A Randomized Study Comparing Filgrastim Versus Lenograstim Versus Molgramostim Plus Chemotherapy for Peripheral Blood Progenitor

Home , Filgrastim, Lenograstim, Molgramostim, Pegfilgrastim

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

1Department of Oncology and Hematology, Istituto Oncologico Romagnolo, Santa Maria delle Croci Hospital, Ravenna, Italy; 2Department 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

We conducted a prospective randomized clinical trial to Introduction assess the mobilizing efficacy of filgrastim, lenograstim and molgramostim following a disease-specific chemother- The most common approach to mobilize peripheral blood apy regimen. Mobilization consisted of high-dose cyclo- progenitor cells (PBPCs) consists of a chemotherapeutic phosphamide in 45 cases (44%), and cisplatin/ifosfamide/ regimen followed by a myeloid growth factor.1 PBPC etoposide or vinblastine in 22 (21%), followed by collection is performed after administration of disease- randomization to either filgrastim or lenograstim or specific mobilizing chemotherapy followed by a myeloid molgramostim at 5 lg/kg/day. One hundred and three growth factor, asgranulocyte colony-stimulatingfactor patients were randomized, and 82 (79%) performed (G-CSF) or granulocyte–macrophage colony-stimulating apheresis. Forty-four (43%) patients were chemonaive, factor (GM-CSF).2–4 A strong correlation between the whereas 59 (57%) were pretreated. A median number of number of PBPC collected and then reinfused and the one apheresis per patient (range, 1–3) was performed. The hematological recovery after high-dose chemotherapy has median number of CD34 þ cells obtained after mobiliza- been demonstrated.5 Asconsequence,it isof paramount tion was 8.4 Â 106/kg in the filgrastim arm versus importance to identify the best myeloid growth factor to 5.8 Â 106/kg in the lenograstim arm versus 4.0 Â 106/kg improve PBPC collection. Studiesconducted on healthy in the molgramostim arm (P ¼ 0.1). A statistically donors showed a possible advantage of the glycosylated significant difference was observed for the median number form of G-CSF compared with the non-glycosylated form of days of growth factor administration in favor of in termsof number of colony-forming units-granulocyte– lenograstim (12 days) versus filgrastim (13 days) and macrophage harvested, even if a similar advantage has still molgramostim (14 days) (Po0.0001) and for the sub- to be demonstrated in cancer patients treated with group of chemonaive patients (12 days) versus pretreated mobilizing chemotherapy.6 GM-CSF hasbeen usedin this patients (14 days) (Po0.001). In conclusion, all three context with satisfying results on PBPC harvesting and growth factors were efficacious in mobilizing peripheral possible reduction of duration of thrombocytopenia and blood progenitor cells with no statistically significant mucositis.7–10 difference between CD34 þ cell yield and the different We conducted a prospective randomized study regimens, and the time to apheresis is likely confounded by to compare the mobilizing efficacy of two formsof the different mobilization regimens. G-CSF, one non-glycosylated (filgrastim) and one Bone Marrow Transplantation (2006) 38, 407–412. glycosylated (lenograstim), and a non-glycosylated form doi:10.1038/sj.bmt.1705465 of GM-CSF (molgramostim), following administration of a Keywords: peripheral blood progenitor cells; mobiliza- disease-specific chemotherapy. We evaluated number of tion; filgrastim; lenograstim; molgramostim; randomized CD34 þ cells, the subtypes CD34 þ /CD33, CD34 þ / study 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 Correspondence: Dr B Kopf, Department of Oncology and Hematology, mobilization, we stratified patients in chemonaive and Istituto Oncologico Romagnolo, Santa Maria delle Croci Hospital, Viale Randi 5, Ravenna 48100, Italy. pretreated, who received at least one chemotherapeutic E-mail: [email protected] regimen before the regimen containing high-dose che- Received 22 February 2006; revised 29 June 2006; accepted 2 July 2006 motherapy. PBPC mobilization: a randomized study B Kopf et al 408 Patients and methods enrolled and randomly assigned to the filgrastim arm (n ¼ 38), lenograstim arm (n ¼ 36) or molgramostim Patients and treatment (n ¼ 29). Forty-seven were affected by breast cancer, 27 Patientsolder than 18 yearsand younger than 60 undergoing by germ cell tumor, 14 by non-Hodgkin’slymphoma PBPC transplant were eligible for the study. All patients had (NHL), 5 by Hodgkin’s disease (HD), two by multiple an Eastern Cooperative Oncology Group (ECOG) Perfor- myeloma, two by osteosarcoma and six by other tumors. mance Status p2, with adequate hepatic, cardiac and renal Fifty-nine had received prior chemotherapy and 44 were function. The study was approved by the Institutional Review chemonaive. The patient characteristics are listed in Table 1. Board. Patientsgave written informed consent. PBPC transplant was given mostly to patients with solid Of 103 assessable patients, 21 (20%) did not undergo tumorsin our Institution.Different mobilizing chemo- apheresis: 15 patients failed to mobilize CD34 þ cells(10 therapy regimenshave been usedaccording to tumor type. affected by germ cell tumors, two HD, one NHL, one Anthracyclines alone or in association with paclitaxel were nasopharynx carcinoma and one breast cancer), whereas used for patients affected by breast cancer, osteosarcoma, one patient was detected to be positive for hepatitis B virus, and small cell lung cancer (n ¼ 26), cyclophosphamide one had fungal pneumonitis, one bone marrow metastases, (CTX) 4 or 7 g/m2 for patientsaffected by lymphoma or one an unspecified heart disease, one a hemorrhagic cystitis breast cancer (n ¼ 45), CTX and etoposide or ifosfamide after mobilization and one the diagnosis of metastatic and cisplatin plus vinblastine (VeIP) or etoposide (VIP) for disease after randomization changing treatment policy. patientswith Ewing’ssarcomaor germ cell tumor ( n ¼ 24), Most of patients that did not mobilize (15/21) had been epirubycin, ifosfamide and etoposide (IEV) for some of the heavily pretreated with chemotherapy. patientswith lymphoma ( n ¼ 6). Patientswere centrally randomized by a computer Toxicity and hematological recovery after mobilization generated random list in one of the following three groups: All patientswere evaluable for the effectsof growth factor filgrastim 5 mg/kg/day, lenograstim 5 mg/kg/day and mol- regimenson toxicity and hematological recovery after gramostim 5 mg/kg/day. Myeloid growth factor adminis- mobilizing chemotherapy in the three groups. Twenty-six of tration started 24 h after the last day of the mobilizing 103 patients (25%) needed transfusions of red blood cells chemotherapy. (RBC), independently from the arm, whereasplatelet transfusion was necessary in 20 (19%) patients: 13 (34%) PBPC collection in the filgrastim arm, two (6%) in the lenograstim arm, and Three days after the first administration of the myeloid five (17%) in the molgramostim arm, respectively, with a growth factor, blood cell count wasperformed to monitor statistically significant difference in favor of lenograstim the recovery of white blood cells(WBC), with determina- and molgramostim (P ¼ 0.007). There wasno difference in tion of the number of CD34 þ cellsin the peripheral blood the number of transfused units of platelets and RBC per when WBC count X1000/cm3. Apheresis was performed patient among the three groups. Grade 4 neutropenia when the absolute number of circulating CD34 þ cellsin occurred in 72 (70%) patients: 28 (74%) in the filgrastim the peripheral blood was X20 ml.11 One or more aphereses arm, 19 (53%) the lenograstim arm and 25 (86%) in the were performed until cumulative yield of CD34 þ cellswas molgramostim, respectively. Median duration to recovery X2 Â 106/kg, the threshold fixed to guarantee a safe of ANC40.5 Â 109/l was4 days(range, 1–18) in the hematological recovery.12 The PBPC harvest was per- filgrastim arm, 3 days (range, 1–15) in the lenograstim arm formed using the spectra COBE BCT, Aphaeresis System and 6 days(range, 3–11) in the molgramostimarm. The (Lakewood, CO, USA). difference among the three treatment arms was statistically significant in favor of lenograstim for both parameters: Statistical analysis frequency and duration of neutropenia (P ¼ 0.001 and For non-normal distributed values, data were summarized 0.0005, respectively). No statistically significant difference asmedian and range. Differencesamong groupswere for occurrence and duration of grade 4 thrombocytopenia evaluated by w2 test13 for categorical variablesand median was observed among treatment arms. test14 for continuous variables. All analyses were performed using SAS Statistical software15 and P-valueslessthan Non-hematological toxicity a ¼ 0.05 were considered to be statistically significant. The Fever (4381C) was observed in 29 (28.1%) patients, number of CD34 þ cellscollected Â 106/kg/apheresis was without any significant difference for incidence and calculated by dividing the total number of CD34 þ cells duration in the three treatment arms. Other grade 3–4 collected from each patient by the number of daily non-hematological toxicities, based exclusively on che- aphaeresis. motherapy 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, Results and one of diarrhea in the filgrastim arm. Because of the low incidence and the different chemotherapy regimens Patients used for mobilization, it was not possible to evaluate One hundred and three consecutive patients, 59 females differencesamong treatment armsfor the occurrence of and 44 males, median age 37 years (range 18–60), were toxicity.

Bone Marrow Transplantation PBPC mobilization: a randomized study B Kopf et al 409 Table 1 Patient characteristics

Overall Filgrastim Lenograstim Molgramostim no. of patients (%) no. of patients (%) no. of patients (%) no. of patients (%)

No. of patients103 (100) 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 44 (42.7) 15 (39.5) 15 (41.7) 14 (48.3) Female 59 (57.3) 23 (60.5) 21 (58.3) 15 (51.7)

Diagnosis Breast cancer 47 (45.6) 18 (47.5) 17 (47.2) 12 (41.3) Germ cell tumors27 (26.2) 8 (21.1) 10 (27.8) 9 (31.0) NHL 14 (13.6) 6 (15.8) 3 (8.3) 5 (17.2) Hodgkin’s disease 5 (4.8) 1 (2.6) 3 (8.3) 1 (3.5) Multiple myeloma 2 (1.9) 1 (2.6) 0 1 (3.5) Osteosarcoma 2 (1.9) 1 (2.6) 0 1 (3.5) Other 6 (5.8) 3 (7.8) 3 (8.3) 0

Previously treated with CT 59 (57.3) 21 (55.3) 21 (58.3) 17 (58.6)

Number of CT regimens Median (range) 1 (1–3) 1 (1–3) 1 (1–3) 1 (1–2)

Mobilizing chemotherapy EPI/ADM7paclitaxel 26 (25.2) 6 (15.8) 14 (38.9) 6 (20.7) CTX 45 (43.7) 23 (60.5) 7 (19.4) 15 (51.8) CE 4 (3.9) 1 (2.6) 2 (5.6) 1 (3.0) VIP/VeIP 22 (21.4) 6 (15.8) 10 (27.8) 6 (20.7) IEV 6 (5.8) 2 (5.3) 3 (8.3) 1 (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’slymphoma; VIP/VeIP ¼ cisplatin, ifosfamide and etoposide or vinblastine.

Table 2 Apheresis yield according to the treatment arms

Overall Filgrastim Lenograstim Molgramostim P

No. of patients82 (100%) 29 (76.3%) 29 (80.5%) 24 (82.7%) No. of aphereses median (range) 1 (1–3) 1 (1–2) 1 (1–3) 1 (1–2) NS Day of ﬁrst apheresis median (range) 13 (10–20) 13 (10–17) 12 (11–16) 14 (12–20) o0.0001 CD34+ cells Â 106/kg per apheresis median (range) 5.8 (0.5–31.6) 8.4 (1.8–31.6) 5.8 (0.6–19.2) 4.0 (0.5–14.0) NS (P ¼ 0.1)

Abbreviation: NS ¼ not signiﬁcant.

Mobilizing efficacy of filgrastim,lenograstim and Median duration of growth factor administration until molgramostim day of apheresis was 13 days (range, 10–20). The number of Of 103 assessable patients, 82 (79%) mobilized and days was less for the lenograstim arm with a median underwent one or more apheresis procedures. A median number of 12 days(range, 11–16) versus13days(range, number of one apheresis per patient (range, 1–3) was 10–17) for the filgrastim arm and 14 days (range, 12–20) for performed resulting in a median total CD34 þ cell yield the molgramostim arm (Po0.0001) (Table 2). A statisti- of 5.8 Â 106/kg (range, 0.5–31.6). The median number of cally significant advantage (Po0.001) was also observed CD34 þ cellsobtained after mobilization was8.4 Â 106/kg for the subgroup of chemonaive patients with a median in the filgrastim arm versus 5.8 Â 106/kg in the lenograstim duration of growth factor administration of 12 days (range, arm versus 4.0 Â 106/kg in the molgramostim arm (P ¼ 0.1) 10–20) with respect to pretreated patients with a median (Table 2). number of 14 days(range, 12–17) (Table 3). Of patients underwent apheresis, 28 (97%) in the No statistically significant difference among treatment filgrastim arm, 25 (86%) in the lenograstim arm, and 21 arms and subgroups were observed in terms of number of (87.5%) in the molgramostim arm yielded an adequate apheresis procedures necessary for the collection of an number of CD34 þ cells( X2 Â 106/kg). Thirty-seven of adequate number of CD34 þ cells. 59 (86%) were in the pretreated patient group and 37 of The day of first apheresis, WBC count reached an overall 44 (95%) in the chemonaive patient group. A significant median value of 10.9 Â 103/ml (range, 2.1–51.6), with difference among treatment armsor pretreated/not- statistically significantly higher values in the filgrastim pretreated subgroups was not observed. arm (14.7 Â 103/ml; range, 4.1–43), and lenograstim arm

Bone Marrow Transplantation PBPC mobilization: a randomized study B Kopf et al 410 Table 3 Apheresis yield in pretreated and chemonaive patients

Pretreated Not pretreated P

No. of patients37 (86.1) 37 (94.9) No. of aphereses median (range) 1 (1–3) 1 (1–2) NS Day of ﬁrst apheresis median (range) 14 (11–17) 12 (10–20) 0.001 CD34+ cells Â 106/kg per apheresis median (range) 4.16 (0.6–19.2) 9 (0.5–31.6) 0.001

Abbreviation: NS ¼ not signiﬁcant.

(14 Â 103/ml; range, 2.1–51.6), versus the molgramostim a high-dose chemotherapy treatment.5 A not statistically arm (5.1 Â 103/ml; range, 2.2–11.5) (Po0.0001), whereas significant trend in favor of filgrastim was observed when there wasno difference in WBC count for the subgroupsof considering the median number of CD34 þ cellscollected pretreated and not-pretreated patients. (Table 2). No difference among treatment armsand A correlation wasobservedamong count of leukocytes subgroups was observed in harvesting CD34 þ /CD33 and CD34 þ cellsin the peripheral blood the day of cells, CD34 þ /CD38 cellsand CD34 þ /Thy1 þ cells. A apheresis, which resulted highest in the filgrastim arm statistically significant advantage in favor of lenograstim (median value 146.4/ml CD34 þ cells; range, 20.4–688), for median number of daysuntil apheresis(12daysversus versus 81.2/ml (range, 14.2–585) in the lenograstim arm, and 13 daysin the filgrastimarm and 14 daysin the 61.6/ml (range, 16.4–489) in the molgramostim arm, with a molgramostim arm) was observed, but not for number of significant P-value (Po0.015). This was not associated with aphereses performed (Table 2). These data are in line with a higher CD34 þ cell yield in any of the treatment arms. other authors. Arora et al.23 showed that mobilization with There was instead a significant difference for the number of chemotherapy plus G-CSF versus GM-CSF results in CD34 þ cellscollected in favor of the chemonaive group of similar CD34 þ progenitor collections, even in patients patientsthat obtained a median number of 9 Â 106/kg/ pretreated with multiple cyclesof alkylator-basedche- apheresis (range, 0.5–31.6), compared to a median number motherapy. Earlier neutrophil and platelet recovery was of 4.6 Â 106/kg/apheresis (range, 0.6–19.2) in the pretreated seen with G-CSF priming. Vice versa, there is questionable patients(Table 3). clinical benefit with PBPC productsmobilized with the A statistically significant difference in harvesting of combination of G-CSF and GM-CSF versus G-CSF subgroups CD34 þ /CD33 cells, CD34 þ /CD38 cells alone.24 Spitzer et al.25 reported 50 patientswith either and CD34 þ /Thy1 þ cellswasobservedneither among the lymphoid or selected solid tumor malignancies that three treatment arms, nor between the two groups of apheresed an identical number of times for PBPC collection pretreated and chemonaive patients. 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 ( Â 106/kg) collected by each Discussion method of stem cell mobilization was not significantly different. Several clinical studies have addressed the issue of the In our study, we also observed a correlation between benefitsof usingmyeloid growth factorsfollowing mobiliz- WBC count the day of apheresis (filgrastim arm 14.7 Â 106 ing chemotherapy.16–18 and lenograstim arm 14 Â 106 in comparison to molgra- In our randomized study, we compared filgrastim versus mostim arm 5.1 Â 106) and median number of CD34 þ lenograstim versus molgramostim plus chemotherapy to cells/ml in the peripheral blood (146.4/ml versus 81.2/ml and evaluate their ability to mobilize CD34 þ cellsand their 61/ml, respectively), but not between these circulating less commissioned precursors in the peripheral blood. To CD34 þ cellsand CD34 þ cell harvest. These results were our knowledge, this is the first randomized study compar- discordant with those described by other authors who ing the mobilizing capacity of these three myeloid growth reported a number of CD34 þ cellsin the peripheral blood factors following disease-specific chemotherapy. The ad- resulted a reliable predictor for estimating PBPC yield.6,26 ministered dose of the three myeloid growth factors was Demirer et al.27 reported that preleukapheresis circulating 5 mg/kg/day according to other authorswho showedthat CD34 þ cells/ml correlated significantly better with the increasing the dose of CSFs after mobilizing chemotherapy yield of collected CD34 þ cellsthan WBC and platelet did not lead to faster hematopoietic recovery.19,20 counts on the first day of apheresis with a threshold level of Of 103 assessable patients, 82 (79%) mobilized and circulating CD34 þ cells before apheresis, which was underwent a median of one apheresis (range 1–3). The around the 30–50/ml. In our study, the lowest level was nearly 20% mobilization failure rate isquite high, and 61/ml (in the molgramostim arm). A possible reason for not could be partially justified with the high percentage of seeing a correlation may be being beyond the threshold pretreated patients(57%), and the significantpercentage of level in each group. Marques et al.28 conducted a study GCT (26%) and NHL (13%) patients, who could have a about CD34 þ cell mobilization with chemotherapy and mobilization failure rate of about 20–30%.21,22 growth factorsin patientswith hematological malignancies, Of patients who underwent apheresis, 70% obtained at and found a linear correlation between the daysfor WBC least 2 Â 106/kg CD34 þ cells, which was considered the recovery and number of aphereses needed to collect the minimum threshold value to guarantee the clinical safety of target of CD34 þ cells, suggesting that an early WBC

Bone Marrow Transplantation PBPC mobilization: a randomized study B Kopf et al 411 recovery could be considered as an important predictor of a providesan effective mobilizing regimen to supportthree low number of aphereses. courses of high-dose dense chemotherapy in patients with high- In our study, chemonaive patients obtained a signifi- risk stage II–IIIA breast cancer. Bone Marrow Transplant cantly higher median CD34 þ cell harvest and needed 2003; 32: 251–255. fewer days until apheresis compared to pretreated patients, 4 De Giorgi U, Rosti G, Papiani G, Marangolo M. The status of but no difference between the two subgroups was observed high-dose chemotherapy with hematopoietic stem cell transplantation in germ cell tumor patients. Haematologica 2002; for the number of patientswho achieved minimum thresh- 87: 95–104. old value of CD34 þ cells. These results confirmed those of 5 Siena S, Schiavo R, Pedrazzoli P, Carlo-Stella C. Therapeutic previous studies that showed that prior treatment influ- relevance of CD 34+ cell dose in blood cell transplantation for encesnegatively the ability to mobilize PBPC. 21 cancer therapy. J Clin Oncol 2000; 18: 1360–1377. With respect to recovery of hematological toxicity, we 6 Hoeglund M, Smedmyr B, Bengtsson M, Toetterman TH, did not observe a reduction of thrombocytopenia in the Yver A, Cour-Chabernaud V et al. Mobilization of CD34+ patient group treated with GM-CSF, asdescribedin other cells by glycosylated and nonglycosylated G-CSF in healthy studies.6,7 Moreover, no statistically significant difference volunteers– a comparative study. Eur J Haematol 1997; 59: among treatment armswasobservedfor incidence and 177–183. duration of grade 4 thrombocytopenia, whereashigher 7 Gianni AM, Siena S, Bregni M, Di Nicola M, Orefice S, Cusumano F et al. Granulocyte–macrophage colony stimulat- incidence and duration of grade 4 neutropenia in the ing factor to harvest circulating hemopoietic stem cells for molgramostim arm occurred. As regards non-hemato- autotransplantation. Lancet 1989; 2: 580–585. logical toxicity, there wasno significantdifference for 8 Bregni M, Siena S, Di Nicola M, Dodero A, Peccatori F, occurrence and duration of fever. Evaluation of mucositis Ravagnani F et al. Comparative effectsof granulocyte– was not possible because of the low incidence in the macrophage colony stimulating factor and of granulocyte treatment armsand the not homogeneousmobilizing colony stimulating factor after high-dose cyclofosfamide chemotherapy regimensadministrated.However, the three cancer therapy. J Clin Oncol 1996; 14: 628–635. groupsof patientswere not well balanced for chemother- 9 Dazzi C, Cariello A, GiovanisP, Monti M, Vertogen B, Leoni apy regimen. In particular, 53.8% of the patientstreated M et al. Prophylaxiswith GM-CSF mouthwashesdoesnot with anthracycline/taxane received lenograstim, 51.1% reduce frequency and duration of severe oral mucositis in patients with solid tumors undergoing high-dose chemother- treated with high-dose CTX received filgrastim and 45% apy with autologous peripheral stem cell transplantation treated with VIP/VeIP received molgramostim (Table 1). rescue: a double blind, randomized, placebo-controlled study. This may partially explain the statistically significant Ann Oncol 2003; 14: 559–563. differencesobservedin toxicity and hemopoietic recovery. 10 Correale P, Campoccia G, Tsang KY, Micheli L, Cusi MG, Recently, pegylated growth factorshave been introduced Sabatino M et al. Recruitment of dendritic cellsand enhanced in clinical practice, distinguished by a prolonged half-life antigen-specific immune reactivity in cancer patients treated compared to native growth factors that do not necessitate with hr-GM-CSF (molgramostim) and hr-IL-2. Results from a of daily injections.29,30 Several studies are investigating phase Ib clinical trial. Eur J Cancer 2001; 37: 892–902. pegfilgrastim to evaluate its ability to mobilize PBPC and 11 Bengala C, Pazzaglia F, Tibaldi C, Favre C, Vanacore R, et al. to improve the quality of life of these patients. Greco F Mobilization, collection, and characterization of peripheral blood hemopoietic progenitorsafter chemotherapy In conclusion, all three growth factors resulted effica- with epirubicin, paclitaxel and granulocyte-colony stimulating cious to mobilize PBPC with no statistically significant factor administered to patients with metastatic breast carcino- difference between CD34 þ yield and the different regi- ma. Cancer 1998; 82: 867–873. mens, and the time to apheresis is likely confounded by the 12 Pedrazzoli P, Ferrante P, Kulekci A, Schiavo R, De Giorgi U, vast difference in mobilization regimens. An advantage on Carminati O et al. Autologoushematopoietic stemcell platelet recovery with molgramostim, suggested by other transplantation for breast cancer in Europe: critical evaluation authors was not confirmed by our results. of data from the European Group for Blood and Marrow Transplantation (EBMT) Registry 1990–1999. Bone Marrow Transplant 2003; 32: 489–494. 13 Siegel S, Castellan Jr NJ. Statistica Non Parametrica, 2nd edn. Acknowledgements McGraw-Hill: New York, 1992. 14 Armitage P, Berry G. Statistical Methods in Medical Research, This study was supported by a special grant from Istituto 2nd edn. Blackwell Scientific Publications: Cambridge, MA, Oncologico Romagnolo. 1987. 15 SAS Institute Inc. SAS/STAT User’s Guide, version 8.02, vol. 1. SAS Institute: Cary, NC, 1989. References 16 Seggewiss R, Buss EC, Herrmann D, Goldschmidt H, Ho AD, Fruehauf S. Kineticsof peripheral blood stemcell mobilization 1 Gratwohl A, Baldomero H, Demirer T, Rosti G, Dini G, following G-CSF-supported chemotherapy. Stem Cells 2003; Ladenstein R et al. Hematopoietic stem cell transplantation for 21: 568–574. solid tumors in Europe. Ann Oncol 2004; 15: 653–660. 17 Milone G, Leotta S, Indelicato F, Mercurio S, Moschetti G, Di 2 Demirer T, Buckner CD, Bensinger WI. Optimization of Raimondo F et al. G-CSF alone vscyclophosphamideplus peripheral blood stem cell mobilization. Stem Cells 1996; 14: G-CSF in PBPC mobilization of patientswith lymphoma: 106–116. results depend on degree of previous pretreatment. Bone 3 De Giorgi U, Rosti G, Zaniboni A, Ballardini M, Minzi MR, Marrow Transplant 2003; 31: 747–754. Baioni M et al. High-dose epirubicin, preceded by dexrazox- 18 GoterrisR, Hernandez-Boluda JC, Teruel A, Gomez C, ane, given in combination with paclitaxel plusfilgrastim LisMJ, Terol MJ et al. Impact of different strategies of

Bone Marrow Transplantation PBPC mobilization: a randomized study B Kopf et al 412 second-line stem cell harvest on the outcome of autologous granulocyte–macrophage colony-stimulating factor plus transplantation in poor peripheral blood stem cell mobilizers. granulocyte colony-stimulating factor versus granulocyte Bone Marrow Transplant 2005; 36: 847–853. colony-stimulating factor for mobilization of dendritic cell 19 Andre M, Baudoux E, Bron D, Canon JL, D’Hondt V, subsets in hematopoietic progenitor cell products. Biol Blood Fassotte MF et al. Phase III randomized study comparing 5 or Marrow Transplant 2004; 10: 848–857. 10 microg per kg per day of filgrastim for mobilization of 25 Spitzer G, AdkinsD, MathewsM, VelasquezW, BowersC, peripheral blood progenitor cellswith chemotherapy, followed Dunphy F et al. Randomized comparison of G-CSF + GM- by intensification and autologous transplantation in patients CSF vsG-CSF alone for mobilization of peripheral blood with nonmyeloid malignancies. Transfusion 2003; 43: 50–57. stem cells: effects on hematopoietic recovery after 20 Kim S, Kim HJ, Park JS, Lee J, Chi HS, Park CJ et al. high-dose chemotherapy. Bone Marrow Transplant 1997; 20: Prospective randomized comparative observation of single- vs 921–930. split-dose lenograstim to mobilize peripheral blood progenitor 26 Yu J, Leisenring W, Bensinger WI, Holmberg LA, Rowley SD. cellsfollowing chemotherapy in patientswith multiple The predictive value of white cell or CD34+ cell count in the myeloma or non-Hodgkin’slymphoma. Ann Hematol 2005; peripheral blood for timing apheresis and maximizing yield. 84: 742–747. Transfusion 1999; 39: 442–450. 21 Dazzi C, Cariello A, Rosti G, Monti G, Sebastiani L, Argnani 27 Demirer T, Ilhan O, Ayli M, Arat M, Dagli M, Ozcan M et al. M et al. Peripheral blood progenitor cell (PBPC) mobilization Monitoring of peripheral blood CD34+ cell countson the first in heavily pretreated patientswith germ cell tumours:e report day of apheresis is highly predictive for efficient CD34+ cell of 34 cases. Bone Marrow Transplant 1999; 23: 529–532. yield. Ther Apher 2002; 6: 384–389. 22 Olivieri A, Brunori M, Capelli D, Montanari M, Massidda D, 28 MarquesJFC, Vigorito AC, Aranha FJP, Lorand-Metz I, Gini G et al. Salvage therapy with an outpatient DHAP Miranda ECM, Lima Filho EC et al. Early total white blood schedule followed by PBSC transplantation in 79 lymphoma cell recovery isa predictor of low number of apheresisand patients: an intention to mobilize and transplant analysis. Eur good CD34+ cell yield. Transfus Sci 2000; 23: 91–100. J Haematol 2004; 72: 10–17. 29 Steidl U, Fenk R, BrunsI, Neuman F, Kondakci M, Hoyer B 23 Arora M, BurnsLJ, Barker JN, Miller JS, Defor TE, et al. Successful transplantation of peripheral blood stem cells Olujohungbe AB et al. Randomized comparison of granulo- mobilized by chemotherapy and a single dose of pegylated cyte colony-stimulating factor versus granulocyte–macrophage G-CSF in patientswith multiple myeloma. Bone Marrow colony-stimulating factor plus intensive chemotherapy for Transplant 2005; 35: 33–36. peripheral blood stem cell mobilization and autologous 30 BrunsI, Steidl U, Kronenwett R, Fenk R, Graef T, Rohr UP transplantation in multiple myeloma. Biol Blood Marrow et al. A single dose of 6 or 12 mg of pegfilgrastim for peripheral Transplant 2004; 10: 395–404. blood progenitor cell mobilization results in similar yields of 24 Lonial S, Hicks M, Rosenthal H, Langston A, Redei I, Torre CD34+ progenitorsin patientswith multiple myeloma. C et al. A randomized trial comparing the combination of Transfusion 2006; 46: 180–185.

Bone Marrow Transplantation