Characterisation of infections in patients with acute myeloid leukaemia receiving venetoclax and a hypomethylating agent.

We investigated the incidence of invasive fungal infections (IFIs) and other infectious complications in patients receiving venetoclax and hypomethylating agent therapy for acute myeloid leukaemia (AML). This retrospective, multicentre cohort study included adult patients with AML who received at least one cycle of venetoclax and either azacitidine or decitabine between January 2016 and August 2020. The primary outcome was the incidence of probable or confirmed IFI. Secondary outcomes included antifungal prophylaxis prescribing patterns, incidence of bacterial infections, and incidence of neutropenic fever hospital admissions. Among 235 patients, the incidence of probable or confirmed IFI was 5.1%. IFI incidence did not differ significantly according to age, antifungal prophylaxis use, or disease status. In the subgroup of patients with probable or confirmed IFIs, six (50%) were receiving antifungal prophylaxis at the time of infection. The overall incidence of developing at least one bacterial infection was 33.6% and 127 (54%) patients had at least one hospital admission for febrile neutropenia. This study demonstrated an overall low risk of developing probable or confirmed IFI as well as a notable percentage of documented bacterial infections and hospital admissions due to neutropenic fever.

Use of a lipid-coated mesoporous silica nanoparticle platform for synergistic gemcitabine and paclitaxel delivery to human pancreatic cancer in mice.

Recently, a commercial albumin-bound paclitaxel (PTX) nanocarrier (Abraxane) was approved as the first new drug for pancreatic ductal adenocarcinoma in almost a decade. PTX improves the pharmaceutical efficacy of the first-line pancreatic cancer drug, gemcitabine (GEM), through suppression of the tumor stroma and inhibiting the expression of the GEM-inactivating enzyme, cytidine deaminase (CDA). We asked, therefore, whether it was possible to develop a mesoporous silica nanoparticle (MSNP) carrier for pancreatic cancer to co-deliver a synergistic GEM/PTX combination. High drug loading was achieved by a custom-designed coated lipid film technique to encapsulate a calculated dose of GEM (40 wt %) by using a supported lipid bilayer (LB). The uniform coating of the 65 nm nanoparticles by a lipid membrane allowed incorporation of a sublethal amount of hydrophobic PTX, which could be co-delivered with GEM in pancreatic cells and tumors. We demonstrate that ratiometric PTX incorporation and delivery by our LB-MSNP could suppress CDA expression, contemporaneous with induction of oxidative stress as the operating principle for PTX synergy. To demonstrate the in vivo efficacy, mice carrying subcutaneous PANC-1 xenografts received intravenous (IV) injection of PTX/GEM-loaded LB-MSNP. Drug co-delivery provided more effective tumor shrinkage than GEM-loaded LB-MSNP, free GEM, or free GEM plus Abraxane. Comparable tumor shrinkage required coadministration of 12 times the amount of free Abraxane. High-performance liquid chromatography analysis of tumor-associated GEM metabolites confirmed that, compared to free GEM, MSNP co-delivery increased the phosphorylated DNA-interactive GEM metabolite 13-fold and decreased the inactivated and deaminated metabolite 4-fold. IV injection of MSNP-delivered PTX/GEM in a PANC-1 orthotopic model effectively inhibited primary tumor growth and eliminated metastatic foci. The enhanced in vivo efficacy of the dual delivery carrier could be achieved with no evidence of local or systemic toxicity. In summary, we demonstrate the development of an effective LB-MSNP nanocarrier for synergistic PTX/GEM delivery in pancreatic cancer.