A randomised phase II study of the efficacy, safety and cost-effectiveness of pegfilgrastim and filgrastim after autologous stem cell transplant for lymphoma and myeloma (PALM study)

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Abstract

Aim

To evaluate in a multicentre randomised study the effect on duration of febrile neutropenia (FN), the safety and cost-effectiveness of a single subcutaneous pegfilgrastim injection compared with daily injections of filgrastim after peripheral blood stem cell transplantation in patients receiving high dose chemotherapy for myeloma and lymphoma.

Methods

Patients were randomly assigned to a single dose of pegfilgrastim at day 5 (D5) or daily filgrastim from D5 to the recovery of absolute neutrophil count (ANC) to 0.5 G/L. Duration of FN, of neutrophil and platelet recovery, transfusion and antibiotic requirements were the main end-points of the study. Costs were calculated from D0 until transplant unit discharge. The incremental cost-effectiveness ratio was expressed as the cost per day of FN prevented. Probabilistic sensitivity analysis was performed by non-parametric bootstrap methods.

Results

Between October 2008 and September 2009, 10 centres enrolled 151 patients: 80 patients with lymphoma and 71 patients with myeloma. The mean duration of FN was 3.07 days (standard deviation (SD) 1.96) in the pegfilgrastin arm and 3.29 (SD 2.54) in the filgrastim one. Mean total costs were 23,256 and 25,448 euros for pegfilgrastim and filgrastim patients, respectively. There was a 62% probability that pegfilgrastim strictly dominates filgrastim.

Concluding statement

Pegfilgrastim after PBSC transplantation in myeloma and lymphoma is safe, effective when compared with filgrastim and could represent a cost-effective alternative in this setting.

Introduction

High-dose chemotherapy followed by autologous peripheral blood stem cell transplantation (HDC-SCT) is an established treatment that improves outcome in certain patients with lymphoma and multiple myeloma.1, 2, 3, 4 Post-transplant Granulocyte Colony-Stimulating Factor (G-CSF) such as filgrastim accelerates neutrophil engraftment and reduces duration of hospitalisation and medical costs. It has been approved in Europe in accordance with the American Society of Clinical Oncology (ASCO) and the European Organisation for Research and Treatment of Cancer (EORTC) guidelines5, 6 for the reduction in the duration of neutropenia in patients undergoing myeloablative therapy followed by bone marrow transplantation considered to be at increased risk of prolonged severe neutropenia.

Pegylation of filgrastim decreases plasma clearance and increases its half-life without loss of clinical activity.7, 8 A single dose of pegfilgrastim seems as effective as many daily doses of filgrastim in cancer patients treated by conventional dose chemotherapy.9, 10, 11, 12

The efficacy and tolerance of pegfilgrastim after HDC-SCT have been evaluated in non-comparative studies.13, 14, 15, 16, 17 All of them reported the feasibility of using pegfilgrastim in this setting. Haematological reconstitution is similar when retrospectively compared with filgrastim. A decrease of the duration of febrile neutropenia (FN) was observed in one small randomised study in myeloma.18 When the present study was designed, there was no convincing prospective studies comparing pegfilgrastim and filgrastim in HDC followed by Peripheral Blood Stem Cell (PBSC) and the economic issues were not properly addressed. We therefore undertook a phase II, randomised controlled trial in order to evaluate the efficacy and the cost effectiveness of pegfilgrastim in preventing FN.

Section snippets

Patients

Eligible patients had to be at least 18 years old, with a diagnosis of myeloma or lymphoma requiring HDC-SCT. Conditioning was achieved without total body irradiation. Patients undergoing a second HDC-SCT were eligible if their first such treatment was more than 100 days preceding enrolment. All patients had to have an absolute neutrophil count (ANC) ⩾ 1.5 × 109/L, a platelet count ⩾100 × 109/L and at least 2 × 106 cryopreserved CD34 cells/kg before conditioning. Patients were hospitalised in the

Patient characteristics

From October 2008 to September 2009, 151 patients were enrolled by ten French centres (80 patients with lymphoma and 71 patients with myeloma). All patients except one were evaluable for the primary outcome. Patient characteristics at baseline are summarised in Table 1. Disease characteristics, treatment history, conditioning protocols and number of stem calls reinfused were similar in the two groups. Median age was greater in the pegfilgrastim arm (59 years versus 55, Wilcoxon test, p = 0.021).

Efficacy

In

Discussion

The use of GCSF after PBSC transplantation is recommended by most of the guidelines because it hastens neutrophil recovery, shortens hospital stay by 1 or 2 days and decreases the rate of documented infections.5, 6 With a longer half life, a single dose of pegfilgrastim is as effective as repeated doses of filgrastim in reducing the duration of neutropenia in cancer patients including those experiencing intensive chemotherapy prior to PBSC transplantation. In recent studies of autologous stem

Funding

This work was supported by Amgen (Europe) GmbH, Zug, Switzerland.

Conflict of interest statement

None declared.

Acknowledgements

Drs. Biron, Lachenal, Bouafia, Nicolini, Ducastelle (Lyon), Drs. Blin, Le Gouill (Nantes), Drs. Ifrah, Hunault (Angers), Dr. Cacheux (Clermont-Ferrand), Dr. Cartron (Montpellier), Drs. Jardin, Leprètre (Rouen), Drs. Renaud, Colombat (Tours) and their teams for patient inclusion; A. Belleville, O. Perol and M. Hureau for data-management; Amgen for financial support.

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