Pretransplantation conditioning influence on the occurrence of cyclosporine or FK-506 neurotoxicity in allogeneic bone marrow transplantation

Abstract

Background and purpose: Transplantation conditioning regimens have been shown to affect the brain imaging appearance in patients with cyclosporine or FK-506 neurotoxicity. We assessed whether the occurrence of neurotoxicity was affected by the choice of conditioning regimen used before allogeneic bone marrow transplantation (allo-BMT).

Methods: An allo-BMT was performed in 290 patients conditioned before transplantation with myeloablative therapy. Neurotoxicity from cyclosporine or FK-506 developed in 21 (7.2%) of these patients, as confirmed with CT or MR imaging. Two hundred seventy-four (94%) of these 290 patients were conditioned with minor variations of one of five fundamental regimens: cyclophosphamide (Cy)/busulfan (n = 97), Cy/total body irradiation (TBI) (n = 122), Cy/thiotepa/TBI (n = 40), bischloroethylnitrosourea/etoposide/cytarabine/melphalan, or BEAM (n = 10), and Cy/thiotepa/busulfan (n = 5). The remaining 16 patients were prepared with variable regimens. The rates of occurrence of cyclosporine or FK-506 neurotoxicity relative to these conditioning regimens were compared.

Results: The lowest rate of cyclosporine or FK-506 neurotoxicity was found in those patients conditioned with Cy (2 days)/busulfan (4 days) (5.1%) or Cy (2 days)/TBI (4 days) (5.9%). Rate of neurotoxicity increased with lengthier conditioning regimens. A high rate of neurotoxicity was present in those patients conditioned with Cy (4 days)/TBI (4 days) (13.7%), and this was statistically significant (P <.05) when compared with Cy (2 days)/busulfan (4 days).

Conclusion: The rate of occurrence of cyclosporine or FK-506 neurotoxicity varies with the conditioning regimen used, with lengthier regimens associated with a higher rate of neurotoxicity. As the length of the conditioning regimen equates to the total dose of chemotherapy administered, it suggests that the intensity of the regimen is correlated to the predisposition to neurotoxicity from cyclosporine or FK-506.

Fig 1.

Images in a 40-year-old woman with non-Hodgkin lymphoma who presented 27 days after allo-BMT with a seizure. Conditioning regimen was BEAM therapy. Blood pressure was 114/64 mm Hg and FK-506 level at the time of toxicity was 12.7 ìg/L (normal range, 5–20 ìg/l). A–D, FLAIR images demonstrate abnormal signal intensity in the cortex and subcortical white matter of the left inferior temporal-occipital junction (arrowhead in A), occipital poles (large arrows in A), parietal region (short arrows in B and C), and frontal lobes (long arrows in C and D) bilaterally, typical of cyclosporine or FK-506 neurotoxicity. The brain lesions in this patient are somewhat confluent and demarcate the junction between lateral cerebral hemispheric branches from the middle cerebral artery and medial hemispheric supply from the anterior and posterior cerebral arteries.