Vadhan-Raj S, Broxmeyer H E, Hittelman W N, Papadopoulos N E, Chawla S P, Fenoglio C, Cooper S, Buescher E S, Frenck R W, Holian A
Department of Clinical Immunology and Biological Therapy, University of Texas, MD Anderson Cancer Center, Houston 77030.
J Clin Oncol. 1992 Aug;10(8):1266-77. doi: 10.1200/JCO.1992.10.8.1266.
The purpose of this study was to optimize the dose, schedule, and timing of recombinant granulocyte-macrophage colony-stimulating factor (GM-CSF) administration that would best abrogate myelosuppression in patients with sarcoma.
Sarcoma patients who had experienced severe myelosuppression after chemotherapy with Cytoxan (cyclophosphamide; Bristol-Myers Squibb Co, Evansville, IN), Adriamycin (doxorubicin; Adria Laboratories, Columbus, OH), and dacarbazine ([CyADIC], cycle 1) were eligible. GM-CSF was administered during a 14-day period until 1 week before cycle 2 of CyADIC and was resumed 2 days after cycle 2 completion. The schedule subsequently was modified to allow the earlier administration of GM-CSF in which CyADIC was compressed from 5 days to 3 days, and GM-CSF was administered immediately after the discontinuation of CyADIC in cycle 2. To understand better the impact of GM-CSF on bone marrow stem cells, the proliferative status of bone marrow progenitors was examined during treatment. To evaluate the effects of GM-CSF on effector cells, select functions of mature myeloid cells were also examined.
In the seven patients who were treated on the initial schedule, GM-CSF enhanced the rate of neutrophil recovery; however, severe neutropenia was not abrogated, By using the modified schedule in 17 patients, GM-CSF significantly reduced both the degree and the duration of neutropenia and myeloid (neutrophils, eosinophils, and monocytes) leukopenia. The mean neutrophil and mature myeloid nadir counts were 100/mm3 and 280/mm3 in cycle 1 and 290/mm3 and 1,540/mm3 in cycle 2 (P less than .01 and P less than .001). The duration of severe neutropenia (neutrophil count less than 500/mm3) and myeloid leukopenia (myeloid leukocyte count less than 1,000/mm3) were reduced from 6.2 and 6.8 days in cycle 1 to 2.8 and 1.4 days in cycle 2 (P less than .001). While 16 of 17 patients experienced severe myeloid leukopenia (less than 500/mm3) in cycle 1, only two of 17 experienced severe myeloid leukopenia in cycle 2 (P less than .001). Overall, severe neutropenia was abrogated in seven patients, which made them eligible for dose-escalation of Adriamycin. The fraction of cycling progenitors increased threefold on GM-CSF and decreased dramatically below the baseline within 1 day of GM-CSF discontinuation.
The modified schedule improved the beneficial effects of GM-CSF by enhancing myeloprotection and permitting dose-intensification of chemotherapy. The increased myeloid mass and quiescent progenitors at the initiation of chemotherapy suggest that GM-CSF might allow further chemotherapy dose-rate intensification by shortening the interval between courses.
本研究的目的是优化重组粒细胞-巨噬细胞集落刺激因子（GM-CSF）的给药剂量、方案和时间，以最佳地消除肉瘤患者的骨髓抑制。
符合条件的肉瘤患者在接受环磷酰胺（赛氮芥；百时美施贵宝公司，印第安纳州埃文斯维尔）、阿霉素（多柔比星；阿德里亚实验室，俄亥俄州哥伦布）和达卡巴嗪（[CyADIC]，第1周期）化疗后出现严重骨髓抑制。GM-CSF在14天内给药，直至CyADIC第2周期前1周，并在第2周期完成后2天恢复给药。随后修改了方案，以便更早地给予GM-CSF，其中CyADIC从5天缩短至3天，GM-CSF在第2周期的CyADIC停药后立即给药。为了更好地了解GM-CSF对骨髓干细胞的影响，在治疗期间检查了骨髓祖细胞的增殖状态。为了评估GM-CSF对效应细胞的作用，还检查了成熟髓细胞的某些功能。
按照初始方案治疗的7例患者中，GM-CSF提高了中性粒细胞恢复率；然而，严重中性粒细胞减少症并未消除。在17例患者中采用修改后的方案，GM-CSF显著降低了中性粒细胞减少症和髓细胞（中性粒细胞、嗜酸性粒细胞和单核细胞）减少症的程度和持续时间。第1周期中性粒细胞和成熟髓细胞的平均最低点计数分别为100/mm³和280/mm³，第2周期分别为290/mm³和1540/mm³（P<0.01和P<0.001）。严重中性粒细胞减少症（中性粒细胞计数<500/mm³）和髓细胞减少症（髓细胞计数<1000/mm³）的持续时间从第1周期的6.2天和6.8天减少到第2周期的2.8天和1.4天（P<0.001）。17例患者中有16例在第1周期出现严重髓细胞减少症（<500/mm³），而在第2周期只有2例出现严重髓细胞减少症（P<0.001）。总体而言，7例患者的严重中性粒细胞减少症得到消除，这使他们有资格增加阿霉素的剂量。在GM-CSF作用下循环祖细胞的比例增加了三倍，并在GM-CSF停药后1天内急剧降至基线以下。
修改后的方案通过增强骨髓保护作用和允许化疗剂量强化，改善了GM-CSF的有益效果。化疗开始时髓细胞数量增加和祖细胞静止表明，GM-CSF可能通过缩短疗程间隔来进一步强化化疗剂量率。
