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Comparative Efficacy of Reduced or Standard Doses of Lenograstim for Peripheral Blood Stem Cell Mobilisation and Transplantation – A Review

Published Online: June 3rd 2011 European Oncology, 2010;6(1):76-9 DOI: https://doi.org/10.17925/EOH.2010.06.1.76
Authors: Mustafa Öztürk, Fikret Arpaci
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Abstract
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Abstract:
Overview

Recombinant human granulocyte colony-stimulating factors (G-CSFs) are used for mobilisation of peripheral blood stem cells (PBSCs) and their subsequent infusion. Lenograstim is the glycosylated recombinant form of human G-CSF. Compared with filgrastim, lenograstim has a greater capacity to stimulate the colony growth in vitro of both purified CD34 and unmanipulated PBSCs. Due to the increased potency of lenograstim, several clinical studies were carried out to show the comparative efficacy of reduced or standard doses of lenograstim for PBSC mobilisation and transplantation. In vivo prospective randomised studies indicate that lenograstim is more potent than filgrastim. Shortcourse low-dose lenograstim was found to be as effective as the standard dose in reducing neutrophil engraftment time following high-dose chemotherapy and PBSC recovery. Lenograstim at a 25% lower dose does not negatively affect the number of CD34+ stem cells harvested or the engraftment results.

Keywords

Granulocyte colony-stimulating factor, aphaeresis, lenograstim, filgrastim, peripheral blood stem cell mobilisation, transplantation

Article:

Recombinant human granulocyte colony-stimulating factors (G-CSFs) are the only currently available agents that are used for mobilisation of peripheral blood stem cells (PBSCs) and their subsequent infusion. Lenograstim is the glycosylated recombinant form of human G-CSF. Compared with filgrastim, lenograstim has a greater capacity to stimulate the colony growth in vitro of both purified CD34 and unmanipulated PBSCs.1 Other in vitro studies indicate that lenograstim is more potent than filgrastim on a weight-for-weight basis.2–4 It has been shown that 1μg of filgrastim was equivalent to 100,000 units of activity, whereas 1μg of lenograstim was equivalent to 127,750 units of activity, demonstrating that lenograstim is 27% more potent than filgrastim in vitro.5,6 Lenograstim also mobilises CD34+ cells more efficiently in unit dose terms than filgrastim and has been used successfully to mobilise PBSCs from healthy donors for allogeneic transplantation.7 However, both products are recommended at the same dosage of 10μg/kg for PBSC mobilisation if used without chemotherapy.8 Due to the increased potency of lenograstim, several clinical studies were performed to show the comparative efficacy of reduced or standard doses of lenograstim for PBSC mobilisation and transplantation. In this review, data were collected to show the comparative efficacy of reduced or standard doses of lenograstim for PBSC mobilisation and transplantation.

Methodology

Computerised literature searches of MEDLINE, PreMEDLINE and PubMed were undertaken to identify reports of relevant clinical studies. The studies were required to be published in the English language between 31 December 1993 and 30 August 2009. Studies with reduced- and standard-dose lenograstim were examined involving adults >18 years of age. Details of this search, which included data published to date on the use of lenograstim for autologous and allogeneic stem cell transplantation, can be found in Tables 1 and 2.

Results and Discussion
Studies with Lenograstim on Peripheral Blood Stem Cell Mobilisation in Autologous Transplantation

Prospective randomised clinical trials were carried out to find the optimal dosage of lenograstim in autologous stem cell transplantation (ASCT) patients. Some studies compared different GCSFs; others compared reduced doses of lenograstim with standard doses in terms of mobilisation and engraftmant kinetics.

De Arriba et al. conducted an in vivo prospective randomised study in 30 patients and compared the efficacy of bioequivalent doses in terms of biological activity of lenograstim and filgrastim for mobilisation of PBSCs (0.82MU/kg/day lenograstim or 0.84MU/kg/day filgrastim for four days or until completion of leukapheresis). When they compared the effect of the administration of the same number of IU of each product, they saw that 31% more filgrastim was needed to achieve the same result (8.4 versus 6.4μg/kg/day).9
Ria et al. compared the efficiency of lenograstim and filgrastim in mobilising PBSCs in a total of 86 patients who were consecutively enrolled for mobilisation with cyclophosphamide plus either lenograstim or filgrastim, and underwent leukapheresis. Lenograstim mobilised more CD34+ cells than did filgrastim in terms of reaching a collection level of >3×106 CD34+/kg bodyweight in two leukaphereses.10 Ataergin et al. showed in a randomised study that filgrastim 10μg/kg/day and lenograstim 7.5μg/kg/day resulted in successful mobilisation of CD34+ cells in patients undergoing high-dose chemotherapy (HDC) and PBSC transplantation. Successful mobilisation with the first apheresis was achieved in 10 of 20 patients (50%) in the filgrastim group versus nine of 20 patients (46%) in the lenograstim group. No significant difference was seen in the median number of CD34+ cells mobilised, the median number of aphereses, the median volume of apheresis, the percentage of CD34+ cells or CD34+ cell number. This study showed that lenograstim at a 25% lower dose does not negatively affect the number of CD34+ stem cells harvested.11

Another prospective randomised study conducted by Öztürk et al. compared 49 patients undergoing autologous peripheral stem cell transplantation (APSCT) and mobilisation. This study compared patients with a low dose (7.5μg/kg/day) or a standard dose (10μg/kg/day) of lenograstim. Successful mobilisation with the first apheresis was achieved in 10 of 24 patients (42%) in the low-dose group versus 14 of 25 patients (56%) in the standard-dose group. No significant difference was seen in the median number of CD34+ cells mobilised, the median number of aphereses, the median volume of apheresis, the percentage of CD34+ cells or CD34+ cell number.12

A prospective, randomised clinical trial was conducted by Kopf et al. to assess the mobilising efficacy of filgrastim, lenograstim and molgramostim. Following a disease-specific chemotherapy regimen, randomisation to filgrastim, lenograstim or molgramostim at 5μg/kg/day was performed. The median number of CD34+ cells obtained after mobilisation 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=0.1). All three growth factors were efficacious in mobilising peripheral stem cells, with no statistically significant difference.13

Another prospective randomised study, by Karanth et al., compared the efficiency of PBSC mobilisation using either cyclophosphamide (2g/m²) and lenograstim at 5μg/kg (n=39) or lenograstim alone at 10μg/kg (n=40). Successful mobilisation was achieved in 28 of 40 (70%) in the G-CSF group versus 22 of 39 (56.4%) in the cyclophosphamide–G-CSF group (p=0.21). There was no significant difference in the median number of mobilised CD34+ cells. However, nausea, vomiting and total time spent in the hospital during mobilisation were significantly increased after cyclophosphamide– lenograstim (p<0.05). Lenograstim at 10μg/kg was as efficient at mobilising stem cells as the combination of cyclophosphamide and lenograstim at 5μg/kg but with reduced hospitalisation and fewer side effects.14

Despite several prospective studies showing that lenograstim is more effective on a weight-for-weight basis, a retrospective study in 126 patients by Lefrère et al. showed that there is no statistically significant difference between lenograstim and filgrastim groups in terms of number of leukaphereses necessary to obtain a minimal number of 3×106 CD34+ cells/kg.15

Studies with Lenograstim on Peripheral Blood Stem Cell Mobilisation in Allogeneic Transplantation

Ho’glund et al. showed in a dose-finding trial in healthy volunteers that lenograstim 10μg/kg/day for six days mobilises PBSCs more efficiently than 3.5 and 7.5μg/kg/day, and the average CD34+ cell number was higher with lenograstim administration than with filgrastim. Lenograstim produced 103.6 cells/μg versus 82.2 cells/μg with filgrastim, meaning that an additional 27% CD34+ cells were produced with lenograstim.16 In vitro studies indicate that lenograstim is more potent than filgrastim on a weight-for-weight basis.

Höglund et al. showed in 32 healthy male volunteers that lenograstim 10μg/kg/day mobilises PBSCs more efficiently than the identical dose of filgrastim, indicating a difference in in vivo potency between the two G-CSFs.7 In a similar cross-over study by Watts et al., filgrastim and lenograstim was administered at a dose of 5μg/kg/day subcutaneously for six days. The blood peak level of white blood cells and granulocyte monocyte colony-forming units (CFU-GM) was significantly higher with lenograstim than with filgrastim.17 A study by Ings et al. showed similar results to these.18

A prospective study with unrelated volunteers conducted by Heuft et al. showed that lenograstim at 3.1μg/kg plus dexamethasone 8mg orally (n=29) was as effective as lenograstim 11.8μg/kg without dexamethasone (n=23) in terms of stem cell mobilisation and collection.19 This study showed that the combination of lenograstim – even at 3.1μg/kg concentration – with dexamethasone can be beneficial for stem cell transplantation patients, and further studies should be carried out.

Studies with Lenograstim on Post-transplant Engraftment for Autologous Transplantation

A randomised trial conducted by Linch et al. showed that G-CSF after PBSC transplantation in lymphoma patients significantly accelerated neutrophil recovery and shortened time in hospital.20 In another study, Brice et al. showed that the duration of neutropenia and hospitalisation were both lower in patients who received lenograstim (150μg/m2/day) compared with those who received no treatment. Savings were largely attributable to decreased expenditure on hospitalisation in the lenograstim-treated group.21 Schmitz et al. showed, in a double-blind, randomised trial, that the administration of lenograstim after high-dose therapy (HDT) and ASCT significantly reduced the incidence of infections until neutrophil recovery and also led to less use of antibiotics and earlier discharge from hospital.22

A prospective randomised study was performed by Suh et al. on 33 patients undergoing ASCT. Patients were randomly administered 100 or 250μg lenograstim daily starting after stem cell reinfusion. There were no significant differences in neutrophil and platelet engraftment, episodes of clinically documented infections or red blood cell or platelet transfusion. This study showed that administration of lower doses of lenograstim was as effective as standard doses of lenograstim in terms of neutrophil engraftment after ASCT.23

A double-blind, placebo-controlled, randomised trial was performed by Nolan et al. to determine whether short-course low-dose or standard-dose lenograstim would influence recovery of haematopoiesis following HDT and PBSC recovery. Sixty-one patients were randomised to receive standard-dose lenograstim (263μg/day), low-dose lenograstim (105μg/day) or placebo injections. Short-course low-dose lenograstim was found to be as effective as standard-dose lenograstim in reducing neutrophil engraftment time following HDT and PBSC recovery.24
A prospective, randomised trial conducted by Jang et al. showed that administration of split doses of lenograstim was not associated with superior clinical efficacy compared with conventional daily singledose administration for haematopoietic recovery after ASCT.25

Ataergin et al. showed in a randomised study that filgrastim 10μg/kg/day and lenograstim 7.5μg/kg/day resulted in successful mobilisation of CD34+ cells in patients undergoing HDC and PBSC transplantation. In the post-transplant period, lenograstim was given at 5μg/kg/day for both groups until leukocyte engraftment. Leukocyte and platelet engraftments, the number of days requiring G-CSF and parenteral antibiotics and the number of transfusions were similar in both groups in the post-transplant period.11

Another prospective randomised study, conducted by Öztürk et al., compared patients undergoing APSCT and mobilisation with a low dose (7.5μg/kg/day) or a standard dose (10μg/kg/day) of lenograstim. In the post-transplant period, lenograstim was given at 5μg/kg/day for both groups until leukocyte engraftment. Leukocyte and platelet engraftments, parenteral antibiotics and the number of transfusions were similar in both groups in the post-transplant period.12

Studies with Lenograstim on Post-transplant Engraftment for Allogeneic Transplantation

Ocheni et al. compared a single, subcutaneous, fixed dose of 6mg pegfilgrastim on day +5 with daily lenograstim 263μg from day +5 and continued until neutrophil engraftment after allogeneic PBSC transplantation. Neutrophil engraftment was significantly faster (p=0.006) in the pegfilgrastim compared with the lenograstim group. No significant difference was seen in terms of platelet engraftment.26

Conclusion

In vitro studies indicate that lenograstim is more potent than filgrastim on a weight-for-weight basis. Short-course, low-dose lenograstim was found to be as effective as the standard dose in reducing neutrophil engraftment time following HDT and PBSC recovery. Lenograstim at a 25% lower dose does not negatively affect the number of CD34+ stem cells harvested or engraftment results. ■

Article Information:
Disclosure

The authors have no conflicts of interest to declare.

Correspondence

Mustafa Öztürk, Gulhane Medical Academy, Department of Medical Oncology, General Tevfik Saglam Caddesi, 06018 Etlik/Ankara, Turkey. E: drmustafaozturk@yahoo.com

Received

2009-10-03T00:00:00

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