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 comparing high-dose ifosfamide + GM-CSF vs high-dose + 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 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 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 , 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, 1600 mg/m2, Ara-C 1600 mg/m2 and Refractory 11 11 cyclophosphamide 140 mg/kg) in 22 and 20 patients of both No. previous chemotherapy 11 (3–22) 12 (4–23) 0.3 groups, respectively. BEAM regimen (BCNU, etoposide cycles (median, range) and Ara-C at the same doses, and 140 mg/m2) + IFO = ifosfamide 10 g/m2;CY= cyclophosphamide 4 g/m2; NHL = non- was used in six and eight patients of the IFO GM-CSF and Hodgkin’s lymphoma; HD = Hodgkin’s disease; MM = multiple myeloma; CY+GM-CSF groups, respectively. The patients received CR = complete remission. prophylactic bowel decontamination and antibiotic combi-

Bone Marrow Transplantation High-dose ifosfamide vs cyclophosphamide for stem cell mobilization J Vela-Ojeda et al 1143 nation therapy was administered for fever Ͼ38.5°C, while and 6 (0–21) for the CY+GM-CSF group (P = 0.001). The fluconazole (Diflucan; Pfizer, New York, NY, USA) was median number of days with fever was 0 (0–6) and 3 (0– given for systemic fungal prophylaxis. Patients did not 9) for both groups, respectively (P = 0.006). Systemic anti- receive hematopoietic growth factors following high-dose biotic treatment during mobilization was necessary for a therapy. median of 0 days (0–11) and 7.5 days (0–19), respectively (P = 0.002). There were no differences between the groups Statistical analysis in blood product requirements. The median number of MNC was similar in both groups i.e. 3 × 108/kg (0.5–21) Numeric and string variables were evaluated according to and 3.1 × 108/kg (0.5–13) (P = 0.3). There was a trend for standard statistical methods using a commercially available patients receiving CY+GM-CSF to achieve higher CD34+ computer program (SPSS for Windows, version 8). Differ- cell yields (5.33 × 106/kg (0.08–32)) than patients receiving ences in hematological parameters and patient character- IFO+GM-CSF 3.14 × 106/kg (0.9–11.8)) but not at a stat- istics were evaluated using the Mann–Whitney U test for istically significant level (P = 0.1). Four patients (14%) in independent samples. String variables were analyzed using the IFO+GM-CSF group and three patients (11%) in the the ␹2 test. The correlation between both groups of mobiliz- CY+GM-CSF group did not achieve the target level of ation and dependent variables was analyzed using a logistic Ͼ2 × 106 CD34+ cells/kg. regression model. Overall survival and disease-free survival A logistic regression model showed a correlation were estimated from the day of transplantation until last between IFO+GM-CSF mobilization treatment and fewer follow-up or relapse respectively. A P value of Ͻ0.05 was days of systemic antibiotic use (P = 0.04), fewer days with considered significant. aplasia (P = 0.01), fewer days with fever (0.05), fewer days utilizing GM-CSF (P = 0.0003) and fewer days between chemotherapy and apheresis (P = 0.0005). The costs of Results mobilization and BMT of both regimens are shown in Table 3. In total costs, IFO+GM-CSF was cheaper than Leukapheresis, mononuclear cell and CD-34+ yield CY+GM-CSF ($28 570 ($18 527–$47 028) vs $30 420 ($17 281–$67 591)), saving a median of $1850, but this dif- The efficacy of the two mobilization regimens is shown ference was not statistically significant (P = 0.9). There in Table 2. were no differences between both groups in post-transplant The median interval between the last day of mobilization charges for i.v. antibiotics or blood products. chemotherapy and the first apheresis was 10 days (8–14) Engraftment kinetics after autologous transplantation are for the IFO+GM-CSF group and 13 days (8–25) for the shown in Table 4. Engraftment was not evaluable in three + P = CY GM-CSF group ( 0.002). GM-CSF was adminis- patients in the IFO+GM-CSF group and two patients in the tered for a median of 9 days (7–13) and 15 days (9–31), CY+GM-CSF group due to early transplant-related mor- respectively (P = 0.001). The number of aphereses perfor- tality. After PBPC infusion, the median time to neutrophil med in each group was 3 (1–4) and 3 (2–6), respectively Ͼ × 9 = ( 0.5 10 /l) engraftment was 16 days (10–22) for the (P 0.1). The median number of days with ANC + + Ͻ × 9 + IFO GM-CSF group and 13 (10–24) for the CY GM-CSF 0.5 10 /l was 0.5 (0–10) for the IFO GM-CSF group group (P = 0.02). The median time to platelet engraftment (Ͼ20 × 109/l) was 17 days (11–33) and 15 days (7–41), respectively (P = 0.9). With a median follow-up of 30 Table 2 Results in peripheral blood progenitor cells mobilization months, the disease-free survival (29 and 24 months) (Figure 1) and overall survival (42 and 38 months) Group 1 Group 2 P value ϩ ϩ (Figure 2) were not significantly different between the IFO GM- CY GM-CSF + + CSF n = 28 n = 28 IFO GM-CSF and CY GM-CSF groups. (median, (median, range) range) Mobilization regimen toxicity

Interval chemotherapy to 1st 10 (8–14) 13 (8–25) 0.002 Table 5 shows non-hematological toxicity after mobiliz- apheresis (days) ation. Grade I–II (WHO) nausea and vomiting was present No. of aphereses 3 (1–4) 3 (2–6) 0.1 in six (21%) and five (18%) patients of the IFO+GM-CSF No. GM-CSF doses 9 (7–13) 15 (9–31) 0.0001 and CY+GM-CSF groups. Grade I (microscopic) Failure to achieve 4 (14%) 3 (11%) 0.9 Ͼ2 × 106/kg CD34+ cellsa hemorrhagic cystitis was observed in five (18%) and two MNC ×108/kg 3 (0.5–21.6) 3.1 (0.5–13) 0.3 (5%) patients in both groups. Grade I neurologic complaints CD34+ cells ×106/kg 3.14 (0.9–11.8) 5.33 (0.08–32) 0.1 and grade II acute renal failure occurred in five (18%) and Aplasia (days) 0.5 (0–10) 6 (0–21) 0.001 two (5%) patients in the IFO+GM-CSF group. All these Fever (days) 0 (0–6) 3 (0–9) 0.006 Antibiotics (days) 0 (0–11) 7.5 (0–19) 0.002 complications were mild and reversible within 24–48 h in RBC units (median, range) 0 (0–2) 0 (0–2) 0.8 all cases. Platelet units (median, 0 (0–3) 0 (0–13) 0.2 range) Discussion IFO = ifosfamide 10 g/m2;CY= cyclophosphamide 4 g/m2; MNC = mononuclear cells. For over 15 years, it has been known that high-dose cyclo- aTotal number of patients per group. phosphamide produces an increase in the reconstitutive

Bone Marrow Transplantation High-dose ifosfamide vs cyclophosphamide for stem cell mobilization J Vela-Ojeda et al 1144 Table 3 Costs of PBPC mobilization regimen (median costs per patient)a

IFOϩGM-CSF median (range) CyϩGM-CSF median (range)

Hospitalization 13 900 (8671–20 781) 14 850 (9291–22 731) Blood products 3710 (2950–6800) 4570 (1800–21 800) Chemotherapy 4100 (3800–4400) 2300 (2000–2600) Antibiotics 1650 (540–4236) 2240 (1140–5900) GM-CSF 1850 (1400–2600) 3100 (1800–6200) Surgery and TPN 1660 (316–5716) 1560 (400–5800) Laboratory and radiology 1700 (850–2495) 1800 (850–2560) Total 28 570 (18 527–47 028) 30 420 (17 281–67 591)

aCosts were calculated in American dollars. TPN: Total parenteral nutrition. Costs in a national health insurance hospital.

Table 4 Results after peripheral blood progenitor cell autologous transplantation

Group 1 IFOϩGM-CSF n = 28 Group 2 CYϩGM-CSF n = 28 P value

Diagnosis to mobilization (months, median, range) 21 (6–87) 25 (8–98) 0.8 Conditioning regimen BEAC 22 20 0.7 BEAM 6 8 WBC engraftment (days, median, range) 16 (10–22)a 13 (10–24)b 0.02 Platelet engraftment (days, median, range) 17 (11–33)a 15 (7–41)b 0.09 Days in hospital (median, range) 28 (16–53) 27 (16–46) 0.4 Days i.v. antibiotics (median, range) 14 (0–33) 14 (5–32) 0.5 Disease-free survival (months, median) 24 25 0.6 Overall survival (months, median) 42 38 0.5

IFO = ifosfamide 10 g/m2;CY= cyclophosphamide 4 g/m2; BEAC = BCNU 450 mg/m2, etoposide 1600 mg/m2, Ara-C 1600 mg/m2, cyclophosphamide 140 mg/kg; BEAM = BCNU, etoposide and Ara-C same doses as above plus melphalan 140 mg/m2. a25 evaluable patients. b26 evaluable patients.

1.0 1.0 0.9 0.9 0.8 0.8 IFO + GM-CSF 0.7 IFO + GM-CSF 0.7 0.6 0.6 0.5 P = 0.6 0.5 P = 0.5 CY + GM-CSF 0.4 0.4 CY + GM-CSF 0.3 0.3 Cumulative survival Cumulative survival 0.2 0.2 0.1 0.1 0.0 0.0 0 10 20 30 40 50 60 70 0 10203040506070 Months post transplant Months post transplant Figure 2 Kaplan and Meier survival curve. Overall survival for Figure 1 Kaplan and Meier survival curve. Disease-free survival for ifosfamide+GM-CSF and cyclophosphamide+GM-CSF groups. ifosfamide+GM-CSF and cyclophosphamide+GM-CSF groups. tiple myeloma patients. They found that administration of capacity of progenitor blood cells collected during the 7 g/m2 resulted in statistically significantly higher levels of rebound recovery phase9 but the toxicity (mainly aplasia CD34+ progenitor cells. On the other hand, Alegre et al11 and infection) is considerable. By administering hematopo- have used the drug at 4 g/m2 combined with GM-CSF with ietic growth factors, the quantity of PBPCs increases (8.4- similar results. Using cyclophosphamide + GM-CSF, we fold increase in CFU-GM16) and hematological toxicity is can obtain up to a 1000-fold increase in CFU-GM or reduced. A frequently used combination for PBPC mobiliz- CD34+ cells.17 ation is cyclophosphamide at doses ranging from 4 to Ifosfamide is an oxazophosphorine alkylating agent with 7 g/m2. Goldschmidt et al10 have compared the dose of a broad spectrum of antineoplastic activity. It is an analog cyclophosphamide at 4 g/m2 vs 7 g/m2 plus G-CSF in mul- of cyclophosphamide with translocation of a chlorethyl

Bone Marrow Transplantation High-dose ifosfamide vs cyclophosphamide for stem cell mobilization J Vela-Ojeda et al 1145 Table 5 Non-hematological toxicity after mobilization after therapy. Clinical manifestations consist of mental status changes, cerebellar dysfunction, urinary inconti- WHO Group 1 Group 2 nence, motor system dysfunction, cranial nerve dysfunction IFO CYϩGM-CSF and in severe cases seizures, and coma. GM-CSF n = 28 n = 28 Fortunately, as in our series, all these clinical manifes- tations resolved within 3 days of stopping the infusion.21 22 Grade I–II vomiting 6 5 Watkin et al reported CNS toxicity in 18 out of 82 (22%) Grade I–II hemorrhagic cystitis 5 2 patients treated with ifosfamide. In our study, we observed Grade I neurological toxicity 5 0 SNC disturbances in five out of 28 patients (18%), predomi- Grade II acute renal failure 2 0 nantly confusion and auditory or visual hallucinations. We did not observe urinary incontinence or severe toxicity, the = 2 = 2 = IFO ifosfamide 10 g/m ;CY cyclophosphamide 4 g/m ; WHO symptoms were mild and resolved completely within 24 h World Health Organization toxicity grading system. of the last dose of ifosfamide, without the use of or bicarbonate infusions. group which provides a more effective DNA cross-linking In conclusion, IFO+GM-CSF and CY+GM-CSF are both distance between two independent functional alkylating useful PBPC mobilization regimens. The ifosfamide regi- moieties.18 Preclinical studies demonstrated differences in men offers some advantages during the mobilization phase alkylation kinetics between the two active metabolites: such as a brief period of aplasia, a short interval between phosphoramide mustard (for cyclophosphamide) and iso- chemotherapy and first apheresis, fewer days using GM- fosforamide mustard (for ifosfamide), resulting in a longer CSF, lower incidence of infections, fewer febrile episodes survival of isofosforamide mustard within the cell cyto- and fewer days using antibiotics. However, the CD34+ cell plasm and an increased probability of reaching the nucleus yield is slightly better with CY+GM-CSF but this is not and alkylating DNA.19 Ifosfamide has been used in differ- statistically significant. Disease-free survival and overall ent PBPC mobilization methods at doses ranging from 4 to survival after autologous PBPC transplantation is the same 6 g/m2 but always in combination with other chemotherapy in both groups. Non-hematological toxicity, mainly CNS agents and administered for 3–5 days.14,15 In the present toxicity, hemorrhagic cystitis and acute renal failure are study, our data shows that IFO+GM-CSF and CY+GM- more frequent using IFO+GM-CSF but these toxicities are CSF are both effective regimens for PBPC mobilization, mild and rapidly reversible. To our knowledge, this is the even in heavily pretreated patients (most of the patients had first study using ifosfamide as a single chemotherapy agent received more than 10 cycles of chemotherapy before in combination with GM-CSF for PBPC mobilization. mobilization). During the mobilization phase our patients Because we obtained similar results with cyclophospham- treated with IFO+GM-CSF had: (1) earlier mobilization, (2) ide, we think ifosfamide is an alternative for patients fewer days treated with GM-CSF, (3) fewer days of aplasia already heavily pretreated with cyclophosphamide. and consequently fewer days with fever and antibiotics. On the other hand, we obtained a higher CD34+ cell yield in the group receiving CY+GM-CSF but not at statistically References significant levels. This resulted in a more rapid WBC 1 Gratwohl A, Hermans J, Baldomero H. Haemopoietic precur- engraftment but similar numbers of days in hospital and sors cell transplants in Europe: activity in 1994. Report from days on i.v. antibiotics. Eleven patients in each group the European Group for Blood and Marrow transplantation. underwent transplantation in a refractory phase and they Bone Marrow Transplant 1996; 17: 137–148. had been heavily treated before. This could be one reason 2 Chao NJ, Schriber JR, Grimes K et al. Granulocyte colony to explain the poor CD34+ yields obtained from some stimulating factor ‘mobilized’ peripheral blood progenitor patients, not only in the IFO+GM-CSF group, but also in cells accelerate granulocyte and platelet recovery after high the CY+GM-CSF group. Throughout mobilization and dose chemotherapy. Blood 1993; 81: 2031–2035. transplant procedures, the IFO+GM-CSF regimen saved a 3 Smith TJ, Hillner BE, Schmitz N et al. Economic analysis median of $1850 dollars per patient because of a favorable of a randomized clinical trial to compare filgrastim-mobilized peripheral-blood progenitor-cell transplantation and autolog- balance in costs due to fewer doses of GM-CSF and fewer ous bone marrow transplantation in patients with Hodgkin’s days in hospital during the mobilization phase, although and non-Hodgkin’s lymphoma. J Clin Oncol 1997; 15: 5–10. this difference was not statistically significant. Disease-free 4 Kessinger A, Armitage JO, Landmark JD et al. Reconstitution survival and overall survival were almost the same in of hematopoietic function with autologous cryopreserved cir- both groups. culating stem cells. Exp Hematol 1986; 14: 192–196. Mild and reversible non-hematological toxicity, mainly 5 Duhrsen U, Villeval JL, Boyd J et al. Effects of recombinant hemorrhagic cystitis, acute renal failure and CNS toxicity human granulocyte colony stimulating factor on hematopoietic was more common in the IFO-GM-CSF group. Ifosfamide progenitor cells in patients. Blood 1988; 72: 2074– has been associated with significant CNS toxicity with an 2081. incidence of 12–22%. This complication may be related to 6 Socinski MA, Cannistra SA, Elias A et al. Granulocyte– macrophage colony-stimulating factor expands the circulating high serum levels of chloracetaldehyde, one of the major hematopoietic progenitor cell compartment in man. Lancet metabolites of the drug and may occur when the drug is 1988; 1: 1194–1198. 20 used at standard as well as higher doses. The onset of 7 Ottmann OG, Ganser A, Seipelt G et al. Effects of human symptoms is variable and may occur within 2 h of adminis- recombinant interleukin-3 on human hematopoietic progenitor tration of a bolus dose or might not appear until 28 days and precursor cells in vivo. Blood 1990; 76: 1494–1502.

Bone Marrow Transplantation High-dose ifosfamide vs cyclophosphamide for stem cell mobilization J Vela-Ojeda et al 1146 8 Weaver A, Testa NG. Stem cell factor leads to reduced blood 15 Prince HM, Gardyn J, Millward MJ et al. Ifosfamide in com- processing during apheresis or the use of whole blood to sup- bination with or : regimens which effec- port dose-intensive chemotherapy. Bone Marrow Transplant tively mobilize peripheral blood progenitor cells while demon- 1998; 22: 33–38. strating anti-tumor activity in patients with metastasic breast 9 Bik To L, Shepperd KM, Haylock DN et al. Single high doses cancer. Bone Marrow Transplant 1999; 23: 427–435. of cyclophosphamide enable the collection of high numbers 16 Bishop MR, Anderson JR, Jackson JD. High-dose therapy and of hemopoietic stem cells from the peripheral blood. Exp peripheral blood progenitor cell transplantation: effects of Hematol 1990; 18: 442–447. recombinant human granulocyte–macrophage colony-stimulat- 10 Goldschmidt H, Hegenbart U, Haas R et al. Mobilization of ing factor on the autograft. Blood 1994; 83: 610–616. peripheral blood progenitor cells with high-dose cyclophos- 17 Siena S, Bregni M, Brando B. Circulation of CD34+ hemato- phamide (4 or 7 g/m2) and granulocyte colony-stimulating fac- poietic stem cells in the peripheral blood of high-dose cyclo- tor in patients with multiple myeloma. Bone Marrow Trans- phosphamide treated patients: enhancement by intravenous plant 1996; 17: 691–697. recombinant human granulocyte–macrophage colony stimulat- 11 Alegre A, Toma´s JF, Martı´nez-Chamorro C et al. Comparison ing factor. Blood 1989; 74: 1905–1914. of peripheral blood progenitor cell mobilization in patients 18 Goldin A. Ifosfamide in experimental tumor systems. Semin with multiple myeloma: high-dose cyclophosphamide plus Oncol 1982: 9 (Suppl. 1): 14–23. GM-CSF vs G-CSF. Bone Marrow Transplant 1997; 20: 19 Boal JH, Williamson M, Boyd VL et al. 31P NMR studies 211–217. of the kinetics of bisalkylation by isophosphoramide mustard 12 Dechant KL, Brogden RN, Pilkington T et al. Ifosfamide/ comparisons with phosphoramide mustard. J Med Chem 1989; mesna. A review of its antineoplastic activity, pharmacoki- 32: 1768–1773. netic properties and therapeutic efficacy in cancer. Drugs 20 Antman KH, Elias A, Ryan L et al. Ifosfamide and mesna: 1991; 42: 428–467. response and toxicity at standard and high dose schedules. 13 Creaven PJ, Allen LM. Clinical pharmacology of ifosfamide. Semin Oncol 1990; 17 (Suppl. 4): 68–73. Clin Pharmacol Ther 1974; 16: 77–86. 21 Miller LJ. Ifosfamide-induced neurotoxicity. Cancer Bull 14 Mayer J, Koristek Z, Vasova I et al. Ifosfamide and etoposide- 1991; 43: 456–457. based chemotherapy as salvage and mobilizing regimens for 22 Watkin SW, Husband DJ, Green JA et al. Ifosfamide encepha- poor prognosis lymphoma. Bone Marrow Transplant 1999; lopathy: a reappraisal. Eur J Cancer Clin Oncol 1989; 25: 23: 413–419. 1303–1310.

Bone Marrow Transplantation