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To the Editor: All too often in medical practice, treatment approaches continue to be widely employed despite a lack of evidence supporting benefit, and some therapies even persist in the face of clear evidence for a lack of benefit [1]. Whether due to ideology, a desire to cater to patients' beliefs and preferences, or clinical inertia, old habits die hard. For example, physicians still regularly prescribe antibiotics for self-limited viral infections in otherwise healthy patients, and surgeons persevere in operating upon patients with chronic lower back pain or degenerative knee arthritis, even though these interventions are known to be unhelpful and may do harm. We believe that routine use of anticonvulsant prophylaxis in patients receiving busulfan (BSF) chemotherapy, regardless of the dose, or route of administration, is another example of an outdated clinical practice that persists despite a paucity of good-quality supporting medical evidence.

BSF, a noncell-cycle-specific alkylating agent synthesized in the 1940s and in widespread clinical use for the treatment of chronic myeloid leukemia from the mid-1950s until the dawn of the tyrosine kinase inhibitor era, has been employed for more than 30 years in a variety of conditioning regimens for hematopoietic cell transplantation (HSCT). BSF crosses the blood-brain barrier and at high doses can cause severe neurotoxicity, including seizures that are most commonly tonic-clonic in character [2]. When BSF is employed in the conditioning of patients undergoing HSCT, oral phenytoin, benzodiazepines, or newer anticonvulsants such as levetiracetam are often used seizure prophylaxis [3, 4].

The routine use of concomitant anticonvulsant prophylaxis with BSF-containing HSCT conditioning regimens stems from publications in the early 1980s in which patients developed seizures after receiving oral BSF cumulative doses of at least 12–16 mg/kg [5]. For instance, among 96 patients receiving 16–28 mg/kg BSF in a 1990 pediatric transplant study, the seizure rate in the absence of anticonvulsant prophylaxis was 7.5% [2]. Since then, anticonvulsant prophylaxis has been routinely delivered in both allografted and autografted patients, regardless of the specific dose or route of administration of BSF employed in the conditioning schedule.

Since 1995, we (G.J.R-A. and D.G-A.) have been allografting patients using a reduced intensity conditioning regimen, which employs oral BSF, fludarabine, and cyclophosphamide, using a cumulative BSF dose of 8 mg/kg administered in two consecutive days [6]. Because of the lower dose of BSF administered in this protocol compared with the doses at which neurotoxicity was observed in earlier studies, we have never used anticonvulsant prophylaxis and, after allografting a total of 344 individuals, we have not observed any seizures, nor have we seen other neurologic adverse effects attributable to BSF. The advent of pharmacokinetically targeted intravenous BSF for HSCT conditioning may further increase the margin of safety of this drug [7].

Since anticonvulsants have their own associated adverse effects and can alter the pharmacokinetics of other drugs (including BSF) [8]; perhaps, it is time to reconsider the prophylactic use of anticonvulsants in patients receiving BSF prior to HSCT, at least if the cumulative BSF dose is 8 mg/kg or lower. Clinical progress and evolution of the art of medicine frequently rely on questioning established dogmata, including routine practices that have become familiar and comfortable because they offer protection against threats that may no longer represent a genuinely important danger [9].

References

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  • 1
    Newman DH. Believing in treatments that don't work. The New York Times 2 April 2009. Available at: http://well.blogs.nytimes.com/2009/04/02/the-ideology-of-health-care/.
  • 2
    Vassal G,Deroussent A,Hartmann O, et al. Dose-dependent neurotoxicity of high-dose busulfan in children: a clinical and pharmacological study.Cancer Res 1990; 50: 62036207.
  • 3
    Eberly AL,Anderson GD,Bubalo JS,McCune JS. Optimal prevention of seizures induced by high-dose busulfan. Pharmacotherapy 2008; 28: 15021510.
  • 4
    Soni S,Skeens M,Termuhlen AM, et al. Levetiracetam for busulfan-induced seizure prophylaxis in children undergoing hematopoietic stem cell transplantation. Pediatr Blood Cancer 2012; Epub Feb 29. doi: 10.1002/pbc.24126.
  • 5
    Marcus RE,Goldman JM. Convulsions due to high-dose busulphan. Lancet 1984; 2:1463.
  • 6
    Ruiz-Argüelles GJ,Tarín-Arzaga LC,González-Carrillo ML, et al. Therapeutic choices in patients with Ph1 (+) chronic myelogenous leukemia living in México in the tyrosine kinase inhibitors (TKI) era: Stem cell transplantation or TKI's? Bone Marrow Transplant 2008; 42: 2328.
  • 7
    Yeh RF,Pawlikowski MA,Blough DK, et al. Accurate targeting of daily intravenous busulfan with 8-hour blood sampling in hospitalized adult hematopoietic cell transplant recipients. Biol Blood Marrow Transplant 2012; 18: 265272.
  • 8
    Hassan M,Oberg G,Bjorkholm M, et al. Influence of prophylactic anticonvulsant therapy on high-dose busulphan kinetics. Cancer Chemother Pharmacol 1993; 33: 181186.
  • 9
    Ruiz-Argüelles GJ,Gómez-Almaguer D. Breaking dogmata to help patients: Non-myeloablative hematopoietic stem cell transplantation. Expert Opin Biol Ther 2004; 4: 16931699.

Guillermo J. Ruiz-Argüelles*, David Gomez-Almaguer†, David P. Steensma‡, * Director General, Centro de Hematología y Medicina Interna, Clinica Ruiz de Puebla, México, † Chair. Department of Hematology, Hospital Universitario de Nuevo León, México, ‡ Associate Professor, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts