, Volume 49, Issue 5, pp 767-793
Date: 27 Oct 2012

Lenograstim

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Abstract

Synopsis

Lenograstim is a recombinant glycosylated human granulocyte colony-stimulating factor (rHuG-CSF) which principally regulates the formation and function of neutrophils. Like other colony-stimulating factors (CSFs), lenograstim has been developed for the prevention and treatment of iatrogenic and disease-related neutropenic conditions.

In phase III clinical studies, prophylactic administration of lenograstim shortened the duration of chemotherapy-induced neutropenia in patients with nonmyelogenous cancers who received standard-dose chemotherapy or myeloablative regimens followed by bone marrow transplantation (BMT). A decrease in the incidence of infection after standard regimens and fewer days with infectious and febrile neutropenic episodes during recovery from BMT occurred con-comitantly with the amelioration of neutropenia. In each setting, the decrease in morbidity was associated with shorter hospitalisation times and reduced administration of parenteral antibacterial agents. As with another rHuG-CSF, filgrastim, bone pain (non-serious) was the most common adverse reaction to lenograstim therapy. This occurred in 13% of lenograstim recipients and 5% of placebo recipients treated for chemotherapy-induced neutropenia with standard regimens.

Lenograstim may facilitate dose optimisation and permit limited dose intensification of standard chemotherapy. Furthermore, the drug, used alone or in combination with chemotherapy, is effective in mobilising peripheral blood progenitor cells (PBPCs) for subsequent reinfusion. The latter is a promising technique which may supplement or ultimately replace BMT for stem cell rescue after myeloablative chemotherapy. However, it has yet to be established whether the dose intensification achievable with lenograstim and/or stem cell rescue has a material effect on relapse-free and survival times.

Preliminary data suggest that lenograstim is effective in increasing the neutrophil count in patients with severe chronic neutropenia (Kostmann’s syndrome), as well as patients with AIDS or AIDS-related complex with zidovudine-induced neutropenia.

Thus, lenograstim, like other CSFs, is a valuable adjunct to cytotoxic chemotherapy for the treatment of nonmyelogenous cancers, including myeloablative regimens followed by stem cell rescue with BMT and/or PBPC infusion. Future clinical experience is likely to confirm the usefulness of the drug in the management of disease-related neutropenia, myeloid disorders and neutropenia in patients with AIDS.

Pharmacological Properties

Lenograstim (recombinant glycosylated human granulocyte colony-stimulating factor; rHuG-CSF) is a haematopoietic growth factor (HGF) which acts primarily to stimulate proliferation and differentiation of committed progenitor cells of the granulocyte-neutrophil lineage into functionally mature neutrophils. The mean absolute neutrophil count (ANC) in 30 non-neutropenic patients with cancer exceeded 20 × 109/L after administration of lenograstim ≥2 μg/kg/day for 5 days. Moreover, lenograstim therapy corrected previously defective neutrophil function in this particular patient population. The effect of the drug on other mature haematopoietic cell types appears to be without clinical significance.

Lenograstim increases the number of peripheral blood progenitor cells (PBPCs). Preliminary data suggest that mobilisation of PBPCs is particularly successful if lenograstim is given to enhance chemotherapy-induced progenitor cell rebound. However, following the demonstration of stimulation of leukaemic blast cells by other HGFs in vitro, concerns persist over its possible occurrence in vivo.

The pharmacokinetics of lenograstim have been evaluated in patients with cancer and in healthy volunteers. Peak plasma concentrations of lenograstim were reached within 4 to 8 hours after subcutaneous administration. Bioavailability of this route decreased with increasing dosages and was 30% following the recommended daily dose of 5 μg/kg. Peak plasma concentrations of lenograstim administered subcutaneously increased in a dose-proportional manner with multiple-dose administration over 5 days but decreased in a time-dependent fashion between the first and last days at a particular dose. A similar time-dependent decline has been noted after intravenous administration of the drug. The elimination half-life of lenograstim ranged from 3 to 6 hours, although the mechanism by which the drug is metabolised and excreted is unknown.

Therapeutic Efficacy

Lenograstim is a useful adjunct to chemotherapy for the treatment of non-myelogenous malignancies, including myeloablative chemotherapy followed by bone marrow transplantation (BMT). Clinical benefit has been measured in terms of a reduction in morbidity and use of hospital resources in well-designed clinical trials. The effect of the drug on mortality arising from infection has yet to be conclusively determined.

In phase III studies enrolling 120 patients with inflammatory breast cancer or 162 patients with non-Hodgkin’s lymphoma (NHL), each receiving up to 4 cycles of standard-dose chemotherapy, subcutaneous administration of lenograstim 5 μg/kg/day for up to 10 days significantly shortened the duration of neutropenia (ANC <1 × 109/L) during all 4 cycles. There were significantly fewer culture-confirmed infections and a trend towards a reduction in all infections across all chemotherapy cycles in both studies. This was associated with significant reductions in the duration of hospitalisation and in the duration of parenteral antibacterial use.

Lenograstim facilitated dose optimisation, allowing greater delivery of chemotherapy according to the planned dose and schedule, in patients with NHL. The relative dose intensity for lenograstim recipients was significantly greater than that for placebo recipients (93 vs 80%). Furthermore, preliminary evidence from several studies has indicated that the drug permits limited dose intensification of standard regimens. A study in patients with small cell lung cancer (SCLC) undergoing chemotherapy has shown a trend towards a greater long term survival of lenograstim recipients. However, it remains to be conclusively determined whether the modest increase in relative dose intensity or achievable level of dose intensification with lenograstim has a material effect on relapse-free and survival times in patients with chemosensitive tumours.

In a phase III study of 315 patients undergoing BMT, intravenous administration of lenograstim 5 μg/kg/day for up to 28 days did not decrease the overall incidence of infection compared with placebo (93% in both groups), although the median durations of episodes of culture-confirmed infection and febrile neutropenia were significantly shortened (by 3 and 2 days, respectively). Concomitant with this decrease in morbidity were significant reductions in the median number of days of hospitalisation (by 14%), parenteral antibacterial use (by 21%) and parenteral nutrition requirements (by 33%).

Short term treatment with lenograstim (5 μg/kg/day) was usually effective in increasing neutrophil counts in patients with various refractory anaemias or aplastic anaemia, provided the initial count exceeded 0.1 × 109/L. In a large-scale phase III study in 173 elderly patients with acute myeloid leukaemia, lenograstim therapy was associated with a significant increase in the proportion of patients who experienced a complete response to chemotherapy (70 vs 47% for placebo), but overall survival rates were unaltered. However, lenograstim appeared to have no effect on blast cell proliferation. In another study (n = 121), neutrophil recovery was greater in the lenograstim group and the incidence of fever, febrile neutropenia and use of antibacterial agents were reduced. Blast regrowth >5% occurred in 3 lenograstim recipients and 1 placebo recipient. Pending the availability of further clinical data, lenograstim should be used with caution in pre-malignant and malignant myeloid conditions, and should be accompanied by regular monitoring of leucocyte counts.

Data from 2 randomised studies addressing the use of lenograstim as an adjunct to chemotherapy for acute lymphoblastic leukaemia have shown that neutrophil recovery was enhanced, and there was a trend towards fewer infections and reduced use of antibacterial agents in the larger study (n = 73). However, there was no significant effect on the pattern of infection or antibacterial use in either study.

Preliminary findings suggest that lenograstim is effective in increasing neutrophil counts and decreasing symptoms in patients with severe chronic neutropenias, including congenital, cyclic and idiopathic neutropenias. The drug also increased neutrophil counts in 11 of 12 patients with AIDS or AIDS-related complex with zidovudine-induced neutropenia. The clinical status of a small number of patients with glycogen storage disease (type 1b) who had experienced severe and/or recurrent infections also improved after lenograstim therapy.

Preliminary pharmacoeconomic analyses have been performed on 3 phase III randomised trials in patients with inflammatory breast cancer, NHL and SCLC, and 1 trial involving autologous BMT recipients. At the time of the studies, the use of lenograstim reduced the overall costs of care in 3 of these studies, but increased total health care costs in patients with SCLC because lenograstim recipients were able to receive more chemotherapy than placebo recipients. However, several costs, both direct and indirect, were not included in these analyses.

Tolerability

Available data suggest that lenograstim is generally well tolerated, particularly in the setting of BMT, where no difference has been reported in the overall frequency of adverse clinical or laboratory events compared with placebo. Whether or not lenograstim has an effect on graft-versus-host disease in the setting of allogeneic BMT remains to be firmly established.

Bone pain appears to be the most frequent adverse event related to lenograstim use. In placebo-controlled trials, fewer than 1% of BMT patients reported bone pain (n = 436). However, in patients with chemotherapy-induced neutropenia, the incidence of ‘ non-serious’ bone pain was higher in lenograstim recipients compared with placebo (13 vs 5%; n = 230).

Tolerability data from well-controlled studies addressing the use of lenograstim in disease-related neutropenic conditions are currently unavailable. However, the low prevalence of some of these diseases may preclude such studies. At present there are no data available concerning the long term tolerability of lenograstim.

Dosage and Administration

In Western patients, the recommended dosage of lenograstim is 150 μg/m2/day (equivalent in efficacy to 5 μg/kg/day) administered subcutaneously to those with cancer chemotherapy-induced neutropenia or intravenously to those recovering from bone marrow transplantation. However, in Japanese patients receiving standard-dose chemotherapy, the recommended subcutaneous dosage is lower (2 μg/kg/day). Treatment should be initiated either the day after the final chemotherapy dose or after transplantation. In both instances, therapy should be continued until the post-nadir ANC stabilises within the normal range, or for a maximum of 28 days, whichever occurs first.

The recommended induction dosage to correct and maintain neutrophil counts in Japanese patients with severe chronic neutropenia is 2 μg/kg/day, administered subcutaneously. It is likely that a higher dosage (5 to 20 μg/kg/day) will be required in Western patients.

Normally, a complete blood count should be undertaken twice weekly during treatment, and lenograstim should be discontinued immediately if the post-nadir leococyte count exceeds 50 × 109/L.

As with other HGFs, caution is necessary when administering lenograstim to patients with myelodysplastic syndromes or myeloid leukaemia because of the possibility of the drug promoting progression to malignancy or tumour regrowth.

Various sections of the manuscript reviewed by: M.H. Bronchud, Hospital ‘San Pablo’, Barcelona, Spain; J. Donadieu, Service de Pédiatrie, Centre Hospitalier Régional d’Orléans, Orléans, France; C. Gisselbrecht, Hopital de Jour d’Hémato-Immuno-Oncologie, Hopital Saint-Louis, Paris, France; G.J. Lieschke, Whitehead Institute for Biomedical Research, Cambridge, England; D.C. Linch, Department of Haematology, University College Hospital, London, England; R.B. Livingston, School of Medicine and Medical Center, Division of Oncology, University of Washington, Seattle, Washington, USA; F.M. Muggia, Medical Oncology and Clinical Investigation, Kenneth Norris Jr Comprehensive Cancer Center, University of Southern California, Los Angeles, California, USA; A.-M. Stoppa, Département d’Hématologie, Institut Paoli-Calmettes, Marseilles, France; T. Teshima, The First Department of Internal Medicine, Faculty of Medicine, Kyushu University, Fukuoka, Japan.