A randomised, blinded, placebo-controlled, dose escalation study of the tolerability and efficacy of filgrastim for haemopoietic stem cell mobilisation in patients with severe active rheumatoid arthritis

Abstract

Summary:Autologous haemopoietic stem cell transplantation (HSCT) represents a potential therapy for severe rheumatoid arthritis (RA). As a prelude to clinical trails, the safety and efficacy of haemopoietic stem cell (HSC) mobilisation required investigation as colony-stimulating factors (CSFs) have been reported to flare RA. A double-blind, randomised placebo-controlled dose escalation study was performed. Two cohorts of eight patients fulfilling strict eligibility criteria for severe active RA (age median 40 years, range 24-60 years; median disease duration 10.5 years, range 2-18 years) received filgrastim (r-Hu-methionyl granulocyte(G)-CSF) at 5 and 10 g/kg/day, randomised in a 5:3 ratio with placebo. Patients were unblinded on the fifth day of treatment and those randomised to filgrastim underwent cell harvesting (leukapheresis) daily until 2 ؋ 10 6 /kg CD34 ؉ cells (haemopoietic stem and progenitor cells) were obtained. Patients were assessed by clinical and laboratory parameters before, during and after filgrastim administration. RA flare was defined as an increase of 30% or more in two of the following parameters: tender joint count, swollen joint count or pain score. Efficacy was assessed by quantitation of CD34 ؉ cells and CFU-GM. One patient in the 5 g/kg/day group and two patients in the 10 g/kg/day group fulfilled criteria for RA flare, although this did not preclude successful stem cell collection. Median changes in swollen and tender joint counts were not supportive of filgrastim consistently causing exacerbation of disease, but administration of filgrastim at 10 g/kg/day was associated with rises in median C-reactive protein and median rheumatoid factor compared with placebo. Other adverse events were well recognised for filgrastim and included bone pain (80%) and increases in alkaline phosphatase (four-fold) and lactate dehydrogenase (two-fold). With respect to efficacy, filgrastim at 10 g/kg/day was more efficient with all patients (n = 5) achieving target CD34 ؉ cell counts with a single leuCorrespondence: Dr JA Snowden, Department of Haematology, Royal Hallamshire Hospital, Sheffield S10 2JF, UK Received 2 May 1998; accepted 21 July 1998 kapheresis (median = 2.8, range = 2.3-4.8 ؋ 10 6 /kg, median CFU-GM = 22.1, range = 4.2-102.9 ؋ 10 4 /kg), whereas 1-3 leukaphereses were necessary to achieve the target yield using 5 g/kg/day. We conclude that filgrastim may be administered to patients with severe active RA for effective stem cell mobilisation. Flare of RA occurs in a minority of patients and is more likely with 10 than 5 g/kg/day. However, on balance, 10 g/kg/day remains the dose of choice in view of more efficient CD34 ؉ cell mobilisation.

Complications of autologous hematopoietic stem cell transplantation for patients with autoimmune diseases

“…Usually, mobilization is preceded and facilitated by chemotherapy (e.g., Cy). G-CSF administration has been associated with induction of flares of the underlying autoimmune disease) (27,28).…”

Collection of hematopoietic stem cells from patients with autoimmune diseases

“…32 An Australian study has reported flares of RA in patients receiving G-CSF for progenitor cell mobilization. 33 In contrast, one report in patients with RA and another in patients with SSc conclude that G-CSF may be given without a flare. 34,35 The patients with RA were pre-treated with corticosteroids which may have prevented disease exacerbation.…”

Transplante de células-tronco hematopoéticas em doenças reumáticas parte 1: experiência internacional

“…2) No segundo estudo, foram comparadas as doses de 5 e 10µg/kg/d de G-CSF, isoladamente, para mobilização de CTH. A dose maior de G-CSF foi associada com maior freqüência de reativação da AR, mas foi escolhida para futuros estudos em decorrência de sua maior eficiência (47) . 3) Um outro estudo comparou doses de 100 e 200mg/kg de CY, também isoladamente, para o condicionamento de pacientes submetidos a TCTH não manipulado.…”