Bone Marrow Transplantation (2000) 25, 1141–1146 2000 Macmillan Publishers Ltd All rights reserved 0268–3369/00 $15.00 www.nature.com/bmt Prospective randomized clinical trial comparing high-dose ifosfamide + GM-CSF vs high-dose cyclophosphamide + GM-CSF for blood progenitor cell mobilization J Vela-Ojeda, F Tripp-Villanueva, L Montiel-Cervantes, E Sa´nchez-Corte´s, M Ayala-Sa´nchez, ME Guevara-Moreno, LD Garcı´a-Leo´n, A Rosas-Cabral, MA Garcı´a-Ruiz Esparza and J Gonza´lez-Llaven Bone Marrow Transplant Program, Hospital de Especialidades Centro Me´dico Nacional La Raza, IMSS, Me´xico City, Me´xico Summary: to accelerated hematopoietic recovery, which has resulted in safer2 and cheaper transplants.3 However, the frequency Between August 1994 and June 1999, 56 patients were of progenitors in the peripheral blood under steady-state prospectively randomized to receive ifosfamide conditions is extremely low, making the harvest very costly 10 g/m2 + GM-CSF 5 ␮g/kg/day (IFO+GM-CSF n = 28) and cumbersome to obtain enough PBPC for transplan- and cyclophosphamide 4 g/m2 + GM-CSF 5 ␮g/kg/day tation.4 Chemotherapy with or without the addition of (CY+GM-CSF n = 28). Both groups were comparable growth factors such as G-CSF,5 GM-CSF,6 interleukin 37 for age, gender, diagnosis, disease stage and previous or stem cell factor8 is able to increase the number of PBPC. chemotherapy. The IFO+GM-CSF group demonstrated High-dose cyclophosphamide alone9 (4–7 g/m2) or fol- a shorter median interval between therapy and apher- lowed by G-CSF10 or GM-CSF11 is a frequently used regi- esis (10 days (8–14) vs 13 days (8–25) P = 0.002), median men for PBPC mobilization but it is not exempt from mor- number of doses of GM-CSF (9 (7–13) vs 15 (9–31) bidity. Ten to 14 days are required from the commencement P = 0.001), median of days with aplasia (0.5 (0–10) vs 6 of the mobilizing chemotherapy to completion of (0–21) P = 0.001), median days with fever (0 (0–6) vs 3 harvesting and most patients require hospitalization. (0–9) P = 0.006) and median of days using i.v. antibiotics Ifosfamide is an oxazaphosphorine alkylating agent with (0 (0–11) vs 7.5 (0–19) P = 0.002). The median MNC a broad spectrum of antineoplastic activity. It is a prodrug yield was similar in both groups. The CD34+ cell yield metabolized in the liver by cytochrome P450 to isofosfora- was better in the CY+GM-CSF group (3.14 (0.9–11.8) mide mustard, the active alkylating compound.12 Ifosfamide vs 5.33 (0.08–32)) but not at significant levels (P = 0.1). can elicit responses in patients refractory to numerous anti- White blood cell hematopoietic recovery was more neoplastic drugs, including cyclophosphamide. Approxi- rapid in the CY+GM-CSF group (16 (10–22) vs 13 (10– mately 3.5 g/m2 of ifosfamide has equivalent antineoplastic 24) P = 0.02). Platelet engraftment was similar in both activity to 1 g/m2 of cyclophosphamide.13 This drug has groups. Costs of mobilization and transplantation were been used in PBPC mobilization in combination with other almost the same: $28 570 ($18 527–$47 028) and $30 020 chemotherapy drugs14,15 but has not been described as a ($17 281–$67 591), respectively (P = 0.9). There were no single agent. differences in disease-free survival and overall survival In this paper we report our single center experience with between both groups. Mild and transient non-hemato- 56 randomized patients who underwent high-dose therapy logical toxicity (hemorrhagic cystitis, decrease in serum utilizing PBPC collected after mobilization with high-dose creatinine clearance and CNS dysfunction) was seen ifosfamide plus GM-CSF or high-dose cyclophosphamide most frequently in the IFO+GM-CSF group. Bone Mar- plus GM-CSF. We have compared the PBPC mobilization row Transplantation (2000) 25, 1141–1146. kinetics, toxicities, post-transplant hematologic engraftment Keywords: mobilization; high-dose ifosfamide; cyclo- and costs of mobilization and transplantation of the two phosphamide; GM-CSF different chemotherapy regimens. Overall survival and dis- ease-free survival following HDT were also studied in these patients. In recent years most transplant centers exclusively use per- ipheral blood stem cells rather than bone marrow as a Patients and methods source of hematopoietic stem cells following high-dose therapy (HDT).1 Peripheral blood progenitor cell (PBPC) harvesting avoids the need for general anesthesia and leads Eligibility criteria Between August 1994 and June 1999, 56 patients were pro- Correspondence: J Vela-Ojeda, Apartado Postal 14-878, CP 07001, Me´x- spectively randomized to receive one of the following 2 ico DF, Me´xico PBPC mobilization regimens: ifosfamide 10 g/m plus GM- Received 9 December 1999; accepted 9 March 2000 CSF 5 ␮g/kg/day (IFO+GM-CSF n = 28) or cyclophos- High-dose ifosfamide vs cyclophosphamide for stem cell mobilization J Vela-Ojeda et al 1142 phamide 4 g/m2 plus GM-CSF 5 ␮g/kg/day (CY+GM-CSF pletion of chemotherapy and continued until the last leu- n = 28). Inclusion criteria were: (1) age Ͻ60 years, (2) kapheresis procedure. acceptable performance status (ECOG Ͻ3), and (3) adequate organ function (creatinine clearance Ͼ50 ml/min, CY+GM-CSF: 28 patients. Cyclophosphamide (Genoxal; lung diffusion capacity Ͼ50%, cardiac left ventricular ejec- Asta Me´dica) 4 g/m2 i.v. infusion over 2 h on 2 successive tion fraction Ͼ50%, normal liver function tests). Written days through a central venous catheter. Hyperhydration, informed consent was obtained from all patients and the MESNA and GM-CSF were given at the same dose and protocol was approved by the Institutional Ethics and schedule as the IFO+GM-CSF group. Research Committee of our Hospital. All patients received ondansetron (Zofran; Glaxo Wel- come, UK) 8 mg i.v. three times a day and were hospi- Patients talized during administration of chemotherapy and during aplasia. Patient characteristics are summarized in Table 1. There were no differences in the median ages of the patients or Collection of PBPC and cryopreservation disease type (non-Hodgkin’s lymphoma, Hodgkin’s disease and multiple myeloma) between the two groups. Before Leukapheresis was started when the WBC count exceeded mobilization, 17 cases were in complete remission and 11 a level of 1.0 × 109/l. The target was to collect Ͼ2 × 106/kg had refractory disease in the IFO+GM-CSF group; 15 were of CD34 cells in a minimum of two and a maximum of in complete remission, two in first relapse and 11 had five collections. refractory disease in the CY+GM-CSF group (P = 0.3). The Harvesting was performed with a Fenwal CS 3000 Plus median number of previous chemotherapy cycles was 11 (Baxter Healthcare, Deerfield, IL, USA). For each leukaph- and 12 for both groups, respectively (P = 0.3). The median eresis, 10 l of blood were processed at a flow rate of 50– interval between diagnosis and mobilization chemotherapy 70 ml/min. Dimethylsulfoxide (DMSO; Sigma Chemical, was 21 months (6–87) for the IFO+GM-CSF group and 25 St Louis, MO, USA) at 10% concentration was used as months (8–98) for the CY+GM-CSF group (P = 0.8). Four cryoprotectant. The final 100–110 ml suspension was patients in each group had previously received frozen to −90°C and transferred into liquid-phase nitrogen radiotherapy. and stored at −196°C. PBPC mobilization MNC determinations and quantitation of CD34+ cells IFO+GM-CSF: 28 patients. Ifosfamide (Ifoxan; Asta Me´d- Total cell counts and MNC determinations were performed ica, Frankfurt, Germany) 10 g/m2 i.v. infusion over 2 h, using an automatic cell counter and manual differential divided on 2 successive days through a central venous cath- count was also performed. The numbers of CD34+ cells in eter. Hyperhydration (4 l continuous i.v. infusion over 24 h) the leukapheresis product at the time of collection and after was initiated 24 h before chemotherapy. Mesna thawing were enumerated by flow cytometry (FACScan; (Uromitexan; Asta Me´dica) was given at 20% of the ifosfa- Becton Dickinson, San Jose, CA, USA) using direct CD34 mide dosage at 0, 4 and 8 h after initiation of ifosfamide, immunofluorescence. on each of 2 successive days. RhGM-CSF (Molgramostim; Novartis/Schering Plough, Basel, Switzerland) at a dose of Costs 5 ␮g/kg/day subcutaneously, was started 24 h after com- Total costs of both the mobilization and the transplant pro- cedures were calculated according to our hospital charges Table 1 Patient characteristics (national health insurance) and obtained from the finance department. Costs were calculated for each patient group Group 1 Group 2 P value and given as a median per patient. We included in this IFOϩGM- CYϩGM- = = analysis: days in hospital, apheresis and blood products, CSF n 28 CSF n 28 chemotherapy, i.v. antibiotics, GM-CSF doses, surgery and total parenteral nutrition (TPN) and laboratory and Age (years, median, range) 32 (16–51) 35.5 (16–59) 0.2 Gender (male/female) 20/8 20/8 0.9 radiology studies. Costs are given in American dollars. Disease NHL 14 12 HD 7 9 0.8 High-dose therapy conditioning regimen and intensive MM 7 7 care post transplant Disease state at mobilization 1st or 2nd CR 17 15 The ablative treatment consisted of BEAC regimen (BCNU 1st relapse 0 2 0.3 450 mg/m2, etoposide 1600 mg/m2, Ara-C 1600 mg/m2 and Refractory 11 11 cyclophosphamide 140 mg/kg) in 22 and 20 patients of both No.