PubMed · 5260190
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W A Littler, J M Kay, P S Hasleton, D Heath. 1969. Busulphan lung.. https://doi.org/10.1136/thx.24.6.639
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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.
OBJECTIVE: To evaluate the long-term outcome of 60 leukemia patients undergoing allogeneic hematopoietic stem cell transplantation (allo-HSCT) prepared with busulphan-cyclophosphamide (BU-CTX(2)) conditioning regimen. METHODS: From April 1994 to August 2000, 60 leukemia patients (35 male, 25 female; median age 32 years old), including 20 acute myeloid leukemia (AML, CR(1) n = 19, CR(2) n = 1), 15 acute lymphocytic leukemia (ALL, CR(1) n = 8, CR(2) n = 6, CR(3) n = 1), and 25 chronic myeloid leukemia (CML, CP(1) n = 24, CP(2) n = 1) received allogeneic hematopoietic stem cells from HLA-identical siblings (n = 53), 1-locus mismatched siblings (n = 4), or HLA-identical unrelated donor (n = 3). BU-CTX(2) was used as conditioning regimen. All patients received cyclosporine A and either methotrexate (n = 54) or methylprednisolone (n = 6) for graft-versus-host disease (GVHD) prophylaxis. RESULTS: All 60 patients got sustained engraftment. Acute GVHD (aGVHD) occurred in 22 patients (36.7%), while the incidence of aGVHD was 48.0% for the CML, 30.0% for the AML and 26.7% for the ALL patients. Thirty-eight patients are still alive in complete remission with a median follow-up of 30 (12 approximately 84) months and 22 died. The main causes of death were aGVHD in 3, CMV-IP in 7, and relapse in 11 patients. The remaining one died of pulmonary infection. Among 11 patients who died of relapse, 8 were ALL relapsed in the early posttransplant stage. All 4 long-term survivors of ALL developed chronic GVHD. The probability of DFS at 3 year for CML, AML and ALL patients was 80.0%, 70.0% and 26.7%, respectively. CONCLUSION: BU-CTX(2) is an effective conditioning regimen for patients with AML and CML, resulting in a low relapse and high long-term survival rate. However, it is not effective enough for patients with ALL, because of a higher incidence of relapse.
High-dose chemoradiotherapy conditioning regimens for autologous stem cell transplantation (ASCT) are generally held to give similar results in multiple myeloma (MM), but no specific comparative study has been published. We addressed this issue by comparing the main high-dose chemoradiotherapy regimens used in the Spanish Registry. Patient cohorts included 315 cases treated with 200 mg/m2 melphalan (MEL200), 127 patients with 140 mg/m2 melphalan plus total body irradiation (MEL140 + TBI) and 121 cases with 12 mg/kg busulphan plus 140 mg/m2 melphalan (BUMEL). After ASCT, granulocyte and platelet recovery time was similar in all conditioning groups. There were no differences in transplant-related mortality. All regimens yielded a similar response in reference to pre-ASCT MM status, although BUMEL produced a slightly better overall response when compared with the other regimens (97% vs. 89% and 92%, P = 0.003). The 5-year overall survival (OS) with BUMEL was 47% [95% confidence interval (CI) 26-68] compared with 43% (CI 31-54) for MEL140 + TBI and 37% (CI: 18-56) for MEL200. The median survival for the BUMEL group was 64 months compared with 45 and 37 months for the MEL200 and MEL140 + TBI groups respectively. These differences were non-significant (P = 0.2). The median event-free survival (EFS) was better for BUMEL (32 months) than for MEL200 (22 months) or for MEL140 + TBI (20 months). The differences in EFS between BUMEL and the other conditioning regimens reached statistical significance (P = 0.01). Nevertheless, the adjusted multivariate analysis for OS and EFS revealed that the conditioning regimens had no independent prognostic value. We concluded that three different conditioning regimens, commonly used for ASCT in MM, have a similar antimyeloma effect. However, the trend for better results observed in our series with BUMEL requires a prospective trial.