Hiddemann W, Wörmann B, Reuter C, Schleyer E, Zühlsdorf M, Böckmann A, Büchner T
Department of Internal Medicine, University of Göttingen, Germany.
Semin Oncol. 1994 Dec;21(6 Suppl 16):33-8.
The application of hematopoietic growth factors in the treatment on acute myeloid leukemia (AML) may principally aim at shortening the period of treatment associated neutropenia and reducing the rate of infectious complications by their post-therapeutic administration but may also be used to increase the sensitivity of leukemic blasts to antileukemic therapy by pretherapeutic growth stimulation. Both aspects were addressed in subsequent clinical phase II studies and preclinical investigations. In a first clinical trial, 36 patients with high-risk AML received granulocyte-macrophage colony-stimulating factor (GM-CSF) after successful cytoreductive chemotherapy and experienced a shortening of the period of post-therapeutic neutropenia by 6 to 9 days, leading to a significant reduction of treatment-associated deaths from 39% to 14%. In preclinical studies an enhancement of the cytotoxicity of cytosine arabinoside (AraC) on leukemic blasts could be shown by pretreatment with GM-CSF or IL-3. Investigations on the impact of hematopoietic growth factors on the intracellular metabolism of AraC indicated that this effect was primarily mediated by an increase in the activity of DNA-polymerase-alpha. The evaluation of different doses of AraC showed the most marked increase after the combination of GM-CSF with conventional rather than high doses of AraC. Based on these preclinical experiments, a prospective randomized trial was subsequently initiated investigating the effect of GM-CSF before and during induction, consolidation, and the first two cycles of maintenance chemotherapy in newly diagnosed AML. This ongoing trial has enrolled 67 patients at the current time. An early interim analysis showed no differences in remission rates but a tendency toward a longer remission duration in patients receiving GM-CSF. These data indicate that hematopoietic growth factors like GM-CSF in particular may provide a new perspective in the treatment of acute myeloid leukemia with the possibility of reducing treatment associated mortality and perhaps of increasing the efficacy of antileukemic treatment.
造血生长因子在急性髓系白血病（AML）治疗中的应用，主要目的可能是通过治疗后给药来缩短治疗相关中性粒细胞减少期，并降低感染并发症的发生率，但也可通过治疗前的生长刺激来提高白血病原始细胞对抗白血病治疗的敏感性。后续的临床II期研究和临床前研究都涉及了这两个方面。在第一项临床试验中，36例高危AML患者在成功进行细胞减灭化疗后接受了粒细胞-巨噬细胞集落刺激因子（GM-CSF）治疗，治疗后中性粒细胞减少期缩短了6至9天，使治疗相关死亡率从39%显著降至14%。在临床前研究中，用GM-CSF或IL-3预处理可显示阿糖胞苷（AraC）对白血病原始细胞的细胞毒性增强。对造血生长因子对AraC细胞内代谢影响的研究表明，这种作用主要是由DNA聚合酶α活性的增加介导的。对不同剂量AraC的评估显示，GM-CSF与常规剂量而非高剂量AraC联合使用后增加最为显著。基于这些临床前实验，随后启动了一项前瞻性随机试验，研究GM-CSF在新诊断AML诱导、巩固及维持化疗的前两个周期之前和期间的作用。目前这项正在进行的试验已招募了67例患者。早期中期分析显示，缓解率没有差异，但接受GM-CSF治疗的患者缓解期有延长的趋势。这些数据表明，像GM-CSF这样的造血生长因子尤其可能为急性髓系白血病的治疗提供新的视角，有可能降低治疗相关死亡率，并可能提高抗白血病治疗的疗效。
