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ORIGINAL ARTICLE

A randomized study comparing filgrastim versus lenograstim versus molgramostim plus chemotherapy for peripheral blood progenitor cell mobilization B Kopf1, U De Giorgi1, B Vertogen1, G Monti2, A Molinari1, D Turci1, C Dazzi1, M Leoni1, A Tienghi1, A Cariello1, M Argnani3, L Frassineti4, E Scarpi5, G Rosti1 and M Marangolo1 1

Department of Oncology and Hematology, Istituto Oncologico Romagnolo, Santa Maria delle Croci Hospital, Ravenna, Italy; Department of Clinical Pathology, Santa Maria delle Croci Hospital, Ravenna, Italy; 3Blood Bank, Santa Maria delle Croci Hospital, Ravenna, Italy; 4Department of Oncology, Pierantoni Hospital, Forlı`, Italy and 5Unit of Biostatistics and Clinical Trials, Pierantoni Hospital, Forlı`, Italy 2

We conducted a prospective randomized clinical trial to assess the mobilizing efficacy of filgrastim, lenograstim and molgramostim following a disease-specific chemotherapy regimen. Mobilization consisted of high-dose cyclophosphamide in 45 cases (44%), and cisplatin/ifosfamide/ etoposide or vinblastine in 22 (21%), followed by randomization to either filgrastim or lenograstim or molgramostim at 5 lg/kg/day. One hundred and three patients were randomized, and 82 (79%) performed apheresis. Forty-four (43%) patients were chemonaive, whereas 59 (57%) were pretreated. A median number of one apheresis per patient (range, 1–3) was performed. The median number of CD34 þ cells obtained after mobilization was 8.4 106/kg in the filgrastim arm versus 5.8 106/kg in the lenograstim arm versus 4.0 106/kg in the molgramostim arm (P ¼ 0.1). A statistically significant difference was observed for the median number of days of growth factor administration in favor of lenograstim (12 days) versus filgrastim (13 days) and molgramostim (14 days) (Po0.0001) and for the subgroup of chemonaive patients (12 days) versus pretreated patients (14 days) (Po0.001). In conclusion, all three growth factors were efficacious in mobilizing peripheral blood progenitor cells with no statistically significant difference between CD34 þ cell yield and the different regimens, and the time to apheresis is likely confounded by the different mobilization regimens. Bone Marrow Transplantation (2006) 38, 407–412. doi:10.1038/sj.bmt.1705465 Keywords: peripheral blood progenitor cells; mobilization; filgrastim; lenograstim; molgramostim; randomized study

Correspondence: Dr B Kopf, Department of Oncology and Hematology, Istituto Oncologico Romagnolo, Santa Maria delle Croci Hospital, Viale Randi 5, Ravenna 48100, Italy. E-mail: [email protected] Received 22 February 2006; revised 29 June 2006; accepted 2 July 2006

Introduction The most common approach to mobilize peripheral blood progenitor cells (PBPCs) consists of a chemotherapeutic regimen followed by a myeloid growth factor.1 PBPC collection is performed after administration of diseasespecific mobilizing chemotherapy followed by a myeloid growth factor, as granulocyte colony-stimulating factor (G-CSF) or granulocyte–macrophage colony-stimulating factor (GM-CSF).2–4 A strong correlation between the number of PBPC collected and then reinfused and the hematological recovery after high-dose chemotherapy has been demonstrated.5 As consequence, it is of paramount importance to identify the best myeloid growth factor to improve PBPC collection. Studies conducted on healthy donors showed a possible advantage of the glycosylated form of G-CSF compared with the non-glycosylated form in terms of number of colony-forming units-granulocyte– macrophage harvested, even if a similar advantage has still to be demonstrated in cancer patients treated with mobilizing chemotherapy.6 GM-CSF has been used in this context with satisfying results on PBPC harvesting and possible reduction of duration of thrombocytopenia and mucositis.7–10 We conducted a prospective randomized study to compare the mobilizing efficacy of two forms of G-CSF, one non-glycosylated (filgrastim) and one glycosylated (lenograstim), and a non-glycosylated form of GM-CSF (molgramostim), following administration of a disease-specific chemotherapy. We evaluated number of CD34 þ cells, the subtypes CD34 þ /CD33, CD34 þ / CD38 and CD34 þ /Thy1 þ harvested, and time to hemopoietic recovery of absolute neutrophil count (ANC)4500/ml and platelets 420 000/ml after mobilizing chemotherapy. In addition, as previously administered chemotherapy is an important factor in success of mobilization, we stratified patients in chemonaive and pretreated, who received at least one chemotherapeutic regimen before the regimen containing high-dose chemotherapy.

PBPC mobilization: a randomized study B Kopf et al

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Patients and methods Patients and treatment Patients older than 18 years and younger than 60 undergoing PBPC transplant were eligible for the study. All patients had an Eastern Cooperative Oncology Group (ECOG) Performance Status p2, with adequate hepatic, cardiac and renal function. The study was approved by the Institutional Review Board. Patients gave written informed consent. PBPC transplant was given mostly to patients with solid tumors in our Institution. Different mobilizing chemotherapy regimens have been used according to tumor type. Anthracyclines alone or in association with paclitaxel were used for patients affected by breast cancer, osteosarcoma, and small cell lung cancer (n ¼ 26), cyclophosphamide (CTX) 4 or 7 g/m2 for patients affected by lymphoma or breast cancer (n ¼ 45), CTX and etoposide or ifosfamide and cisplatin plus vinblastine (VeIP) or etoposide (VIP) for patients with Ewing’s sarcoma or germ cell tumor (n ¼ 24), epirubycin, ifosfamide and etoposide (IEV) for some of the patients with lymphoma (n ¼ 6). Patients were centrally randomized by a computer generated random list in one of the following three groups: filgrastim 5 mg/kg/day, lenograstim 5 mg/kg/day and molgramostim 5 mg/kg/day. Myeloid growth factor administration started 24 h after the last day of the mobilizing chemotherapy. PBPC collection Three days after the first administration of the myeloid growth factor, blood cell count was performed to monitor the recovery of white blood cells (WBC), with determination of the number of CD34 þ cells in the peripheral blood when WBC count X1000/cm3. Apheresis was performed when the absolute number of circulating CD34 þ cells in the peripheral blood was X20 ml.11 One or more aphereses were performed until cumulative yield of CD34 þ cells was X2 106/kg, the threshold fixed to guarantee a safe hematological recovery.12 The PBPC harvest was performed using the spectra COBE BCT, Aphaeresis System (Lakewood, CO, USA). Statistical analysis For non-normal distributed values, data were summarized as median and range. Differences among groups were evaluated by w2 test13 for categorical variables and median test14 for continuous variables. All analyses were performed using SAS Statistical software15 and P-values less than a ¼ 0.05 were considered to be statistically significant. The number of CD34 þ cells collected 106/kg/apheresis was calculated by dividing the total number of CD34 þ cells collected from each patient by the number of daily aphaeresis.

Results Patients One hundred and three consecutive patients, 59 females and 44 males, median age 37 years (range 18–60), were Bone Marrow Transplantation

enrolled and randomly assigned to the filgrastim arm (n ¼ 38), lenograstim arm (n ¼ 36) or molgramostim (n ¼ 29). Forty-seven were affected by breast cancer, 27 by germ cell tumor, 14 by non-Hodgkin’s lymphoma (NHL), 5 by Hodgkin’s disease (HD), two by multiple myeloma, two by osteosarcoma and six by other tumors. Fifty-nine had received prior chemotherapy and 44 were chemonaive. The patient characteristics are listed in Table 1. Of 103 assessable patients, 21 (20%) did not undergo apheresis: 15 patients failed to mobilize CD34 þ cells (10 affected by germ cell tumors, two HD, one NHL, one nasopharynx carcinoma and one breast cancer), whereas one patient was detected to be positive for hepatitis B virus, one had fungal pneumonitis, one bone marrow metastases, one an unspecified heart disease, one a hemorrhagic cystitis after mobilization and one the diagnosis of metastatic disease after randomization changing treatment policy. Most of patients that did not mobilize (15/21) had been heavily pretreated with chemotherapy.

Toxicity and hematological recovery after mobilization All patients were evaluable for the effects of growth factor regimens on toxicity and hematological recovery after mobilizing chemotherapy in the three groups. Twenty-six of 103 patients (25%) needed transfusions of red blood cells (RBC), independently from the arm, whereas platelet transfusion was necessary in 20 (19%) patients: 13 (34%) in the filgrastim arm, two (6%) in the lenograstim arm, and five (17%) in the molgramostim arm, respectively, with a statistically significant difference in favor of lenograstim and molgramostim (P ¼ 0.007). There was no difference in the number of transfused units of platelets and RBC per patient among the three groups. Grade 4 neutropenia occurred in 72 (70%) patients: 28 (74%) in the filgrastim arm, 19 (53%) the lenograstim arm and 25 (86%) in the molgramostim, respectively. Median duration to recovery of ANC40.5 109/l was 4 days (range, 1–18) in the filgrastim arm, 3 days (range, 1–15) in the lenograstim arm and 6 days (range, 3–11) in the molgramostim arm. The difference among the three treatment arms was statistically significant in favor of lenograstim for both parameters: frequency and duration of neutropenia (P ¼ 0.001 and 0.0005, respectively). No statistically significant difference for occurrence and duration of grade 4 thrombocytopenia was observed among treatment arms. Non-hematological toxicity Fever (4381C) was observed in 29 (28.1%) patients, without any significant difference for incidence and duration in the three treatment arms. Other grade 3–4 non-hematological toxicities, based exclusively on chemotherapy regimen, were three cases of hemorrhagic cystitis, one in each arm; one case of diarrhea and mucositis and one of nausea and vomiting in the lenograstim arm, and one of diarrhea in the filgrastim arm. Because of the low incidence and the different chemotherapy regimens used for mobilization, it was not possible to evaluate differences among treatment arms for the occurrence of toxicity.


409 Table 1

Patient characteristics Overall no. of patients (%)

No. of patients

Filgrastim no. of patients (%)

103 (100)

Lenograstim no. of patients (%)

Molgramostim no. of patients (%)

38 (36.9)

36 (34.9)

29 (28.2)

Age (years) Median (range)

37 (18–60)

43 (19–60)

35 (18–58)

36 (21–56)

Gender Male Female

44 (42.7) 59 (57.3)

15 (39.5) 23 (60.5)

15 (41.7) 21 (58.3)

14 (48.3) 15 (51.7)

Diagnosis Breast cancer Germ cell tumors NHL Hodgkin’s disease Multiple myeloma Osteosarcoma Other

47 27 14 5 2 2 6

18 8 6 1 1 1 3

17 10 3 3

12 9 5 1 1 1

Previously treated with CT

59 (57.3)

21 (55.3)

21 (58.3)

17 (58.6)

1 (1–3)

1 (1–3)

1 (1–3)

1 (1–2)

Number of CT regimens Median (range) Mobilizing chemotherapy EPI/ADM7paclitaxel CTX CE VIP/VeIP IEV

26 45 4 22 6

(45.6) (26.2) (13.6) (4.8) (1.9) (1.9) (5.8)

(25.2) (43.7) (3.9) (21.4) (5.8)

6 23 1 6 2

(47.5) (21.1) (15.8) (2.6) (2.6) (2.6) (7.8)

(47.2) (27.8) (8.3) (8.3) 0 0 3 (8.3)

(15.8) (60.5) (2.6) (15.8) (5.3)

14 7 2 10 3

(38.9) (19.4) (5.6) (27.8) (8.3)

6 15 1 6 1

(41.3) (31.0) (17.2) (3.5) (3.5) (3.5) 0

(20.7) (51.8) (3.0) (20.7) (3.4)

Abbreviations: CT ¼ chemotherapy; CE ¼ cisplatin and etoposide; CTX ¼ cyclophosphamide; EPI/ADM ¼ epirubicin or adryamicin; IEV ¼ ifosfamide, epirubicin, etoposide; NHL ¼ Non-Hodgkin’s lymphoma; VIP/VeIP ¼ cisplatin, ifosfamide and etoposide or vinblastine.

Table 2

Apheresis yield according to the treatment arms Overall

No. of patients No. of aphereses median (range) Day of first apheresis median (range) CD34+ cells 106/kg per apheresis median (range)

82 1 13 5.8

(100%) (1–3) (10–20) (0.5–31.6)

Filgrastim 29 1 13 8.4

(76.3%) (1–2) (10–17) (1.8–31.6)

Lenograstim

Molgramostim

29 1 12 5.8

24 1 14 4.0

(80.5%) (1–3) (11–16) (0.6–19.2)

(82.7%) (1–2) (12–20) (0.5–14.0)

P NS o0.0001 NS (P ¼ 0.1)

Abbreviation: NS ¼ not significant.

Mobilizing efficacy of filgrastim, lenograstim and molgramostim Of 103 assessable patients, 82 (79%) mobilized and underwent one or more apheresis procedures. A median number of one apheresis per patient (range, 1–3) was performed resulting in a median total CD34 þ cell yield of 5.8 106/kg (range, 0.5–31.6). The median number of CD34 þ cells obtained after mobilization was 8.4 106/kg in the filgrastim arm versus 5.8 106/kg in the lenograstim arm versus 4.0 106/kg in the molgramostim arm (P ¼ 0.1) (Table 2). Of patients underwent apheresis, 28 (97%) in the filgrastim arm, 25 (86%) in the lenograstim arm, and 21 (87.5%) in the molgramostim arm yielded an adequate number of CD34 þ cells (X2 106/kg). Thirty-seven of 59 (86%) were in the pretreated patient group and 37 of 44 (95%) in the chemonaive patient group. A significant difference among treatment arms or pretreated/notpretreated subgroups was not observed.

Median duration of growth factor administration until day of apheresis was 13 days (range, 10–20). The number of days was less for the lenograstim arm with a median number of 12 days (range, 11–16) versus 13 days (range, 10–17) for the filgrastim arm and 14 days (range, 12–20) for the molgramostim arm (Po0.0001) (Table 2). A statistically significant advantage (Po0.001) was also observed for the subgroup of chemonaive patients with a median duration of growth factor administration of 12 days (range, 10–20) with respect to pretreated patients with a median number of 14 days (range, 12–17) (Table 3). No statistically significant difference among treatment arms and subgroups were observed in terms of number of apheresis procedures necessary for the collection of an adequate number of CD34 þ cells. The day of first apheresis, WBC count reached an overall median value of 10.9 103/ml (range, 2.1–51.6), with statistically significantly higher values in the filgrastim arm (14.7 103/ml; range, 4.1–43), and lenograstim arm Bone Marrow Transplantation


410 Table 3

Apheresis yield in pretreated and chemonaive patients Pretreated

No. of patients No. of aphereses median (range) Day of first apheresis median (range) CD34+ cells 106/kg per apheresis median (range)

37 1 14 4.16

(86.1) (1–3) (11–17) (0.6–19.2)

Not pretreated 37 1 12 9

(94.9) (1–2) (10–20) (0.5–31.6)

P NS 0.001 0.001

Abbreviation: NS ¼ not significant.

(14 103/ml; range, 2.1–51.6), versus the molgramostim arm (5.1 103/ml; range, 2.2–11.5) (Po0.0001), whereas there was no difference in WBC count for the subgroups of pretreated and not-pretreated patients. A correlation was observed among count of leukocytes and CD34 þ cells in the peripheral blood the day of apheresis, which resulted highest in the filgrastim arm (median value 146.4/ml CD34 þ cells; range, 20.4–688), versus 81.2/ml (range, 14.2–585) in the lenograstim arm, and 61.6/ml (range, 16.4–489) in the molgramostim arm, with a significant P-value (Po0.015). This was not associated with a higher CD34 þ cell yield in any of the treatment arms. There was instead a significant difference for the number of CD34 þ cells collected in favor of the chemonaive group of patients that obtained a median number of 9 106/kg/ apheresis (range, 0.5–31.6), compared to a median number of 4.6 106/kg/apheresis (range, 0.6–19.2) in the pretreated patients (Table 3). A statistically significant difference in harvesting of subgroups CD34 þ /CD33 cells, CD34 þ /CD38 cells and CD34 þ /Thy1 þ cells was observed neither among the three treatment arms, nor between the two groups of pretreated and chemonaive patients.

Discussion Several clinical studies have addressed the issue of the benefits of using myeloid growth factors following mobilizing chemotherapy.16–18 In our randomized study, we compared filgrastim versus lenograstim versus molgramostim plus chemotherapy to evaluate their ability to mobilize CD34 þ cells and their less commissioned precursors in the peripheral blood. To our knowledge, this is the first randomized study comparing the mobilizing capacity of these three myeloid growth factors following disease-specific chemotherapy. The administered dose of the three myeloid growth factors was 5 mg/kg/day according to other authors who showed that increasing the dose of CSFs after mobilizing chemotherapy did not lead to faster hematopoietic recovery.19,20 Of 103 assessable patients, 82 (79%) mobilized and underwent a median of one apheresis (range 1–3). The nearly 20% mobilization failure rate is quite high, and could be partially justified with the high percentage of pretreated patients (57%), and the significant percentage of GCT (26%) and NHL (13%) patients, who could have a mobilization failure rate of about 20–30%.21,22 Of patients who underwent apheresis, 70% obtained at least 2 106/kg CD34 þ cells, which was considered the minimum threshold value to guarantee the clinical safety of Bone Marrow Transplantation

a high-dose chemotherapy treatment.5 A not statistically significant trend in favor of filgrastim was observed when considering the median number of CD34 þ cells collected (Table 2). No difference among treatment arms and subgroups was observed in harvesting CD34 þ /CD33 cells, CD34 þ /CD38 cells and CD34 þ /Thy1 þ cells. A statistically significant advantage in favor of lenograstim for median number of days until apheresis (12 days versus 13 days in the filgrastim arm and 14 days in the molgramostim arm) was observed, but not for number of aphereses performed (Table 2). These data are in line with other authors. Arora et al.23 showed that mobilization with chemotherapy plus G-CSF versus GM-CSF results in similar CD34 þ progenitor collections, even in patients pretreated with multiple cycles of alkylator-based chemotherapy. Earlier neutrophil and platelet recovery was seen with G-CSF priming. Vice versa, there is questionable clinical benefit with PBPC products mobilized with the combination of G-CSF and GM-CSF versus G-CSF alone.24 Spitzer et al.25 reported 50 patients with either lymphoid or selected solid tumor malignancies that apheresed an identical number of times for PBPC collection after being randomized to receive either G-CSF 10 mg/kg/ day, alone, or G-CSF at the same dose with GM-CSF 5 mg/ kg/day. CD34 þ cell count ( 106/kg) collected by each method of stem cell mobilization was not significantly different. In our study, we also observed a correlation between WBC count the day of apheresis (filgrastim arm 14.7 106 and lenograstim arm 14 106 in comparison to molgramostim arm 5.1 106) and median number of CD34 þ cells/ml in the peripheral blood (146.4/ml versus 81.2/ml and 61/ml, respectively), but not between these circulating CD34 þ cells and CD34 þ cell harvest. These results were discordant with those described by other authors who reported a number of CD34 þ cells in the peripheral blood resulted a reliable predictor for estimating PBPC yield.6,26 Demirer et al.27 reported that preleukapheresis circulating CD34 þ cells/ml correlated significantly better with the yield of collected CD34 þ cells than WBC and platelet counts on the first day of apheresis with a threshold level of circulating CD34 þ cells before apheresis, which was around the 30–50/ml. In our study, the lowest level was 61/ml (in the molgramostim arm). A possible reason for not seeing a correlation may be being beyond the threshold level in each group. Marques et al.28 conducted a study about CD34 þ cell mobilization with chemotherapy and growth factors in patients with hematological malignancies, and found a linear correlation between the days for WBC recovery and number of aphereses needed to collect the target of CD34 þ cells, suggesting that an early WBC


411

recovery could be considered as an important predictor of a low number of aphereses. In our study, chemonaive patients obtained a significantly higher median CD34 þ cell harvest and needed fewer days until apheresis compared to pretreated patients, but no difference between the two subgroups was observed for the number of patients who achieved minimum threshold value of CD34 þ cells. These results confirmed those of previous studies that showed that prior treatment influences negatively the ability to mobilize PBPC.21 With respect to recovery of hematological toxicity, we did not observe a reduction of thrombocytopenia in the patient group treated with GM-CSF, as described in other studies.6,7 Moreover, no statistically significant difference among treatment arms was observed for incidence and duration of grade 4 thrombocytopenia, whereas higher incidence and duration of grade 4 neutropenia in the molgramostim arm occurred. As regards non-hematological toxicity, there was no significant difference for occurrence and duration of fever. Evaluation of mucositis was not possible because of the low incidence in the treatment arms and the not homogeneous mobilizing chemotherapy regimens administrated. However, the three groups of patients were not well balanced for chemotherapy regimen. In particular, 53.8% of the patients treated with anthracycline/taxane received lenograstim, 51.1% treated with high-dose CTX received filgrastim and 45% treated with VIP/VeIP received molgramostim (Table 1). This may partially explain the statistically significant differences observed in toxicity and hemopoietic recovery. Recently, pegylated growth factors have been introduced in clinical practice, distinguished by a prolonged half-life compared to native growth factors that do not necessitate of daily injections.29,30 Several studies are investigating pegfilgrastim to evaluate its ability to mobilize PBPC and to improve the quality of life of these patients. In conclusion, all three growth factors resulted efficacious to mobilize PBPC with no statistically significant difference between CD34 þ yield and the different regimens, and the time to apheresis is likely confounded by the vast difference in mobilization regimens. An advantage on platelet recovery with molgramostim, suggested by other authors was not confirmed by our results.

Acknowledgements This study was supported by a special grant from Istituto Oncologico Romagnolo.

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