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Pediatric acute myeloid leukemia (AML) is a devastating disease with a high risk of relapse. Current risk classification designates patients as high or low risk (LR) based on molecular features and therapy response. However, 30% of LR patients still suffer relapse, indicating a need for improvement in risk stratification. Cytokine levels, such as IL-6 and IL-10, have been shown to be prognostic in adult AML but have not been well studied in children. Previously, we reported elevated IL-6 levels in pediatric AML bone marrow to be associated with inferior prognosis. Here, we expanded our investigation to assess cytokine levels in diagnostic peripheral blood plasma (PBP) of pediatric AML patients and determined correlation with outcome. Diagnostic PBP was obtained from 80 patients with LR AML enrolled on the Children's Oncology Group AAML1031 study and normal PBP from 11 controls. Cytokine levels were measured and correlation with clinical outcome was assessed. IL-6, TNFα, MIP-3a, and IL-1β were significantly higher in AML patients versus controls when corrected by the Bonferroni method. Furthermore, elevated TNFα and IL-10 were significantly associated with inferior outcomes. Our data demonstrate that in diagnostic PBP of LR pediatric AML patients, certain cytokine levels are elevated as compared to healthy controls and that elevated TNFα and IL-10 are associated with inferior outcomes, supporting the idea that an abnormal inflammatory state may predict poor outcomes. Studies are needed to determine the mechanisms by which these cytokines impact survival, and to further evaluate their use as prognostic biomarkers in pediatric AML. [ABSTRACT FROM AUTHOR]

Simple Summary: Children with acute myeloid leukemia (AML) experience unacceptably poor survival outcomes and are at high risk of relapse. Current treatment options are limited, and standard strategies rely on intensive chemotherapy to achieve remission, frequently resulting in treatment-related morbidities and significant late adverse effects. The use of an ex vivo drug sensitivity platform has potential clinical utility to aid individualized patient risk assignment, and it could allow for personalized treatment regimens, including identifying novel therapies for patients who are identified to be at a very high risk of treatment failure. In this study, we show that ex vivo drug sensitivity correlates with clinical response measures in a cohort of children with AML who received conventional chemotherapy. We also demonstrate preferential sensitivity ex vivo between conventional chemotherapy and the combination of bortezomib and panobinostat in a subset of patient samples. Our results support the value of an ex vivo drug sensitivity platform to identify individualized precision therapy for children with AML. Acute myeloid leukemia (AML) is a heterogeneous disease that accounts for ~20% of all childhood leukemias, and more than 40% of children with AML relapse within three years of diagnosis. Although recent efforts have focused on developing a precise medicine-based approach towards treating AML in adults, there remains a critical gap in therapies designed specifically for children. Here, we present ex vivo drug sensitivity profiles for children with de novo AML using an automated flow cytometry platform. Fresh diagnostic blood or bone marrow aspirate samples were screened for sensitivity in response to 78 dose conditions by measuring the reduction in leukemic blasts relative to the control. In pediatric patients treated with conventional chemotherapy, comprising cytarabine, daunorubicin and etoposide (ADE), ex vivo drug sensitivity results correlated with minimal residual disease (r = 0.63) and one year relapse-free survival (r = 0.70; AUROC = 0.94). In the de novo ADE analysis cohort of 13 patients, AML cells showed greater sensitivity to bortezomib/panobinostat compared with ADE, and comparable sensitivity between venetoclax/azacitidine and ADE ex vivo. Two patients showed a differential response between ADE and bortezomib/panobinostat, thus supporting the incorporation of ex vivo drug sensitivity testing in clinical trials to further evaluate the predictive utility of this platform in children with AML. [ABSTRACT FROM AUTHOR]

Rubinstein-Taybi syndrome (RSTS) is a rare disorder characterized by developmental delay, short stature, dysmorphic facies and skeletal abnormalities. RSTS has been linked to a variety of malignant and benign tumors, but the frequency and characteristics of RSTS-related neoplasms remain unclear. We describe a unique case of near haploid B-cell lymphoblastic leukemia (B-ALL) in a 6-year-old girl with RSTS who harbors a likely pathogenic variant in CREBBP. Somatic CREBBP variants are enriched in some subsets of ALL; however, germline variants have not been previously described in childhood leukemia and may represent an underrecognized predisposition to malignancy. Our patient's disease responded poorly to conventional chemotherapy and relapsed following a complete remission achieved with CD19 CAR T cell therapy. We propose that the constitutional CREBBP variant may have played a significant role in the leukemia's resistance to chemotherapy and this patient's poor response to therapy. [ABSTRACT FROM AUTHOR]

FPD-MM is characterized by thrombocytopenia and a 35-40% lifetime risk of developing hematologic malignancies, namely myelodysplastic syndrome and acute myeloid leukemia (AML), with an average onset of 33 years.[1] The majority of I RUNX1 i mutations in FPD-MM are identified through NGS testing, however, this approach can miss exon level deletions. Discussion Thrombocytopenia, a strong family history of hematologic malignancies, and a germline I RUNX1 i pathogenic variant are diagnostic of FPD-MM. Novel RUNX1 mutations in familial platelet disorder with enhanced risk for acute myeloid leukemia: clues for improved identification of the FPD/AML syndrome. Familial platelet disorder with associated myeloid malignancy (FPD-MM) is an inherited disorder caused by germline mutations in the I RUNX family transcription factor 1 i ( I RUNX1 i ) gene. [Extracted from the article]

A case study of a 3-month-old term previously healthy African American female presented with 1 day of right arm pain and decreased movement. Topics include patient was born to a nulliparous woman with sickle cell trait who received routine prenatal care beginning in the first trimester; and plain films of the right upper extremity demonstrated osteolytic lesions of the proximal humerus and ulna with periosteal reaction.