Treatment for Acute Myelogenous Leukemia by Low-Dose, Total-Body, Irradiation-Based Conditioning and Hematopoietic Cell Transplantation From Related and Unrelated Donors
ABSTRACT The use of low-dose, irradiation-based preparative regimens have allowed the extension of allografting to older and medically infirm patients. The study reported here assessed outcomes for patients with acute myeloid leukemia (AML) in different stages of their disease, who were not considered candidates for conventional hematopoietic cell transplantation (HCT) because of age and/or other known risk factors and were given minimal conditioning followed by HCT from related or unrelated donors.
The present study included 122 patients with AML, who were conditioned with 2 Gy total-body irradiation (TBI) on day 0 with or without preceding fludarabine (30 mg/m2/d from days -4 to -2), and given postgrafting cyclosporine at 6.25 mg/kg twice daily from day -3 and mycophenolate mofetil at 15 mg/kg twice daily from day 0.
Durable engraftment was observed in 95% of the patients. Cumulative incidences of acute graft-versus-host disease grades 2 to 4 at 6 months were 35% after related and 42% after unrelated HCT, respectively. With a median follow-up of 44 months (range, 26 to 79 months), 51 patients were alive, of whom 48 were in complete remission (CR). Cumulative nonrelapse mortalities were 10% and 22%, and cumulative mortalities from disease progression were 47% and 33% at 2 years for related and unrelated recipients, respectively. Overall, 2-year survival was 48%, and disease-free survival was 44%. Patients receiving transplantation in CR1 had 2-year overall survivals of 44% after related and 63% after unrelated HCT, respectively.
We conclude that HCT from related and unrelated donors after low-dose TBI is a promising treatment for elderly patients with AML.
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ABSTRACT: Graduation date: 2010 This dissertation presents a research series demonstrating the use of pharmacokinetic modeling and simulations as tools to assess drug concentration and disposition in patient populations. For drugs requiring therapeutic drug monitoring, these tools are necessary to ensure patients are receiving a safe and effective dose of medication to address their medical condition. The second chapter describes a prospective study to validate pharmacokinetic modeling simulation aimed at determining optimal inter and intradialytic dosing of vancomycin for hemodialysis patients. Fifty percent of the patients with evaluable data maintained trough concentrations within the therapeutic range (15-20mg/L). The remaining fifty percent of the patients required individualization of dosing to produce troughs in the therapeutic range. Given this, it is advisable to use a weight-based dosing regimen as a start for patient treatment. Therapeutic drug monitoring and individualization should be implemented as well to ensure therapeutic drug concentrations. The third chapter involves noncompartmental analysis of aprepitant plasma concentrations in an antiemetic regimen for patients undergoing hematopoietic stem cell transplantation. This study regimen has a first dose of 125mg on day 1, and 80mg daily until 4 days after the hematopoietic stem cell transplant. In spite of drug interactions from concomitant drug therapy, therapeutic concentrations of aprepitant were maintained. The study regimen can be applied in patients undergoing hematopoietic stem cell transplantation. The fourth chapter examines the unique characteristics of vancomycin pharmacokinetics in patients with Acute Myelogenous Leukemia. (AML) Demographics and vancomycin drug concentration versus time data were gathered from a retrospective cohort. One-compartment pharmacokinetic equations with population pharmacokinetic parameters were used to predict drug concentrations. These were compared with measured concentrations. A shortened half-life and increased clearance for vancomycin was found in AML patients compared to a general population. Because of this, the vancomycin dose in a 24 hour period should be doubled relative to the general population. The fifth chapter evaluates The University of Southern California Lab of Applied Pharmacokinetics MM-USC*PACK population modeling software using multiple model Bayesian pharmacokinetics for dosing vancomycin in AML patients. Of interest is the ability of the software’s included vancomycin population PK database to fit assayed drug concentrations of AML patients given the vancomycin dosing regimen. The root mean squared prediction error was not greater than 5.25 mg/L, given multiple options for estimation of creatinine clearance as a covariate in the modeling. Using the MM- USC*PACK software with a population model developed from the cohort being evaluated should yield the best predictive performance and be a feasible dosing tool for patient care. Evaluation of pharmacokinetics of clinically available data as applied to improving drug dosing in patients is a consistent and common objective of the research in this thesis.
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ABSTRACT: Treatment of acute myeloid leukemia (AML) in older adults remains a tremendous challenge. Standard approaches to treatment have resulted in progression-free survival in only a small minority of patients with AML over the age of 60. Elucidation of the molecular genetic events that contribute to the pathogenesis of AML in older patients are providing insights into mechanisms of resistance. This knowledge is also providing new opportunities to begin to refine and direct novel therapies for these heterogeneous diseases. In this case-based review, prognostic factors for treatment outcome in older adults will be covered along with discussion of a risk-based approach to potential therapeutic options, ranging from palliative care to novel therapies and reduced-intensity allogenic transplant.Hematology 02/2006; DOI:10.1182/asheducation-2006.1.185 · 2.86 Impact Factor