Severe congenital neutropenia and pegfilgrastim

Severe congenital neutropenia (SCN) is characterised by an absolute neutrophil count persistently below 0.50 × 109/L with maturation arrest of neutrophil precursors in the bone marrow (BM) at the promyelocyte/myelocyte stage (1, 2). HAX-1 mutation leads to the recessive (3, 4) and ELA-2 mutation to the dominant form of SCN (5). The empiric use of the polypeptide granulocyte colony stimulating factor (G-CSF) has changed the clinical outcome of this condition in the vast majority of patients (6). G-CSF has been used since the beginning of 1990’s targeting to neutrophil count >1 but <5 × 109/L (1). There has been concern that G-CSF treatment may accelerate the risk of leukaemia (7). Pegfilgrastim, the pegylated covalent conjugate of GCSF, is a longer acting form of filgrastim. The safety and efficacy profile of pegfilgrastim are shown to be comparable with filgrastim. We present here our experience on pegfilgrastim for SCN. Our patient was born in 1985. He presented with skin infection at the age of 3 wk, and was referred to further examinations because of recurrent perianal infections at the age of 4 months. His absolute neutrophil count (ANC) was 0.05 × 109/L. BM analysis showed maturation arrest in neutrophils. His immunological parameters were widely tested with normal results. Monthly infections continued until G-CSF treatment was initiated in 1991. The timing of injections was once in every 1–3 d. His growth, bone mineral density, and BM findings have been in normal range. However, during winter time there has been need for repeated treatments with oral antibiotics. In August 2004, the patient wanted to discuss about the possibility of changing filgrastim to the pegylated form. He had found description of the product in the Internet. Neither the manufacturer nor the colleagues abroad had any reports on using pegfilgrastim in SCN. The experimental use of pegfilgrastim (6 mg) was started in November 2004. The development of WBC and ANC is presented in Fig. 1. The plan was to inject pegfilgrastim with 14 d interval. Patient himself, however, decided to test the duration of the drug effect. He ended up to having high fever and an abscess in his tongue (January 2005). This episode was treated with parenteral antibiotics combined with daily filgrastim doses. Thereafter, he continued with pegfilgrastim at 14 d intervals. BM examination was performed in July 2005. G-CSF receptor was found unmutated but an ELA2-mutation was detected. The first episode with pegfilgrastim. Arrow upwards = 6 mg pegfilgrastim injection (16.11., 21.12. and 15.1.). Horizontal arrows = symptoms of infection. Filgrastim (0.3 mg) was injected on 10., 12. and 14.12. During the second symptomatic episode, filgrastim was given on 15.–18.1. and on 20.1. In August 2005 (Fig. 2), another episode of high neutropenic fever emerged after having kept too long interval between pegfilgrastim injections. Since Spring 2006, he has preferred a 7 d interval between pegfilgrastim injections as with shorter intervals the bone pains seemed to diminish. In April 2008, he told that no antibiotics had been needed during the last 26 months (fluorokinilones were used as prophylaxis when travelling in Far-East). During the last 2 yr the patient has been seen only once a year by an adult haematologist. The second episode of febrile infection. Symptomatic episode (horizontal arrow) was treated with filgrastim (7., 8., 9., 12., 15., 18., 21. and 24.8.). Pegfilgrastim was taken when the infection was cleared (22.8.2005), and next on the 4th of September. Arrow upwards = pegfilgrastim injection (6 mg). The experience of 40 months on pegfilgrastim seems promising as after the user’s learning phase this product has functioned well. Our patient did not need daily injections of filgrastim. However, he is of the opinion that his quality of life is better when using pegfilgrastim. He feels that pegfilgrastim is too slow if severe symptoms of infection emerge during the interval of injections and, thus, he has injected additional two or three daily doses of filgrastim in such rare situations. By this treatment policy, the need for antimicrobial treatment has decreased and no inpatient periods have been encountered. Proper cost-benefit calculations have not been done. It seems, however, that with current prices of 6 mg pegfilgrastim every 7–10 d the product costs will be slightly higher than with daily dosing of 0.3 mg filgrastim. There are no data available on the long-term effects of pegfilgrastim, but one would assume that no major differences exist between the two product forms especially as the clearance of pegylated molecule is dominated by a self-regulating mechanism (8). Our patient had the typical maturation arrest in his BM, and a mutation in elastase gene. Both of these findings are reported to be associated with risk of myelodysplasia/acute myeloid leukaemia (MDS/AML). Thus, regular BM examinations are recommended (9). Despite this single patient experience only, we conclude that pegfilgrastim seems to function at least as well as filgrastim in the prevention of infections for our SCN patient. It certainly improves the quality of life of the patient by reducing the number of regular injections.