Background: This study was performed to examine the feasibility and toxicity of the combination of mitoxantrone, fludarabine, cytarabine as bolus (B) or continuous infusion (CI) and granulocyte- colony stimulating factor (G-CSF) in patients with recurrent and refractory acute myeloid leukemia (AML). Patients and Methods: 29 patients with relapsed (n =17) or refractory (n =12) AML were treated with the Mito-FLAG protocol consisting of mitoxantrone (7 mg/m², days 1/3/5), fludarabine (15mg/m², every 12 h, days 1–5), cytarabine (Ara-C) as bolus infusion (1000 mg/m² over 1 h, every 12 h, days 1–5) (n =15) or as continuous infusion (100–150 mg/m² over 24 h, days 1–5) (n =14), and G-CSF (5 µg/ kg/day, day 0 until a neutrophile count of 0.5 ×10⁹/l). Results: 17 patients (59%) and 1 patient (3%) achieved complete remission (CR) and partial remission (PR), respectively; thus the overall response rate was 62%. Following Mito-FLAG, 5 patients with CR underwent high-dose therapy (HDT) with allogeneic (n = 2) or autologous (n = 3) stem cell transplantation (SCT).With a median follow-up of 28 (range 6–54) months, 4 transplanted patients are alive in CR (n = 2) or in relapse (n = 2). The median duration of event-free survival (EFS) and overall survival (OS) was 3.2 and 6.8 months, and probabilities of EFS and OS after 1 year were 14 and 34%, respectively. The 1-year rates for EFS and OS in this group were 18 and 53%, respectively. Median duration of WHO grade 4 granulocytopenia and thrombocytopenia was 20 and 23 days, respectively. Nonhematological side effects were moderate, predominantly reaching WHO grades 1–2. Neutropenic fever was seen in 85% of courses, with a median duration of 4 (1–38) days. Four patients (14%) suffered an early death because of aplasia (n = 2), pneumonia (n =1) or progressive AML (1 nonresponding patient). Conclusions: Our data suggest that the Mito-FLAG protocol is feasible and can be safely performed with both schedules of Ara-C. In this study the regimens have shown high efficacy and acceptable toxicity in patients with relapsed or refractory AML. We currently examine the importance of bolus versus continuous infusion of Ara-C as part of the Mito-FLAG regimen in a prospective randomized multicenter trial.

The equivalency of AUC after 200 mg/m2 of oral and 100 mg/m2 of intravenous etoposide support the use of the oral preparation in patients treated with the CHOEP regimen, which makes the chemotherapy more convenient for the patients and help to reduce costs.

The addition of etoposide to the CHOP protocol (CHOEP) has been shown to improve outcome particularly in younger patients (<60 years) with aggressive non-Hodgkin’s lymphoma [Pfreundschuh, Blood 2004]. In the previous trials a dose of 100 mg/m2 etoposide was given intravenously on three consecutive days representing a disadvantage of CHOEP compared to standard CHOP in terms of patients’ convenience. Therefore we investigated the pharmacokinetic equivalency of etoposide as an oral preparation on days 2 and 3 compared to the intravenous route. Ten patients (male, n=7; female, n=3; median age 56 years) with aggressive B-cell- (n=9) or T-cell- (n=1) lymphoma were included. The CHOEP regimen consisted of cyclophosphamide 750 mg/m2, doxorubicin 50 mg/m2, vincristine 2 mg/m2 and prednisone 100 mg orally days 1 to 5. Etoposide 100 mg/m2 was given intravenously on day 1, and 200 mg/m2 orally on days 3 and 4, respectively. EDTA blood for pharmacokinetic study were taken on days 1 (i.v. study) and 3 (p.o. study) before etoposide and after administration at 30, 60 and 90 min, every hour until 8 hours, followed by samplings at 16, 20, 24 and 48 hours. The samples were centrifuged immediately at 5°C for 15 min, and the plasma was aliquoted into cryo vials and stored at −20°C until assayed. Etoposide levels in plasma were determined by high-performance liquid chromatography (HPLC). The area under the plasma etoposide concentration versus time curve (AUC), plasma etoposide clearance (CL), volume of distribution in steady state (VDss) and terminal etoposide plasma half-life (t½) for the intravenous and oral administered drug were calculated based on the TOPFIT computer program. The median bioavailability after oral etoposide was 58 % with an interpatient variation (coefficient of variation, CV) of 26 %. AUC was very similar after 200 mg/m2 oral etoposide and intravenous administration of 100 mg/m2 of the drug, however the pharmacokinetic variation was higher after oral uptake compared to the parenteral route (35 % vs. 23 %). Data are presented in detail (medians and ranges) in Table #1. We conclude that, within the CHOEP regimen, the intravenous administration of 100 mg/m2 etoposide on days 2 and 3 can be replaced by 200 mg/m2 of the oral preparation, which simplifies the treatment in the outpatient setting. Table #1 100 mg/m2 Etoposide i.v. 200 mg/m2 Etoposide p.o. C max [μg/ml] 16.7 (10.1 – 21.1) 13.4 (5.8 – 16.8) V ss [L] 14.4 (10.7 – 18.3) 15.1 (10.6 – 25.4) CL total [ml/min] 45.9 (29.6 – 62.8) 82.5 (45.5 – 151.0) CL renal [ml/min] 17.2 (9.4 – 52.6) 16.3 (4.7 – 39.7) t 1/2 [h] 4.1 (3.8 – 5.4) 5.8 (3.2 – 8.3) AUC [μg × h/ml] 72.5 (44.3 – 93.4) 81.6 (44.0 – 147.0)

MIFAP is an effective salvage protocol for patients with poor-risk recurrent or refractory HD and NHL. The observed toxicity seems to be acceptable considering the unfavorable prognosis and intensive pretreatment. The results in patients responding to MIFAP and afterwards undergoing HDT with autologous stem cell support are even comparable to those published in patients with prognostically more favorable diseases.

Introduction: The development of the escalated BEACOPP regimen let to an improved outcome in patients with advanced Hodgkin Lymphoma (HD9 study of the GHSG). However, the application of high dose etoposide (cumulative 4,8 g/m2 per 8 cycles) seems to be associated with an increased incidence of secondary MDS and AML, respectively. Therefore, the aim of our multicenter pilot study was to evaluate the efficacy and toxicity of the etoposide free as well as dose intensified BACOPP-D protocol. Methods: Since May 2000 a total of 115 patients with Hodgkin Lymphoma (HL) stage IIB, III, and IV were treated with BACOPP-D which included cyclophosphamide 1250 mg/m2 (d1), adriamycin 25 mg/m2 (d1+2), dacarbazine 250 mg/m2 (d1-3), procarbazine 100 mg/m2 (d1-7), prednisolone 40 mg/m2 (d1-14), bleomycin 10 mg/m2 (d8) and vincristine 1,4 mg/m2 (maximum 2 mg, d8) at three-weekly intervals with granulocyte colony-stimulating factor (G-CSF). A consolidating involved field radiation (30 Gy) was performed only in patients who achieved less than CR following chemotherapy. Post-treatment follow-up included PET imaging. Results: Until now 97 patients (median age 35 years, range 17-65; 61 male, 36 female) are assessable for toxicity and treatment outcome. We analyzed the acute toxicity for 728 cycles of BACOPP-D. CTC/WHO grade III/IV haematological toxicities per patient were observed as follows: leukopenia 93%, anemia 39%, and thrombocytopenia 33%. CTC grade III/IV non-haematological side effects included documented infection (4%) and lung toxicity (one patient). A total of 85 patients (88%) achieved complete remission, 9 patients (9%) achieved partial remission, three patients (3%) had progressive disease. At a median observation time of 39 months (0,9-77 months), five patients have relapsed, and nine deaths were documented (4 HL-specific and 3 treatment related deaths, 1 death due to ruptured Meckel diverticulum with peritonitis, one 65 year-old woman died in CR following myocardial infarction). One patient developed a second neoplasia (hypopharyngeal carcinoma in an alcoholic). The overall survival and freedom from treatment failure rates at 39 months were 91% and 85%, respectively. FDG-PET scans after BACOPP-D chemotherapy were performed in 68 of 97 patients. PET scans revealed no increased FDG uptake in 48/68 patients (71%), in 20 patients (29%) increased FDG uptake was detected. In the group of patients with increased FDG uptake, one patient developed progressive disease and four patients relapsed. In the group with PET-negative findings no patient relapsed. Diskussion: BACOPP-D regimen appears as a feasible and effective treatment which induced a complete morphologic and metabolic remission in a high proportion of patients with advanced HL. The treatment was associated with moderate acute toxicity. No secondary AML or MDS occurred until now.