanisms of post-HCT lung injury.