Beelen D W, Quabeck K, Kaiser B, Wiefelspütz J, Scheulen M E, Graeven U, Grosse-Wilde H, Sayer H G, Schaefer U W
Department of Bone Marrow Transplantation, University Hospital Essen, Federal Republic of Germany.
Transplantation. 1990 Sep;50(3):421-7. doi: 10.1097/00007890-199009000-00013.
The feasibility and toxicity of six-week continuous intravenous 3 mg/kg/day cyclosporine (CsA) treatment in conjunction with a short course of methotrexate (MTX) was studied in 69 consecutive patients after HLA genotypically identical bone marrow transplantation. In light of the uncertain efficacy of prolonged oral CsA immunoprophylaxis in preventing de novo chronic graft-versus-host disease (GVHD). CsA treatment was terminated three months after BMT. Sixty-one (88%) patients received the full intravenous regimen and no patient exclusions were necessary due to intolerable adverse effects. Weekly median blood CsA concentrations ranged between 820 ng/ml in the first and 648 ng/ml in the sixth week of treatment. No significant correlation existed between blood CsA concentrations and CsA dosages. Major adverse effects of the regimen included hypertension in 36%, acute nephrotoxicity in 36%, acute hepatotoxicity in 41%, and central nervous system toxicity in 4% of the patients. Since hepatotoxicity occurred predominantly in the early posttransplant period (median onset day 9), the relatively high incidence of this untoward effect might have been additionally caused by MTX and/or the preparative regimen. Blood CsA concentrations and CsA dosages did not significantly correlate with serum creatinine or total and conjugated bilirubin levels. In addition, blood CsA and serum creatinine levels did not differ between hypertensive and normotensive patients. Acute GVHD developed in 16% of the patients. Median CsA doses and blood CsA concentrations were identical for each week after BMT for patients contracting acute GVHD as compared with those without acute GVHD. In 55 patients surviving without acute or secondary chronic GVHD, the cumulative probability of de novo chronic GVHD after termination of CsA treatment was 13%. In conclusion, this regimen was tolerable and provided constant blood CsA concentrations for six posttransplant weeks that were not adversely influenced by the development of acute GVHD. Restriction of CsA treatment to the first three months after BMT appeared not to increase the risk of de novo chronic GVHD, which challenges regimens employing oral CsA immunoprophylaxis for 6-12 months after BMT.
在69例接受HLA基因分型相同的骨髓移植的连续患者中，研究了为期六周、每天静脉注射3mg/kg环孢素（CsA）联合短期甲氨蝶呤（MTX）治疗的可行性和毒性。鉴于延长口服CsA免疫预防在预防新发慢性移植物抗宿主病（GVHD）方面疗效不确定，CsA治疗在骨髓移植后三个月终止。61例（88%）患者接受了完整的静脉给药方案，且没有患者因无法耐受的不良反应而被排除。治疗第一周和第六周的每周CsA血药浓度中位数分别为820 ng/ml和648 ng/ml。血CsA浓度与CsA剂量之间无显著相关性。该方案的主要不良反应包括36%的患者出现高血压、36%的患者出现急性肾毒性、41%的患者出现急性肝毒性以及4%的患者出现中枢神经系统毒性。由于肝毒性主要发生在移植后早期（中位发病时间为第9天），这种不良影响的相对高发生率可能还由MTX和/或预处理方案导致。血CsA浓度和CsA剂量与血清肌酐或总胆红素及结合胆红素水平无显著相关性。此外，高血压患者和血压正常患者的血CsA和血清肌酐水平无差异。16%的患者发生了急性GVHD。与未发生急性GVHD的患者相比，发生急性GVHD的患者在骨髓移植后每周的CsA中位剂量和血CsA浓度相同。在55例未发生急性或继发性慢性GVHD而存活的患者中，CsA治疗终止后新发慢性GVHD的累积概率为13%。总之，该方案耐受性良好，在移植后六周内可提供稳定的血CsA浓度，且不受急性GVHD发生的不利影响。将CsA治疗限制在骨髓移植后的前三个月似乎不会增加新发慢性GVHD的风险，这对骨髓移植后采用口服CsA进行6 - 12个月免疫预防的方案提出了挑战。
