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Abstract Background Fanconi anemia (FA) is an inherited disorder characterized by congenital malformations, bone marrow failure and malignancies. Hematopoietic cell transplant (HCT) is the only proven cure for the hematological complications. FA patients have increased chromosomal instability and aberrant DNA repair and thus can only tolerate low doses of chemotherapy or radiation as part of conditioning prior to HCT. Yet, they are still prone to severe regimen related toxicities (RRT) including hemorrhagic cystitis (HC) from cyclophosphamide (CY). Objective As CYP2B6 is a primary enzyme responsible for the catalyzation of the prodrug form of CY, understanding the association between CYP2B6 genetic variants and HC in FA patients may predict which patients will be more susceptible to developing HC. Study Design: A descriptive genetic association study was performed to identify genetic variants associated with HC in patients with FA who underwent HCT between 1999 and 2017. All patients received a CY-based preparative regimen and had pretransplant recipient DNA available for genomic analysis. Results Forty FA pediatric patients were eligible for this analysis. They had received HCT from matched sibling donors (n = 6) or alternative donors (n = 34) for marrow failure (n = 38) or myelodysplastic syndrome (n = 2). The incidence of HC was 32.5% which occurred at a median of 32 days (range 20–180) after HCT. Nine patients had a concomitant viral infection (BK virus, n = 8 both adenovirus and BK virus, n = 1). No genetic variants were significantly associated with HC. The top variants were rs2279343 (g.23060A > G), and rs2279344 (g.23280G > A) in the CYP2B6 gene. The incidence of HC among FA patients with the rs2279343 variant was 42% (CI 22–62%) compared to 20% (CI 0–40%) among those without the variant (p = 0.19). The incidence of HC among patients with the variant in rs2279344 was 40% (CI 22–58%) compared to 10% (CI 0–28%) among those without (p = 0.11). Conclusion No variants in our analysis were statistically associated with HC. The data suggest that CYP2B6 variants may increase the risk for HC in FA patients who received a CY based preparative therapy but these risk variants must be further evaluated in a larger population.

AbstractCoronavirus disease 2019 (COVID‐19) infection causes a variety of extrapulmonary complications in pediatric patients. Multisystem inflammatory syndrome and hemophagocytic lymphohistiocytosis (HLH) are related to hypercytokinemia in COVID‐19 patients. HLH is a disorder of exaggerated inflammation resulting in a cytokine storm and unrestricted hemophagocytosis. HLH can be primary (familial) or secondary (acquired). Secondary HLH (sHLH) can occur in patients with rheumatologic, oncologic, or infectious diseases. The link between COVID‐19 and HLH has been reported in pediatric patients. Here we report a case of a pediatric patient who developed refractory sHLH secondary to COVID‐19 infection and required a hematopoietic cell transplant for the cure.

e22515 Background: Osteosarcoma is a skeletal malignancy affecting children, adolescents, and young adults. Surgical resection and chemotherapy are the mainstay of therapy with a three-drug regimen - cisplatin, doxorubicin, and methotrexate. However, prognosis remains poor mainly due to chemo-resistance and/or metastases. Emerging evidence has shown that long non-coding RNAs (lncRNAs) are implicated in drug sensitivity and cancer metastasis. Our lab has recently identified strong significant association between cellular sensitivity to cisplatin and doxorubicin and expression of a lncRNA ANRIL in a collection of osteosarcoma cell lines. Methods: SiRNA knockdown experiments were carried out in an osteosarcoma cell line, SAOS2. Cells were exposed to multiple concentrations of cisplatin or doxorubicin. Cellular sensitivity to these two drugs was quantified after siRNA experiment with siRNA targeting ANRIL and scramble control at 24, 48 and 72h. Clinical outcome analysis was performed using data from the Therapeutically Applicable Research to Generate Effective Treatments (TARGET) initiative. Results: We successfully knocked down ANRIL expression in SAOS2 cells with 88.5% efficiency. A significant decreased rate of proliferation was detected for cisplatin (7 uM, 72h) in knockdown cells (16.5% +/- 4.1) compared to scramble control (26.4% +/- 0.8). The cisplatin IC50 was decreased in the siRNA knockdown condition as compared to scramble control at 72h (p = 0.02). For doxorubicin, the IC50 was also significantly decreased in the siRNA knockdown condition as compared to scramble control (p = 0.002 and 0.007 at 24h and 72h, respectively). Survival outcomes, metastases at diagnosis, and percent necrosis (an indicator of treatment response) were evaluated in TARGET osteosarcoma patients (n = 121 and n = 43 for OS, percent necrosis, respectively) with varying degrees of ANRIL expression. Above the median ANRIL expression was associated with a greater number of death (p = 0.004) and higher chances of metastases at diagnosis (p = 0.013). Conclusions: Reducing ANRIL expression led to increased cellular sensitivity to cisplatin and doxorubicin, two key treatment agents for osteosarcoma. Higher ANRIL expression was significantly associated with higher rates of osteosarcoma death and metastases at diagnosis in a clinical cohort of patients. These findings may suggest ANRIL serves as a novel biomarker of cisplatin and doxorubicin sensitivity in osteosarcoma.