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Bone Marrow Transplantation (2007) 39, 743–750 & 2007 Nature Publishing Group All rights reserved 0268-3369/07 $30.00

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ORIGINAL ARTICLE

Efficient mobilization of peripheral blood stem cells following CAD chemotherapy and a single dose of pegylated G-CSF in patients with multiple myeloma S Fruehauf1,2, J Klaus2, J Huesing3, MR Veldwijk4,5, EC Buss2, J Topaly2, T Seeger2,4, LWJ Zeller4, T Moehler2, AD Ho2 and H Goldschmidt2 1

Department of Tumor Diagnostics and Therapy, Paracelsus Hospital, Osnabrueck, Germany; 2Department of Internal Medicine V, University of Heidelberg, Heidelberg, Germany; 3Coordination Centre for Clinical Trials, Heidelberg, Germany; 4Department G402, Pharmacology of Cancer Treatment, German Cancer Research Center, Heidelberg, Germany and 5Department of Radiation Oncology, Mannheim Medical Center, University of Heidelberg, Mannheim, Germany

High-dose chemotherapy followed by autologous blood stem cell transplantation is the standard treatment for myeloma patients. In this study, CAD (cyclophosphamide, adriamycin, dexamethasone) chemotherapy and a single dose of pegfilgrastim (12 mg) was highly effective in mobilizing peripheral blood stem cells (PBSCs) for subsequent transplantation, with 88% of patients (n ¼ 26) achieving the CD34 þ cell harvest target of X7.50 106 CD34 þ cells/kg body weight, following a median of two apheresis procedures (range 1–4) and with first apheresis performed at a median day 13 after CAD application (range 10–20). Patients treated with pegfilgrastim showed a reduced time to first apheresis procedure from mobilization compared with filgrastim-mobilized historical matched controls (n ¼ 52, P ¼ 0.015). The pegfilgrastim mobilization regimen allowed for transplantation of a median of 3.58 106 CD34 þ cells/kg body weight while leaving sufficient stored cells for a second high-dose regimen and back-ups in most patients. Engraftment following transplantation was comparable to filgrastim, with a median time of 14 days to leucocyte X1.0 109/l (range 10–21) and 11 days to platelets X20 109/l (range 0–15). The results of this study thus provide further support for the clinical utility of pegfilgrastim for the mobilization of PBSC following chemotherapy in cancer patients scheduled for transplantation. Bone Marrow Transplantation (2007) 39, 743–750; doi:10.1038/sj.bmt.1705675; published online 23 April 2007 Keywords: pegfilgrastim; myeloma; peripheral blood stem cell; mobilization

Correspondence: Professor Dr S Fruehauf, Department of Tumor Diagnostics and Therapy, Paracelsus Hospital, Am Natruper Holz 69, 49076 Osnabrueck, Germany. E-mail: [email protected] Received 5 July 2006; revised 8 March 2007; accepted 14 March 2007; published online 23 April 2007

Introduction Autologous peripheral blood stem cell (PBSC) transplantation has been shown to be associated with significant prolongation of survival in patients with a variety of malignancies. For multiple myeloma patients up to the age of 70 years, high-dose therapy followed by PBSC transplantation (PBSCT) is the standard treatment.1 The combination of chemotherapy and granulocyte colonystimulating factor (G-CSF) treatment has proven to be highly effective in mobilizing PBSC.2 The optimal dosing schedule for established G-CSF formulations (half-life: 3–4 h) has been shown to be twice daily. However, new G-CSF formulations with longer plasma half-life such as pegylated filgrastim (pegfilgrastim: 33 h) offer the potential for single-administration treatment by generating clinically effective serum levels until neutrophil recovery, due to its decreased renal elimination.3 This results in reduced patient strain and increased compliance thereby improving PBSC mobilization regimens. The extended lifespan of glycosylated G-CSF (Neulasta) in vivo and the suggestion that a single injection is sufficient to ensure similar progenitor mobilization as that achieved by several daily injections of unconjugated G-CSF is attractive. On the occasions that a daily injection schedule of conventional G-CSF has been missed, the mobilization process fails and is not rescued by subsequent later injections of G-CSF, even if the dose is increased. Phase III studies comparing pegfilgrastim with filgrastim have shown high efficacy of pegfilgrastim in decreasing the incidence and duration of febrile neutropenia following chemotherapy in breast cancer patients, with no increase in adverse events.4–7 In the transplant setting, pegfilgrastim has been shown to produce efficient mobilization of CD34 þ cells after chemotherapy in patients with haematologic malignancies.8–10 The results of other recent studies support the feasibility of pegfilgrastim mobilization regimens for a variety of other malignancies as well.11–15 The present study evaluated the efficacy of a single dose of

Pegfilgrastim for PBSC mobilization in myeloma S Fruehauf et al

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pegfilgrastim in mobilizing PBSC following myeloablative chemotherapy in patients with stage II and III myeloma.

Patients and methods Study design This phase II study was conducted at a single centre in Germany. The aim of the study was to assess the efficacy and tolerability of pegfilgrastim used in combination with chemotherapy for the mobilization of PBSCs for subsequent autologous transplantation in patients with stage II or III myeloma. The study was carried out in accordance with Good Clinical Practice and the stipulations of the declaration of Helsinki (1996); furthermore, the study protocol was approved by the local ethics committee. In addition, written informed consent was obtained from patients. Patients and treatment Patients aged 18–65 years with stage II or III multiple myeloma, with a World Health Organization (WHO) performance status of 0–3, were eligible for study entry. Exclusion criteria were as follows: clinically manifest heart failure (New York Heart Association (NYHA) grade II or above, left ventricular ejection fraction o65% on echocardiograph), any hepatic disorders resulting in their transaminase or bilirubin levels being raised to more than three times the upper limits of normal values, active uncontrolled infections or HIV infection, or another malignant disorder within the past 5 years (except basal cell carcinoma or cervical cancer stage 0). Further exclusion criteria included pregnancy/lactation (contraception was required for female patients of child-bearing age), depression and any known intolerance to the study treatments. Figure 1 illustrates the treatment plan for the study. Patients received a variety of induction regimens (Table 1), with most patients (58%) receiving chemotherapy with

vincristine (0.4 mg/day, days 1–4 (d-1–4)), doxorubicin (9 mg/m2/day d-1–4) and dexamethasone (40 mg/day d-1–4, d-9–12 and d-17–20) (VAD). In addition, six patients (23%) also received radiotherapy (two patients left shoulder, 20 Gy each; one patient vertebra T 6; one patient right os pubis, 20 Gy; one patient vertebra T 6-L 1, L 4, C 7, 40 Gy each; one patient thoracic spine, 30 Gy). The mobilization regimen consisted of 4 days of chemotherapy with cyclophosphamide 1 g/m2 on d-1, doxorubicin 15 mg/m2 d-1–4, dexamethasone 40 mg d-1–4 (CAD (cyclophosphamide, adriamycin, dexamethasone)) and a single administration of pegfilgrastim 12 mg s.c. (given as two pre-filled syringes of Neulasta 6 mg, Amgen,

Table 1

Patient characteristics

Parameter No. of patients Male/female Median age at leukapheresis (years) (range) Median body weight (kg) (range) Salmon and Durie disease status II III Induction therapy (%) 1 ID, 2 VAD 1 VID, 2 VAD VAD (2 to 6 ) 2 VAD+1 TAD 3 TAD 4 MP, 3 VAD Radiotherapy (%)

d2

d3

d4

d5

d6

d7

d8

d9 d10 d11 d12 d13 d14 d15 d16 d17 d18 d19

Pegfilgrastim 12 mg fixed dose

Cyclophosphamide Doxorubicin Dexamethasone Figure 1

Study procedures.

Bone Marrow Transplantation

4 22

1 1 15 1 6 2 6

(4) (4) (58) (4) (22) (8) (24)

Abbreviations: ID ¼ idarubicin, dexamethasone; MP ¼ melphalan, prednisone; TAD ¼ thalidomide, doxorubicin, dexamethasone; VAD ¼ vincristine, doxorubicin, dexamethasone; VID ¼ vincristine, idarubicin, dexamethasone.

CD 34+ determination: Leukaphereses >20/l

d1

26 12/14 57 (40–65) 72 (51–100)

Filgrastim + Leukapheresis 2x5g/kg BW (only if inadequate mobilization following Pegfilgrastim)


745

Thousand Oaks, CA, USA) on d-5. For patients with a CD34 þ cell count of X20 106 cells/l (dayX10), leukapheresis was started from days 15–20 and stopped when the CD34 þ cell count fell to p5 106/l or the target harvest of 7.5 106 CD34 þ cells/kg body weight was achieved. Multiple apheresis procedures were performed when required. For patients with a CD34 þ cell count between 5 and 20 106/l (day X13) and a platelet count of 430 109/l, leukapheresis was performed until the target CD34 þ cell harvest was achieved. Patients whose CD34 þ cell count fell from day 16 by 425% per day without reaching the target count of 20 106 cells/l received an additional mobilization treatment with filgrastim (2 5 mg/kg, Neupogen, Amgen Roche, Switzerland). The concentration of CD34 þ cells was determined according to the International Society of Haematotherapy and Graft Engineering (ISHAGE) guidelines.16 After leukapheresis, PBSCs were cryopreserved in liquid nitrogen and checked for viability before transplantation. Following harvest of PBSC cells, all patients received high-dose melphalan (100 mg/m2/day), on days 3 and 2 prior transplantation on d-0 for conditioning.

Assessments Patients underwent a physical examination at their initial screening visit and samples were obtained for assessment of laboratory parameters, including comprehensive blood count. In addition, blood was monitored two- to three times per week during the study period and daily after leucocyte recovery to 45.0 109/l and platelet recovery to 480 109/l to determine CD34 þ counts in peripheral blood until the initiation of stem cell harvesting. Adverse events observed during the study period were documented.

Study end points The primary end point was the CD34 þ cell yield mobilized by pegfilgrastim treatment, in terms of the percentage of patients in whom a target harvest of X7.5 106 cells/kg body weight was achieved following subsequent leukapheresis. Secondary end points were as follows:

Table 2

the number of apheresis procedures required to harvest the target CD34 þ cell yield of 3 2.5 106 cells/kg body weight or cumulative 7.5 106 cells/kg body weight, for each patient; the CD34 þ cell count per apheresis procedure; the time to leucocyte recovery to X1.0 109/l and to platelets X20 109/l and X50 109/l; the kinetics of CD34 þ cell counts following pegfilgrastim administration; the tolerability of pegfilgrastim treatment. The data for CD34 þ cell yields were compared with historical matched controls (n ¼ 52) from the Department’s myeloma database, which contains details of 892 patients mobilized with filgrastim. These controls were myeloma patients matched for prior therapy, stage of disease and response to induction therapy before mobilization. A oneto-two match was performed.

Statistics All pairwise comparisons have been carried out with help of the U-test by Mann and Whitney. Confidence intervals (CIs) for group differences, where given, are obtained as described in Bauer.17

Results The demographic and baseline clinical characteristics of the 26 evaluable patients are summarized in Table 1. Most of the patients were X50 years old, with 14 patients (54%) aged 50–59 years, 10 patients (38%) aged X60 years, and only two patients (8%) aged p49 years. Fourteen patients were women and 12 patients men. Of 30 patients screened to enter the study, two patients were excluded from analysis because they were aged 465 years. These patients achieved a comparatively high CD34 þ cell count after CAD and pegfilgrastim treatment (128 and 158 106 cells/l, respectively) and had CD34 þ cell yields of 9.90 and 10.70 106/kg, respectively. Blood reconstitution in these patients occurred within the usual timeframe (Table 2). Further, two patients were non-

Excluded patients

Parameter Patients Male/female Age at leukapheresis (years) Body weight (kg) Day of first leukapheresis Total amount of harvest CD34+ cells ( 106/kg) No. of leukapheresis Median amount of harvest CD34+ cells per leukapheresis ( 106/kg) (range) Transplanted CD34+ cell count ( 106/kg) Days to leucocyte X1.0 109/l Days to platelets X20 109/l Days to platelets X50 109/l Status prior leukapheresis

Patients aged 465 years Pat. I Female 66 72 12 9.80 1 9.80 (—) 3.30 15 10 15 PR

Pat. II Female 68 66 12 21.70 1 21.70 (—) 10.85 13 9 9 PR

Patients with 6 mg pegfilgrastim Pat. I Female 56 78 12 12.70 3 3.60 (2.90–6.20) 6.20 11 10 12 PR

Pat. II Female 53 69 13 13.86 1 13.86 (—) 6.93 12 0 13 PR

Abbreviation: PR ¼ partial response. Bone Marrow Transplantation


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CD34 þ cell mobilization The peak CD34 þ cell count recorded in the patients receiving pegfilgrastim treatment was median 72.57 106 cells/l (range 7.20–842.30 106 cells/l), that is, well within the range to allow for apheresis with acceptable cell yields. The time of the peak CD34 þ cell count from mobilization was reached at d-13 (range 11–22 days). The median day of the first apheresis procedure from mobilization was d-13 (range 11–20 days) with the first apheresis procedure on d-12–14 in 69% of the patients. Up to four aphereses were performed, with a median of two procedures (range 1–4 aphereses) (Table 3). In the historical group (conventional G-CSF), the median peak CD34 þ cell count was 104.36 106 cells/l (range 8.00–1767.00 106 cells/l) with the peak CD34 þ cell count from mobilization on d-15 (range 1–27 days). Median day of first apheresis procedure from mobilization was d-15 (range 5–25 days) with a median of two procedures (range 1–6) per patient (Table 3). A significant difference (P ¼ 0.046) in the time-to-peak CD34 þ cell count (Figure 2) between patients treated with filgrastim and those receiving pegfilgrastim (median 15 vs 13 day) was observed. Additionally, patients treated with

Table 3

pegfilgrastim showed a reduced time to first apheresis procedure from mobilization (Figure 3) compared to patients who received filgrastim (P ¼ 0.015). We found no statistical differences in terms of maximum CD34 þ cell count and number of aphereses between the two groups.

CD34 þ cell yield The median CD34 þ cell yield was 9.70 106/kg body weight (range 4.90–40.50 106/kg) (Table 3). About half of the patients had a yield in the range 9–12 106/kg. Three patients required additional treatment with standard G-CSF to achieve adequate mobilization of CD34 þ cells. In the first patient, the peak CD34 þ cell count was low (7.20 106 cells/l) and 6.60 106 CD34 þ cells/kg were

1.0

Percentage of no CD34+ cell peak

evaluable, as they received only one application of pegfilgrastim (6 mg). In the first patient, the maximum CD34 þ cell count was low (21.9 106 cells/l), yet 12.70 106 CD34 þ cells/kg were collected during three aphereses. The second patient had a high-peak CD34 þ cell count of 408 106 cells/l and a yield of 20.80 106 cells/kg body weight following only one apheresis. Both patients engrafted without complications (Table 2). Before mobilization therapy (after induction therapy) one patient (4%) had a complete response, 20 patients (77%) had a partial response, three patients (11%) had stable disease and two patients (8%) had minimal response (Table 3).

0.8

0.6

0.4

0.2

0.0 0

5

10

15

Time to

CD34+ cell

20

25

peak

Figure 2 Time from mobilization (d-1) to maximum CD34 þ cell peak (in days). Solid line ¼ pegfilgrastim; dashed line ¼ filgrastim.

Leukapheresis and engraftment data

Parameter No. of patients Male/female Median age at leukapheresis (range) Median body weight (kg) (range) Day of first leukapheresis (range) Median total amount of harvest CD34+ cells ( 106/kg) (range) Median no. of leukapheresis (range) Median amount of harvest CD34+ cells per leukapheresis ( 106/kg) (range) Transplanted CD34+ cell count ( 106/kg) (range) Median days to leucocyte X1.0 109/l (range) Median days to platelets X20 109/l (range) Median days to platelets X50 109/l (range) Status prior leukapheresis (%) CR PR MR SD PD NA

Neulasta group

57 72 13 9.70 2 4.40 3.58 14 11 13

1 20 2 3

26 12/14 (40–65) (51–100) (10–20) (4.90–40.50) (1–4) (0.90–40.50) (2.36–13.50) (10–21) (0–15) (10–20)

(4) (77) (8) (11) — —

Historical group

60 73 15 9.95 2 3.40 3.70 14 11 14

1 31 7 9 3 1

52 30/22 (31–70) (52–128) (5–25) (2.60–99.90) (1–6) (0.10–63.60) (2.40–30.3) (8–24) (0–16) (0–64)

(2) (60) (13) (17) (6) (2)

Abbreviations: CR ¼ complete response; MR ¼ minimal response; NA ¼ not available; PD ¼ progressive disease; PR ¼ partial response; SD ¼ stable disease. Bone Marrow Transplantation


747

collected during three leukaphereses. The second patient had a peak of 11.40 106 cells/l and a yield of 4.90 106 CD34 þ cells/kg after four leukaphereses. Both patients received filgrastim on day 16, as the peak CD34 þ cell count was below the threshold of 20 106 cells/l. The third patient had a high-peak CD34 þ cell count of 67.24 106 cells/l and a yield of 9.70 106 cells/kg following three aphereses. This patient received additional filgrastim on day 14 to prevent a drop of the leucocyte cell count. The three patients engrafted without complications (Table 4). Excluding the three patients who received additional doses of filgrastim, 23 patients (88%) had a CD34 þ cell yield X7.50 106/kg body weight. As the 88% ‘success rate’ achieved was greater than the 75% specified in the study protocol and as the protocol specified ‘futility’ rate of 50% of patients achieving the target CD34 þ cell yield was outside the CIs calculated for this primary end point (95% CI 70–98%; 90% CI 73–97%) the pegfilgrastim-based mobilization regimen was considered to be successful.

Percentage of no apheresis

1.0

Compared with historical matched controls (n ¼ 52) mobilized with filgrastim, no significant difference in the amount of CD34 þ cells per apheresis was found (Table 3). Forty-one patients (79%) from the historical group had a CD34 þ cell yield X7.50 106/kg body weight.

Transplantation and engraftment All 26 patients were transplanted. On the day of transplantation, patients received a median of 3.58 106 CD34 þ cells/kg body weight (range 2.36–13.50 106/kg), leaving sufficient stored CD34 þ cells for a second transplantation in most patients. Leucocyte engraftment to X1.0 109/l was achieved after a median time of 14 days (range 10–21 days). The platelet count recovered to X20 109/l in all patients by day 15, with three patients never falling below this limit. The median time to platelet reconstitution X20 109/l was 11 days (range 0–15 days), while the median time to platelet recovery X50 109/l was 13 days (range 10–20 days). The engraftment data of the historical group were comparable (Table 3). Regarding the haematopoietic reconstitution, no statistically significance between patients treated with pegfilgrastim and patients received filgrastim was found. Safety One patient complained of grade I thoracic pain 6 days after administration of pegfilgrastim. The patient’s electrocardiogram was normal and the side effect resolved spontaneously. One patient complained of nausea 1 day after pegfilgrastim administration.

0.8

0.6

0.4

Discussion 0.2

0.0 0

5

10 15 20 Time to first apheresis in days

25

Figure 3 Time from mobilization (d-1) to first apheresis (in days). Solid line ¼ pegfilgrastim; dashed line ¼ filgrastim.

Table 4

High-dose chemotherapy and autologous blood stem cell transplantation are commonly used in myeloma patients,1 with the infusion of approximately 2.50 106 CD34 þ cells/ kg body weight was shown to provide rapid and sustained haematopoietic reconstitution after myeloablative therapy.18 In this study, a regimen of CAD chemotherapy and a single dose of pegfilgrastim 12 mg was shown to be effective

Patients who received supplementary with conventional G-CSF

Parameter Patients Male/female Age at leukapheresis (years) Body weight (kg) Day of first leukapheresis Total amount of harvest CD34+ cells ( 106/kg) No. of leukapheresis Median amount of harvest CD34+ cells per leukapheresis ( 106/kg) (range) Transplanted CD34+ cell count ( 106/kg) Median days to leucocyte X1.0 109/l Median days to platelets X20 109/l Median days to platelets X50 109/l Status prior leukapheresis

Pat. I Female 53 74 20 6.60 3 2.20 (2.00–2.40) 2.40 21 14 18 PR

Pat. II Female 65 62 12 4.90 4 1.20 (0.90–1.60) 2.50 15 12 15 SD

Pat. III Female 53 83 14 9.70 3 3.60 (2.40–3.70) 3.70 10 15 12 PR

Abbreviations: G-CSF ¼ granulocyte colony-stimulating factor; NA ¼ not available; PR ¼ partial response; SD ¼ stable disease. Bone Marrow Transplantation


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in mobilizing PBSCs for subsequent transplantation, with 88% of patients (n ¼ 23/26) achieving the target CD34 þ cell harvest of X7.50 106 CD34 þ cells/kg body weight, following a median of two aphereses procedures (range 1–4) and with the first apheresis performed at a median day 13 (range 10–20 days). No significant difference in the amount of CD34 þ cells per apheresis was found in the present study compared with historical matched controls from our myeloma database mobilized with filgrastim. The median peak CD34 þ cell yield of 72.57 106 cells/l (range 7.20–842.30 106 cells/l) as observed in our study is comparable with the value (78 106 cells/l, range 20– 1055 106 cells/l) reported following the administration of a single dose of pegfilgrastim 12 mg after induction therapy and cyclophosphamide in patients with newly diagnosed myeloma.10 The success of the mobilization regimen described here allowed transplantation of a median of 3.58 106 stem cells/kg body weight while still leaving sufficient stored stem cells for a second high-dose regimen and back-ups in most patients. Engraftment following transplantation was rapid, with a median time of 14 days to leucocyte recovery to X1.0 109/l and 11 days to platelets X20 109/l. Our results, together with currently limited data concerning the clinical utility of pegfilgrastim in the mobilization of PBSC following chemotherapy in cancer patients scheduled for transplantation, seem to be in line with those of other groups,8,10,15 suggesting that pegfilgrastim can provide effective mobilization of PBSCs. In an open label phase II study in 25 patients with nonHodgkin’s lymphoma (NHL) or Hodgkin’s disease, Isidori et al.8 showed that a single dose of pegfilgrastim 6 mg administered 3 days after the end of chemotherapy provided efficient mobilization of CD34 þ cells after salvage therapy with ifosfamide, epirubicin and etoposide. The reinfused cells induced rapid, multilineage haematopoietic recovery.8 In total, 24/25 patients (96%) reached the target dose of 2 106 CD34 þ cells/kg, with a median peak value of 141 106 CD34 þ cells/kg recorded on day 14 (range 13–16 days) and with 23/25 patients (92%) undergoing a single leukapheresis to harvest a median of 8.70 106 CD34 þ cells/kg (range 1.78–17.30 106 CD34 þ cells/kg). In another study with 90 NHL patients,9 a single dose of 6 mg pegfilgrastim was shown to be as effective as a 12 mg dose in mobilizing PBSCs following ifosfamide, carboplatin, etoposide (ICE) chemotherapy, supporting the efficacy of the 6 mg dose and indicating that further investigation of the optimal dose of pegfilgrastim may be required. In this study, both doses of pegfilgrastim showed comparable efficacy in stem cell mobilization to standard filgrastim 5 mg/kg/day. In a study in patients with newly diagnosed myeloma, Steidl et al.10 retrospectively compared the effects of a single dose of pegfilgrastim 12 mg (12 patients) on stem cell mobilization after induction therapy and cyclophosphamide with those observed in patients (n ¼ 12) with similar characteristics who had received daily doses of filgrastim (median 8.50 mg/kg/day, range 4.60–11.90 mg/kg). Mobilization kinetics were similar in the two treatment cohorts with the exceptions that pegfilgrastim treatment was associated with earlier leucocyte recovery to 41.0 109 cells/l (median d-12 vs d-14; P ¼ 0.05) and peak Bone Marrow Transplantation

levels of CD34 þ cells (d-12 vs d-15; Po0.05). In accordance with the earlier appearance of the peripheral blood CD34 þ cell peak, the first apheresis in the pegfilgrastim-treated patients was performed 2 days earlier than in filgrastim-treated patients (median d-13 vs d-15; P ¼ 0.01) which is comparable with our results. A single apheresis was sufficient to harvest X4.00 106 CD34 þ cells/kg body weight in 11/12 pegfilgrastim-treated patients and all filgrastim-treated patients. The remaining patient in the pegfilgrastim group required one further procedure. The study authors postulated that the earlier leucocyte and CD34 þ cell recovery observed in this study may relate to the continuously high serum level of G-CSF produced by pegfilgrastim administration providing a more efficient stimulus for haematopoietic recovery than the pulsatile stimulus of daily G-CSF injections. After high-dose melphalan, autografting was successful with rapid, sustained haematologic recovery in both groups. With a follow-up of 100 þ days, the median time to leucocyte recovery to 41.0 109 cells/l was 16 days in the eight evaluable patients in the pegfilgrastim group and 15 days in filgrastim-treated patients, despite the fact that the pegfilgrastim-treated patients received a median of 3.40 106 CD34 þ cells/l compared with 7.50 106 cells/l in the filgrastim group. In our study, the median time to leucocyte recovery to 41.0 109 cells/l was 14 days in both groups, with a similar transplanted median cell count of 3.58 106 cells/l in the pegfilgrastim group and 3.70 106 cells/l in the historical group. In a recently published study by Hosing et al.,15 19 patients with multiple myeloma received a single dose of pegfilgrastim 12 mg to mobilize PBSC for transplantation. Leukapheresis was started when the CD34 þ cell count was 415 106 cells/l and performed daily until a target harvest of CD34 þ cells was achieved (6.0 106 cells/kg for patients scheduled for a tandem transplant and 43.0 106 cells/kg for those undergoing a single transplant). A median of 8.40 106 CD34 þ cells/kg was collected from a median of 2 leukaphereses to achieve the target harvest. Other studies have demonstrated the efficacy of pegfilgrastim mobilization regimens in other types of malignancy.11–14 Beside the advantages shown, the long half-life of pegfilgrastim in the patient may furthermore provide clinical benefits in terms of allowing better, more convenient dosing schedules and improved compliance because of the reduced number of injections required compared with conventional G-CSF preparations. In 21 patients with multiple myeloma, Fenk et al.19 detected one case of splenic rupture at the day of neutrophil engraftment. They mentioned that it does not seem to be related to the pegylation of the drug because this event has also been observed after the application of all myeloid growth factors. Furthermore, no local inflammation was observed and mild-bone pain in four patients was the only toxicity that could be specially attributed to pegfilgrastim. All 21 patients received a single application of 6 mg pegfilgrastim on day þ 1 after autologous PBSCT. In a study with 40 patients with lymphoma or multiple myeloma, Kroschinsky et al.20 reported that mobilization treatment with 6 mg pegfilgrastim was well tolerated with low-grade chemotherapy-induced nausea and emesis, as


749 Table 5 Comparison of CD34+ cell mobilization in different published studies Author

Indication

Steidl et al.10 Fenk et al.19 Krochinsky et al.20 Bruns et al.23

MM MM MM and lymphoma MM

Fruehauf et al.

MM

CD34 No. of No. of Dose patients PegG-CSF peak apheresisa conc.a (mg) (per ml) 24 42 40

12 6 6

78 94 81

1 (range 1–2) 1 (range 1–2) 1 (range 1–2)

15 15 26

6 12 12

131 85 73

1 (range 1–3) 1 (range 1–2) 2 (range 1–4)

Abbreviations: G-CSF ¼ granulocyte colony-stimulating factor; MM ¼ multiple myeloma. All patients received PEG-filgrastim supported mobilization chemotherapy. a Median values are given, number in brackets are the range.

well as mild to moderate growth factor-associated bone pain which occurred in some patients. Two patients had to be rehospitalized because of febrile neutropenia or grade III bone pain, respectively. An additional patient suffered from severe hypotension during apheresis. In our study, pegfilgrastim therapy was well tolerated with only minor side effects common for G-CSF.6 One patient had a low-grade thoracic pain 6 days after administration of pegfilgrastim which was considered to be possibly due to bone marrow activation. Furthermore, one patient complained of nausea 1 day after pegfilgrastim administration. Morris et al.21 described a graft composition of accessory cells, such as higher monocyte count altered lymphocyte subsets and different patterns of GvHD has been noted in a mouse model as a feature of mobilization with pegfilgrastim compared to other G-CSF. In this study, accessory cell numbers were not determined. Regarding the economics, the current price for one ampule pegylated G-CSF (6 mg) and unconjugated G-CSF (30 mg) is 1524 h and 149 h, respectively. Applying these to our study would result in costs of 3048 h for 12 mg pegylated G-CSF and 1341 h for a 9-day application of unconjugated G-CSF.22 Isidori et al.8 showed that a single dose of pegfilgrastim 6 mg administered 3 days after the end of chemotherapy provided efficient mobilization of CD34 þ cells, which was in line with data from Bruns et al.23 who reported that a single dose of 6 mg pegfilgrastim is equally potent as 12 mg for mobilization and harvest of CD34 þ cells in patients with multiple myeloma (Table 5).8 Taking this into account would reduce the cost for administration of pegylated G-CSF by a half to a similar price to unconjugated G-CSF.24 In summary, this study has shown that a single dose of pegfilgrastim 12 mg following chemotherapy provides effective mobilization of PBSCs in patients with myeloma, allowing collection of more than three autografts in two or fewer aphereses in most patients. Transplantation of the mobilized cells was feasible, with acceptable times to engraftment of leucocytes and platelets. Similar research on the use of 6 mg pegfilgrastim in stem cell mobilization is

warranted. Further prospective randomized studies of this promising approach for the mobilization of PBSC are clearly required.

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