Fridrik M A, Greil R, Hausmaninger H, Krieger O, Oppitz P, Stöger M, Klocker J, Neubauer M, Helm W, Pont J, Fazeny B, Hudec M, Simonitsch I, Radaszkiewicz T
First Department of Medicine, General Hospital Linz, Austria.
Ann Hematol. 1997 Oct;75(4):135-40. doi: 10.1007/s002770050330.
Primary end point of this trial was to reduce neutropenic infections during the treatment of aggressive NHL with CEOP/IMVP-Dexa (cyclophosphamide, epirubicin, vincristine, prednisolone ifosfamide, methotrexate, VP-16, and dexamethasone). Further, we studied the influence of filgrastim on dose intensity of CEOP/IMVP-Dexa, on the rate of complete remissions, on the time to relapse, and on survival. Eighty-five patients with untreated large-cell NHL were randomized to one of two treatment arms; 74 patients were eligible. Thirty-eight patients in arm 1 were treated with CEOP/IMVP-Dexa chemotherapy and filgrastim, 36 in arm 2 with CEOP/IMVP-Dexa chemotherapy alone. In arm 1 filgrastim was self-injected by the patients at 5 micrograms/kg body wt. s.c. daily, except on the days when cytotoxic drugs were given. During treatment we did weekly complete blood counts. Median leukocyte counts were 10.91 x 10(9)/l and 5.46 x 10(9)/l in arm 1 and 2, respectively (p = 10(-6)). Median neutrophil counts were 7.7 x 10(9)/l in arm 1 and 2.72 x 10(9)/l in arm 2 (p < 10(-6)). Median neutrophil nadirs were 0.199 x 10(9)/l and 0.213 x 10(9)/l in arm 1 and 2, respectively (p = 0.09). Mean platelet nadirs were 95 and 152 x 10(9)/l (p = 0.000004) and mean hemoglobin nadirs 83.95 g/l and 92.78 g/l (p = 0.00558) in arm 1 and 2, respectively. Dose intensity of CEOP/IMVP-Dexa was 82.3% and 76.2% in arm 1 and 2, respectively (p = 0.041). Forty-two percent and 58% of patients experienced a febrile neutropenia in arm 1 and 2, respectively (not significant, NS). Median time to first neutropenic infection was in treatment week 11 and 6 in arm 1 and 2, respectively (NS). There was no significant difference in rate, duration, and kind of infection, duration of hospitalization, or antibiotic treatment. Seven toxic deaths occurred, all due to neutropenic infection, 6 and 1 in arm 1 and 2, respectively (p = 0.0732). Four of the six patients, who died of infection in arm 1 were older than 60 years. Complete remission rate was 83% and 66.7% in arm 1 and 2, respectively (NS). After a median observation time of 3 years there was no difference in time to relapse or survival. Filgrastim increases leukocyte and neutrophil counts and dose intensity, if used with CEOP/IMVP-Dexa chemotherapy in high-grade lymphomas. There was no significant effect on febrile neutropenia or infections. The more frequent fatal neutropenic infection rate in the filgrastim arm was not statistically significant. It is most appropriate to explain it by the patient's age in combination with the high dose intensity. The small increase in dose intensity had no effect on survival but probably decreased hemoglobin levels and platelet counts in arm 1. We were unable to show a benefit for filgrastim in combination with CEOP/IMVP-Dexa.
本试验的主要终点是在采用CEOP/IMVP-Dexa方案（环磷酰胺、表柔比星、长春新碱、泼尼松龙、异环磷酰胺、甲氨蝶呤、依托泊苷和地塞米松）治疗侵袭性非霍奇金淋巴瘤（NHL）期间减少中性粒细胞减少性感染。此外，我们研究了非格司亭对CEOP/IMVP-Dexa方案的剂量强度、完全缓解率、复发时间和生存率的影响。85例未经治疗的大细胞NHL患者被随机分为两个治疗组之一；74例患者符合条件。第1组的38例患者接受CEOP/IMVP-Dexa化疗和非格司亭治疗，第2组的36例患者仅接受CEOP/IMVP-Dexa化疗。在第1组中，非格司亭由患者自行皮下注射，剂量为5微克/千克体重，每日1次，但在给予细胞毒性药物的日子除外。治疗期间我们每周进行全血细胞计数。第1组和第2组的白细胞计数中位数分别为10.91×10⁹/L和5.46×10⁹/L（p = 10⁻⁶）。第1组和第2组的中性粒细胞计数中位数分别为7.7×10⁹/L和2.72×10⁹/L（p < 10⁻⁶）。第1组和第2组的中性粒细胞最低值中位数分别为0.199×10⁹/L和0.213×10⁹/L（p = 0.09）。第1组和第2组的血小板最低值平均值分别为95×10⁹/L和152×10⁹/L（p = 0.000004），血红蛋白最低值平均值分别为83.95 g/L和92.78 g/L（p = 0.00558）。CEOP/IMVP-Dexa方案的剂量强度在第1组和第2组分别为82.3%和76.2%（p = 0.041）。第1组和第2组分别有42%和58%的患者发生发热性中性粒细胞减少（无统计学意义，NS）。首次中性粒细胞减少性感染的中位时间在第1组和第2组分别为治疗第11周和第6周（NS）。在感染的发生率、持续时间和类型、住院时间或抗生素治疗方面没有显著差异。发生了7例毒性死亡，均因中性粒细胞减少性感染，第1组和第2组分别为6例和1例（p = 0.0732）。第1组中死于感染的6例患者中有4例年龄超过60岁。第1组和第2组分别的完全缓解率为83%和66.7%（NS）。经过3年的中位观察时间，复发时间或生存率没有差异。在高级别淋巴瘤中，非格司亭与CEOP/IMVP-Dexa化疗联合使用时可增加白细胞和中性粒细胞计数以及剂量强度。对发热性中性粒细胞减少或感染没有显著影响。非格司亭组中更频繁的致命性中性粒细胞减少性感染率没有统计学意义。最恰当的解释是患者年龄与高剂量强度相结合。剂量强度的小幅增加对生存率没有影响，但可能降低了第1组的血红蛋白水平和血小板计数。我们未能证明非格司亭与CEOP/IMVP-Dexa联合使用有获益。
