OUTCOMES OF ORAL VERSUS INTRAVENOUS DELIVERY OF BUSULFAN IN LYMPHOMA PATIENTS UNDERGOING AUTOLOGOUS HEMATOPOIETIC STEM CELL TRANSPLANTATION Open Access

Zhang, Hongzheng (2011)

Permanent URL: https://etd.library.emory.edu/concern/etds/f1881m302?locale=en
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Abstract



Abstract

Improved survival with intravenous (IV) over oral delivery of Busulfan in autologous stem cell
transplantation (ASCT) has been reported in a retrospective study for cohorts of lymphoma patients
treated with high-dose chemotherapy and conditioning regimen of busulfan, cyclophosphamide (Cy)
and etoposide (VP-16). However, the clinical advantage of pharmocokinetic-directed (PK)-based
dosing on regimen-related mortality and overall survival remains unclear. To address this issue we
performed a retrospective cohort study to compare the efficacy of PK-directed oral and IV busulfan-
based conditioning regimen in lymphoma patients undergoing ASCT from 2000-2010 at Emory
University. Sequential cohorts of patients included for analysis received oral (1.0mg/kg every 6 hours
x 16, n=77), IV16 (0.9mg/kg every 6 hours x 16, n=103), or IV4 busulfan (3.6mg/kg daily x 4, n=40)
followed by Cy (60mg/kg qd x 2), VP-16 (10 mg/kg qd x3) and infusion of previous collected
autologous stem cells. PK-directed dosing was performed to achieve a predefined target area under
the curve (AUC) range. For oral, IV16 and IV4 groups, respectively, the initial dose was 66, 63 and
255 mg, the T1/2 was 224, 190 and 188 hours, and the percentage of patients reaching the target range
was 42%, 89% and 88%, which were significantly different across groups (p<0.001). With a median
follow-up of 1761, 895 and 392 days, the 100-day mortality was 2.6%, 2.9% and 5.3% for oral, IV16,
and IV4, respectively (p=0.76). Five-year overall survival was 57.6% and 65.8%, for oral and IV
administration, respectively. In multivariable Cox regression models, age (HR=1.34, p=0.003) but
not the route of delivery had a significant effect on overall survival. Conclusions: PK-directed IV
busulfan improves the consistency of delivering a predefined target AUC over oral PK-directed
busulfan with similar early and late overall survival for lymphoma patients undergoing ASCT.


Table of Contents

Table of Contents

Page Committee members ………………………………….…………………………. 1 ChapterI. Introduction ……………………………….………. 2 Chapter II. Literature Review ………………………………….………. 6 Hematopoietic stem cell transplantation ...…………………..…... 8 Conditioning Regimen and Therapeutic drug monitoring ………………………………….………….. 11 Chapter III. Methodology ……………………………….…. 16 Study Design ………………………………….……………….……........……. 16 Pharmacokinetic-directed dosing ………………………………..….... 17 Statistical Analysis ………………………………….………………......….. 18 Risk Adjustment ………………………………….………….………....…….. 18 Chapter IV. Results ………………………………….………...…...…….. 22 Outcomes ………………………………….……………..………................ 24 Pharmacokinetics characteristics ………………………..….....…... 27 Cost analysis ………………………………….…………………....…...…….. 29 Chapter V. Discussions ………………………………….…….…...…….. 32 References ………………………………….…………………………............. 41 Appendix IRB approval file ………………………………….…………………....…..... 44














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