Portal de Periódicos da CAPES

Darbepoetin alfa for the treatment of anaemia in alpha‐ or beta‐ thalassaemia intermedia syndromes

2011; Wiley; Volume: 154; Issue: 2 Linguagem: Inglês

10.1111/j.1365-2141.2011.08617.x

1365-2141

Sylvia T. Singer, Elliott Vichinsky, Nancy Sweeters, Eliezer A. Rachmilewitz,

Blood groups and transfusion

Thalassaemia intermedia (TI) patients have moderate to severe anaemia and frequently develop progressive complications. Consequently, substantial studies for improving the anaemia were carried out, mostly directed at augmenting fetal haemoglobin (HbF) synthesis. Another approach has utilized the recombinant growth factor, recombinant human erythropoietin (rHuEPO) to stimulate proliferation of erythroid cells. (Rachmilewitz et al, 1995; Bourantas et al, 1997). This resulted in an increase in haemoglobin (Hb), but the relatively high cost and difficulty in administration discouraged the execution of subsequent studies. The new erythropoetic stimulating agent, darbepoetin alfa (DAR), has a longer half-life and could result in further sustained increase of Hb, but has been rarely used for thalassaemia patients. The present study was carried out to assess the response to dose escalation of DAR in patients with TI phenotype and the capacity of responding patients to sustain the increase in Hb during treatment. The study was approved by the institutional review board at Children's Hospital and Research Center at Oakland (#2002–11). TI patients aged ≥14 years, with a Hb ≤ 95 g/l who had not required a blood transfusion for ≥3 months, were enrolled (Table I). DAR (Aranesp; Amgen Inc., Thousands Oaks, CA, USA) was administered at 4·5 μg/kg/week for 8 weeks (equivalent to 20 000 u of rHuEPO three times weekly). For patients whose Hb did not increase by 15 g/l over baseline on two consecutive measurements 1 week apart, the dose was increased to 6·75 μg/kg/week for an additional 8 weeks. If Hb had not increased by the same criteria over baseline, the dose was further increased to 9·0 μg/kg/week for an additional 8 weeks. If, at the end of each 8-week phase, there was an increase in Hb of ≥15 g/l, DAR treatment was continued at the same dose for additional 16 weeks. A complete blood count was performed every 2 weeks and after each dose adjustment. Levels of ferritin, serum iron, transferrin iron binding capacity (TIBC), transferrin receptor (sTfR), folate, vitamin B12, HbF and erythropoietin were measured at enrolment, at changes in DAR dose and while on a steady dose. Statistical analysis was performed using sas software (Cary, NC, USA ). Bivariate Pearson correlations were computed between the various parameters. P values <0·05 were considered significant. Ten patients with a mean baseline Hb level of 73 ± 1 (59–95) g/l received DAR at 4·5 μg/kg/week (9·5 ± 4·3 weeks) (Table I) and all showed increased Hb levels; mean 82 ± 13; 63–106 g/l (P < 0·0001) (Fig 1), although administration at 2-week intervals (10 ± 3·4 weeks) resulted in a 7 ± 6 g/l decline. A weekly dose of 6·75 μg/kg (12·4 ± 5·6 weeks), raised the Hb by 11 g/l from baseline to a mean of 84 ± 10 g/l, and by 13 ± 4 g/l in 6/10, but the same dose administered at 2-week intervals (n = 5; 9·6 ± 3·6 weeks) resulted in inconsistent response. Only 25% (1/4) of patients had an increase in Hb at a dose of 9 μg/kg/week. Haemoglobin returned to the pre-treatment range 2–4 weeks after DAR treatment was discontinued (Fig 1). Individual patients' mean Hb on the various treatment doses administered once a week. *Indicates dose administered in 2-week intervals. Each patient is represented by a different symbol; few overlapping symbols were moved by 1·0–2·0 g/l to allow better examination of the data points. Pre-treatment Hb concentration predicted the increase in Hb using DAR doses of 4·5 and 6·75 μg/kg. (r = 0·9 P < 0·0001 and r = 0·9 P < 0·0005, respectively). Baseline EPO levels (median 126, range 49–1674 iu/l) had a negative correlation with Hb level when 4·5 μg/kg DAR was administered (r = −0·5; P < 0·1), approaching statistical significance at the 6·75 μg/kg dose (r = −0·7, P < 0·02). There was also a correlation between baseline EPO and HbF concentrations (r = 0·8; P < 0·04), but HbF as well as sTfR did not change significantly during DAR treatment (25·3 ± 22% and 26 ± 22% and 136 ± 52 and 130 ± 54 mmol/l, respectively). Absence of spleen did not have a significant effect on the Hb response to DAR. Serum iron and ferritin levels decreased during treatment, from a baseline of 28 ± 14 to 23·6 ± 13 μmol/l and 947 ± 1380 to 744 ± 1100 μg/l, respectively. While treatment at the 4·5 and 6·75 μg/kg doses was well tolerated, DAR at 9 μg/kg caused bone pain in 2/4 patients. One patient, who also received rHuEPO prior to DAR, developed a sacral mass resulting from extra-medullary haematopoiesis. Discontinuation of DAR treatment and 6 months of regular transfusions and hydroxycarbamide resulted in decrease of the mass size and concomitant pain relief. Our preliminary results demonstrate the potential role of DAR for the treatment of moderate anaemia in TI patients, particularly in those with a low EPO level. Weekly DAR administration resulted in a sustained increase in Hb of ≥10 g/l in 80% and ≥15 g/l in 40% of the patients. Increasing the interval of DAR administration was not successful, suggesting a need for continuous stimulation to overcome the ineffective erythropoiesis and haemolysis. EPO levels vary in thalassaemia and were found to be low for the degree of anaemia and to decrease with age (Galanello et al, 1994; Sukpanichnant et al, 1997; O'Donnell et al, 2007), resulting in reduced erythropoietic stimulation and increased apoptosis (Perrine, 2005); providing the rationale for this treatment. The role of DAR in treating symptomatic α thalassaemia patients needs further study; our patient with Hb H-CS had a modest response to DAR, suggesting that DAR stimulation of erythropoiesis may be insufficient to compensate for the higher rate of haemolysis. A positive effect of DAR has been reported, with >20 g/l increase in Hb, in a milder form of α thalassaemia, Hb H disease (Fortenko et al, 2009), as well as successful use in a pregnant woman with Hb H disease (Maccio et al, 2009). Serum iron and ferritin concentrations decreased in our patients; possibly a result of increased mobilization of stored iron as effective erythropoiesis improved. Such reduction in iron stores was described following EPO-stimulated proliferation of erythroid precursors (Cermak, 2006); Therefore, in clinical practice, monitoring of iron stores and possible iron supplementation with continuous DAR treatment should be considered. In summary, our results demonstrate a possible role of DAR for the management of anaemia in β TI; potentially decreasing morbidity and the use of transfusions. Due to the risk of marrow expansion, careful monitoring is indicated. Spine imaging prior to long term therapy and combined use of DAR and hydroxycarbamide, a drug known to reduce the excessive marrow expansion (Meo et al, 2008) could be considered. The research was partially supported by a grant from Amgen Inc. Thousand Oak, California and by grant number UL1RR024131-01 from the National Centre for Research Resources. We thank Tiffany Chin, Drucilla Foote and Bridget Canty for their assistance in coordination of patients' studies and data collection.