Therapeutic Efficacy Of Granulocyte Colony-stimulating F

治疗性粒细胞输注的疗效受到使用标准分离技术获得的相对较少的细胞数量的限制。在以前的研究中，我们证明了供者在粒细胞集落刺激因子(G-CSF)或G-CSF和地塞米松(地塞米松)联合刺激下制备的粒细胞浓缩物的粒细胞数量比单独使用地塞米松制备的产品多2.3倍和3.5倍(产品含量分别是单独使用地塞米松的2.09×10e10细胞和G-CSF和G-CSF+地塞米松的4.87和7.31×10e10细胞)(地塞米松单独或G-CSF加地塞米松的P<0.01)。接受G-CSF加地塞米松治疗的捐献者中，72%的人有躁动、失眠、骨痛或头痛的症状。由于动员方案的不便和不适，10%的捐助者要求停止参加这项研究。56例临床中心患者接受了G-CSF动员的粒细胞。35名患者严重中性粒细胞减少，包括15名严重再生障碍性贫血(SAA)患者，12名干细胞移植接受者，7名淋巴瘤/白血病患者，1名乳腺癌患者。其余21例患者接受CGD治疗。在中性粒细胞减少的患者中，21例为全身丝状真菌感染，11例为细菌感染，2例为念珠菌血症，1例为呼吸道合胞病毒感染。输血后1小时粒细胞计数平均增加2600个/ul，高于基线500个/ul以上的粒细胞计数持续12~24小时。在粒细胞输注开始后存活超过2周的14名中性粒细胞减少、免疫抑制的患者中，有一人发生了HLA同种异体致敏，15名CGD患者中有两人发生了同种异体致敏。在没有人类白细胞抗原同种异体致敏的情况下，粒细胞输注与进行性缺氧、肺浸润性病变和ARDS样事件相关，在15例SAA患者中有4例，而在21例CGD患者中有1例。在有组织霉菌的中性粒细胞减少的患者中，21例中有10例在粒细胞输注治疗期间稳定或改善，但21例中只有5例在住院期间存活。相比之下，11名有细菌过程的患者中有5名出院。21例CGD患者中有18例真菌感染(9/12)或细菌感染(9/9)痊愈。这些对G-CSF动员的粒细胞的初步研究表明，它们可能对精心选择的中性粒细胞减少患者的生存有利，但可能与显著的进行性肺部毒性有关。NHLBI止血/输血医学临床试验网络正在组织一项关于粒细胞集落刺激因子动员的粒细胞输注治疗严重中性粒细胞减少伴丝状真菌感染患者的随机前瞻性多中心研究。

The efficacy of therapeutic granulocyte transfusions is limited by the relatively small number of cells obtained using standard apheresis techniques. In prior studies, we demonstrated that granulocyte concentrates prepared by granulocyte-colony stimulating factor (G-CSF) or the combination of G-CSF and dexamethasone (dexa) stimulation of the donor contained 2.3- and 3.5-fold greater numbers of granulocytes than products prepared using dexamethasone alone (product content 2.09 x 10e10 cells with dexamethasone alone versus 4.87 and 7.31 x 10e10 cells total with G-CSF and G-CSF plus dexa, respectively) (p less than 0.01 for dexa vs G-CSF alone or G-CSF plus dexa). Seventy-two percent of donors getting G-CSF plus dexa had restlessness, insomnia, bone pain, or headache. Ten percent of donors requested discontinuation of participation in the study due to the inconvenience and discomfort of the mobilization regimen. Fifty-six Clinical Center patients have received G-CSF mobilized granulocytes. Thirty-five were profoundly neutropenic, including 15 patients with severe aplastic anemia (SAA), 12 stem cell transplant recipients, 7 patients with lymphoma/leukemia, and 1 with breast cancer. The remaining 21 patients had CGD. In the neutropenic patients, 21 had systemic filamentous fungal infections, 11 had bacterial infections, two had candidemia and one had RSV infection. The mean increment in granulocyte count 1-hour post-transfusion was 2600/uL, and counts greater than 500/uL above baseline were sustained for 12 to 24 hours. One of the 14 neutropenic, immunosuppressed patients who survived longer than 2 weeks after the initiation of granulocyte transfusions developed HLA allosensitization, as did two of the 15 CGD patients. In the absence of HLA allosensitization, granulocyte transfusions were associated with progressive hypoxia, pulmonary infiltrates, and an ARDS-like event in four of 15 SAA patients, versus one of 21 CGD patients. Of the neutropenic patients with tissue molds, 10 of 21 stabilized or improved during granulocyte transfusion therapy, but only 5 of 21 survived hospitalization. In contrast, five of 11 with bacterial processes were discharged from hospital. Eighteen of 21 patients with CGD had resolution of their fungal (9 of 12) or bacterial (9 of 9) infections. These pilot studies of G-CSF mobilized granulocytes suggest that they may confer survival benefit in carefully selected neutropenic patients with life-threatening infections, but may be associated with significant progressive pulmonary toxicity. A randomized prospective multicenter study of the efficacy of G-CSF mobilized granulocyte transfusions in severely neutropenic patients with filamentous fungal infections is being organized by the Hemostasis/Transfusion Medicine Clinical Trials Network of NHLBI.