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Conditioning

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

Bone Marrow Transplantation volume 52, pages 580–587 (2017)Cite this article

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Abstract

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/m2 once daily x4, each dose followed by IV Bu, randomized to 130 mg/m2 (N=107) or PK-guided to average daily SE, AUC of 6000 μM 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.

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Acknowledgements

This work was funded by the National Cancer Institute grants P01-CA49639 and 2P30-CA16672, and by support from Various Donors’ Fund and the Stephen and Lavinia Boyd Fund for Leukemia Research. The authors acknowledge the excellent work of the clinical staff, research nurses and nursing and pharmacy staff of the blood and marrow transplantation unit, without whom this project would not have been possible. The assistance of Mr. Matthew Hernandez in preparation of this manuscript is gratefully acknowledged.

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Author notes

  1. M de Lima & M Fernandez-Vina

    Present address: Department of Medicine-Hematology and Oncology, UH Case Medical Center, Cleveland, OH, USA.,

  2. M Fernandez-Vina

    Present address: Department of Pathology, Stanford University School of Medicine, Stanford, CA, USA.,

Authors and Affiliations

  1. Department of Stem Cell Transplantation & Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    B S Andersson, B C Valdez, G Al-Atrash, J Chen, D Chu, C Martinez, S Parmar, U Popat, Y Nieto, P Kebriaei, A Alousi, M de Lima, G Rondon, E J Shpall, R B Jones & R E Champlin

  2. Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    P F Thall & D R Milton

  3. Division of Pharmacy, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    A Gulbis & T Madden

  4. Division of Laboratory Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    Q H Meng

  5. Division of Pharmacy Research, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    A Myers & J Kawedia

  6. Division of Pediatrics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    L L Worth

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Correspondence to B S Andersson.

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Competing interests

BSA was previously a consultant for Otsuka America Pharmaceuticals, Inc., and REC has received research funding from Otsuka America Pharmaceuticals, Inc.

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Andersson, B., Thall, P., Valdez, B. et al. Fludarabine with pharmacokinetically guided IV busulfan is superior to fixed-dose delivery in pretransplant conditioning of AML/MDS patients. Bone Marrow Transplant 52, 580–587 (2017). https://doi.org/10.1038/bmt.2016.322

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