Greenberg P L, Negrin R, Nagler A
Hematology Division, Stanford University School of Medicine, CA 94305.
Cancer Surv. 1990;9(1):199-212.
Based on the results of preclinical and in vitro studies demonstrating enhanced granulocytic proliferation and differentiation induced by granulocyte-monocyte and granulocyte-colony stimulating factors (GM-CSF and G-CSF), these recombinant human haemopoietic growth factors have been used to treat cytopenic patients with myelodysplastic syndromes (MDS). Laboratory investigations have shown responsiveness of enriched haemopoietic precursors in vitro to the proliferative and granulocytic differentiative stimuli of G-CSF, generally without increased clonal regeneration. To date, five short-term phase I/II clinical trials using GM-CSF have demonstrated that 38 of 45 treated patients had improvements in neutrophil counts, 14 had increased reticulocyte counts, with three of these patients having decreased red blood cell transfusion requirements, and eight had a transient increase in platelets. In 12 patients an increase in marrow and/or peripheral blood blasts was noted. Seven patients progressed to acute myeloid leukaemia (AML), particularly patients with greater than 15% marrow blasts. In a longer term study, five patients received GM-CSF for two to nine weeks, although only one maintained increased neutrophil counts, one developed antibodies to GM-CSF and one's condition evolved into AML. Eighteen patients have been treated for two months in phase I/II clinical trials with G-CSF, 16 of whom had normalization of neutrophil counts with improved marrow maturation, five had increased reticulocyte counts with three having decreased transfusion requirements, four had transient increases in blasts and no substantial changes in platelet counts were noted. Eleven patients have received maintenance therapy with G-CSF for 6-16 months and 10 had persistent increases in neutrophil counts with enhanced marrow myeloid maturation. Decreased infectious episodes were noted in these patients at times at neutrophil improvements. Four of the 18 patients have subsequently developed AML after 6-16 months. Both CSFs were well tolerated, although the incidence of fever, myalgias and bone pain was more prominent in patients receiving GM-CSF at higher doses. In vitro correlates with these in vivo results were demonstrated as laboratory studies showed that G-CSF had greater myeloid differentiative and less proliferative effects for MDS marrow than did GM-CSF. Marrow cytogenetic studies after treatment generally indicated persistence of the initial normal and/or abnormal clones. These studies have demonstrated that both G-CSF and GM-CSF improve neutrophil counts in a high proportion of patients with MDS and that chronic administration of G-CSF elicits persistent neutrophil responses and may decrease infections. Phase III controlled trials are required to determine whether the natural history of this disorder will be altered by use of colony stimulating factors.
基于临床前和体外研究结果显示粒细胞 - 单核细胞集落刺激因子和粒细胞集落刺激因子（GM - CSF和G - CSF）可诱导粒细胞增殖和分化增强，这些重组人造血生长因子已被用于治疗骨髓增生异常综合征（MDS）的血细胞减少患者。实验室研究表明，富集的造血前体细胞在体外对G - CSF的增殖和粒细胞分化刺激有反应，一般不会增加克隆再生。迄今为止，五项使用GM - CSF的短期I/II期临床试验表明，45例接受治疗的患者中有38例中性粒细胞计数有所改善，14例网织红细胞计数增加，其中3例患者的红细胞输血需求减少，8例患者血小板短暂增加。12例患者骨髓和/或外周血原始细胞增加。7例患者进展为急性髓系白血病（AML），尤其是骨髓原始细胞大于15%的患者。在一项长期研究中，5例患者接受GM - CSF治疗2至9周，尽管只有1例患者中性粒细胞计数持续增加，1例患者产生了针对GM - CSF的抗体，1例患者病情演变为AML。18例患者在I/II期临床试验中接受G - CSF治疗两个月，其中16例患者中性粒细胞计数恢复正常，骨髓成熟度改善，5例患者网织红细胞计数增加，3例患者输血需求减少，4例患者原始细胞短暂增加，血小板计数无明显变化。11例患者接受G - CSF维持治疗6至16个月，10例患者中性粒细胞计数持续增加，骨髓髓系成熟度增强。在中性粒细胞改善时，这些患者的感染发作次数减少。18例患者中有4例在6至16个月后随后发展为AML。两种集落刺激因子耐受性良好，尽管在接受高剂量GM - CSF的患者中，发热、肌痛和骨痛的发生率更为突出。实验室研究表明，与这些体内结果的体外相关性表现为，对于MDS骨髓，G - CSF比GM - CSF具有更大的髓系分化作用和更小的增殖作用。治疗后的骨髓细胞遗传学研究一般表明初始正常和/或异常克隆持续存在。这些研究表明，G - CSF和GM - CSF均可使大部分MDS患者的中性粒细胞计数得到改善，长期使用G - CSF可引发持续的中性粒细胞反应，并可能减少感染。需要进行III期对照试验来确定使用集落刺激因子是否会改变这种疾病的自然病程。
