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Glucocorticoids are the cornerstone of B-lymphoblastic leukemia (B-ALL) therapy. Because response to glucocorticoids alone predicts overall outcomes for B-ALL, enhancing glucocorticoid potency should improve treatment. We previously showed that inhibition of the lymphoid-restricted PI3Kδ with idelalisib enhances glucocorticoid activity in B-ALL cells. Here, we show that idelalisib enhances glucocorticoid potency in 90% of primary B-ALL specimens and is most pronounced at sub-saturating doses of glucocorticoids near the EC50. Potentiation is associated with enhanced regulation of all glucocorticoid-regulated genes, including genes that drive B-ALL cell death. Idelalisib reduces phosphorylation of the glucocorticoid receptor (GR) at PI3Kδ/MAPK1 (ERK2) targets S203 and S226. Ablation of these phospho-acceptor sites enhances sensitivity to glucocorticoids with ablation of S226 in particular reducing synergy. We also show that phosphorylation of S226 reduces the affinity of GR for DNA in vitro. We propose that PI3Kδ inhibition improves glucocorticoid efficacy in B-ALL in part by decreasing GR phosphorylation, increasing DNA binding affinity, and enhancing downstream gene regulation. This mechanism and the response of patient specimens suggest that idelalisib will benefit most patients with B-ALL, but particularly patients with less responsive, including high-risk, disease. This combination is also promising for the development of less toxic glucocorticoid-sparing therapies.

Background: Cytarabine is a nucleoside analog used in chemotherapy regimens for the treatment of multiple hematologic malignancies. One of the known adverse effects of cytarabine, particularly in patients receiving high-dose cytarabine (HDAC), is drug-induced fever. Multiple studies have demonstrated an increased risk of viridans group streptococcal bacteremia in patients who have received HDAC. For this reason, our institution and several other institutions across the country routinely include vancomycin as empiric coverage for patients who develop fever during HDAC, due to concern for resistance to cephalosporin monotherapy., Materials and Methods: Patient demographic, diagnosis, treatment, and outcome information was collected by electronic chart review for each HDAC infusion from 2007 to August 2018 at the University of Iowa Stead Family Children's Hospital. If fever was documented during or within 24 hours of HDAC, additional information was collected regarding patient outcome and diagnostic testing., Results: Of 208 HDAC administrations documented, patients developed fevers during the course on 82 occasions (39.4%). A median of 3 blood cultures per febrile period were obtained from time of fever onset during HDAC administration through >24 hours afebrile. One blood culture was positive for an oral flora organism determined by the microbiology lab report to be a likely contaminant. There were no other positive blood cultures in non-neutropenic or neutropenic patients., Conclusion: Fever due to HDAC is relatively common but appears to frequently lack association with bacteremia during the time of HDAC administration. Broad-spectrum empiric antibiotic regimens including vancomycin may be unnecessary for these patients, particularly before they become neutropenic., Competing Interests: The authors declare no conflict of interest., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Glucocorticoids (GCs) are widely used, potent anti-inflammatory and chemotherapeutic drugs. They work by binding to the glucocorticoid receptor (GR), a ligand-activated transcription factor, inducing translocation to the nucleus and regulation of genes that influence a variety of cellular activities. Despite being effective for a broad number of conditions, GC use is limited by severe side effects. To identify ligands that are more selective, we synthesized pairs of regioisomers in the pyrazole ring that probe the expanded binding pocket of GR opened by deacylcortivazol (DAC). Using an Ullmann-type reaction, a deacylcortivazol-like (DAC-like) backbone was modified with five pendant groups at the 1'- and 2'-positions of the pyrazole ring, yielding 9 ligands. Most of the compounds were cytotoxic to leukemia cells, and all required GR expression. Both aliphatic and other aromatic groups substituted at the 2'-position produced ligands with GC activity, with phenyl and 4-fluorophenyl substitutions exhibiting high cellular affinity for the receptor and >5× greater potency than dexamethasone, a commonly used strong GC. Surprisingly, phenyl substitution at the 1'-position produced a high-affinity ligand with ∼10× greater potency than dexamethasone, despite little apparent room in the expanded binding pocket to accommodate 1'-modifications. Other 1'-modifications, however, were markedly less potent. The potency of the 2'-substituted and 1'-substituted DAC-like compounds tracked linearly with cellular affinity but had different slopes, suggesting a different mode of interaction with GR. These data provide evidence that the expanded binding pocket opened by deacylcortivazol is more accommodating that expected, allowing development of new, and possibly selective, GCs by substitution within the pyrazole ring., Competing Interests: The authors have no conflicts of interest to report., (This journal is © The Royal Society of Chemistry.)