Implementation, utilization, and evaluation of a pharmacist-driven romiplostim dosing service for patients with immune thrombocytopenia at a multisite cancer centre.

Introduction: Romiplostim is a thrombopoietin receptor agonist approved for the treatment of patients with chronic immune thrombocytopenia who have had an insufficient response to corticosteroids, immune globulin, or splenectomy. Dose adjustments of romiplostim are based on platelet counts and follow a dosing schema that requires frequent monitoring. As a quality improvement initiative to increase clinical efficiency and promote clinical pharmacy services at our institution, we developed a collaborative practice agreement and implemented a novel pharmacist-driven romiplostim dosing protocol.

Evaluation of a pharmacist-driven rapid infusion rituximab conversion protocol at a multisite cancer center.

Introduction: Infusion-related reactions (IRR) are a common adverse event associated with rituximab, an anti-CD20 monoclonal antibody indicated for the treatment of B-cell lymphomas. IRR risk is highest with the first infusion, which is given by a slow titration over an average of 3.5 hours.

Evaluation of CYP2C19 Genotype-Guided Voriconazole Prophylaxis After Allogeneic Hematopoietic Cell Transplant.

There is a high risk of voriconazole failure in those with subtherapeutic drug concentrations, which is more common in CYP2C19 (cytochrome P450 2C19) rapid/ultrarapid metabolizers (RMs/UMs). We evaluated CYP2C19 genotype-guided voriconazole dosing on drug concentrations and clinical outcomes in adult allogeneic hematopoietic cell transplant recipients. Poor (PMs), intermediate (IMs), and normal metabolizers (NMs) received voriconazole 200 mg twice daily; RMs/UMs received 300 mg twice daily.

Effect of CYP3A4, CYP3A5, and ABCB1 Polymorphisms on Intravenous Tacrolimus Exposure and Adverse Events in Adult Allogeneic Stem Cell Transplant Patients.

Pharmacogenetics influences oral tacrolimus exposure; however, little data exist regarding i.v. tacrolimus.

American Society for Blood and Marrow Transplantation Pharmacy Special Interest Group Survey on Chimeric Antigen Receptor T Cell Therapy Administrative, Logistic, and Toxicity Management Practices in the United States.

Administration of immune effector cell (IEC) therapy is a complex endeavor requiring extensive coordination and communication of various healthcare and administrative teams. Chimeric antigen receptor (CAR) T cells are the most established IEC therapy available. As of July 2018 two commercial gene therapy products, tisagenlecleucel and axicabtagene ciloleucel, have been approved by the US Food and Drug Administration.

Hematopoietic cell transplantation in chronic myeloid leukemia in the age of tyrosine kinase inhibitors.

The development and widespread use of tyrosine kinase inhibitors (TKIs) has relegated the use of hematopoietic cell transplant (HCT), in most countries, to chronic myeloid leukemia (CML) patients who fail or are intolerant to TKIs. Its long-term cost effectiveness compared to TKIs, however, has maintained its use as front-line treatment in some areas. Advances in HCT, including the development of intravenous busulfan and plasma assays permitting dose adjustment, have improved results of HCT in CML.

Defective chromatin recruitment and retention of NHEJ core components in human tumor cells expressing a Cyclin E fragment.

Exposure to genotoxic agents, such as ionizing radiation (IR), produces double-strand breaks, repaired predominantly in mammalian cells by non-homologous end-joining (NHEJ). Ku70 was identified as an interacting partner of a proteolytic Cyclin E (CycE) fragment, p18CycE. p18CycE endogenous generation during IR-induced apoptosis in leukemic cells and its stable expression in epithelial tumor cells sensitized to IR.

A C-terminal fragment of Cyclin E, generated by caspase-mediated cleavage, is degraded in the absence of a recognizable phosphodegron.

We have previously shown that caspase-mediated cleavage of Cyclin E generates p18-Cyclin E in hematopoietic tumor cells. Its expression can induce apoptosis or sensitize to apoptotic stimuli in many cell types. However, p18-cyclin E has a much shorter half-life than Cyclin E, being more effectively ubiquitinated and degraded by the 26 S proteasome.

DNA damage response and apoptosis.

A number of methods have been developed to examine the morphologic, biochemical, and molecular changes that happen during the DNA damage response that may ultimately lead to death of cells through various mechanisms that include apoptosis. When cells are exposed to ionizing radiation or chemical DNA-damaging agents, double-stranded DNA breaks (DSB) are generated that rapidly result in the phosphorylation of histone variant H2AX. Because phosphorylation of H2AX at Ser 139 correlates well with each DSB, phospho-H2AX is a sensitive marker to used to examine the DNA damage and its repair.

Caspase-3 activation is a critical determinant of genotoxic stress-induced apoptosis.

A number of methods have been developed to identify the cells that undergo apoptosis by analyzing the morphological, biochemical, and molecular changes that take place during this universal biological process. The best recognized biochemical hallmark of both early and late stages of apoptosis is the activation of cysteine proteases (caspases). Detection of active caspase-3 in cells and tissues is an important method for apoptosis induced by a wide variety of apoptotic signals.

A jekyll and hyde role of cyclin E in the genotoxic stress response: switching from cell cycle control to apoptosis regulation.

Cyclin E protein levels and associated kinase activity rise in late G(1) phase, reach a peak at the G(1)/S transition, and quickly decline during S phase. The cyclin E/Cdk2 complex has a well-established function in regulating two fundamental biological processes: cell cycle progression and DNA replication. However, cyclin E expression is deregulated in a wide range of tumors.

E2F4 function in G2: maintaining G2-arrest to prevent mitotic entry with damaged DNA.

Mammalian cells undergo cell cycle arrest in response to DNA damage through multiple checkpoint mechanisms. One such checkpoint pathway maintains genomic integrity by delaying mitotic progression in response to genotoxic stress. Transition though the G2 phase and entry into mitosis is considered to be regulated primarily by cyclin B1 and its associated catalytically active partner Cdk1.

Interaction of a cyclin E fragment with Ku70 regulates Bax-mediated apoptosis.

The cyclin E/Cdk2 complex plays an essential role in the G(1)/S cell cycle transition and DNA replication. Earlier we showed that in hematopoietic tumor cells, caspase-mediated cleavage of cyclin E generates p18-cyclin E, which is unable to interact with Cdk2 and therefore plays a role independent of the cell cycle. The expression of a cleavage-resistant cyclin E mutant greatly diminishes apoptosis, indicating the critical role of cyclin E cleavage.