Journal Article

Fludarabine with pharmacokinetically guided IV busulfan is superior to fixed-dose delivery in pretransplant conditioning of AML/MDS patients

Champlin, R E, Chu, D, Parmar, S, Valdez, B C, Rondon, G, Myers, A, Kawedia, J, Chen, J, Nieto, Y, Madden, T, Popat, U, de Lima, M, Al-Atrash, G, Gulbis, A, Andersson, B S, Milton, D R, Fernandez-Vina, M, Meng, Q H, Kebriaei, P, Shpall, E J, Thall, P F, Martinez, C, Alousi, A, Worth, L L, Jones, R B

2017

Overview

We hypothesized that IV busulfan (Bu) dosing could be safely intensified through pharmacokinetic (PK-) dose guidance to minimize the inter-patient variability in systemic exposure (SE) associated with body-sized dosing, and that this should improve outcome of AML/MDS patients undergoing allogeneic stem cell transplantation. To test this hypothesis, we treated 218 patients (median age 50.7 years, male/female 50/50%) with fludarabine 40 mg/m 2 once daily x4, each dose followed by IV Bu, randomized to 130 mg/m 2 ( N =107) or PK-guided to average daily SE, AUC of 6000 μ M  min ( N =111), stratified for remission status and allo-grafting from HLA-matched donors. Toxicity and GvHD rates in the groups were similar; the risk of relapse or treatment-related mortality remained higher in the fixed-dose group throughout the 80-month observation period. Further, PK-guidance yielded safer disease control, leading to improved overall and PFS, most prominently in MDS patients and in AML patients not in remission at allogeneic stem cell transplantation. We conclude that AML/MDS patients receiving pretransplant conditioning treatment with our 4-day regimen may benefit significantly from PK-guided Bu dosing. This could be considered an alternative to fixed-dose delivery since it provides the benefit of precise dose delivery to a predetermined SE without increasing risk(s) of serious toxicity and/or GvHD.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 13/100 / 631/45 / 692/700/565/1436/99 / Acute myelocytic leukemia / Adult / Antineoplastic Combined Chemotherapy Protocols - therapeutic use / Antineoplastic Combined Chemotherapy Protocols - toxicity / Bone marrow / Busulfan / Busulfan - administration & dosage / Busulfan - pharmacokinetics / Busulfan - toxicity / Care and treatment / Cell Biology / Conditioning / Disease control / Dosage / Dosage and administration / Drug Monitoring - methods / Drug therapy / Female / Fludarabine / Graft vs Host Disease - etiology / Graft-versus-host reaction / Hematology / Hematopoietic Stem Cell Transplantation - methods / Hematopoietic Stem Cell Transplantation - mortality / Histocompatibility antigen HLA / Humans / Internal Medicine / Leukemia, Myeloid, Acute - mortality / Leukemia, Myeloid, Acute - therapy / Male / Medicine / Medicine & Public Health / Middle Aged / Myelodysplastic Syndromes - mortality / Myelodysplastic Syndromes - therapy / original-article / Patients / Pharmacokinetics / Pharmacology / Public Health / Recurrence / Remission / Stem cell transplantation / Stem Cells / Survival Analysis / Toxicity / Transplantation / Transplantation Conditioning - methods / Transplantation Conditioning - mortality / Transplantation, Homologous - methods / Transplantation, Homologous - mortality / Treatment Outcome / Vidarabine - administration & dosage / Vidarabine - analogs & derivatives