Bianco J A, Appelbaum F R, Nemunaitis J, Almgren J, Andrews F, Kettner P, Shields A, Singer J W
Marrow Transplant Program, Department of Veterans Affairs Medical Center, Seattle, WA.
Blood. 1991 Sep 1;78(5):1205-11.
Disease relapse and transplant related toxicities have limited the application of bone marrow transplantation (BMT) in the treatment for hematologic malignancies. Because elevated levels of tumor necrosis factor alpha (TNF-alpha) have been correlated with the development of transplant related complications, we conducted a phase I-II trial of pentoxifylline (PTX), a xanthine derivative capable of down-regulating TNF-alpha production, in patients with hematologic malignancies undergoing BMT. Thirty consecutive adult patients (median age, 34) were entered and received either an allogeneic (n = 26) or autologous (n = 4) BMT. Patients were enrolled at increasing dose levels (1,200, 1,600, and 2,000 mg/d) from day -10 through day +100 posttransplant. PTX was well tolerated with no significant adverse side effects noted at any of the dose levels administered. The actuarial day 100 survival for these 30 patients was 90% (95% confidence interval 79% to 100%). When compared with a good risk control group, PTX recipients experienced less mucositis (3.7 +/- 1.1 v 18.7 +/- 1.1 days, P = .004), less hepatic venocclusive disease (10% v 65%, P = .001), a lower incidence of renal insufficiency (3% v 65%, P = .0003), required less days of total parenteral nutrition (TPN) (24.0 +/- 1.3 v 35.0 +/- 2.4, P = .001) and were discharged from the hospital earlier than controls (day 26.0 +/- 1.8 v 37.0 +/- 3.8, P = .01). In addition the incidence of graft-versus-host disease (GVHD) greater than or equal to grade II was also reduced among the PTX recipients (35% v 68%, P = .03). PTX at doses in excess of 1,200 mg/d further reduced the severity of mucositis, and TPN requirements resulting in earlier hospital discharge than patients receiving 1,200 mg/d of PTX. In this study oral administration of PTX in doses up to 2,000 mg/d was well tolerated and associated with a reduction in morbidity and mortality in patients undergoing BMT. Prospective randomized trials are currently in progress to test these preliminary observations.
疾病复发和移植相关毒性限制了骨髓移植（BMT）在血液系统恶性肿瘤治疗中的应用。由于肿瘤坏死因子α（TNF-α）水平升高与移植相关并发症的发生有关，我们对己酮可可碱（PTX）进行了一项I-II期试验，己酮可可是一种能够下调TNF-α产生的黄嘌呤衍生物，用于接受BMT的血液系统恶性肿瘤患者。连续纳入30例成年患者（中位年龄34岁），接受异基因（n = 26）或自体（n = 4）BMT。患者在移植后第-10天至第+100天以递增剂量水平（1200、1600和2000 mg/d）入组。PTX耐受性良好，在所给予的任何剂量水平均未观察到明显的不良副作用。这30例患者的100天精算生存率为90%（95%置信区间79%至100%）。与良好风险对照组相比，PTX接受者的黏膜炎较轻（3.7±1.1天对18.7±1.1天，P = .004），肝静脉闭塞病较少（10%对65%，P = .001），肾功能不全发生率较低（3%对65%，P = .0003），所需全胃肠外营养（TPN）天数较少（24.0±1.3天对35.0±2.4天，P = .001），且比对照组更早出院（第26.0±1.8天对37.0±3.8天，P = .01）。此外，PTX接受者中大于或等于II级移植物抗宿主病（GVHD）的发生率也有所降低（35%对68%，P = .03）。剂量超过1200 mg/d的PTX进一步降低了黏膜炎的严重程度和TPN需求，导致比接受1200 mg/d PTX的患者更早出院。在本研究中，口服剂量高达2000 mg/d的PTX耐受性良好，且与接受BMT患者的发病率和死亡率降低相关。目前正在进行前瞻性随机试验以验证这些初步观察结果。
