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The Oncologist Aug 2022Neutropenia and febrile neutropenia (FN) are common complications of myelosuppressive chemotherapy. This review provides an up-to-date assessment of the patient and cost... (Review)
Review
Neutropenia and febrile neutropenia (FN) are common complications of myelosuppressive chemotherapy. This review provides an up-to-date assessment of the patient and cost burden of chemotherapy-induced neutropenia/FN in the US, and summarizes recommendations for FN prophylaxis, including the interim guidance that was recommended during the coronavirus disease 2019 (COVID-19) pandemic. This review indicates that neutropenia/FN place a significant burden on patients in terms of hospitalizations and mortality. Most patients with neutropenia/FN presenting to the emergency department will be hospitalized, with an average length of stay of 6, 8, and 10 days for elderly, pediatric, and adult patients, respectively. Reported in-hospital mortality rates for neutropenia/FN range from 0.4% to 3.0% for pediatric patients with cancer, 2.6% to 7.0% for adults with solid tumors, and 7.4% for adults with hematologic malignancies. Neutropenia/FN also place a significant cost burden on US healthcare systems, with average costs per neutropenia/FN hospitalization estimated to be up to $40 000 for adult patients and $65 000 for pediatric patients. Evidence-based guidelines recommend prophylactic granulocyte colony-stimulating factors (G-CSFs), which have been shown to reduce FN incidence while improving chemotherapy dose delivery. Availability of biosimilars may improve costs of care. Efforts to decrease hospitalizations by optimizing outpatient care could reduce the burden of neutropenia/FN; this was particularly pertinent during the COVID-19 pandemic since avoidance of hospitalization was needed to reduce exposure to the virus, and resulted in the adaptation of recommendations to prevent FN, which expanded the indications for G-CSF and/or lowered the threshold of use to >10% risk of FN.
Topics: Adult; Aged; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Biosimilar Pharmaceuticals; Chemotherapy-Induced Febrile Neutropenia; Child; Granulocyte Colony-Stimulating Factor; Humans; Neoplasms; Pandemics; COVID-19 Drug Treatment
PubMed: 35552754
DOI: 10.1093/oncolo/oyac074 -
Cancers Sep 2023Bispecific T-cell engagers (BiTEs) and bispecific antibodies (BiAbs) have revolutionized the treatment landscape of hematological malignancies. By directing T cells... (Review)
Review
Bispecific T-cell engagers (BiTEs) and bispecific antibodies (BiAbs) have revolutionized the treatment landscape of hematological malignancies. By directing T cells towards specific tumor antigens, BiTEs and BiAbs facilitate the T-cell-mediated lysis of neoplastic cells. The success of blinatumomab, a CD19xCD3 BiTE, in acute lymphoblastic leukemia spearheaded the expansive development of BiTEs/BiAbs in the context of hematological neoplasms. Nearly a decade later, numerous BiTEs/BiAbs targeting a range of tumor-associated antigens have transpired in the treatment of multiple myeloma, non-Hodgkin's lymphoma, acute myelogenous leukemia, and acute lymphoblastic leukemia. However, despite their generally favorable safety profiles, particular toxicities such as infections, cytokine release syndrome, myelosuppression, and neurotoxicity after BiAb/BiTE therapy raise valid concerns. Moreover, target antigen loss and the immunosuppressive microenvironment of hematological neoplasms facilitate resistance towards BiTEs/BiAbs. This review aims to highlight the most recent evidence from clinical trials evaluating the safety and efficacy of BiAbs/BiTEs. Additionally, the review will provide mechanistic insights into the limitations of BiAbs whilst outlining practical applications and strategies to overcome these limitations.
PubMed: 37760519
DOI: 10.3390/cancers15184550 -
Leukemia Jul 2022Maintenance therapy (MT) with oral methotrexate (MTX) and 6-mercaptopurine (6-MP) is essential for the cure of acute lymphoblastic leukemia (ALL). MTX and 6-MP interfere... (Review)
Review
Maintenance therapy (MT) with oral methotrexate (MTX) and 6-mercaptopurine (6-MP) is essential for the cure of acute lymphoblastic leukemia (ALL). MTX and 6-MP interfere with nucleotide synthesis and salvage pathways. The primary cytotoxic mechanism involves the incorporation of thioguanine nucleotides (TGNs) into DNA (as DNA-TG), which may be enhanced by the inhibition of de novo purine synthesis by other MTX/6-MP metabolites. Co-medication during MT is common. Although Pneumocystis jirovecii prophylaxis appears safe, the benefit of glucocorticosteroid/vincristine pulses in improving survival and of allopurinol to moderate 6-MP pharmacokinetics remains uncertain. Numerous genetic polymorphisms influence the pharmacology, efficacy, and toxicity (mainly myelosuppression and hepatotoxicity) of MTX and thiopurines. Thiopurine S-methyltransferase (encoded by TPMT) decreases TGNs but increases methylated 6-MP metabolites (MeMPs); similarly, nudix hydrolase 15 (encoded by NUDT15) also decreases TGNs available for DNA incorporation. Loss-of-function variants in both genes are currently used to guide MT, but do not fully explain the inter-patient variability in thiopurine toxicity. Because of the large inter-individual variations in MTX/6-MP bioavailability and metabolism, dose adjustments are traditionally guided by the degree of myelosuppression, but this does not accurately reflect treatment intensity. DNA-TG is a common downstream metabolite of MTX/6-MP combination chemotherapy, and a higher level of DNA-TG has been associated with a lower relapse hazard, leading to the development of the Thiopurine Enhanced ALL Maintenance (TEAM) strategy-the addition of low-dose (2.5-12.5 mg/m/day) 6-thioguanine to the 6-MP/MTX backbone-that is currently being tested in a randomized ALLTogether1 trial (EudraCT: 2018-001795-38). Mutations in the thiopurine and MTX metabolism pathways, and in the mismatch repair genes have been identified in early ALL relapses, providing valuable insights to assist the development of strategies to detect imminent relapse, to facilitate relapse salvage therapy, and even to bring about changes in frontline ALL therapy to mitigate this relapse risk.
Topics: Humans; Mercaptopurine; Methotrexate; Methyltransferases; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Recurrence; Thioguanine
PubMed: 35654820
DOI: 10.1038/s41375-022-01591-4 -
Antimicrobial Agents and Chemotherapy Aug 2019Linezolid is administered as a fixed dose to all patients despite evidence of increased exposure and myelosuppression in renal impairment. The objectives of these...
Linezolid is administered as a fixed dose to all patients despite evidence of increased exposure and myelosuppression in renal impairment. The objectives of these studies were to assess the risk of thrombocytopenia with standard-dose linezolid in renal impairment and to identify an alternate dosing strategy. In study 1, data from adult patients receiving linezolid for ≥10 days were retrospectively reviewed to determine the frequency of thrombocytopenia in patients with and without renal impairment. Time-to-event analyses were performed using Cox proportional-hazards models. In study 2, population pharmacokinetic modeling was employed to build covariate-structured models using an independent data set of linezolid concentrations obtained during routine therapeutic drug monitoring (TDM). Monte Carlo simulations were performed to identify linezolid dosing regimens that maximized attainment of therapeutic trough concentrations (2 to 8 mg/liter) across various renal-function groups. Toxicity analysis (study 1) included 341 patients, 133 (39.0%) with renal impairment. Thrombocytopenia occurred more frequently among patients with renal impairment (42.9% versus 16.8%; < 0.001), and renal impairment was independently associated with this toxicity in multivariable analysis (adjusted hazard ratio [aHR], 2.37; 95% confidence interval [CI], 1.52 to 3.68). Pharmacokinetic analyses (study 2) included 1,309 linezolid concentrations from 603 adult patients. Age, body surface area, and estimated glomerular filtration rate (eGFR) were identified as covariates of linezolid clearance. Linezolid dose reductions improved the probability of achieving optimal exposures in simulated patients with eGFR values of <60 ml/min. Thrombocytopenia occurs more frequently in patients with renal impairment receiving standard linezolid doses. Linezolid dose reduction and trough-based TDM are predicted to mitigate this treatment-limiting toxicity.
Topics: Anti-Bacterial Agents; Area Under Curve; Drug Monitoring; Female; Glomerular Filtration Rate; Humans; Linezolid; Male; Middle Aged; Monte Carlo Method; Renal Insufficiency; Retrospective Studies; Thrombocytopenia
PubMed: 31109977
DOI: 10.1128/AAC.00605-19