Open-Label Phase II Prospective, Randomized, Controlled Study of Romyelocel-L Myeloid Progenitor Cells to Reduce Infection During Induction Chemotherapy for Acute Myeloid Leukemia.

PURPOSE: Standard cytotoxic induction chemotherapy for acute myeloid leukemia (AML) results in prolonged neutropenia and risk of infection. Romyelocel-L is a universal, allogeneic myeloid progenitor cell product being studied to reduce infection during induction chemotherapy. PATIENTS AND METHODS: One hundred sixty-three patients with de novo AML (age ≥ 55 years) receiving induction chemotherapy were randomly assigned on day 0 (d0), of whom 120 were evaluable. Subjects received either romyelocel-L infusion on d9 with granulocyte colony-stimulating factor (G-CSF) starting daily d14 (treatment group) or G-CSF daily alone on d14 (control) until absolute neutrophil count recovery to 500/µL. End points included days in febrile episode, microbiologically defined infections, clinically diagnosed infection, and days in hospital. RESULTS: Mean days in febrile episode was shorter in the treatment arm from d15 through d28 (2.36 v 3.90; P = .02). Similarly, a trend toward decreased microbiologically defined infections and clinically diagnosed infection in the treatment arm was observed from d9 to d28 (35.6% v 47.5%; P = .09), reaching a statistically significant difference from d15 to d28 (6.8% v 27.9%; P = .002). Because of this, antibacterial or antifungal use for treatment of an infection was significantly less in the treatment group (d9-d28: 44.1% v 63.9%; P = .01). Significantly fewer patients in the treatment arm received empiric antifungals from d9 tod28 (42.4% v 63.9%; P = .02) and d15-d28 (42.4% v 62.3%; P = .02). Patients in the treatment arm also had 3.2 fewer hospital days compared with control (25.5 v 28.7; P = .001). Remission rates and days to absolute neutrophil count recovery were similar in the two groups. No patients in the romyelocel-L plus G-CSF group died because of infection compared with two patients in the control arm. No graft-versus-host disease was observed. CONCLUSION: Subjects receiving romyelocel-L showed a decreased incidence of infections, antimicrobial use, and hospitalization, suggesting that romyelocel-L may provide a new option to reduce infections in patients with AML undergoing induction therapy.

Clinical activity of carfilzomib correlates with inhibition of multiple proteasome subunits: application of a novel pharmacodynamic assay.

While proteasome inhibition is a validated therapeutic approach for multiple myeloma (MM), inhibition of individual constitutive proteasome (c20S) and immunoproteasome (i20S) subunits has not been fully explored owing to a lack of effective tools. We utilized the novel proteasome constitutive/immunoproteasome subunit enzyme-linked immunosorbent (ProCISE) assay to quantify proteasome subunit occupancy in samples from five phase I/II and II trials before and after treatment with the proteasome inhibitor carfilzomib. Following the first carfilzomib dose (15-56 mg/m(2) ), dose-dependent inhibition of c20S and i20S chymotrypsin-like active sites was observed [whole blood: ≥67%; peripheral blood mononuclear cells (PBMCs): ≥75%]. A similar inhibition profile was observed in bone marrow-derived CD138(+) tumour cells. Carfilzomib-induced proteasome inhibition was durable, with minimal recovery in PBMCs after 24 h but near-complete recovery between cycles. Importantly, the ProCISE assay can be used to quantify occupancy of individual c20S and i20S subunits. We observed a relationship between MM patient response (n = 29), carfilzomib dose and occupancy of multiple i20S subunits, where greater occupancy was associated with an increased likelihood of achieving a clinical response at higher doses. ProCISE represents a new tool for measuring proteasome inhibitor activity in clinical trials and relating drug action to patient outcomes.

Bronchodilator therapy in acute decompensated heart failure patients without a history of chronic obstructive pulmonary disease.

STUDY OBJECTIVE: Inhaled bronchodilators are often used in the emergency department (ED) before a definitive diagnosis is made. We evaluated the association between inhaled bronchodilators and outcomes in acute decompensated heart failure patients without chronic obstructive pulmonary disease. METHODS: We conducted an analysis of the Acute Decompensated Heart Failure National Registry Emergency Module registry of patients with a principal discharge diagnosis of acute decompensated heart failure enrolled at 76 academic or community EDs. Dichotomous outcomes (mortality, ED discharges, ICU admission, ED i.v. vasodilator use, new dialysis, ED or in patient endotracheal intubation, ED BiPAP, and asymptomatic at discharge) in patients without a history of chronic obstructive pulmonary disease who were given bronchodilators were compared to those who were not given bronchodilators using logistic regression; odds ratios (ORs) and 95% confidence intervals (CIs) were calculated; and propensity score adjustments were made. RESULTS: Of the 10,978 patients enrolled, 7299 (66.5%) did not have a history of chronic obstructive pulmonary disease. Bronchodilators were administered by the EMS or in the ED to 2317 (21%) patients. Patients without chronic obstructive pulmonary disease given bronchodilators were more likely to receive ED i.v. vasodilators (28.4% vs. 16.9%; propensity adjusted OR 1.40 [95% CI 1.18-1.67]) and in-patient mechanical ventilation (6.0% vs. 2.4%; propensity adjusted OR 1.69 [95% CI 1.21-2.37]) than patients without chronic obstructive pulmonary disease who were not given bronchodilators. Hospital mortality in patients without chronic obstructive pulmonary disease was similar regardless of bronchodilator treatment (3.4% vs. 2.6%, propensity adjusted OR 1.02 [95% CI 0.67, 1.56]). CONCLUSION: Many acute decompensated heart failure patients without a history of chronic obstructive pulmonary disease receive inhaled bronchodilators. Bronchodilator use was associated with a greater need for aggressive interventions and monitoring, and this may reflect an adverse effect of bronchodilators or it may be a marker for patients with more severe disease.