Bettelheim P, Valent P, Andreeff M, Tafuri A, Haimi J, Gorischek C, Muhm M, Sillaber C, Haas O, Vieder L
First Medicine Department, University of Vienna, Austria.
Blood. 1991 Feb 15;77(4):700-11.
Based on in vitro data suggesting that recombinant human granulocyte-macrophage colony-stimulating factor (rhGM-CSF) is capable of stimulating acute myeloid leukemia (AML) blast cells to become more sensitive to cell-cycle-specific drugs we conducted a phase I/II study in de novo AML patients (pts). rhGM-CSF (250 micrograms/m2/d, continuous intravenous infusion) was administered in 18 pts suffering from de novo AML in combination with standard induction chemotherapy (3 + 7 = daunorubicin 45 mg/m2 days 1 through 3, cytosine-arabinoside [Ara-C] 200 mg/m2 continuous infusion days 1 through 7). GM-CSF was started 48 or 24 hours before chemotherapy (prephase) in 14 pts. In four pts with high white blood cell counts (WBC) rhGM-CSF was started after chemotherapy-induced cell reduction (WBC less than 30,000/mm3). During prephase GM-CSF induced an increase in neutrophil and blast cell counts in 13 of 14 and 10 of 14 pts, respectively. In vivo recruitment of leukemic cells into drug-sensitive phases of the cell cycle could be demonstrated by multiparameter cell-cycle analyses in peripheral blood (n = 7) and bone marrow (n = 4) specimens. On day 14, complete aplasia was evident in 17 of 18 pts. GM-CSF was administered until recovery from chemotherapy-induced myelosuppression (absolute neutrophil counts, [ANC] greater than 500/mm3). Fifteen pts (83%) achieved complete remission, 12 did so with one cycle. A shorter duration of neutropenia was evident in these pts compared with historical controls (n = 39), (ANC greater than 500/mm3, day 22.5 +/- 3.4 v 25.2 +/- 3.7, P less than .05). Three pts achieved complete remission after a second cycle (same combination of rhGM-CSF and 3 + 7). Two pts died during bone marrow aplasia because of invasive pulmonary aspergillosis. Clinical side effects possibly related to GM-CSF, mainly fever, diarrhea, and weight gain were mild and tolerable (World Health Organization toxicity grade less than or equal to 2). Together, rhGM-CSF recruits kinetically quiescient AML cells in vivo to enter drug-sensitive phases of the cell cycle and promotes early myeloid recovery from aplasia after exposure to standard induction chemotherapy for AML.
基于体外数据表明重组人粒细胞巨噬细胞集落刺激因子（rhGM-CSF）能够刺激急性髓系白血病（AML）原始细胞对细胞周期特异性药物变得更敏感，我们对初治AML患者进行了一项I/II期研究。18例初治AML患者接受rhGM-CSF（250微克/平方米/天，持续静脉输注）联合标准诱导化疗（3 + 7方案 = 柔红霉素45毫克/平方米，第1至3天，阿糖胞苷[Ara-C]200毫克/平方米持续输注，第1至7天）。14例患者在化疗前48或24小时开始使用GM-CSF（前期）。4例白细胞计数（WBC）高的患者在化疗诱导细胞减少后（WBC低于30,000/mm³）开始使用rhGM-CSF。在前期，GM-CSF分别使14例患者中的13例和14例患者中的10例中性粒细胞和原始细胞计数增加。通过外周血（n = 7）和骨髓（n = 4）标本的多参数细胞周期分析可以证明白血病细胞在体内被募集到细胞周期的药物敏感阶段。第14天，18例患者中有17例出现明显的全血细胞减少。GM-CSF持续给药直至化疗诱导的骨髓抑制恢复（绝对中性粒细胞计数[ANC]大于500/mm³）。15例患者（83%）达到完全缓解，12例患者一个周期即达到完全缓解。与历史对照（n = 39）相比，这些患者的中性粒细胞减少持续时间明显缩短（ANC大于500/mm³，第22.5±3.4天对25.2±3.7天，P < 0.05）。3例患者在第二个周期（rhGM-CSF与3 + 7相同组合）后达到完全缓解。2例患者在骨髓抑制期因侵袭性肺曲霉病死亡。可能与GM-CSF相关的临床副作用主要是发热、腹泻和体重增加，程度较轻且可耐受（世界卫生组织毒性分级小于或等于2级）。总之，rhGM-CSF在体内促使处于动力学静止期的AML细胞进入细胞周期的药物敏感阶段，并促进在接受AML标准诱导化疗后从骨髓抑制中早期髓系恢复。
