PubMed · 6929249
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T Ogada. 1980. Myelogenous leukemia: current practice.. https://pubmed.ncbi.nlm.nih.gov/6929249/
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The incidence, risk factors and mortality of veno-occlusive disease (VOD) were identified for 142 pediatric hematopoietic stem cell (HSC) transplant recipients with hematological malignancies (83), solid tumors (41) and nonmalignant diseases (18). This historical cohort of 142 HSC transplant patients, from January 1993 through June 2000, was assessed by chart review. Risk factors for the development of VOD and mortality were assessed by multiple logistic regression and Kaplan-Meier survival curves respectively. The incidence of VOD was 18.3% (26/142 transplants). Multivariate analysis reconfirmed the known pretransplant risk factors of induction therapy with busulfan and transplantation with matched unrelated donor cells as significant risk factors for the development of VOD. In addition, two new risk factors, positive CMV serology in the recipient and TPN provided in the 30 days prior to transplant, were identified. Mortality in transplant patients at 100 days was greater in the VOD-positive group (10/26 (38.5%)) compared to the VOD-negative group (11/116 (9.5%) (P=0.001)). The risk of death was 4.97 times higher with 95% CIs (2.11, 11.71) for the VOD-positive group. Decreasing the risk factors for VOD may decrease mortality in this patient population.
Busulphan (Bu) is an alkylating agent used in preparative regimen before stem cell transplantation (SCT). Bu has a narrow therapeutic window, and underdosing or overdosing may have a fatal outcome for the patient. Therapeutic drug monitoring (TDM) combined with dose adjustment is currently used to optimize and individualize therapy with Bu. However, this approach is limited to centers with laboratory facilities. An automated and easy method for measurement of Bu plasma concentrations may facilitate TDM for Bu and thus improve the clinical outcome. A solid-phase microextraction (SPME) on line with gas chromatography (GC) and mass-spectrometric detection to quantify Bu in human plasma samples was developed using in-vial derivatization. Bu was mixed with reagent in a 2-mL vial and shaken for 15 minutes at 80 degrees C; subsequently, the SPME fiber was immersed into the vial for 15 minutes. The fiber was washed in water for 10 seconds before injection. Several parameters influencing the extraction and recovery were studied, such as absorption and desorption times, the effects of the temperature on the reaction, and the shaking time on the derivatization yield. Carbowax-divinylbenzene, polyacrylate, and polydimethylsiloxane fibers were tested. The carbowax-divinylbenzene fiber resulted in the highest recovery in plasma samples. The validation of the method showed a high chromatographic selectivity and a good sensitivity (LOQ = 20 ng/mL). Coefficient of variation for SPME was less than 15%. The results showed good correlation between Bu concentrations and response within the range of 40 to 2500 ng/mL (R2 = 0.999). The accuracy ranged from 94% to 106%. This is well in line with the international criteria for validation. The present method was applied to patient plasma. The obtained results were comparable with the results obtained from GC with electron capture detection. The authors conclude that this method has shortened the analysis time considerably and is fully automated, which benefits TDM of Bu in SCT patients.
BACKGROUND: High-dose busulfan is widely used as part of conditioning regimens for patients who are undergoing hematopoietic stem cell or bone marrow transplantation. High plasma concentrations of busulfan have been linked to the occurrence of hepatic venoocclusive disease (VOD), a severe complication associated with a high mortality. Because conjugation with glutathione, the major route of biotransformation of busulfan, is predominantly catalyzed by the isozyme glutathione S-transferase A1 (GSTA1), we hypothesized that low expression or function of GSTA1 in liver caused by genetic polymorphisms may be the mechanism underlying VOD. METHODS: Immunoblot analysis of GSTA and measurement of busulfan-glutathione conjugation by liquid chromatography-mass spectrometry were performed in 48 normal human liver samples. To search for polymorphisms, the complete GSTA1 coding regions and the promoter fragment were sequenced. All results were compared by multivariate analysis. RESULTS: Absolute levels of GSTA protein and formation rates of busulfan-glutathione conjugate displayed a 7- and 8-fold range, from 240 to 1600 pmol/mg and 25 to 205 pmol/min per milligram of total cytosolic protein, respectively, and correlate (r2 = 0.49, P <.0001). A total of 8 single nucleotide polymorphisms (SNPs) of GSTA1 were identified, 1 of which was a silent mutation in exon 5 (A375G); all others were found in the promoter region. Haplotype analysis revealed the existence of 5 defined alleles. There was no significant relationship between any of the GSTA1 SNPs or haplotypes and either hepatic glutathione S-transferase A (GSTA) expression or GSTA1 function. CONCLUSIONS: The identified GSTA1 polymorphisms are not likely to be related to the VOD because they do not appear to be associated with changes in GSTA expression or function. Compared with other members of the GST family, GSTA1 displays surprisingly little variation.