Nand S, Sosman J, Godwin J E, Fisher R I
Section of Hematology/Oncology, Loyola University of Chicago, Stritch School of Medicine, Maywood, IL 60153.
Blood. 1994 Jan 15;83(2):357-60.
In this phase I/II study, 9 patients with myelodysplastic syndromes (MDS) were treated with interleukin-3 (IL-3) followed by granulocyte-macrophage colony-stimulating factor (GM-CSF). Each treatment cycle was 28 days long and administered as follows: 1 microgram/kg/d IL-3 on days 1 through 7 and 3 micrograms/kg/d GM-CSF for days 8 through 21, followed by a 7-day rest period. IL-3 dose escalations were planned, but the dose of GM-CSF was fixed. Three patients had refractory anemia, 4 had refractory anemia with ringed sideroblasts, and 2 had refractory anemia with excess blasts. Six patients were dependent on red blood cell transfusions, 1 on platelet transfusions, and 2 on both. The absolute neutrophil count improved in 7 (77%) patients and the platelet count improved in 3 (33%) patients during therapy. Hemoglobin levels were unchanged. A clinically relevant response was seen in only 1 patient with thrombocytopenia, and he received five cycles of therapy. The neutrophil count decreased in 2 patients and the platelet count decreased in 4 patients during treatment. The toxicity of the treatment was significant. In the first cohort of 3 patients, 1 patient developed supraventricular tachycardia and congestive heart failure. In the second group, 1 patient developed progressive granulocytopenia and died of gram-negative septicemia. Because of the disparate toxicity, 3 more patients were treated at the same dose level. One of these experienced a high fever and bone pain requiring hospitalization. Because of these adverse effects, the IL-3 dose was not escalated and all patients received 1 microgram/kg/d for 7 days. We believe that sequential therapy with IL-3 and GM-CSF at these dose levels causes unacceptable toxicity in patients with MDS. The major toxic events occurred during weeks 4 and 5 after starting treatment and may have been primarily caused by GM-CSF therapy. Although neutrophil counts improve in most patients, the effect on red blood cells and platelets is minimal. At present, this form of therapy remains problematic and appears to have a limited potential in the management of MDS.
在这项I/II期研究中，9例骨髓增生异常综合征（MDS）患者先接受白细胞介素-3（IL-3）治疗，随后接受粒细胞-巨噬细胞集落刺激因子（GM-CSF）治疗。每个治疗周期为28天，给药方案如下：第1至7天给予1微克/千克/天的IL-3，第8至21天给予3微克/千克/天的GM-CSF，随后休息7天。计划逐步增加IL-3剂量，但GM-CSF剂量固定。3例患者为难治性贫血，4例为环形铁粒幼细胞性难治性贫血，2例为原始细胞过多性难治性贫血。6例患者依赖红细胞输血，1例依赖血小板输血，2例两者均依赖。治疗期间，7例（77%）患者的绝对中性粒细胞计数改善，3例（33%）患者的血小板计数改善。血红蛋白水平未改变。仅1例血小板减少患者出现了临床相关反应，该患者接受了5个周期的治疗。治疗期间，2例患者中性粒细胞计数下降，4例患者血小板计数下降。治疗毒性显著。在首批3例患者中，1例出现室上性心动过速和充血性心力衰竭。在第二组中，1例出现进行性粒细胞减少，死于革兰阴性菌败血症。由于毒性差异，又有3例患者在相同剂量水平接受治疗。其中1例出现高热和骨痛，需要住院治疗。由于这些不良反应，未增加IL-3剂量，所有患者均接受1微克/千克/天，共7天。我们认为，在这些剂量水平下，IL-3和GM-CSF序贯治疗对MDS患者会产生不可接受的毒性。主要毒性事件发生在开始治疗后的第4周和第5周，可能主要由GM-CSF治疗引起。虽然大多数患者中性粒细胞计数有所改善，但对红细胞和血小板的影响极小。目前，这种治疗方式仍然存在问题，在MDS的治疗中似乎潜力有限。
