RANDOMIZED OPEN-LABEL PHASE-III TRIAL OF CEOP IMVP-DEXA ALTERNATING CHEMOTHERAPY AND FILGRASTIM VERSUS CEOP/IMVP-DEXA ALTERNATING CHEMOTHERAPY FOR AGGRESSIVE NON-HODGKINS-LYMPHOMA (NHL) - A MULTICENTER TRIAL BY THE AUSTRIAN WORKING GROUP FOR MEDICAL TUMOR-THERAPY/

Primary end point of this trial was to reduce neutropenic infections d uring the treatment of aggressive NHL with CEOP/IMVP-Dexa (cyclophosph amide, epirubicin, vincristine, prednisolone ifosfamide, methotrexate, VP-16, and dexamethasone). Further, we stud led the influence of filg rastim on dose intensity of CEOP/IMVP-Dexa, on the rate of complete re missions, on the time to relapse, and on survival. Eighty five patient s with untreated large-cell NHL were randomized to one of two treatmen t 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-i njected by the patients at 5 mu g/kg body wt. s.c. daily, except on th e days when cytotoxic drugs were given. During treatment we did weekly complete blood counts. Median leukocyte counts were 10.91 x 10(9)/l a nd 5.46 x 10(9)/l in arm 1 and 2, respectively (p = 10(-6)). Median ne utrophil 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 0.21 3 x 10(9)/l in arm 1 and 2, respectively (p = 0.09). Mean platelet nad irs were 95 and 152 x 10(9)/l (p = 0.000004) and mean hemoglobin nadir s 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, r espectively (p = 0.041). Forty-two percent and 58% of patients experie nced a febrile neutropenia in arm 1 and 2, respectively (not significa nt, NS). Median time to first neutropenic infection was in treatment w eek 11 and 6 in arm 1 and 2, respectively (NS). There was no significa nt difference in rate, duration, and kind of infection, duration of ho spitalization, or antibiotic treatment. Seven toxic deaths occurred, a ll 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% i n arm 1 and 2, respectively (NS). After a median observation time of 3 years there was no difference in time to relapse or survival. Filgras tim increases leukocyte and neutrophil counts and dose intensity, if u sed with CEOP/IMVP-Dexa chemotherapy in high-grade lymphomas. There wa s no significant effect on febrile neutropenia or infections. The more frequent fatal neutropenic infection rate in the filgrastim arm was n ot statistically significant. It is most appropriate to explain it by the patient's age in combination with the high dose intensity. The sma ll increase in dose intensity had no effect on survival but probably d ecreased hemoglobin levels and platelet counts in arm 1. We were unabl e to show a benefit for filgrastim in combination with CEOP/IMVP-Dexa.