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Lenograstim

An Update of its Pharmacological Properties and Use in Chemotherapy-Induced Neutropenia and Related Clinical Settings

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Summary

Abstract

Lenograstim is the glycosylated recombinant form of human granulocyte colony stimulating factor. The drug is used to reduce the risk of life-threatening infection in patients with neutropenia, particularly after cytotoxic chemotherapy.

Lenograstim accelerates neutrophil recovery significantly after chemotherapy, with beneficial effects on clinical end-points such as incidence of laboratory-confirmed infection and length of hospital stay. Chemotherapy dose intensity has also been increased in patients receiving lenograstim, notably those with breast or small cell lung cancer, although improvements in tumour response and survival have not been demonstrated.

Lenograstim also assists neutrophil recovery in patients undergoing bone marrow transplantation, and stimulates the production of peripheral blood stem cells (PBSCs) for autologous transfusion after aggressive chemotherapy. 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.

Randomised trials have shown increases in rates of disease remission after lenograstim therapy in patients with acute myeloid leukaemia, with no evidence of stimulation of malignant blasts. The drug has also shown potential in the mobilisation of nonmalignant PBSCs for autotransplantation in patients with chronic myeloid leukaemia. Other studies show efficacy of lenograstim in patients with acute lymphoblastic leukaemia, aplastic anaemia, in children with severe chronic neutropenia and in the reversal of neutropenia related to antiviral therapy in patients with AIDS, although data are not extensive.

Cost analyses of lenograstim have been carried out from a hospital perspective, although results have been inconclusive. Cost-effectiveness or cost-benefit data are lacking at present.

Lenograstim is well tolerated, with bone pain and injection site reactions being reported most frequently in clinical trials.

Conclusions: Lenograstim has been confirmed as a valuable adjunct to minimise the haematological toxicity of myelosuppressive chemotherapy in patients with malignant disease. The drug also enhances neutrophil recovery in patients undergoing stem cell rescue, and assists PBSC mobilisation. Data indicate clinical benefit with lenograstim in myeloid disorders, with no evidence of malignant blast cell proliferation. Further studies are required to assess more fully the pharmacoeconomic implications of the use of lenograstim and other recombinant growth factors, to provide more data on the efficacy of the drug in the management of disease-related neutropenia, and to clarify fully its position relative to filgrastim.

Pharmacological Properties

Lenograstim is the glycosylated recombinant form of human granulocyte colony stimulating factor (rHuG-CSF). The drug supports the differentiation of neutrophil-committed colony-forming cells and increases absolute neutrophil counts (ANC) in a dose-dependent manner.

Postulated functional effects of lenograstim on neutrophils include increased phagocytic activity, activation, recruitment and adhesion. These effects appear to be mediated by changes in a variety of neutrophil surface proteins. Current data suggest that rHuG-CSFs do not stimulate the proliferation of leukaemic blasts in vivo, although the safety of these agents in patients with myeloid conditions remains to be fully confirmed.

Lenograstim exhibits dose-dependent pharmacokinetic characteristics, with peak serum levels being proportional to the injected dose. There is no evidence of accumulation after repeated administration. Absolute bioavailability after subcutaneous doses of 2 to 5 μg/kg is approximately 30%, and the apparent volume of distribution is approximately 1 L/kg. Serum elimination half-lives after subcutaneous or intravenous injection are approximately 3 or 1 to 1.5 hours, respectively. Routes of metabolism and excretion have not been fully ascertained, but a very small proportion only of each dose is excreted unchanged in urine.

Therapeutic Use

Standard Dose Chemotherapy. A phase II randomised placebo-controlled study in 64 patients showed significant reductions (p < 0.05) in the median duration of neutropenia after chemotherapy with 14-day courses of subcutaneous lenograstim 0.5, 2, 5 or 10 μg/kg/day, and the authors recommended the 5 μg/kg/day dosage for future use.

Results from 2 randomised placebo-controlled phase III trials showed significant reductions in median duration of neutropenia (<1.0 × 109/L) after 8- to 10-day courses of lenograstim 5 μg/kg/day subcutaneously between chemotherapy cycles in patients with inflammatory breast cancer or non-Hodgkin’s lymphoma (NHL). Effects persisted throughout all 4 treatment cycles in both studies, and there were significant reductions in incidence of laboratory-confirmed infection, duration of hospital stay for treatment of infection and use of antibiotics. Increases in dose intensity made possible by treatment with lenograstim did not translate into improvements in tumour response or 3-year survival, however.

Similar efficacy in terms of rate of hospitalisation for febrile leucopenia has been shown for subcutaneous lenograstim 263 μg/day compared with oral ciprofloxacin 500 mg/day plus amphotericin B 2 g/day in a nonblind randomised comparison in 40 patients with breast cancer. The incidence of leucopenia (<1.0 × 109/L) after chemotherapy was significantly lower, but that of febrile leucopenia significantly higher, with lenograstim.

Chemotherapy Dose Intensification. The use of subcutaneous lenograstim 5 μg/kg/day on day 2 to day 14 of treatment cycles based on fluorouracil, epirubicin and cyclophosphamide in patients with breast cancer resulted in a reduction in cycle time from 3 to 2 weeks. Encouraging tumour response rates have been reported in anthracycline-resistant or heavily pretreated patients receiving lenograstim with docetaxel or paclitaxel. Preliminary reports from phase III studies in patients with breast cancer also show increases in relative dose intensity in patients receiving lenograstim, although subsequent effects on tumour response and survival are not clear.

Reductions in cycle length have also been achieved with the addition of lenograstim in patients with small cell lung cancer (SCLC) undergoing cisplatinor anthracycline-based chemotherapy. Phase III data from 280 patients with SCLC have shown the addition of lenograstim 150 μg/m2/day subcutaneously to each of 6 cycles of doxorubicin, cyclophosphamide and etoposide to be associated with a significantly decreased requirement for chemotherapy dose reduction (≥1 reduction in 17.3 vs 27.7% of patients receiving chemotherapy alone; p = 0.037), although there was no significant increase in median survival time in patients who received lenograstim. Intensification of chemotherapy regimens has also been achieved with lenograstim in patients with soft tissue sarcoma, NHL or ovarian cancer, although clinical benefit in terms of improved tumour response and survival requires further investigation.

High Dose Chemotherapy with Stem Cell Rescue. After significantly accelerated neutrophil recovery was observed in patients undergoing bone marrow transplantation (BMT) who received lenograstim in a phase II trial, a phase III randomised, double-blind and placebo-controlled study has shown 30 and 41% reductions, respectively, in median times to achieve ANC ≥0.5 and 1.0 × 109/L (both p < 0.001 vs placebo) with lenograstim 5 μg/kg/day intravenously after BMT. In this study of 298 evaluable patients with lymphoma, myeloma, acute lymphoblastic leukaemia or other malignancies, there were also significant reductions relative to placebo in median durations of hospitalisation, antibiotic use, total parenteral nutrition (TPN; intravenous hyperalimentation), infection and febrile neutropenia, although there were no significant effects of lenograstim on the actuarial risk of disease relapse or the 1-year survival rate.

As well as assisting neutrophil recovery after BMT, lenograstim has been used to stimulate the production of peripheral blood stem cells for autologous transfusion after aggressive chemotherapy. Two studies in 141 previously treated patients with lymphoma showed median times to achieve ANC ≥0.5 × 109/L of 11 to 12 days after chemotherapy followed by lenograstim-assisted autologous PBSC transplantation (PBSCs collected after mobilisation with lenograstim 263 μg/day subcutaneously after cyclophosphamide 1.5 g/m2 on day 1). Approximately half the patients enrolled received filgrastim 10 μg/kg/day in 1 study; although results were presented collectively, stem cell mobilisation effects were stated to be similar between agents.

Similar median neutrophil recovery times (13 to 15 days to ANC >0.5 × 109/L) were shown with PBSC transplantation after subcutaneous lenograstim 5, 7.5 or 10 μg/kg/day with cyclophosphamide for mobilisation in 29 children with solid tumours treated with high dose melphalan in a double-blind dose-finding study.

Data from a randomised nonblind comparison in 61 patients receiving stem cell support from matched sibling donors indicate similar efficacy of lenograstim and filgrastim (median dosages 4 and 10.3 μg/kg/day, respectively) when either drug was given after stem cell transplantation.

The feasibility of using lenograstim to mobilise PBSCs from healthy donors for allogeneic transplantation has been demonstrated in Japanese and European trials, and reflects a trend towards allogeneic PBSC transplantation since the early 1990s. In dose-response terms, lenograstim mobilises CD34+ cells (the number of which affects the probability of successful engraftment) more efficiently than filgrastim in healthy volunteers. In a pilot study, 54 patients with leukaemia or myelodysplasia received PBSCs obtained from sibling donors who had received a priming regimen of lenograstim 10 μg/kg/day subcutaneously for 5 days. After initial myeloablation with high intensity chemo- and/or radiotherapy, 51 patients achieved an ANC of 0.5 × 109/L within 15 days. The rate of survival was 50% after a median 25-month follow-up.

Myeloid Leukaemias. Although the use of rHuG-CSF in patients with myeloid conditions is controversial because of fears of stimulation of leukaemic blast cells, clinical studies of lenograstim have been carried out in this setting.

Randomised placebo-controlled trials carried out in Japan have shown accelerated neutrophil recovery and evidence of infection-related clinical benefit with lenograstim 5 μg/kg/day intravenously for 14 days after consolidation chemotherapy in patients with acute myeloid leukaemia (AML). In addition, European placebo-controlled trials have shown significant improvements in neutrophil recovery times, together with increased rates of complete remission of disease, with lenograstim after induction chemotherapy in patients with AML. Increases over placebo in complete haematological remission in 2 of these studies were 49 and 38% with lenograstim, although the reason for this effect has not been determined: high rates of complete remission of AML have also been reported after treatment with idarubicin-based protocols with and without addition of lenograstim. Integrated European data show reductions against placebo in incidence and duration of infection in lenograstim recipients aged 55 years and over.

Data are also available to indicate a potential role for lenograstim in the mobilisation of PBSCs for autotransplantation as an alternative to autologous BMT in patients with AML.

Studies conducted recently show that lenograstim might be used for the mobilisation of Philadelphia chromosome (Ph)-negative (i.e. nonmalignant) PBSCs for autotransplantation in patients with chronic myeloid leukaemia (CML) who are not eligible for conventional allogeneic BMT. Administration of lenograstim 150 μg/m2/day subcutaneously or intravenously as part of a cytarabine-based mobilisation protocol resulted in complete cytogenetic remission in the leucapheretic product in 21% of 29 patients in 1 study; the same dosage of lenograstim was associated with a Ph-positive cell content of less than 35% in 91% of 47 evaluable leucaphereses from 20 patients in a second trial.

Increases from baseline in leucocyte counts have been achieved after 7 to 14 days’ lenograstim therapy (5 μg/kg/day or 263 μg/day) in 2 small studies in patients with myelodysplasia, with no evidence of progression to AML.

Acute Lymphoblastic Leukaemia. Augmentation of neutrophil recovery, but no effect on patterns of infection or antibiotic use, was shown with intravenous or subcutaneous lenograstim in 2 randomised studies in patients with acute lymphoblastic leukaemia (ALL) or acute undifferentiated leukaemia (AUL).

Increased chemotherapy dose intensities with decreased duration of fever, hospitalisation and intravenous antibiotic treatment were achieved in children with ALL receiving lenograstim 5 μg/kg/day, but there was no improvement in 3-year disease-free survival.

Aplastic Anaemia. Addition of lenograstim 5 μg/kg/day subcutaneously to immunosuppressive therapy with antilymphocyte globulin, methylprednisolone and cyclosporin in 40 patients with severe aplastic anaemia (SAA) resulted in trilineage-complete responses and transfusion independence in 82% of participants, with actuarial survival of 92% after median follow-up of 428 days. Phase III data have shown addition of subcutaneous lenograstim 5 μg/kg/day in 53 of 102 patients undergoing immunosuppressive therapy with cyclosporin and antithymocyte globulin to increase the proportion of patients with complete ANC response (≥1.5 × 109/L) significantly after 112 days (83 vs 44.9% without lenograstim; p = 0.001). There was no apparent effect of lenograstim on long term haematopoietic recovery or survival after a median follow-up of 23 months.

Other Neutropenic Conditions. Rates of infection and hospitalisation were reduced significantly relative to figures obtained before lenograstim treatment in a phase II study in 19 children with severe chronic neutropenia who received subcutaneous therapy with lenograstim. An induction dosage of 5 μg/kg/day was sufficient to obtain a neutrophil response in 15 patients. Clinical improvement has also been noted in children with glycogen storage disease Ib who received subcutaneous lenograstim at a median initial dosage of 5 μg/kg/day.

Encouraging results have been obtained with lenograstim therapy in a small number of patients with Felty’s syndrome, and subcutaneous treatment has been used successfully to manage immunosuppressant-induced leucopenia after renal transplantation. In addition, preliminary data from a randomised single-blind phase II study have indicated lenograstim 50 μg/m2/day subcutaneously to be suitable for the management of ganciclovir-induced neutropenia in patients with AIDS.

Pharmacoeconomic Considerations

Pharmacoeconomic studies of lenograstim have to date focused on cost issues from a hospital perspective. Attempts have not been made to assign values to health outcomes such as improvements in quality of life or years of life gained.

Pharmacoeconomic evaluations of lenograstim in 3 phase III studies showed lenograstim therapy to be associated with reductions in hospitalisation and total direct costs in patients with breast cancer or NHL, and reduced cost of antibiotic therapy in patients with breast cancer, NHL or SCLC. Intensification of chemotherapy in patients who received lenograstim to assist neutrophil recovery resulted in an increase in chemotherapy drug costs. Increasing interest in allogeneic PBSC transplantation in preference to BMT has led to a case control study (n = 17) in which the direct medical costs associated with transplantation of lenograstim-mobilised PBSCs were shown to be substantially (29%; p = 0.006) lower than those in a historical control group of 17 patients undergoing allogeneic BMT.

Results are available from a well designed and robust cost analysis in which children with NHL were randomised to receive 2 courses of intensive induction chemotherapy with (n = 75) or without (n = 72) lenograstim 5 μg/kg/day subcutaneously for 6 to 15 days. The total cost from a hospital perspective of lenograstim-assisted induction therapy was $US29 765 per patient; without lenograstim, the cost was $US30 774 (1996 values). Overall, the acquisition cost of lenograstim was balanced by 2 additional days in hospital in patients who did not receive the drug.

A saving of approximately $US1800 (1997 values) per course of chemotherapy from a hospital perspective was indicated when lenograstim 150 μg/m2/day rather than filgrastim 10 μg/kg/day was used after autologous BMT in a series of 36 patients (55 chemotherapy courses) with solid tumours undergoing intensive chemotherapy. This saving was attributed to a difference in acquisition cost between the 2 growth factors.

Tolerability

Data from clinical studies indicate overall adverse reaction rates with lenograstim therapy to be similar with those seen with placebo. Bone pain and injection site reactions were the most commonly reported events in patients receiving lenograstim for chemotherapy-induced neutropenia, and were more frequent than with placebo. A database of pooled adverse reaction reports from 1495 patients shows incidences of adverse events attributed to lenograstim as follows: fever 1.2%; lumbar pain 1.1%; increased blast cell counts in patients with AML 0.9%; hepatic disturbances 0.5%; bone pain 0.4%; eruptions/rashes 0.4%.

No association has been found between clonal cytogenetic abnormalities and dysplasia of bone marrow in patients receiving lenograstim, but all rHuG-CSFs have been linked to isolated episodes of interstitial pneumonia and respiratory distress syndrome. There are no tolerability data relevant to the use of lenograstim in pregnant or nursing women, the elderly, infants or patients with hepatic or renal dysfunction.

Dosage and Administration

There are variations between Western countries and Japan in the recommended dosages and licensed indications for lenograstim. International dosage and administration guidelines for Western patients recommend a dosage of 150 μg/m2/day (equivalent to 5 μg/kg/day as used in clinical trials) to reduce the duration of chemotherapy-induced neutropenia and to assist PBSC mobilisation. Subcutaneous administration is recommended, except after BMT where a 30-minute intravenous infusion should be used to assist recovery from neutropenia.

Lenograstim should not be given at the same time as cytotoxic chemotherapy, and the drug is not recommended in patients with severe hepatic or renal insufficiency, or in nursing mothers. There are no dosage recommendations for the elderly, infants or pregnant women.

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  1. Adis International Limited, 41 Centorian Drive, Private Bag 65901, Mairangi Bay, Auckland 10, New Zealand

    Christopher J. Dunn & Karen L. Goa

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Correspondence to Christopher J. Dunn.

Additional information

Various sections of the manuscript reviewed by: F. Bertolini, European Institute of Oncology, Milan, Italy; D. Bissett, Department of Clinical Oncology, Aberdeen Royal Infirmary, Aberdeen, Scotland; L.A. Boxer, Department of Pediatric Hematology/Oncology, University of Michigan Hospital, Ann Arbor, Michigan, USA; A.M. Carella, Universitaire Convenzionate, Ospedale San Martino, Genoa, Italy; C. Chevreau, Institut Claudius Regaud, Toulouse, France; J. Donadieu, Service d’Hémato-Oncologie, Hôpital Trousseau, Paris, France; V.V. Garcia, Unidad de Hematología y Oncología Clínica, Hospital General Universitario, Murcia, Spain; M. Höglund, Department of Internal Medicine, University Hospital, Uppsala, Sweden; F. Huguet, Clinique Dieulafoy, Hôpital Purpan, Toulouse, France; N. Niitsu, First Department of Internal Medicine, Toho University School of Medicine, Tokyo, Japan; M. Watts, Haematology Department, University College London, London, England.

Data Selection

Sources: Medical literature published in any language since 1995 on Lenograstim, identified using AdisBase (a proprietary database of Adis International, Auckland, New Zealand) and Medline. Additional references were identified from the reference lists of published articles. Bibliographical information, including contributory unpublished data, was also requested from the company developing the drug.

Search strategy: AdisBase search terms were ‘Lenograstim’. Medline search terms were ‘Lenograstim’. Searches were last updated 28.2.2000.

Selection: Studies in patients with neutropenia who received lenograstim. Inclusion of studies was based mainly on the methods section of the trials. When available, large, well controlled trials with appropriate statistical methodology were preferred. Relevant pharmacodynamic and pharmacokinetic data are also included.

Index terms: Lenograstim, recombinant human granulocyte colony stimulating factor, rHuG-CSF, cancer, chemotherapy, bone marrow transplantation, peripheral blood stem cell transplantation, leukaemia, aplastic anaemia, congenital neutropenia, AIDS, pharmacodynamics, pharmacokinetics, therapeutic use, pharmacoeconomics, tolerability, dosage and administration.

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Dunn, C.J., Goa, K.L. Lenograstim. Drugs 59, 681–717 (2000). https://doi.org/10.2165/00003495-200059030-00017

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