High-Dose Ifosfamide and Etoposide with Filgrastim for Stem Cell Mobilization in Patients with Advanced Ovarian Cancer

Bone Marrow Transplantation (2000) 25, 1137–1140 2000 Macmillan Publishers Ltd All rights reserved 0268–3369/00 $15.00 www.nature.com/bmt High-dose ifosfamide and etoposide with filgrastim for stem cell mobilization in patients with advanced ovarian cancer ML Donato1, D Gershenson2, C Ippoliti3, JT Wharton2, RC Bast Jr4, A Aleman1, P Anderlini1, JG Gajewski1, S Giralt1, J Molldrem1, N Ueno1, J Lauppe1, M Korbling1, J Boyer1, D Bodurka-Bevers2, M Bevers2, T Burke2, R Freedman2, C Levenback2, J Wolf2 and RE Champlin1 Departments of 1Blood and Marrow Transplantation, 2Gynecologic Oncology, 4Clinical Investigation and 3Division of Pharmacy, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA Summary: 33% 5-year survival rate with this treatment approach. Transplantation of autologous PBSC is generally associated High-dose chemotherapy combined with autologous with more rapid hematological recovery than transplan- peripheral blood stem cell transplantation has shown tation of bone marrow.3–5 Many studies have indicated that promise as treatment for recurrent or persistent epi- hematopoietic recovery is related to the number of CD34+ thelial ovarian cancer. We evaluated the stem cell mobi- cells infused and suggest a target of 2–5 × 106 CD34+ lization regimen of high-dose ifosfamide plus etoposide cells/kg body weight for a single myeloablative intensifi- in 32 patients with epithelial ovarian cancer, who had cation cycle.6,7 a positive second-look laparatomy or recurrent disease. PBSCs are commonly harvested during cytokine treat- Ifosfamide was given at 10 g/m2 by continuous i.v. from ment6 at the time of recovery of peripheral blood counts days 1 to 3. Etoposide was given at 150 mg/m2 every from chemotherapy.8 The ideal stem cell mobilization regi- 12 h for six doses on days 1–3. Filgrastim was given at men allows successful stem cell harvest with a minimum 10 ␮g/kg/d s.c. from day 5 until the completion of per- number of aphereses, is well tolerated, and produces effec- ipheral blood stem cell harvest. Fourteen of 32 patients tive antitumor activity. Cyclophosphamide, in doses rang- had measurable or evaluable disease before mobiliz- ing from 3 to 7 g/m2 is the agent most commonly used for ation therapy and were assessed for response. In nine stem cell mobilization.9–11 In recent years, investigators (64%) of the 14 patients, treatment response was dem- have combined cyclophosphamide with paclitaxel with onstrated, and these patients received a second cycle of promising results.12 In this study, we evaluated a regimen mobilization therapy. The target CD34+ cell dose of high-dose ifosfamide plus etoposide with filgrastim for (Ͼ8 × 106 cells/kg) was achieved with a median of one PBSC mobilization in patients with advanced ovarian can- apheresis (range 1–5). A median of 25.1 (range 8.0– cer. The aim was to assess the stem cell yield, hematologic 122.5) × 106 CD34+ cells/kg body weight was collected. and non-hematologic toxicities, and overall antitumor Non-hematologic toxicity was limited to grade 2 renal activity produced by this regimen. dysfunction in one patient and grade 2 hepatic dysfunction in three patients. In this patient group, high-dose ifosfamide plus etoposide with filgrastim support was Patients and methods well tolerated, lead to successful stem cell harvest and had antitumor activity. Bone Marrow Transplantation Patients (2000) 25, 1137–1140. Between October 1997 and March 1999, we studied 32 Keywords: ovarian cancer; stem cell collection; ifosfamide; etoposide patients with epithelial ovarian cancer who were under- going stem cell mobilization and apheresis (Table 1). Most of the patients were enrolled in a phase I trial of high-dose Patients with recurrent or persistent epithelial ovarian can- Table 1 Patient demographics (n = 32) cer have a poor prognosis and there are few long-term sur- vivors. In recent studies,1,2 treatment with high-dose Age median 49 years (range 28–64 chemotherapy and peripheral blood stem cell (PBSC) or years) bone marrow transplantation has shown promising results Prior chemotherapy regimens median 2 (range 1–4) 2 Disease status prior to in selected patients. In a study by Stiff et al, patients with ifosfamide/etoposide recurrent, platinum-sensitive disease had approximately a Progressive disease 10 Stable disease 3 Partial remission 8 Correspondence: Dr ML Donato, Department of Blood and Marrow Clinical complete remission 11 Transplantation, Box 24, The University of Texas MD Anderson Cancer Number of patients with prior 2 Center, 1515 Holcombe Blvd, Houston, Texas, 77030, USA PBSC transplants Received 14 October 1999; accepted 22 February 2000 Ifosfamide/etoposide regimen for PBSC mobilization ML Donato et al 1138 chemotherapy and autologous stem cell transplantation for a day. Patients without measurable or evaluable disease, the treatment of ovarian cancer. Patients were eligible for including those with clinical CR at trial enrollment, or our study if they had invasive epithelial ovarian cancer with patients who did not demonstrate at least a PR to recurrent disease or a positive second-look laparotomy. ifosfamide/etoposide went on to receive the high-dose Prior to enrollment in the study, all patients with recurrent chemotherapy arm of the overall treatment plan. Patients disease were reinduced with standard-dose chemotherapy whose disease progressed were taken off the study. until maximal response was achieved. Response to reinduc- tion chemotherapy was not required. However, in all patients, the largest tumor mass could not exceed 2 cm. Fol- lowing standard-dose salvage chemotherapy or second-look Stem cell collection and CD34+ cell–dose analysis surgery and immediately prior to initiation of the ifosfamide/etoposide regimen, 10 patients had progressive For all patients, apheresis was performed using the COBE disease, three had stable disease, eight were in partial Spectra Version 4.7 cell separator (COBE BCT, Lakewood, remission, and 11 were in complete clinical remission (CR). CO, USA). If the patients platelet count was Ͻ30 × 109/l, Of the 11 patients in clinical CR, six had had a positive twice their blood volume was processed. Venous access second-look laparatomy and five were in second or greater was established via a Mahurkar dual-lumen hemodialysis CR following standard-dose salvage chemotherapy. Two of catheter (Quinton Instrument, Bothell, WA, USA) and anti- the 32 patients had received prior stem cell transplantation. coagulant citrate dextrose (ACD-A) solution was used to The median number of prior chemotherapy regimens per prevent clotting. The CD34+ cell content of the collection patient was two (range 1–4). All patients had received at product was measured immediately after apheresis. The least six cycles of platinum and paclitaxel. cells were subsequently cryopreserved using programmed freezing. The apheresis products and the CD34+ cell con- Treatment plan centration were analyzed by two-color flow cytometry. A Hewlett-Packard 340 computer system and LYSYS-II For PBSC mobilization and pretransplant cytoreduction, patients received ifosfamide at 10 g/m2 (total dose) by con- software (Becton Dickinson Immunocytometry, San Jose, tinuous i.v. over 72 h (days 1–3) and etoposide at CA, USA) were used for acquisition of total events and 2 analysis of the list-mode data. From a dot plot of forward 150 mg/m in 2 h i.v. infusions every 12 h during the same ° 72 h period (for a total of six doses). Filgrastim was given and 90 light scatter, a gate was established to include all at 5 ␮g/kg twice a day s.c. from day 5 until completion of lymphocytes and monocytes, excluding granulocytes. 2 Quadrant statistics were obtained from a two-axis dot plot stem cell harvest. Mesna was given at 2 g/m by i.v. + + infusion before and at the completion of the ifosfamide. (CD34 and CDw90) to obtain the percentage of CD34 2 cells within the gated population. The absolute number of Mesna also was given at 8 g/m by i.v. infusion concomi- + tant with the ifosfamide infusion (Table 2). Patients were CD34 cells was obtained by multiplying the number of also given oral prophylactic antibiotics consisting of peni- total nucleated cells by the percentage of gated events and cillin, norfloxacin, valacyclovir, and fluconazole starting on the percentage of positive events within the gate. day 5. Patients were hospitalized during the administration of the mobilization regimen and discharged after the final dose of mesna. Patients who demonstrated a clinical response to Statistical methods and definition of response this treatment could receive a second cycle of ifosfamide/etoposide followed by filgrastim 5 ␮g/kg once All analyses were performed using Statistica for Windows Release 5.1 (StatSoft, Tulsa, OK, USA). Patients were considered to have measurable disease if they had tumor that Table 2 Mobilization regimena could be measured in two dimensions by imaging scans or physical examination. Patients were considered to have Drug Dose Administration Duration evaluable disease if they had no measurable disease on 2 scans or physical examination but had an elevated serum Ifosfamide 10 g/m (total continuous days 1–3 Ͼ dose) infusion CA-125 level ( 40 U/ml) in two samples. Response to Etoposide 150 mg/m2 × 6 2 h infusion, days 1–3 treatment for patients with measurable disease was deter- every 12 h mined according to the World Health Organization G-CSF 5 ␮g/kg subcutaneously, day 5 until 13 every 12 h completion of stem response criteria. Response to treatment for patients with cell harvest evaluable disease was based on CA-125 serum levels, as Mesna 2 g/m2 intravenously before first dose and described by Rustin et al14 and Bridgewater et al15: (1) A after final dose of 50% response is declared if there is a 50% decrease in CA- ifosfamide 8 g/m2 (total continuous days 1–3 125 serum levels.

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