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And G-CSF (filgrastim) After Cyclophosphamide (4 G/M2) Enhance the Peripheral Blood Progenitor Cell Harvest: Results of Two Randomized Studies Including 120 Patients

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And G-CSF (filgrastim) After Cyclophosphamide (4 G/M2) Enhance the Peripheral Blood Progenitor Cell Harvest: Results of Two Randomized Studies Including 120 Patients Bone Marrow Transplantation (2006) 38, 275–284 & 2006 Nature Publishing Group All rights reserved 0268-3369/06 $30.00 www.nature.com/bmt ORIGINAL ARTICLE Low doses of GM-CSF (molgramostim) and G-CSF (filgrastim) after cyclophosphamide (4 g/m2) enhance the peripheral blood progenitor cell harvest: results of two randomized studies including 120 patients P Quittet1, P Ceballos1, E Lopez1,ZYLu2, P Latry1, C Becht1, E Legouffe1, N Fegueux1, C Exbrayat1, DPouessel 1, V Rouille´ 1, JP Daures3, B Klein2,4 and JF Rossi1,4 1Service He´matologie et Oncologie me´dicale, Hopital Lapeyronie, Montpellier, France; 2Unite´ de The´rapie Cellulaire, Hopital St-Eloi, Montpellier, France; 3Unite´ de Biostatistiques, IURC, Montpellier, France and 4INSERM U475, Montpellier, France The use of a combination of G-CSF and GM-CSF versus of hematopoietic growth factors (HGFs) alone or in G-CSF alone, after cyclophosphamide (4 g/m2) was combination with chemotherapy, in which case a higher compared in two randomized phase III studies, including yield of CD34 þ cells can be reached and collected.6 It is 120 patients. In study A, 60 patients received 5 Â 2 lg/kg/ generally recognized that granulocyte colony-stimulating day of G-CSF and GM-CSF compared to 5 lg/kg/day of factor (G-CSF) as a single agent mobilizes more CD34 þ G-CSF. In study B, 60 patients received 2.5 Â 2 lg/kg/ cells than does granulocyte–macrophage colony stimulating day G-CSF and GM-CSF compared to G-CSF alone factor (GM-CSF).7–9 Other HGFs, such as interleukin-3,10 (5 lg/kg/day). With the aim to collect at least 5 Â 106/kg Flt3 ligand,11 stem cell factor12–13 and erythropoietin 14 or CD34 cells in a maximum of three large volume antagonists of SDF-1-CXCR415 have been tested generally leukapherises (LK), 123 LK were performed in study A, in combination for mobilizing PBPC. The recommended showing a significantly higher number of patients reaching dose of G-CSF after chemotherapy is 5 mg/kg/d.16 Increas- 10 Â 106/kg CD34 cells (21/29 in G þ GM-CSF arm vs ing the dose of G-CSF to more than 5 mg/kg/d17,18 or 11/27 in G-CSF arm, P ¼ 0.00006). In study B, 109 LK changing the administration schedule19 has not been proven were performed, with similar results (10/27 vs 15/26, to improve PBPC mobilization. The use of a single dose of P ¼ 0.003). In both the study, the total harvest of CD34 pegfilgrastim was demonstrated as equivalent to a daily cells/kg was twofold higher in G-CSF plus GM-CSF administration of filgrastim for mobilizing PBPC.20 The group (18.3 Â 106 in study A and 15.85 Â 106 in study B) infusion of CD34 þ cells higher then 3–5 Â 106 CD34/kg than in G-CSF group (9 Â 106 in study A and 8.1 Â 106 in results in rapid engraftment, reduces the transfusion need study B), a significant difference only seen in multiple and may have a clinical influence.21–23 The synergistic effect myeloma, with no significant difference in terms of of coadministration of HGFs like G-CSF and GM-CSF on mobilized myeloma cells between G-CSF and GM-CSF PBPC mobilization has been suggested in phase I/II groups. study,24 for improving the harvest of CD34 cells.25 Several Bone Marrow Transplantation (2006) 38, 275–284. non-randomized or randomized clinical trials have been doi:10.1038/sj.bmt.1705441 performed, showing a little or no benefit for sequential Keywords: G-CSF; GM-CSF; hematopoietic stem cells administration of standard doses (5–10 mg/kg/d) of GM- CSF and G-CSF.26–37 Neverthelesss, the use of these HGFs was not well explored and particularly the minimal efficient dose for their concomitant administration, following high dose cyclophosphamide (CY). We report here two rando- Introduction mized studies comparing G-CSF to the association of G-CSF and GM-CSF. Autologous peripheral blood progenitor cells (PBPC) provide a rapid and sustained hematopoı¨ etic recovery after the administration of high-dose therapy in patients with hematological malignancies and certain solid tumors.1–5 Materials and methods The mobilization of PBPC is usually achieved with the use Study design As shown in Figure 1, this was a randomized, open-label, unicenter study, including two parts (study A and study B). Correspondence: Dr JF Rossi, Service He´ matologie et Oncologie The primary objective of this study was to achieve a me´ dicale, Hopital Lapeyronie, 34295 Montpellier, and INSERM 6 U475, France. maximal of 10 Â 10 CD34 cells/kg in a minimal number of E-mail: [email protected] leukapheresis. Calculation of the number of subjects was Received 1 August 2005; revised and accepted 29 May 2006 based on the fact that the percentage of the subjects G-CSF vs G-CSF plus GM-CSF for mobilization/collection of PBPC P Quittet et al 276 Measure of WBC Stem cell collection Cyclophosphamide and White blood counts (WBC) were assessed daily after the 2 CD34 cell counts 4 g/m beginning of chemotherapy. When it reaches 0.5 Â 109/l, the percentage of circulating CD34 cells was monitored daily Growth factors according to the ISHAGE protocol, by using a phyco- (G-CSF or G-CSF + GM-CSF) erythrin-conjugated (PE) antibody to CD34 (Q-Bend 10, Immunotech, Marseille, France) using a FACScan (Becton- D 1 D 2 Dickinson, San-Jose, CA, USA).38 The estimated number of CD34 cells/kg that can be collected in one LK was Determination of CD34 cell calculated by the central laboratory according to the in each leukapheresis following formula: (%CD34 Â WBC Â 8/kg body weight Figure 1 Design of the study: mobilization and collection of CD34 cells. (eight being a coefficient corresponding approximately to 2 blood volumes in liter). Then, a LK was started if the estimation of harvestable CD34 number was X106 CD34/ 6 kg. If the estimation of harvestable CD34 cell number reaching more than 10 Â 10 CD34 cells/kg in the combina- 6 tion arm will be twice than that observed in the single- was below 10 CD34/kg the collection was delayed. A maximum of three LK was attempted to reach a minimum cytokine arm. With a power of 90% and a 5% risk, the 6 number of patients is 25 per arm. For that reason, we target of 5 Â 10 CD34/kg. For MM patients, at this time, decide to include 30 patients per arm due to the possibility we performed a CD34 selection in order to decrease of unevaluable patients. There was no stratification. The contaminating tumoral cells. For that reason, due to the loss of cells during this procedure, we attempt to collect secondary objectives of this study include tolerance, factors 6 influencing the mobilization of progenitor cells, percentage 10 Â 10 CD34/kg. Large volume LK was performed of myeloma cells mobilized in PB, and difference of through a dual peripheral venous puncture using a Cobe mobilization at the level of 5 Â 106 CD34 cells/kg between Spectra separator version 4 (CS 3000; Baxter Healthcare the two arms. In study A, 60 patients were randomized Corp Lakewood, CO, USA). Median time of processing to receive after CY (4 g/m2)5mg/kg/day (d) of rHu-GM- was 5 h and the mean volume of processed blood ranged CSF (Molgramostim, Schering-Plough, Kenilworth, NJ, between 12 and 16 l. USA) and 5 mg/kg/d of rHu-G-CSF (Filgrastim, Amgen, Thousand Oaks, CA, USA) (G þ GM-CSF, total HGF Analysis of product of leukapheresis dose ¼ 10 mg/kg/d) compared to 5 mg/kg/d of G-CSF The determination of CD34 cell content in the LK was (Filgrastim). In study B, 60 subsequent patients have carried out according to the following procedure. Incuba- received the same design of treatment with 2.5 mg/kg/d of tion of 106 cells with 30% AB serum (100 ml) for 10 min, GM-CSF and 2.5 mg/kg/d of G-CSF (G þ GM-CSF, total two washings with PBS, suspension in a final volume of dose of HGF ¼ 5 mg/kg/d) compared to 5 mg/kg/d of G- 100 ml, incubation with 20 ml of monoclonal antibody CD34 CSF. The 4 g/m2 CY was administered by intravenous (i.v.) conjugated with PE, or 20 ml of murine IgG recognizing no route to all the patients followed 24 h later by the HGF human antigen and conjugated with PE as a negative administration subcutaneously until the last day of control, or 5 ml anti-CD45 conjugated with PE as a positive leukapheresis (LK). For patients receiving the two HGFs, control for 30 mn at 41C, cell lysis followed by two they were injected in separate sites. washings and resuspension in 200 ml PBS. At least 30 000 events were acquired for each sample. In patients with multiple myeloma (MM), myeloma cells were enumerated Patient eligibility by FACS analysis using the FITC-conjugated MI15 (anti- Written informed consent was obtained from all patients CD138 mAb.39 106 cells were incubated with 1 mg MI15- enrolled in the study. Patients with histologically confirmed FITC (10 ml) or to 1 mg IgGFITC negative control (20 ml) and history of cancer and requiring a high dose myeloablative fluorescence was analyzed with FACSCAN cytofluoro- chemotherapy with PBPC rescue were eligible. Disease meter.
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