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Fludarabine-induced severe necrotizing leukoencephalopathy in pediatric hematopoietic cell transplantation

Bone Marrow Transplantation volume 48, pages 729–731 (2013)Cite this article

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Fludarabine was nearly discarded from clinical use because of severe neurotoxicity at high doses.1 It is now a critical component of reduced intensity conditioning (RIC) hematopoietic cell transplantation (HCT) at lower doses. Currently, transplantation literature ascribes most drug-induced neurotoxicity to radiation, BU, CYA and MTX.1, 2 Beitinjaneh et al.3 recently described a heterogeneous group of patients with fludarabine-associated leukoencephalopathy (LE). However, all the patients had received CYA, the most common diagnosis was posterior reversible encephalopathy syndrome, and the acute toxic leukoencephlopathy (ATL) subset had imaging features of periventricular LE.4 In addition, Lee et al.5 recently described retrogeniculate blindness in adults exposed to fludarabine and radiation (GVHD prophylaxis unkown). We hypothesize that despite the use of a well-established fludarabine dose regimen, and the absence of BU, CYA and MTX in the transplant regimen, fludarabine can be unexpectedly and irreversibly neurotoxic. In all, 2 out of 157 children who received fludarabine-containing RIC HCT in our institution developed fludarabine-induced debilitating visual, corticospinal and sensory pathway-necrotizing LE, and eventually succumbed to sepsis.

The first patient was a previously described6 14-year-old boy with hypodiploid ALL. He had a history of vincristine neuropathy with induction therapy and had received 18 Gy craniospinal radiation and multiple courses of triple intrathecal chemotherapy for central nervous system (CNS) relapse. A second (BM) relapse occurred on therapy. After achieving a third CR, he was treated with a haploidentical donor HCT (no available HLA-matched donor). His last intrathecal therapy was 33 days prior to transplant. His preparative regimen included fludarabine 40 mg/m2 per day × 5 days, thiotepa, melphalan and OKT3, with mycophenolate and T-cell depletion as additional GVHD prophylaxis.7

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Acknowledgements

This work was supported in part by a Center of Excellence Grant from the State of Tennessee, the Assisi Foundation of Memphis and the American Lebanese Syrian Associated Charities (ALSAC). This study was approved by the St Jude Institutional Review Board prior to data review.

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Authors and Affiliations

  1. Department of Radiological Sciences, St Jude Children’s Research Hospital, Memphis, TN, USA

    K J Helton & Z Patay

  2. Department of Bone Marrow Transplantation and Cellular Therapy, St Jude Children’s Research Hospital, Memphis, TN, USA

    B M Triplett

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  1. K J Helton
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  2. Z Patay
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Correspondence to K J Helton.

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The authors declare no conflict of interest.

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This study was presented in part at the American Society of Neuroradiology, New York, NY, USA, May 2012.

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Helton, K., Patay, Z. & Triplett, B. Fludarabine-induced severe necrotizing leukoencephalopathy in pediatric hematopoietic cell transplantation. Bone Marrow Transplant 48, 729–731 (2013). https://doi.org/10.1038/bmt.2012.196

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