Efficacy of Azacitidine and Prophylactic Donor Lymphocyte Infusion after HSCT in Pediatric Patients with Acute Myelogenous Leukemia: A Retrospective Pre-Post Study.

Pediatric patients with acute myeloid leukemia (AML) who undergo allogeneic hematopoietic stem cell transplantation (HSCT) continue to have high rates of relapse. In 2018, Phoenix Children's Hospital started using post-HSCT maintenance therapy in patients with AML in attempt to decrease the number of relapses after HSCT. This therapy consisted of the hypomethylating agent azacitidine (AZA; 6 cycles starting on day +60) and prophylactic donor lymphocyte infusion (DLI; 3 escalating doses beginning after day +120). We aimed to compare 2-year leukemia-free survival (LFS) post-HSCT between patients with AML who received post-HSCT maintenance therapy with AZA and prophylactic DLI and historical control patients who did not receive post-HSCT therapy. This retrospective pre-post study was conducted at Phoenix Children's Hospital and included patients with AML who underwent HSCT between January 1, 2008, and May 31, 2022. We compared LFS, overall survival (OS), and immune reconstitution patterns post-HSCT between patients with AML who received post-HSCT maintenance therapy with AZA and prophylactic DLI (postintervention group) and historical control patients who did not receive this post-HSCT maintenance therapy (preintervention group). Sixty-three patients were evaluable. After excluding 7 patients who died or relapsed prior to day +60, 56 patients remained, including 39 in the preintervention group and 17 in the postintervention group. The median age at transplantation was 9.1 years in the preintervention group and 11 years in the postintervention group (P = .33). The 2-year LFS was 61.5% in the preintervention group, compared to 88.2% in the postintervention group (P = .06). The 2-year OS was 69.2% in the preintervention group and 88.2% in the postintervention group (P = .15). The rates of CD3+CD4+ T cell and CD19+ B cell recovery were faster in the preintervention group compared to the postintervention group (P = .004 and .0006, respectively). In this limited retrospective study, post-HSCT maintenance therapy using AZA and prophylactic DLI was well tolerated; however, its efficacy is yet to be fully determined.

Assessing Safe Discharge Criteria for Pediatric Oncology Patients Admitted for Febrile Neutropenia.

Recent studies suggest outpatient therapy, oral antibiotics, or earlier discharge could be appropriate in some pediatric patients admitted with febrile neutropenia; supporting data are lacking. Retrospective chart review of patients admitted from September 2005 through October 2016 identified 131 "early discharge" febrile neutropenia admissions with discharge absolute neutrophil count (ANC) <500/µl and negative cultures. All were afebrile and discharged without outpatient antibiotics. Eleven of 131 patients (8%) were readmitted. Two patients called back for late positive cultures. Nine were readmitted with febrile neutropenia; 2 had positive cultures on readmission. All 4 patients with positive cultures were safely treated with appropriate antibiotics. The remaining 7 patients had uneventful readmissions. Average ANC (SD) at discharge was lower for patients readmitted versus those not readmitted (69 [70] vs. 196 [145], P≤0.001), as was absolute phagocyte count (APC) at discharge (97 [82] vs. 453 [431], P≤0.001). APC on admission was not significantly lower for those readmitted (165 [254] vs. 321 [388], P=0.09). Few patients required readmission; those with bacterial infections were easily identified and appropriately treated. Higher ANC or APC criteria for discharge would increase length of hospital stay without decreasing morbidity. A subset of patients admitted with febrile neutropenia can be safely discharged before count recovery without oral antibiotics.

Azacitidine and prophylactic donor lymphocyte infusions after hematopoietic stem cell transplantation for pediatric high-risk acute myeloid leukemia.

Post-hematopoietic stem cell transplantation (HSCT) maintenance therapy using azacitidine and prophylactic donor lymphocyte infusions (DLI) was implemented for high-risk acute myeloid leukemia. Azacitidine was started on day +60 as a 5 day course every 28 days for 6 cycles. DLI was given every 6 weeks for 3 doses starting after day +120. Ten patients were treated on this protocol. With a 90% one-year disease free survival, we report this post-HSCT maintenance therapy is feasible, safe, and well tolerated.

The large zinc finger protein ZAS3 is a critical modulator of osteoclastogenesis.

BACKGROUND: Mice deficient in the large zinc finger protein, ZAS3, show postnatal increase in bone mass suggesting that ZAS3 is critical in the regulation of bone homeostasis. Although ZAS3 has been shown to inhibit osteoblast differentiation, its role on osteoclastogenesis has not been determined. In this report we demonstrated the role of ZAS3 in bone resorption by examining the signaling mechanisms involved in osteoclastogenesis. METHODOLOGY/PRINCIPAL FINDINGS: Comparison of adult wild-type and ZAS3 knockout (ZAS3-/-) mice showed that ZAS3 deficiency led to thicker bones that are more resistant to mechanical fracture. Additionally, ZAS3-/- bones showed fewer osteoclasts and inefficient M-CSF/sRANKL-mediated osteoclastogenesis ex vivo. Utilizing RAW 264.7 pre-osteoclasts, we demonstrated that overexpression of ZAS3 promoted osteoclastogenesis and the expression of crucial osteoclastic molecules, including phospho-p38, c-Jun, NFATc1, TRAP and CTSK. Contrarily, ZAS3 silencing by siRNA inhibited osteoclastogenesis. Co-immunoprecipitation experiments demonstrated that ZAS3 associated with TRAF6, the major receptor associated molecule in RANK signaling. Furthermore, EMSA suggested that nuclear ZAS3 could regulate transcription by binding to gene regulatory elements. CONCLUSION/SIGNIFICANCE: Collectively, the data suggested a novel role of ZAS3 as a positive regulator of osteoclast differentiation. ZAS3 deficiency caused increased bone mass, at least in part due to decreased osteoclast formation and bone resorption. These functions of ZAS3 were mediated via activation of multiple intracellular targets. In the cytoplasmic compartment, ZAS3 associated with TRAF6 to control NF-kB and MAP kinase signaling cascades. Nuclear ZAS3 acted as a transcriptional regulator for osteoclast-associated genes. Additionally, ZAS3 activated NFATc1 required for the integration of RANK signaling in the terminal differentiation of osteoclasts. Thus, ZAS3 was a crucial molecule in osteoclast differentiation, which might potentially serve as a target in the design of therapeutic interventions for the treatment of bone diseases related to increased osteoclast activity such as postmenopausal osteoporosis, Paget's disease, and rheumatoid arthritis.