Aim Novel immunotherapies have generated high response rates and unique adverse effects among patients with relapsed or refractory acute lymphoblastic leukemia. Therapies engaging endogenous T-cells against acute lymphoblastic leukemia are emerging for children and adults with various poor prognostic factors, thus accurate knowledge of immunotherapies is necessary for their effective implementation in the future. In this review, we evaluate clinical trial data regarding chimeric antigen receptor T-cells and blinatumomab, for the treatment of relapsed or refractory acute lymphoblastic leukemia. Summary In the relapsed or refractory setting, response rates rapidly diminish after subsequent lines of chemotherapy and cumulative toxicities may cause significant patient harm. Immunotherapies provide an approach to improve response rates and minimize traditional toxicities via novel mechanisms of action. Two therapies targeting CD19 antigens expressed on B-cell acute lymphoblastic leukemia lineages, chimeric antigen receptor T-cells, and blinatumomab have induced complete remissions among high-risk patient populations, especially those refractory to multiple therapies. Adverse effects such as cytokine release syndrome and neurologic sequelae remain serious precautions of each therapy. Conclusion Knowledge of immunotherapy mechanisms and clinical outcomes associated with immunotherapies is critical for the optimization of treating patients with relapsed or refractory acute lymphoblastic leukemia. Future use of chimeric antigen receptor T-cells and blinatumomab demands proper assessment of a patient's disease and treatment history in addition to unique monitoring and supportive care interventions.
Background/rationale Romiplostim is a thrombopoietin receptor agonist recommended as a second-line therapy for immune thrombocytopenia. An initial dose of 1 mcg/kg/week subcutaneously with weekly 1 mcg/kg dose escalation is recommended per package labeling. Optimizing romiplostim dosing for hospitalized, corticosteroid- and intravenous immunoglobulin-refractory patients with severe thrombocytopenia secondary to immune thrombocytopenia may be critical for improving platelet responses, reducing the risk of bleeding, and decreasing hospital length of stay. Limited data are available evaluating the efficacy and safety of higher initial doses. Objective The primary objective of this study was to compare the time to platelet ≥ 10 × 10/L between patients who received an initial romiplostim dose of ≥2 mcg/kg/week compared to the standard initial dose of 1 mcg/kg/week. Secondary objectives included time to platelet response ≥ 30 × 10/L and ≥50 × 10/L, percentage of patients achieving platelet responses, hospital length of stay, and incidence of adverse events and bleeding complications. Methods This was a retrospective, single-center, cohort study including hospitalized adults with corticosteroid- and intravenous immunoglobulin-refractory immune thrombocytopenia. A baseline platelet < 10 × 10/L was required. Patients were stratified by their initial romiplostim dose into Cohort 1 (1 mcg/kg/week) and Cohort 2 (≥2 mcg/kg/week). A review of electronic medical records and descriptive statistics generated findings. Results A total of 18 patients were included, 4 in Cohort 1 and 14 in Cohort 2. Patients in Cohort 2 had a median initial dose of 4.5 mcg/kg/week. Patients in Cohort 2 achieved a platelet ≥ 10 × 10/L in a median of 2 days versus 4.5 days for Cohort 1. More patients in Cohort 2 achieved a platelet ≥ 30 × 10/L (42.9% vs. 25%) and platelet ≥ 50 × 10/L (28.6% vs. 25%). The median hospital length of stay was shorter in Cohort 2 (13.5 vs. 20 days). Clinically relevant nonmajor bleeding was noted less frequently in Cohort 2 (28.6% vs. 75%), while major bleeding was more frequent in Cohort 2 (14.3% vs. 0%). No thrombotic events occurred. Conclusion Our study suggests that higher initial romiplostim doses may be safe for hospitalized patients with treatment-refractory immune thrombocytopenia. Compared to Food and Drug Administration-approved dosing, higher initial doses may shorten time to platelet responses and hospital length of stay. Further large-scale studies are needed to confirm these findings.
Background: Recommended loading doses (LDs) of phenytoin and fosphenytoin range from 10 to 25 mg/kg. Few studies have examined the LD requirements in male versus female patients and in patients who are obese. Objectives: To examine the influence of obesity and sex on phenytoin LDs. Methods: This was a retrospective cohort study comparing free phenytoin or fosphenytoin serum concentrations following LDs in male versus female and nonobese versus obese patients. An equation used for determining LDs in obese patients was evaluated. Results: There were 141 nonobese and 54 obese patients. When adjusted for total body weight, the obese cohort received a smaller LD than the nonobese cohort (17 mg/kg, interquartile range [IQR] = 14.9-20.0, vs 20 mg/kg, IQR = 18.6-20.0, respectively; P < 0.001). There was no difference between the 2 cohorts in the measured free phenytoin concentration following the LD (obese: 1.7 µg/mL [IQR = 1.4-2.0]; nonobese: 1.8 µg/mL [IQR = 1.5-2.1]; P = 0.16). In the obese cohort, men received a significantly lower weight-based phenytoin dose compared with women (15 mg/kg [IQR = 14.0-19.2], vs 19.9 mg/kg [IQR = 15.0-20.0], respectively; P = 0.008). Postload free phenytoin concentrations were similar between the 2 groups (male: 1.6 µg/mL [IQR = 1.2-2.1]; female: 1.7 µg/mL [IQR = 1.4-2.0]; P = 0.24). Conclusion and Relevance: Phenytoin and fosphenytoin LDs of at least 15 mg/kg of actual body weight are more likely to lead to desired free phenytoin concentrations. Obese female patients need a larger weight-based dose than male patients to achieve similar postload phenytoin concentrations.
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