Comparison Between Filgrastim and Lenograstim Plus Chemotherapy For

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ORIGINAL ARTICLE Comparison between ﬁlgrastim and lenograstim plus chemotherapy for mobilization of PBPCs

R Ria, T Gasparre, G Mangialardi, A Bruno, G Iodice, A Vacca and F Dammacco

Department of Biomedical Sciences and Human Oncology, Section of Internal Medicine and Clinical Oncology, University of Bari Medical School, Bari, Italy

Recombinant human (rHu) G-CSF has been widely used during transplantation.4 However, the use of G-CSF after to treat neutropenia and mobilize PBPCs for their autologous PBPC transplantation has been queried, as its autologous and allogeneic transplantation. It shortens further reduction in time to a safe neutrophil count5,6 does neutropenia and thus reduces the frequency of neutropenic not always imply fewer significant clinical events, such as fever. We compared the efficiency of glycosylated rHu infections, length of hospitalization, extrahematological and non-glycosylated Hu G-CSF in mobilizing hemato- toxicities or mortality.7,8 Even so, the ASCO guidelines still poietic progenitor cells (HPCs). In total, 86 patients were recommend the use of growth factors after autologous consecutively enrolled for mobilization with CY plus either PBPC transplantation.9 glycosylated or non-glycosylated G-CSF, and under- G-CSF induces the proliferation and differentiation of went leukapheresis. The HPC content of each collection, myeloid precursor cells, and also provides a functional toxicity, days of leukapheresis needed to reach the activity that influences chemotaxis, respiratory burst and minimum HPC target and days to recover WBC (X500 Ag expression of neutrophils. Comparison of HPC- and 41000/mm3) and plts (450 000/mm3) were evalu- mobilizing regimens is greatly impeded by the considerable ated. Glycosylated G-CSF mobilized more CD34 þ cells variability of their responses. The two G-CSF recombinant than did the non-glycosylated form. The ability to reach a preparations (lenograstim and filgrastim) currently avail- collection target of 43 Â 106 CD34 þ /kg body weight in able for HPC mobilization are produced in different ways. two leukaphereses was higher for glycosylated G-CSF. No Lenograstim is obtained from Chinese hamster ovarian significant differences between the two regimens were cells, and consists of 174 amino acids with 4% glycosyla- observed with regard to toxicity and days to WBC and plt tion.10 Filgrastim is produced using Escherichia coli, has a recovery. High-dose CY plus glycosylated G-CSF methionine group at its N-terminal end and is not achieved adequate mobilization and the collection target glycosylated.11 more quickly and with fewer leukaphereses. In this study, we compared the HSC-mobilizing efficacy Bone Marrow Transplantation (2010) 45, 277–281; of glycosylated vs non-glycosylated G-CSF in terms of the doi:10.1038/bmt.2009.150; published online 6 July 2009 number of CD34 þ cells collected and the number of Keywords: G-CSF; mobilization; PBPCs; recombinant leukaphereses needed to reach their collection target. human glycosylated G-CSF; recombinant non-glycosylated Secondary end points were the following: days to recover G-CSF WBC and plts, and assessment of toxicity and percentage of patients who achieved the collection target in a single course of mobilization (high-dose CY plus G-CSF plus three leukaphereses). Introduction

GG-CSF-mobilized PBPCs have become the most widely Patients and methods used source of hematopoietic progenitor cells (HPCs) for transplantation procedures, and their mobilization is Patients clinically safe. G-CSF is used to mobilize PBPCs in patients A total of 86 patients (48 men and 38 women, Table 1) who with malignancies, as well as in healthy donors for underwent auto-SCT for multiple myeloma (MM: 44 autologous and allogeneic PBPC transplantation.1–3 It patients), non-Hodgkin’s lymphoma (NHL: 31 patients) reduces the aplasia period and hence fever and infections or Hodgkin’s lymphoma (HL: 11 patients) between 2000 and 2008 were consecutively included in this controlled, non-randomized study. Correspondence: Dr R Ria, Department of Internal Medicine and Inclusion criteria were the same as those for auto-SCT: Clinical Oncology, University of Bari Medical School, Policlinico— age o70 years, serum creatinine o200 mmol/l, cardiac Piazza Giulio Cesare, 11, I-70124 Bari, Italy. E-mail: [email protected] ejection fraction 450%, DLCO (diffusing capacity of the Received 6 October 2008; revised 5 May 2009; accepted 26 May 2009; lung for carbon monoxide) 450% and no active infection published online 6 July 2009 or other disease causing comorbidity.12 Lenograstim vs ﬁlgrastim in PBPCs mobilization R Ria et al 278 Table 1 Patient characteristics

Characteristics Total number of patients Treated with lenograstim Treated with ﬁlgrastim

Numbers 86 55 31 Sex, M/F 48/38 29/26 19/12 Age, median (range) years 53.7 (36–64) 52.2 (36–64) 49.5 (34–60) MM/NHL/HL 44/31/11 32/16/7 12/15/4 Status at mobilization: CR/PR/SD/PD 11/58/11/6 7/39/6/3 4/19/5/3 Patients receiving radiotherapy 8 6 2 Patients with BM involvement 11 7 4

Mobilizing chemotherapy (MM/NHL/HL) CTX 7 g/m2 0/31/11 0/16/7 0/15/4 CTX 4 g/m2 32/0/0 23/0/0 9/0/0 CTX 3 g/m2 12/0/0 9/0/0 3/0/0

Abbreviations: F ¼ female; HL ¼ Hodgkin’s lymphoma; M ¼ male; MM ¼ multiple myeloma; NML ¼ non-Hodgkin’s lymphoma.

Overall 55 patients (29 men and 26 women; median age those from the day of high-dose CY administration (day 0) 53.7 years, range 36–64) were enrolled in Arm A and 31 to the day of counts recovery. patients (19 males and 12 females; median age 49.5 years, range 34–60) were enrolled in arm B. At mobilization, 11 Statistical analysis patients had achieved CR, 58 had achieved PR, 11 had Data were analyzed with the SPSS (Chicago, IL, USA) stable disease and 6 had disease progression. This was a software package. All results are presented as median±1 single-center prospective study in which patients were s.d. (range). The medians were compared with the Mann– assigned 1.5:1 to the two arms, paying attention to their Whitney U-test. P values o0.005 were considered sig- characteristics to equilibrate the arms. Also the patient niﬁcant. One-way ANOVA analysis was used to compare groups were well equilibrated for factors that could affect all parameters between patients with MM, NLH and HL, mobilization, such as number of earlier chemotherapy, also with respect to CY doses, earlier therapy and BM radiation therapy and BM involvement. involvement. The study was approved by the Local Ethical Commit- tee, and all patients gave their informed consent according to the Declaration of Helsinki Principles. Results

Treatment program Results of mobilization and leukapheresis All patients received only induction therapy with dexametha- A signiﬁcantly higher CD34 þ collection was obtained sone, adriamycin, vincristin (DAV) Â 4 courses (MM from patients in Arm A (glycosylated Hu G-CSF) than patients), CHOP Â 6 courses (NHL patients) or ABVD Â 6 from patients in Arm B (non-glycosylated rHu G-CSF): courses (HL patients). The transplant indication in NHL and 15.34±3.1 Â 106 CD34 þ cells/kg b.w. vs 11.04±2.41 Â 106 HL patients was related to high-risk disease: International CD34 þ /kg b.w., respectively (Po0.01) (Figure 1a), and Prognostic Index (IPI) 2–4 or refractory disease in NHL, the percentage of patients who reached the minimum refractory disease in HL. The mobilization regimen was collection target after two leukaphereses was higher in administered after 45±5 days after the end of induction those treated with glycosylated G-CSF (75 vs 48%, 2 therapy. In MM patients, it consisted of CY 3 or 4 g/m at respectively, Po0.001). The apheresis’ mean volume after day 0, on the basis of disease status at mobilization and plasma detraction was 54±14 ml in Arm A and 57±16 ml performance status; in patients with lymphomas, it was 7 g/m2 in Arm B. These results show that glycosylated G-CSF at day 0. Thereafter, patients received 10 mg/kg/day s.c. of provided more adequate mobilization and accelerated the glycosylated Hu G-CSF (Arm A) or non-glycosylated rHu target collection time, indicating that it mobilizes BM G-CSF (Arm B) on days 1–12. From day 12, patients were HSCs more effectively and in greater numbers. apheresed for 2 days and the CD34 þ cell content was No differences were observed between the MM, NLH evaluated by FACS analysis. If the patient did not reach the or HL groups, nor with regard to the different CY doses minimum CD34 þ cells target, a third apheresis was (3, 4 or 7 g/m2). Arm A ¼ MM patients: 14.21±2.8 Â 106 performed. The apheresis mean volume after plasma CD34 þ /kg b.w.; LNH patients: 16.14±3.6 Â 106 CD34 þ / detraction was 84±14 ml in Arm A and 87±16 ml in Arm kg b.w.; LH patients: 15.81±3.8 Â 106 CD34 þ /kg b.w. 6 B. If the minimum HPC target (X3 Â 10 /CD34 þ cells/kg (P ¼ NS). Arm B ¼ MM patients: 10.82±2.33 Â 106 body weight (b.w.)) was not reached after three apheretic CD34 þ /kg b.w.; LNH patients: 12.23±1.9 Â 106 procedures, patients were re-mobilized after at least CD34 þ /kg b.w.; LH patients 12.84±2.84 Â 106 CD34 þ / 1 month. kg b.w. (P ¼ NS). The percentage of patients who reached the minimum collection target after two aphereses was 73% Toxicity in MM patients, 76% in LNH patients and 78% in LH All adverse events were considered during the mobilization patients for Arm A (P ¼ NS) vs 46, 48 and 48%, period (days 0–15). The days to WBC and plt recovery were respectively, in Arm B (P ¼ NS).

Bone Marrow Transplantation Lenograstim vs ﬁlgrastim in PBPCs mobilization R Ria et al 279 20 when responders are compared with nonresponders.13,14 In 18 p<0.01 1988, G-CSF was found to mobilize HPCs into the 16 14 Lenograstim bloodstream, and this effect was even greater when it was administered after myelosuppressive chemotherapy.15 As 12 Filgrastim 10 a result, chemotherapy is no longer used alone as a 8

n. of cells mobilizing agent, but in combination with a hematopoietic 6 cytokine, usually G-CSF.16 Mobilization of HPCs in 4 2 patients with malignancies is a routine practice in high- 0 dose therapy and auto-SCT.17 The factors predicting the CD34+/Kg b.w. magnitude of HPC mobilization have been well documen- ted.18–20 The mobilizing regimen usually consists of CY of 14 3–7 g/m2 or disease-speciﬁc agents. 12 This study looked for differences in HPC mobilization 10 in response to glycosylated Hu or nonglycosylated rHu 8 G-CSF in patients with hematological tumors that are the

Days 6 most frequent candidates for auto-SCT and that require 4 combined mobilization with chemotherapy and G-CSF. 2 The appropriate schedule of mobilization in terms of type 0 of chemotherapy, doses and timing of G-CSF administra- WBC ≥ 500/mm3 WBC ≥ 1,000/mm3 tion has been discussed in several studies,3,18,21–26 whereas the role of G-CSF glycosylation is still not well defined. 20 Our primary objective was to determine whether non- 18 glycosylated G-CSF (filgrastim) or glycosylated G-CSF 16 14 (lenograstim) was more suitable for HPC mobilization. 12 Glycosylation impacts G-CSF’s pharmacokinetics. It is 10 cleared through different pathways: a non-saturable Days 8 6 mechanism in spleen and kidney, and a saturable mechan- 4 ism in neutrophils.27–29 2 Other studies have shown that G-CSF is degraded by 0 serum enzymes, particularly elastases. Carter et al.30 PLT ≥ 50,000/mm3 showed that glycosylation reduces this elastase-dependent Figure 1 Collection of CD34 þ cells (a) and differences observed in terms inactivation. It may thus prolong G-CSF’s activity and 3 of days to WBC recovery to X500 and X1000/mm (b) and plts to make it more effective. It has also been suggested that X50 000/mm3 (c) in patients treated with glycosylated Hu G-CSF and rHu non-glycosylated G-CSF. matrix metalloprotease-9 has a role in HPC mobilization as its serum levels increase on days 4 and 5 after G-CSF administration.31 Perhaps, matrix metalloprotease-9 facil- Table 2 Adverse events itates cell mobilization by degrading SDF-1, upregulating the CXCR4 expression of the CD34 þ cells and increasing Total adverse Treated with Treated with 32 events lenograstim filgrastim their migration ability. Moreover, there is experimental evidence that the Fever 5 2 3 quantity of sugars linked to proteins (glycosylation rate is Fatigue 3 2 1 4% of its MW) is important in determining neutrophil Bone pain 4 2 2 Pseudomonas infection 1 0 1 activities. Neutrophils mobilized by lenograstim (glycosy- Mucositis grade II 1 0 1 lated G-CSF) display a higher expression of the maturity Staphylococcal infection 1 1 0 markers33 involved in recognition, adhesion, phagocytosis and interaction with Igs. The underlying mechanism for these greater effects remains elusive. The functions of Adverse events neutrophils are modified by G-CSF, probably on account Toxicity associated with the two regimens was similar in of the functional immaturity of mobilized cells occasioned terms of bone pain, fatigue, fever, mucositis and infections by their accelerated release into the blood. This lower (Table 2). All infections were controlled with antibiotics function may be responsible for the reduction of neutro- and resolved after WBC recovery. Finally, no differences phils after mobilization, and hence, less efficacy in reducing within groups were observed in terms of days to WBC infections. The clinical significance of these observations 3 recovery to X500 and X1000/mm (Figure 1b) and plts to remains to be elucidated by larger clinical studies evaluat- 3 X50 000/mm (Figure 1c). No plt transfusions were needed. ing the relationship between modified functional activity of in vivo-primed neutrophils and clinical outcome. In healthy donors,24 a significant difference was observed Discussion in the number of CD34 þ cells mobilized by glycosylated and non-glycosylated G-CSF.31 In male donors mobilized Several studies have shown that the response to high-dose with lenograstim on the morning of the first apheresis, chemotherapy and auto-SCT influences survival, especially circulating CD34 þ cells were marginally higher than in

Bone Marrow Transplantation Lenograstim vs filgrastim in PBPCs mobilization R Ria et al 280 those receiving filgrastim, but this difference was not randomized study. However, center-to-center variations in confirmed in the CD34 þ collection. In contrast, Martino the auto-SCT procedures prevented us in planning a et al.34 did not find any difference in healthy donors multicenter phase III trial. Our study considered three types mobilized with glycosylated and non-glycosylated G-CSF. of hematological malignancies, but this was needed to reach No clear data have been obtained in patients who a sufficiently large population to be examined. We did not underwent auto-SCT and who received chemotherapy plus monitor serum G-CSF levels or other parameters related to G-CSF during mobilization. Lefre` re et al.35 did not find the mobilization process, which could possibly show some any difference between glycosylated and non-glycosylated clues with regard to the lack of between-group differences. G-CSF in 126 patients with hematological malignancies Parameters of this type, however, may be studied in a who underwent PBSC mobilization for auto-SCT. Also, prospective randomized manner. The results obtained here Kopf et al.36 did not find any difference in CD34 þ cell may be regarded as a preliminary one: larger randomized mobilization between patients receiving lenograstim, fil- trials are needed to confirm this conclusion and delineate the grastim or molgramostim. However, this study prevalently still unrevealed process of HPC mobilization by G-CSF after enrolled patients with solid tumors: in fact, it included only chemotherapy in patients with malignancies. 14 NHL, 5 HL and 2 MM patients, of whom 2 HL and 1 NHL failed to mobilize. Also, the mobilizing therapy by Kopf et al. was very different from ours, and the G-CSF Acknowledgements dose was lower than 5 mg/kg/day, hence much lower dose than the 10 mg/kg/day was used here. Moreover, the timing This work was supported by Associazione Italiana per la Ricerca of the CD34 þ collection and the minimum target of sul Cancro (AIRC), Milan; the Ministry of Health, Project collected CD34 þ cells differed from those used here: ‘Oncologia’ and ‘Alleanza contro il Cancro’ 2006, IRCCS aphereses were performed when circulating CD34 þ cells Humanitas Mirasole S.p.A; and the Ministry of Education, were X20/ml, whereas we performed them at day 12; University and Research (MIUR, PRIN Projects 2008), I-00100 Rome, Italy. CD34 þ cells were X2 Â 106/kg, whereas they were X3 Â 106/kg in our study. The lack of differences between lenograstim and filgrastim in the Kopf et al. study may be thus explained by the different study design and patients’ References features. Despite these differences, Kopf et al. evidenced a 1 Anderlini P, Donato M, Chan KW, Huh YO, Gee AP, Lauppe more rapid mobilization in patients receiving lenograstim MJ et al. Allogeneic blood progenitor cell collection in normal (day median number ¼ 12) than in those receiving filgrastim donors after mobilization with filgrastim: the M.D Anderson (day median number ¼ 13), which is in line with our results. Cancer experience. Transfusion 1999; 39: 555–560. The randomized study by Ataergin et al.37 on patients with 2 Bensinger WI, Weaver CH, Appelbaum FR, Rowley S, solid and hematological tumors agrees with our results, as Demirer T, Sanders J et al. Transplantation of allogeneic it indicates that a lower dose of glycosylated G-CSF is as peripheral blood stem cells mobilized by recombinant effective as the standard dose of non-glycosylated G-CSF human granulocyte colony-stimulating factor. Blood 1995; for PBPC mobilization in patients undergoing auto-SCT. 85: 1655–1658. 3 Dreger P, Haferlach T, Eckstein V, Jacobs S, Suttorp M, Our results show that CY in association with glycosy- Lo¨ffler H et al. G-CSF mobilized peripheral blood progenitor lated Hu G-CSF results in more adequate mobilization, cells for allogeneic transplantation: safety, kinetics of mobili- and the HSC collection target is reached more quickly and zation, and composition of the graft. Br J Haematol 1994; 87: requires fewer leukaphereses. The patients studied here 609–613. were affected by MM, NHL or HL, hence they were typical 4 Gisselbrecht C, Prentice HG, Bacigalupo A, Biron P, Milpied candidates for auto-SCT and for combined mobilization N, Rubie H et al. Placebo-controlled phase III trial of with chemotherapy and G-CSF. Patients’ parameters were lenograstim in bone marrow transplantation. Lancet 1994; well balanced between Arm A (glycosylated Hu G-CSF) 343: 696–700. and Arm B (non-glycosylated rHu G-CSF), and there were 5 Tarella C, Castellino C, Locatelli F, Caracciolo D, Corradini et al. no between-group differences that could affect the PBPC P, Falda M G-CSF administration following peripheral blood progenitor cell (PBPC) autograft in lymphoid malig- yield. The higher efficacy of glycosylated Hu G-CSF was nancies: evidence for clinical benefits and reduction of not influenced by the disease: no significant differences in treatment costs. Bone Marrow Transplant 1998; 21: 401–407. terms of collected CD34 þ cells and percentage of patients 6 Klumpp TR, Mangan KF, Goldberg SL, Pearlman ES, achieving the target with two aphereses were shown Macdonald JS. Granulocyte colony-stimulating factor accel- between MM, LNH or LH patients, nor between patients erates neutrophil engraftment following peripheral-blood treated with 3, 4 or 7 g/m2 of CY. 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