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

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A Randomized Study Comparing Filgrastim Versus Lenograstim Versus Molgramostim Plus Chemotherapy for Peripheral Blood Progenitor Bone Marrow Transplantation (2006) 38, 407–412 & 2006 Nature Publishing Group All rights reserved 0268-3369/06 $30.00 www.nature.com/bmt 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 /CD33À, CD34 þ / study CD38À 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
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