Cyclophosphamide metabolism, liver toxicity, and mortality following hematopoietic stem cell transplantation

Abstract

Liver toxicity caused by high-dose myeloablative therapy leads to significant morbidity after hematopoietic cell transplantation. We examined the hypothesis that liver toxicity after cyclophosphamide and total body irradiation is related to cyclophosphamide through its metabolism to toxins. Cyclophosphamide was infused at 60 mg/kg over 1 to 2 hours on each of 2 consecutive days, followed by total body irradiation. Plasma was analyzed for cyclophosphamide and its major metabolites. Liver toxicity was scored by the development of sinusoidal obstruction syndrome (veno-occlusive disease) and by total serum bilirubin levels. The hazards of liver toxicity, nonrelapse mortality, tumor relapse, and survival were calculated using regression analysis that included exposure to cyclophosphamide metabolites (as the area under the curve). Of 147 patients, 23 (16%) developed moderate or severe sinusoidal obstruction syndrome. The median peak serum bilirubin level through day 20 was 2.6 mg/dL (range, 0.5-41.1 mg/dL). Metabolism of cyclophosphamide was highly variable, particularly for the metabolite ocarboxyethyl-phosphoramide mustard, whose area under the curve varied 16-fold. Exposure to this metabolite was statistically significantly related to sinusoidal obstruction syndrome, bilirubin elevation, nonrelapse mortality, and survival, after adjusting for age and irradiation dose. Patients in the highest quartile of o-carboxyethyl-phosphoramide mustard exposure had a 5.9-fold higher risk for nonrelapse mortality than did patients in the lowest quartile. Engraftment and tumor relapse were not statistically significantly related to cyclophosphamide metabolite exposure. Increased exposure to toxic metabolites of cyclophosphamide leads to increased liver toxicity and nonrelapse mortality and lower overall survival after hematopoietic cell transplantation.

Pharmacogenomic associations in ABCB1 and CYP3A5 with acute kidney injury and chronic kidney disease after myeloablative hematopoietic cell transplantation

“…1 The demographics of the 121 patients for whom DNA was available did not differ significantly from those of the cohort as a whole.…”

“…The clinical risk factors for SOS and AKI in this cohort have been reported previously. 1,2 Seven days before the infusion of stem cells, cyclophosphamide was infused through a central venous access catheter for over 1-2 h at a dose of 60 mg/kg body weight. On the following day, a second infusion of the same dose of cyclophosphamide was given.…”

“…The pharmacokinetics and pharmacodynamics of cyclophosphamide and metabolites in this cohort of patients has been published. 1 After a day of rest, total body irradiation (9-14.2 Gy) was given daily for three or four subsequent days in hyperfractionated doses from opposing cobalt sources. The kidneys were not shielded.…”

“…However, patient survival is limited by regimen-related toxicities. 1 Renal disease is a major complication post-HCT with acute kidney injury (AKI) and chronic kidney disease (CKD) significantly contributing to nonrelapse mortality in these patients. 2,3 The genesis of renal disease after myeloablative allogeneic HCT is multifactorial and the identification of risk factors for both AKI and CKD is critical to allow for preventive measures.…”

Mutations in the gene encoding the PML nuclear body protein Sp110 are associated with immunodeficiency and hepatic veno-occlusive disease

“…We performed a targeted SP110 SNP association study using 69 SNPs with an average inter-SNP distance of 0.826 kb in a cohort of 47 affected individuals and 62 controls who had received standardized myeloablative conditioning therapy 5 . Measures of association between hVOD and alleles of SP110 did not reach statistical significance.…”