ABBV-319: a CD19-targeting glucocorticoid receptor modulator antibody-drug conjugate therapy for B-cell malignancies.

ABSTRACT: Glucocorticoids are key components of the standard-of-care treatment regimens for B-cell malignancy. However, systemic glucocorticoid treatment is associated with several adverse events. ABBV-319 is a CD19-targeting antibody-drug conjugate engineered to reduce glucocorticoid-associated toxicities while possessing 3 distinct mechanisms of action (MOA) to increase therapeutic efficacy: (1) antibody-mediated delivery of a glucocorticoid receptor modulator (GRM) payload to activate apoptosis, (2) inhibition of CD19 signaling, and (3) enhanced fragment crystallizable (Fc)-mediated effector function via afucosylation of the antibody backbone. ABBV-319 elicited potent GRM-driven antitumor activity against multiple malignant B-cell lines in vitro, as well as in cell line-derived xenografts and patient-derived xenografts (PDXs) in vivo. Remarkably, a single dose of ABBV-319 induced sustained tumor regression and enhanced antitumor activity compared with repeated dosing of systemic prednisolone at the maximum tolerated dose in mice. The unconjugated CD19 monoclonal antibody (mAb) also displayed antiproliferative activity in a subset of B-cell lymphoma cell lines through the inhibition of phosphoinositide 3-kinase signaling. Moreover, afucosylation of CD19 mAb enhanced Fc-mediated antibody-dependent cellular cytotoxicity. Notably, ABBV-319 displayed superior efficacy compared with afucosylated CD19 mAb in human CD34+ peripheral blood mononuclear cell-engrafted NSG-Tg(Hu-IL15) transgenic mice, demonstrating enhanced antitumor activity when multiple MOAs are enabled. ABBV-319 also showed durable antitumor activity across multiple B-cell lymphoma PDX models, including nongerminal center B-cell diffuse large B-cell lymphoma and relapsed lymphoma after R-CHOP treatment. Collectively, these data support the ongoing evaluation of ABBV-319 in a phase 1 clinical trial.

Factors associated with increased risk of postoperative blood transfusion in patients undergoing total hip arthroplasty at an Irish University Hospital.

INTRODUCTION: Approximately 7000 total hip arthroplasty (THA) surgeries occur in Ireland each year. A number of preoperative factors have been identified that increase the risk of postoperative blood transfusion after THA, including anaemia. The ability to identify patients at risk may allow preoperative management strategies to reduce blood transfusions. Data from Irish orthopaedic patients is currently lacking. AIM: To investigate if preoperative anaemia and other factors are associated with postoperative blood transfusions in patients who undergo THA. METHODS: A retrospective cohort study of all patients who underwent THA in 2019 in SIVUH, Cork, using medical chart review. RESULTS: In total, 350 charts met the inclusion criteria, with 291 charts reviewed. 8.9% of the patients who underwent THA had preoperative anaemia. Among these, 19.2% had a postoperative blood transfusion, compared to 1.5% of patients who were not anaemic preoperatively. The odds of receiving a blood transfusion was 15.5 times greater in the preoperative anaemia group compared to the non-anaemic group. Increasing age and higher ASA scores were associated with preoperative anaemia and postoperative blood transfusions. Length of stay was increased by 2.2 days (p < 0.00016) if blood transfusion was required. CONCLUSION: Preoperative anaemia was common in an Irish orthopaedic population undergoing THA. Preoperative anaemia predisposes patients to the greatest increased risk of postoperative blood transfusions. The other factors associated with the need for postoperative transfusion were ASA grade 3 or more and age greater than 65 years. Patients who received postoperative blood transfusions had a significantly increased length of hospital stay.