Estey E, Thall P F, Kantarjian H, O'Brien S, Koller C A, Beran M, Gutterman J, Deisseroth A, Keating M
Department of Hematology, University of Texas M.D. Anderson Cancer Center, Houston 77030.
Blood. 1992 May 1;79(9):2246-55.
We gave 56 patients with newly diagnosed acute myelogenous leukemia (AML) granulocyte-macrophage colony-stimulating factor (GM-CSF) 20 or 125 micrograms/m2 once daily subcutaneously before (for up to 8 days or until GM-CSF-related complications developed) and during, or only during (patients presenting with blast counts greater than 50,000 or other leukemia-related complications) ara-C (1.5 g/m2 daily x 4 by continuous infusion) and daunorubicin (45 mg/m2 daily x 3) chemotherapy. Because results seemed independent of GM-CSF schedule, we compared results in these 56 patients with results in 176 patients with newly diagnosed AML given the same dose and schedule of ara-C without GM-CSF (110 patients ara-C alone, 66 patients ara-C + amsacrine or mitoxantrone). Comparison involved fitting a logistic regression model predicting probability of complete remission (CR) and a Cox regression model to predict survival (most patients in all three studies were dead) with treatment included as a covariate in both analyses. After adjusting for other prognostically significant covariates [presence of an antecedent hematologic disorder, an Inv (16), t(8;21), or abnormalities of chromosomes 5 and/or 7, performance status, age, bilirubin], treatment with ara-C + daunorubicin + GM-CSF was predictive of both a lower CR rate and a lower survival probability. There were no treatment-covariate interactions, suggesting that the negative effect of this GM-CSF treatment regime was not an artifact of some imbalance in patient characteristics. The unadjusted Kaplan-Meier hazard rate of the ara-C + daunorubicin + GM-CSF group was not uniquely high during the initial 4 weeks after start of therapy, but was highest among the three treatment groups throughout weeks 5 to 16, suggesting that the negative effect of this treatment was not caused by acute toxicity. Patients who did not enter CR with this treatment tended to have persistent leukemia rather than prolonged marrow aplasia, suggesting that this treatment and, in particular, GM-CSF may increase resistance of myeloid leukemia cells to chemotherapy. To date, relapse rates are similar in all three groups (P = .43) (as are survival rates once patients are in CR) but much of the remission duration data is heavily censored, unlike the survival data. Our results suggest caution in the use of GM-CSF to sensitize myeloid leukemia cells to daunorubicin + ara-C chemotherapy.
我们给予56例新诊断的急性髓性白血病（AML）患者粒细胞-巨噬细胞集落刺激因子（GM-CSF），剂量为20或125微克/平方米，每日一次皮下注射，在阿糖胞苷（ara-C）（1.5克/平方米，每日持续输注4天）和柔红霉素（45毫克/平方米，每日3天）化疗之前（最多8天或直至出现GM-CSF相关并发症）、期间或仅在期间（原始细胞计数大于50,000或有其他白血病相关并发症的患者）使用。由于结果似乎与GM-CSF给药方案无关，我们将这56例患者的结果与176例接受相同剂量和方案的ara-C但未使用GM-CSF的新诊断AML患者的结果进行了比较（110例仅接受ara-C治疗，66例接受ara-C + 安吖啶或米托蒽醌治疗）。比较包括拟合一个预测完全缓解（CR）概率的逻辑回归模型和一个预测生存的Cox回归模型（所有三项研究中的大多数患者均已死亡），在两项分析中均将治疗作为协变量纳入。在调整了其他预后显著的协变量[存在前驱血液系统疾病、Inv(16)、t(8;21)或染色体5和/或7异常、体能状态、年龄、胆红素]后，ara-C + 柔红霉素 + GM-CSF治疗预测CR率和生存概率均较低。不存在治疗-协变量相互作用，这表明这种GM-CSF治疗方案的负面影响并非患者特征某些不平衡导致的假象。ara-C + 柔红霉素 + GM-CSF组未经调整的Kaplan-Meier风险率在治疗开始后的最初4周内并非特别高，但在第5至16周期间在三个治疗组中最高，这表明这种治疗的负面影响并非由急性毒性引起。接受这种治疗未进入CR的患者往往患有持续性白血病而非骨髓再生障碍延长，这表明这种治疗，尤其是GM-CSF可能会增加髓系白血病细胞对化疗的耐药性。迄今为止，三组的复发率相似（P = 0.43）（患者进入CR后的生存率也相似），但与生存数据不同，大部分缓解持续时间数据存在大量删失。我们的结果提示在使用GM-CSF使髓系白血病细胞对柔红霉素 + ara-C化疗敏感时应谨慎。
