Prospective randomized clinical trial comparing high-dose ... - Nature

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 Sańchez-Corte´s, M Ayala-Sańchez, ME Guevara-Moreno, LD Garcıá-Leoń, A Rosas-Cabral, MA Garcıá-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: Between August 1994 and June 1999, 56 patients were prospectively randomized to receive ifosfamide 10 g/m2 + GM-CSF 5 ␮g/kg/day (IFO+GM-CSF n = 28) and cyclophosphamide 4 g/m2 + GM-CSF 5 ␮g/kg/day (CY+GM-CSF n = 28). Both groups were comparable for age, gender, diagnosis, disease stage and previous chemotherapy. The IFO+GM-CSF group demonstrated a shorter median interval between therapy and apheresis (10 days (8–14) vs 13 days (8–25) P = 0.002), median number of doses of GM-CSF (9 (7–13) vs 15 (9–31) P = 0.001), median of days with aplasia (0.5 (0–10) vs 6 (0–21) P = 0.001), median days with fever (0 (0–6) vs 3 (0–9) P = 0.006) and median of days using i.v. antibiotics (0 (0–11) vs 7.5 (0–19) P = 0.002). The median MNC yield was similar in both groups. The CD34+ cell yield was better in the CY+GM-CSF group (3.14 (0.9–11.8) vs 5.33 (0.08–32)) but not at significant levels (P = 0.1). White blood cell hematopoietic recovery was more rapid in the CY+GM-CSF group (16 (10–22) vs 13 (10– 24) P = 0.02). Platelet engraftment was similar in both groups. Costs of mobilization and transplantation were almost the same: $28 570 ($18 527–$47 028) and $30 020 ($17 281–$67 591), respectively (P = 0.9). There were no differences in disease-free survival and overall survival between both groups. Mild and transient non-hematological toxicity (hemorrhagic cystitis, decrease in serum creatinine clearance and CNS dysfunction) was seen most frequently in the IFO+GM-CSF group. Bone Marrow Transplantation (2000) 25, 1141–1146. Keywords: mobilization; high-dose ifosfamide; cyclophosphamide; GM-CSF

In recent years most transplant centers exclusively use peripheral blood stem cells rather than bone marrow as a 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 Correspondence: J Vela-Ojeda, Apartado Postal 14-878, CP 07001, Me´xico DF, Me´xico Received 9 December 1999; accepted 9 March 2000

to accelerated hematopoietic recovery, which has resulted in safer2 and cheaper transplants.3 However, the frequency of progenitors in the peripheral blood under steady-state conditions is extremely low, making the harvest very costly and cumbersome to obtain enough PBPC for transplantation.4 Chemotherapy with or without the addition of growth factors such as G-CSF,5 GM-CSF,6 interleukin 37 or stem cell factor8 is able to increase the number of PBPC. High-dose cyclophosphamide alone9 (4–7 g/m2) or followed by G-CSF10 or GM-CSF11 is a frequently used regimen for PBPC mobilization but it is not exempt from morbidity. Ten to 14 days are required from the commencement of the mobilizing chemotherapy to completion of harvesting and most patients require hospitalization. Ifosfamide is an oxazaphosphorine alkylating agent with a broad spectrum of antineoplastic activity. It is a prodrug metabolized in the liver by cytochrome P450 to isofosforamide mustard, the active alkylating compound.12 Ifosfamide can elicit responses in patients refractory to numerous antineoplastic drugs, including cyclophosphamide. Approximately 3.5 g/m2 of ifosfamide has equivalent antineoplastic activity to 1 g/m2 of cyclophosphamide.13 This drug has been used in PBPC mobilization in combination with other chemotherapy drugs14,15 but has not been described as a single agent. In this paper we report our single center experience with 56 randomized patients who underwent high-dose therapy utilizing PBPC collected after mobilization with high-dose ifosfamide plus GM-CSF or high-dose cyclophosphamide plus GM-CSF. We have compared the PBPC mobilization kinetics, toxicities, post-transplant hematologic engraftment and costs of mobilization and transplantation of the two different chemotherapy regimens. Overall survival and disease-free survival following HDT were also studied in these patients.

Patients and methods Eligibility criteria Between August 1994 and June 1999, 56 patients were prospectively randomized to receive one of the following PBPC mobilization regimens: ifosfamide 10 g/m2 plus GMCSF 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

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phamide 4 g/m2 plus GM-CSF 5 ␮g/kg/day (CY+GM-CSF n = 28). Inclusion criteria were: (1) age ⬍60 years, (2) acceptable performance status (ECOG ⬍3), and (3) adequate organ function (creatinine clearance ⬎50 ml/min, lung diffusion capacity ⬎50%, cardiac left ventricular ejection fraction ⬎50%, normal liver function tests). Written informed consent was obtained from all patients and the protocol was approved by the Institutional Ethics and Research Committee of our Hospital. Patients

pletion of chemotherapy and continued until the last leukapheresis procedure. CY+GM-CSF: 28 patients. Cyclophosphamide (Genoxal; Asta Me´dica) 4 g/m2 i.v. infusion over 2 h on 2 successive days through a central venous catheter. Hyperhydration, MESNA and GM-CSF were given at the same dose and schedule as the IFO+GM-CSF group. All patients received ondansetron (Zofran; Glaxo Welcome, UK) 8 mg i.v. three times a day and were hospitalized 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 disease type (non-Hodgkin’s lymphoma, Hodgkin’s disease and multiple myeloma) between the two groups. Before mobilization, 17 cases were in complete remission and 11 had refractory disease in the IFO+GM-CSF group; 15 were in complete remission, two in first relapse and 11 had refractory disease in the CY+GM-CSF group (P = 0.3). The median number of previous chemotherapy cycles was 11 and 12 for both groups, respectively (P = 0.3). The median interval between diagnosis and mobilization chemotherapy was 21 months (6–87) for the IFO+GM-CSF group and 25 months (8–98) for the CY+GM-CSF group (P = 0.8). Four patients in each group had previously received radiotherapy.

Leukapheresis was started when the WBC count exceeded a level of 1.0 × 109/l. The target was to collect ⬎2 × 106/kg of CD34 cells in a minimum of two and a maximum of five collections. Harvesting was performed with a Fenwal CS 3000 Plus (Baxter Healthcare, Deerfield, IL, USA). For each leukapheresis, 10 l of blood were processed at a flow rate of 50– 70 ml/min. Dimethylsulfoxide (DMSO; Sigma Chemical, St Louis, MO, USA) at 10% concentration was used as cryoprotectant. The final 100–110 ml suspension was frozen to −90°C and transferred into liquid-phase nitrogen and stored at −196°C.

PBPC mobilization

MNC determinations and quantitation of CD34+ cells

IFO+GM-CSF: 28 patients. Ifosfamide (Ifoxan; Asta Me´dica, Frankfurt, Germany) 10 g/m2 i.v. infusion over 2 h, divided on 2 successive days through a central venous catheter. Hyperhydration (4 l continuous i.v. infusion over 24 h) was initiated 24 h before chemotherapy. Mesna (Uromitexan; Asta Me´dica) was given at 20% of the ifosfamide dosage at 0, 4 and 8 h after initiation of ifosfamide, on each of 2 successive days. RhGM-CSF (Molgramostim; Novartis/Schering Plough, Basel, Switzerland) at a dose of 5 ␮g/kg/day subcutaneously, was started 24 h after com-

Total cell counts and MNC determinations were performed using an automatic cell counter and manual differential count was also performed. The numbers of CD34+ cells in the leukapheresis product at the time of collection and after thawing were enumerated by flow cytometry (FACScan; Becton Dickinson, San Jose, CA, USA) using direct CD34 immunofluorescence.

Table 1

Patient characteristics

Age (years, median, range) Gender (male/female) Disease NHL HD MM Disease state at mobilization 1st or 2nd CR 1st relapse Refractory No. previous chemotherapy cycles (median, range)

Group 1 IFO⫹GMCSF n = 28

Group 2 CY⫹GMCSF n = 28

P value

32 (16–51) 20/8

35.5 (16–59) 20/8

0.2 0.9

14 7 7

12 9 7

0.8

17 0 11 11 (3–22)

15 2 11 12 (4–23)

0.3 0.3

IFO = ifosfamide 10 g/m2; CY = cyclophosphamide 4 g/m2; NHL = nonHodgkin’s lymphoma; HD = Hodgkin’s disease; MM = multiple myeloma; CR = complete remission. Bone Marrow Transplantation

Collection of PBPC and cryopreservation

Costs Total costs of both the mobilization and the transplant procedures were calculated according to our hospital charges (national health insurance) and obtained from the finance department. Costs were calculated for each patient group and given as a median per patient. We included in this analysis: days in hospital, apheresis and blood products, chemotherapy, i.v. antibiotics, GM-CSF doses, surgery and total parenteral nutrition (TPN) and laboratory and radiology studies. Costs are given in American dollars. High-dose therapy conditioning regimen and intensive care post transplant The ablative treatment consisted of BEAC regimen (BCNU 450 mg/m2, etoposide 1600 mg/m2, Ara-C 1600 mg/m2 and cyclophosphamide 140 mg/kg) in 22 and 20 patients of both groups, respectively. BEAM regimen (BCNU, etoposide and Ara-C at the same doses, and melphalan 140 mg/m2) was used in six and eight patients of the IFO+GM-CSF and CY+GM-CSF groups, respectively. The patients received prophylactic bowel decontamination and antibiotic combi-


nation therapy was administered for fever ⬎38.5°C, while fluconazole (Diflucan; Pfizer, New York, NY, USA) was given for systemic fungal prophylaxis. Patients did not receive hematopoietic growth factors following high-dose therapy. Statistical analysis Numeric and string variables were evaluated according to standard statistical methods using a commercially available computer program (SPSS for Windows, version 8). Differences in hematological parameters and patient characteristics were evaluated using the Mann–Whitney U test for independent samples. String variables were analyzed using the ␹2 test. The correlation between both groups of mobilization and dependent variables was analyzed using a logistic regression model. Overall survival and disease-free survival were estimated from the day of transplantation until last follow-up or relapse respectively. A P value of ⬍0.05 was considered significant. Results Leukapheresis, mononuclear cell and CD-34+ yield The efficacy of the two mobilization regimens is shown in Table 2. The median interval between the last day of mobilization chemotherapy and the first apheresis was 10 days (8–14) for the IFO+GM-CSF group and 13 days (8–25) for the CY+GM-CSF group (P = 0.002). GM-CSF was administered for a median of 9 days (7–13) and 15 days (9–31), respectively (P = 0.001). The number of aphereses performed in each group was 3 (1–4) and 3 (2–6), respectively (P = 0.1). The median number of days with ANC ⬍0.5 × 109/l was 0.5 (0–10) for the IFO+GM-CSF group

Table 2

Results in peripheral blood progenitor cells mobilization Group 1 IFO⫹GMCSF n = 28 (median, range)

Group 2 CY⫹GM-CSF n = 28 (median, range)

Interval chemotherapy to 1st 10 (8–14) 13 (8–25) apheresis (days) No. of aphereses 3 (1–4) 3 (2–6) No. GM-CSF doses 9 (7–13) 15 (9–31) Failure to achieve 4 (14%) 3 (11%) ⬎2 × 106/kg CD34+ cellsa 8 MNC ×10 /kg 3 (0.5–21.6) 3.1 (0.5–13) 3.14 (0.9–11.8) 5.33 (0.08–32) CD34+ cells ×106/kg Aplasia (days) 0.5 (0–10) 6 (0–21) Fever (days) 0 (0–6) 3 (0–9) Antibiotics (days) 0 (0–11) 7.5 (0–19) RBC units (median, range) 0 (0–2) 0 (0–2) Platelet units (median, 0 (0–3) 0 (0–13) range)

P value

and 6 (0–21) for the CY+GM-CSF group (P = 0.001). The median number of days with fever was 0 (0–6) and 3 (0– 9) for both groups, respectively (P = 0.006). Systemic antibiotic treatment during mobilization was necessary for a median of 0 days (0–11) and 7.5 days (0–19), respectively (P = 0.002). There were no differences between the groups in blood product requirements. The median number of MNC was similar in both groups i.e. 3 × 108/kg (0.5–21) and 3.1 × 108/kg (0.5–13) (P = 0.3). There was a trend for patients receiving CY+GM-CSF to achieve higher CD34+ cell yields (5.33 × 106/kg (0.08–32)) than patients receiving IFO+GM-CSF 3.14 × 106/kg (0.9–11.8)) but not at a statistically significant level (P = 0.1). Four patients (14%) in the IFO+GM-CSF group and three patients (11%) in the CY+GM-CSF group did not achieve the target level of ⬎2 × 106 CD34+ cells/kg. A logistic regression model showed a correlation between IFO+GM-CSF mobilization treatment and fewer days of systemic antibiotic use (P = 0.04), fewer days with 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 mobilization and BMT of both regimens are shown in Table 3. In total costs, IFO+GM-CSF was cheaper than CY+GM-CSF ($28 570 ($18 527–$47 028) vs $30 420 ($17 281–$67 591)), saving a median of $1850, but this difference was not statistically significant (P = 0.9). There were no differences between both groups in post-transplant charges for i.v. antibiotics or blood products. Engraftment kinetics after autologous transplantation are shown in Table 4. Engraftment was not evaluable in three patients in the IFO+GM-CSF group and two patients in the CY+GM-CSF group due to early transplant-related mortality. After PBPC infusion, the median time to neutrophil (⬎0.5 × 109/l) engraftment was 16 days (10–22) for the IFO+GM-CSF group and 13 (10–24) for the CY+GM-CSF group (P = 0.02). The median time to platelet engraftment (⬎20 × 109/l) was 17 days (11–33) and 15 days (7–41), respectively (P = 0.9). With a median follow-up of 30 months, the disease-free survival (29 and 24 months) (Figure 1) and overall survival (42 and 38 months) (Figure 2) were not significantly different between the IFO+GM-CSF and CY+GM-CSF groups.

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Mobilization regimen toxicity 0.002 0.1 0.0001 0.9 0.3 0.1 0.001 0.006 0.002 0.8 0.2

IFO = ifosfamide 10 g/m2; CY = cyclophosphamide 4 g/m2; MNC = mononuclear cells. a Total number of patients per group.

Table 5 shows non-hematological toxicity after mobilization. Grade I–II (WHO) nausea and vomiting was present in six (21%) and five (18%) patients of the IFO+GM-CSF and CY+GM-CSF groups. Grade I (microscopic) hemorrhagic cystitis was observed in five (18%) and two (5%) patients in both groups. Grade I neurologic complaints and grade II acute renal failure occurred in five (18%) and two (5%) patients in the IFO+GM-CSF group. All these complications were mild and reversible within 24–48 h in all cases. Discussion For over 15 years, it has been known that high-dose cyclophosphamide produces an increase in the reconstitutive Bone Marrow Transplantation


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Table 3

Costs of PBPC mobilization regimen (median costs per patient)a IFO⫹GM-CSF median (range)

Hospitalization Blood products Chemotherapy Antibiotics GM-CSF Surgery and TPN Laboratory and radiology Total

13 900 3710 4100 1650 1850 1660 1700 28 570

Cy⫹GM-CSF median (range)

(8671–20 781) (2950–6800) (3800–4400) (540–4236) (1400–2600) (316–5716) (850–2495) (18 527–47 028)

14 850 4570 2300 2240 3100 1560 1800 30 420

(9291–22 731) (1800–21 800) (2000–2600) (1140–5900) (1800–6200) (400–5800) (850–2560) (17 281–67 591)

a

Costs 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 IFO⫹GM-CSF n = 28

Diagnosis to mobilization (months, median, range) Conditioning regimen BEAC BEAM WBC engraftment (days, median, range) Platelet engraftment (days, median, range) Days in hospital (median, range) Days i.v. antibiotics (median, range) Disease-free survival (months, median) Overall survival (months, median)

Group 2 CY⫹GM-CSF n = 28

P value

21 (6–87)

25 (8–98)

0.8

22 6 16 (10–22)a 17 (11–33)a 28 (16–53) 14 (0–33) 24 42

20 8 13 (10–24)b 15 (7–41)b 27 (16–46) 14 (5–32) 25 38

0.7 0.02 0.09 0.4 0.5 0.6 0.5

1.0

1.0

0.9

0.9

0.8

0.8

0.7

Cumulative survival

Cumulative survival

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. a 25 evaluable patients. b 26 evaluable patients.

IFO + GM-CSF

0.6

P = 0.6

0.5 0.4

CY + GM-CSF

0.3 0.2

0.7 0.6 0.5

P = 0.5 CY + GM-CSF

0.4 0.3 0.2 0.1

0.1 0.0

IFO + GM-CSF

0.0

0

10

20

30

40

50

60

70

Months post transplant Figure 1 Kaplan and Meier survival curve. Disease-free survival for ifosfamide+GM-CSF and cyclophosphamide+GM-CSF groups.

capacity of progenitor blood cells collected during the rebound recovery phase9 but the toxicity (mainly aplasia and infection) is considerable. By administering hematopoietic growth factors, the quantity of PBPCs increases (8.4fold increase in CFU-GM16) and hematological toxicity is reduced. A frequently used combination for PBPC mobilization is cyclophosphamide at doses ranging from 4 to 7 g/m2. Goldschmidt et al10 have compared the dose of cyclophosphamide at 4 g/m2 vs 7 g/m2 plus G-CSF in mulBone Marrow Transplantation

0

10

20

30

40

50

60

70

Months post transplant Figure 2 Kaplan and Meier survival curve. Overall survival for ifosfamide+GM-CSF and cyclophosphamide+GM-CSF groups.

tiple myeloma patients. They found that administration of 7 g/m2 resulted in statistically significantly higher levels of CD34+ progenitor cells. On the other hand, Alegre et al11 have used the drug at 4 g/m2 combined with GM-CSF with similar results. Using cyclophosphamide + GM-CSF, we can obtain up to a 1000-fold increase in CFU-GM or CD34+ cells.17 Ifosfamide is an oxazophosphorine alkylating agent with a broad spectrum of antineoplastic activity. It is an analog of cyclophosphamide with translocation of a chlorethyl


Table 5

Non-hematological toxicity after mobilization

WHO

Grade Grade Grade Grade

I–II vomiting I–II hemorrhagic cystitis I neurological toxicity II acute renal failure

Group 1 IFO GM-CSF n = 28

Group 2 CY⫹GM-CSF n = 28

6 5 5 2

5 2 0 0

IFO = ifosfamide 10 g/m2; CY = cyclophosphamide 4 g/m2; WHO = World Health Organization toxicity grading system.

group which provides a more effective DNA cross-linking distance between two independent functional alkylating moieties.18 Preclinical studies demonstrated differences in alkylation kinetics between the two active metabolites: phosphoramide mustard (for cyclophosphamide) and isofosforamide mustard (for ifosfamide), resulting in a longer survival of isofosforamide mustard within the cell cytoplasm and an increased probability of reaching the nucleus and alkylating DNA.19 Ifosfamide has been used in different PBPC mobilization methods at doses ranging from 4 to 6 g/m2 but always in combination with other chemotherapy agents and administered for 3–5 days.14,15 In the present study, our data shows that IFO+GM-CSF and CY+GMCSF are both effective regimens for PBPC mobilization, even in heavily pretreated patients (most of the patients had received more than 10 cycles of chemotherapy before mobilization). During the mobilization phase our patients treated with IFO+GM-CSF had: (1) earlier mobilization, (2) fewer days treated with GM-CSF, (3) fewer days of aplasia 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 significant levels. This resulted in a more rapid WBC engraftment but similar numbers of days in hospital and days on i.v. antibiotics. Eleven patients in each group underwent transplantation in a refractory phase and they had been heavily treated before. This could be one reason to explain the poor CD34+ yields obtained from some patients, not only in the IFO+GM-CSF group, but also in the CY+GM-CSF group. Throughout mobilization and transplant procedures, the IFO+GM-CSF regimen saved a median of $1850 dollars per patient because of a favorable balance in costs due to fewer doses of GM-CSF and fewer days in hospital during the mobilization phase, although this difference was not statistically significant. Disease-free survival and overall survival were almost the same in both groups. Mild and reversible non-hematological toxicity, mainly hemorrhagic cystitis, acute renal failure and CNS toxicity was more common in the IFO-GM-CSF group. Ifosfamide has been associated with significant CNS toxicity with an incidence of 12–22%. This complication may be related to high serum levels of chloracetaldehyde, one of the major metabolites of the drug and may occur when the drug is used at standard as well as higher doses.20 The onset of symptoms is variable and may occur within 2 h of administration of a bolus dose or might not appear until 28 days

after therapy. Clinical manifestations consist of mental status changes, cerebellar dysfunction, urinary incontinence, motor system dysfunction, cranial nerve dysfunction and in severe cases seizures, encephalopathy and coma. Fortunately, as in our series, all these clinical manifestations resolved within 3 days of stopping the infusion.21 Watkin et al22 reported CNS toxicity in 18 out of 82 (22%) patients treated with ifosfamide. In our study, we observed SNC disturbances in five out of 28 patients (18%), predominantly confusion and auditory or visual hallucinations. We did not observe urinary incontinence or severe toxicity, the symptoms were mild and resolved completely within 24 h of the last dose of ifosfamide, without the use of methylene blue or bicarbonate infusions. In conclusion, IFO+GM-CSF and CY+GM-CSF are both useful PBPC mobilization regimens. The ifosfamide regimen offers some advantages during the mobilization phase such as a brief period of aplasia, a short interval between chemotherapy and first apheresis, fewer days using GMCSF, lower incidence of infections, fewer febrile episodes and fewer days using antibiotics. However, the CD34+ cell yield is slightly better with CY+GM-CSF but this is not statistically significant. Disease-free survival and overall survival after autologous PBPC transplantation is the same in both groups. Non-hematological toxicity, mainly CNS toxicity, hemorrhagic cystitis and acute renal failure are more frequent using IFO+GM-CSF but these toxicities are mild and rapidly reversible. To our knowledge, this is the first study using ifosfamide as a single chemotherapy agent in combination with GM-CSF for PBPC mobilization. Because we obtained similar results with cyclophosphamide, we think ifosfamide is an alternative for patients already heavily pretreated with cyclophosphamide.

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