Raghavachar A, Ganser A, Freund M, Heimpel H, Herrmann F, Schrezenmeier H
Department of Internal Medicine III, University of Ulm, Germany.
Cytokines Mol Ther. 1996 Dec;2(4):215-23.
We have assessed in a phase I/II clinical study the tolerability and efficacy of long-term application of recombinant human interleukin-3 (rh-IL-3) in combination with antithymocyte globulin (ATG) and cyclosporin A (CSA) in 13 patients with aplastic anemia who were refractory to or relapsed after previous immunosuppressive treatment. Four cohorts of three patients were consecutively enrolled so that they received rh-IL-3 on days 9, 6, 3 and 1 after start of ATG/CSA treatment. Yeast-derived recombinant human IL-3 was administered by daily subcutaneous injection until day 90 at a dosage of 250 micrograms/m2. Long-term application of rh-IL-3 was well tolerated. The combination of rh-IL-3 with immunosuppression did not modify the known toxicities of ATG and CSA. Incidence and severity of rh-IL-3-related adverse events was less than in other phase I/II trials of rh-IL-3 as single-agent therapy. One might speculate that co-medication with CSA alleviates rh-IL-3-induced side effects. Three of eight patients with refractory AA and all four patients with relapsed AA responded to the combined treatment within four months. The median time to response was 91.5 days. There was evidence for an rh-IL-3-dependent response in two patients. Long-term rh-IL-3 did not cause stem cell exhaustion. One patient died early during the course of the study from EBV-driven lymphoproliferative disease. Two patients developed acute myeloid leukemia 4 and 22 months after cessation of rh-IL-3. In conclusion, long-term rh-IL-3 in combination with immunosuppression is well tolerated. The response rate to the combined treatment in refractory and relapsed AA was high. Recombinant human IL-3-dependent responses suggest efficacy. A prospective randomized trial comparing immunosuppression alone versus a combination with rh-IL-3 is warranted.
我们在一项I/II期临床研究中评估了重组人白细胞介素-3（rh-IL-3）与抗胸腺细胞球蛋白（ATG）及环孢素A（CSA）联合长期应用于13例再生障碍性贫血患者的耐受性和疗效，这些患者对先前的免疫抑制治疗无效或复发。连续纳入四组，每组三名患者，使他们在ATG/CSA治疗开始后的第9、6、3和1天接受rh-IL-3治疗。酵母衍生的重组人IL-3通过每日皮下注射给药，剂量为250微克/平方米，直至第90天。rh-IL-3的长期应用耐受性良好。rh-IL-3与免疫抑制联合应用并未改变ATG和CSA已知的毒性。与rh-IL-3相关的不良事件的发生率和严重程度低于其他rh-IL-3单药治疗的I/II期试验。有人可能推测，与CSA联合用药可减轻rh-IL-3诱导的副作用。8例难治性再生障碍性贫血患者中的3例以及所有4例复发再生障碍性贫血患者在四个月内对联合治疗有反应。中位反应时间为91.5天。有证据表明两名患者出现了rh-IL-3依赖性反应。长期rh-IL-3未导致干细胞耗竭。一名患者在研究过程中早期死于EBV驱动的淋巴增殖性疾病。两名患者在rh-IL-3停药后4个月和22个月发生急性髓系白血病。总之，rh-IL-3与免疫抑制联合长期应用耐受性良好。难治性和复发性再生障碍性贫血患者对联合治疗的反应率很高。重组人IL-3依赖性反应提示有疗效。有必要进行一项前瞻性随机试验，比较单独免疫抑制与联合rh-IL-3治疗的效果。
