Ersi Voskaridou

The effect of prolonged administration of hydroxyurea on morbidity and mortality in adult patients with sickle cell syndromes: results of a 17-year, single-center trial (LaSHS)

The aim of this prospective study was to evaluate the long-term efficacy and safety of hydroxyurea (HU) in patients with sickle cell disease (SCD). Thirty-four patients with sickle cell anemia (hemoglobin S [HbS]/HbS), 131 with HbS/beta(0)-thal, and 165 with HbS/beta(+)-thal participated in this trial. HU was administered to 131 patients, whereas 199 patients were conventionally treated. The median follow-up period was 8 years for HU patients and 5 years for non-HU patients. HU produced a dramatic reduction in the frequency of severe painful crises, transfusion requirements, hospital admissions, and incidence of acute chest syndrome. The probability of 10-year survival was 86% and 65% for HU and non-HU patients, respectively (P = .001), although HU patients had more severe forms of SCD. The 10-year probability of survival for HbS/HbS, HbS/beta (0)-thal, and HbS/IVSI-110 patients was 100%, 87%, and 82%, respectively, for HU patients and 10%, 54%, and 66%, for non-HU patients. The multivariate analysis showed that fetal hemoglobin values at baseline and percentage change of lactate dehydrogenase between baseline and 6 months were independently predicted for survival in the HU group. These results highlight the beneficial effect of HU, which seems to modify the natural history of SCD and raise the issue of expanding its use in all SCD patients.

New insights into the pathophysiology and management of osteoporosis in patients with beta thalassaemia

Osteoporosis represents an important cause of morbidity in adult patients with thalassaemia major (TM). The pathogenesis of osteoporosis in TM is multifactorial, and includes bone marrow expansion, endocrine dysfunction and iron overload. Additional genetic factors, such as the COLIA 1 gene polymorphism, seem to play an important role in the development of low bone mass in these patients. However, the mechanisms through which these factors lead to bone loss have not been completely clarified. The diminished osteoblast function is accompanied by a comparable or even greater increase in osteoclast activity. The receptor activator of nuclear factor‐kappa B (RANK)/RANK ligand (RANKL)/osteoprotegerin (OPG) pathway has been recently recognized as the final, dominant mediator of osteoclast proliferation and activation. There is increased evidence that this pathway interferes in the pathogenesis of thalassaemia‐induced osteoporosis. Currently, bisphosphonates that are potent inhibitors of osteoclast function have been used in TM patients with encouraging results. This review attempts to summarize all the novel data for the biology of bone damage in TM. It also describes the results of all major studies that have investigated the effects of different treatment modalities for TM‐induced osteoporosis, their mode of action, and the future implications of their use.

Magnetic resonance imaging in the evaluation of iron overload in patients with beta thalassaemia and sickle cell disease

Magnetic resonance imaging (MRI) appears to be useful for monitoring iron overload in thalassaemia. We studied 106 patients with beta‐thalassaemia: 80 with thalassaemia major (TM) and 26 with thalassaemia intermedia (TI). Thirty‐five patients with sickle cell disease (SCD) were also evaluated. Serum ferritin, liver and myocardial T2‐relaxation time and liver iron concentration (LIC) were measured. LIC values, based on biopsies from 29 patients, showed a close inverse correlation with the respective liver T2‐values, along with a strong positive correlation with ferritin levels in all patients. Heart T2‐values correlated with left ventricular ejection fraction in TM and SCD, but not in TI patients. Both liver and heart T2‐values were significantly lower in TM patients than those of TI, and SCD patients. Ferritin levels showed a strong correlation with liver T2‐values in all three groups of patients. Similarly, a negative correlation was found between serum ferritin levels and heart T2‐values in TM, but not in TI and SCD patients. Heart and liver T2‐values showed a significant correlation only in TM patients. These results suggest that the MRI technique (T2 relaxation time) used in our study, is a reliable, safe and non‐invasive method for the assessment of the deposition of iron in the liver; results for the heart become reliable only when there is heavy iron deposition.

Bone resorption is increased in young adults with thalassaemia major

Bone disease in patients with thalassaemia major is a multifactorial and still poorly understood process. The present study evaluated 45 thalassaemic patients using dual X‐ray absorptiometry at three sites (lumbar spine, head of femur and forearm) to assess bone mineral density, in parallel with a series of biochemical markers to measure bone formation and bone resorption. To identify possible interfering factors, our patients were grouped according to whether or not they needed transfusion therapy; the presence of hypogonadism was also considered. Our results showed that patients on regular transfusions had a markedly low bone mineral density in contrast to those not requiring blood support and that this finding was more pronounced in the hypogonadic group, irrespectively of sex. The decrease of bone mineral density values was more prominent in the forearm, thus making this site particularly interesting for such studies. Bone formation, as evidenced by the levels of serum alkaline phosphatase and osteocalcin, did not appear to be impaired, while bone resorption was grossly increased in all patient groups. The latter process was clearly evident using the recently introduced measurement of the urinary N‐terminal peptides of collagen type I, the sensitivity of which has already been established in other groups of osteoporotic patients. Our conclusion is that, in spite of the severe bone destruction that occurs in thalassaemia major, the fact that bone formation remains intact calls for a more intensive treatment comprising hormonal replacement, bisphosphonates and other agents.

Pamidronate is an effective treatment for osteoporosis in patients with beta‐thalassaemia

Summary.  Osteoporosis in beta‐thalassaemia is multifactorial; increased osteoclast function seems to play an important role in its pathogenesis. The aim of this study was to evaluate the effect of pamidronate on the osteoporosis of thalassaemia. To this effect we studied 26 patients who received this drug in doses of 30 or 60 mg i.v. once a month over 12 months. The effects were monitored by measuring bone mineral density (BMD) in association with markers of osteoclast function [soluble receptor activator of nuclear factor‐kappa B ligand (sRANKL), osteoprotegerin (OPG)] and of bone remodelling [N‐telopeptide of collagen type‐I (NTX), tartrate‐resistant acid phosphatase isoform‐5b (TRACP‐5b), bone‐alkaline phosphatase (bALP), and osteocalcin (OC)]. Thirty healthy individuals were also studied, as controls. NTX, TRACP‐5b, bALP and OC levels were significantly higher in thalassaemic patients compared with controls; in contrast, OPG levels were significantly lower, while the levels of sRANKL varied within normal limits. Administration of pamidronate was followed by a clear decrease of NTX, TRACP‐5b, OPG, and OC, and by a significant increase in the BMD of the lumbar spine, which was similar in patients of both treatment groups. These data suggest that pamidronate, at a monthly dose of 30 mg, is an effective treatment for thalassaemic osteoporosis.

Arterial Calcifications in β-Thalassemia

The purpose of this study was to define the incidence of arterial calcifications in patients with β-Thalassemia. β-thalassemia patients have been shown to present a high preva lence of angioid streaks and skin lesions characteristic of pseudoxanthoma elasticum (PXE). Given the fact that vascular involvement in the form of arterial calcifications is also a common manifestation of PXE, the authors investigated radiographically the presence of arterial calcifications in β-thalassemia patients. They studied 40 patients with β-thalassemia over 30 years of age. Forty healthy, age- and sex-matched subjects were chosen as a control group. Radiographs of the tibias were performed in order to disclose arterial calcifications. The occurrence of PXE skin lesions and of angioid streaks (AS) was also investigated. Arterial calcifications were detected in the posterior tibial artery in 22 (55%) β-thalassemia patients and in six (15%) controls (P<0.01 for the comparison). PXE skin lesions and AS were found in eight (20%) and 21 (52%) patients respectively. A total of 34 patients (85%) had at least one of the three lesions, namely, arterial calcifications, angioid streaks, and/or PXE-like skin lesions. Stepwise logistic regression analysis did not reveal prognostic value in independent variables such as transfusions, chelation therapy, pseudoxanthoma elasticum skin lesions and/or angioid streaks, diabetes, hemoglobin, serum ferritin, and uric acid. It was concluded that arterial calcifications are common in older β-thalassemia patients. This finding could be a manifestation of an acquired PXE syndrome associated with β-thalassemia, and consequently, vascular events complicating PXE should be expected in these patients.

Pamidronate is superior to ibandronate in decreasing bone resorption, interleukin‐6 and β2‐microglobulin in multiple myeloma

Abstract: Objectives: Bisphosphonates have been found to reduce skeletal events in patients with multiple myeloma (MM). This is the first randomised trial to compare the efficacy of pamidronate and ibandronate, a third‐generation aminobisphosphonate, in bone turnover and disease activity in MM patients. Methods: Patients with MM, stage II or III, were randomly assigned to receive either pamidronate 90 mg (group I: 23 patients) or ibandronate 4 mg (group II: 21 patients) as a monthly intravenous infusion in addition to conventional chemotherapy. Skeletal events, such as pathologic fractures, hypercalcaemia, and bone radiotherapy were analysed. Bone resorption markers [N‐terminal cross‐linking telopeptide of type‐I collagen (NTX) and tartrate‐resistant acid phosphatase type 5b (TRACP‐5b)], bone formation markers (bone alkaline phosphatase and osteocalcin), markers of disease activity (paraprotein, CRP, β2‐microglobulin), and interleukin‐6 (IL‐6) were also studied. Results: In both groups, the combination of chemotherapy with either pamidronate or ibandronate produced a reduction in bone resorption and tumour burden as measured by NTX, IL‐6, paraprotein, CRP, and β2‐microglobulin from the second month of treatment, having no effect on bone formation. TRACP‐5b also had a significant reduction in the pamidronate group from the second month of treatment and in the ibandronate group from the sixth month. However, there was a greater reduction of NTX, IL‐6, and β2‐microglobulin in group I than in group II, starting at the second month of treatment (P = 0.002, 0.001, and 0.004, respectively) and of TRACP‐5b, starting at the fourth month (P = 0.014), that being continued throughout the 10‐month follow‐up of this study. There was no difference in skeletal events during this period. A significant correlation was observed between changes of NTX and changes of TRACP‐5b, IL‐6, and β2‐microglobulin from the second month for patients of both groups. Conclusions: These results suggest that a monthly dose of 90 mg of pamidronate is more effective than 4 mg of ibandronate in reducing osteoclast activity, bone resorption, IL‐6, and possibly tumour burden in MM. TRACP‐5b has also proved to be a useful new marker for monitoring bisphosphonates treatment in MM.

Clinical and laboratory effects of long‐term administration of hydroxyurea to patients with sickle‐cell/β‐thalassaemia

Hydroxyurea (HU), a widely used cytostatic, has been given over a long period of time to 14 adult Caucasian compound heterozygotes for βs and various β‐thalassaemia genes. All patients had severe pain crises and other complications prior to receiving the drug. After 4‐8 weeks on high ‘sub‐toxic’doses of HU all patients responded with a multifold increase of fetal haemoglobin (HbF) and a marked increase of MCV and MCH; they also felt significantly better and ceased having pains or other complaints. Haematological toxicity was minimal and rapidly reversible. Follow‐up of the patients has now exceeded 100 weeks and goes up to 180 weeks in two of them. Pain crises have never recurred. Maintenance of high levels of HBF requires continuous administration of high doses of HU; whenever the latter were decrease in various attempts to avoid potential long‐term toxicity, the observed changes gradually faded. The effect of HU in HbS/β‐thalassaemia may be better than that reported for homozygous HbS disease because the synthesized λ‐chains not only inhibit the sickling process but they also neutralize the noxious effects of the excess α‐chains and cut down the ineffective erythropoiesis of the patients.

Sickle‐cell disease and the heart: review of the current literature

Sickle cell disease (SCD) is an inherited chronic haemolytic anaemia whose clinical manifestations arise from the tendency of the haemoglobin to polymerize and deform red blood cells into the characteristic sickle shape due to a single nucleotide change in the β‐globin. Vascular occlusion of small and large vessels can lead to chronic damage of multiple organs including brain, lung, bone, kidney, liver, spleen, and retina. However, the extent to which SCD impacts myocardial function is not very clear. Cardiovascular manifestations include both right and left ventricular systolic and diastolic dysfunction, elevated cardiac output, cardiomegaly and myocardial ischaemia. Progressive heart damage from iron overload occurs in patients requiring routine transfusion therapy. Pulmonary hypertension resulting from intravascular haemolysis has also been recognized as a major complication that independently correlates with survival. This review summarizes all available data for the heart complications in SCD to update the physicians for their appearance, diagnostic procedures and possible management.

Successful chelation therapy with the combination of deferasirox and deferiprone in a patient with thalassaemia major and persisting severe iron overload after single‐agent chelation therapies

Iron overload occurs commonly in patients with beta-thalassaemia major (TM) mainly as a result of the frequent blood transfusions. Without adequate iron chelation therapy, almost all patients will accumulate potentially fatal iron levels that are toxic to the heart, liver and endocrine glands. Deferoxamine has been the standard of care for transfusional iron overload for more than 40 years, although subcutaneous infusion negatively affects patient compliance (Delea et al, 2007). The oral iron chelators, deferiprone and deferasirox, are effective in reducing iron burden, while at the same time they improve compliance and patients’ quality of life (Cappellini et al, 2006; Roberts et al, 2007). Combinations of one oral chelator with deferoxamine have been used to increase the efficacy and induce negative iron balance in some patients with severe iron overload (Galanello et al, 2010). However, there are very limited data in the literature for effective combinations of two oral chelators. We report here a case of TM who had refractory severe iron overload and was successfully chelated with the combination of the two available oral agents, deferiprone and deferasirox. A 34-year-old female with beta TM (IVSI-110/IVSI-110) had been regularly transfused with two units of packed red blood cell, every 20 d, from the age of 2 years. The patient was put on chelation therapy with deferoxamine but the she failed to comply with the treatment. Given that the liver and cardiac magnetic resonance imaging (MRI) T2* were 1Æ11 and 9Æ36 ms respectively (both indicative of severe iron overload; normal values of heart T2* are >20 ms) and serum ferritin was persistently more than 2800 lg/l, the patient started on deferasirox, in 2006. MRI was performed as previously described (Voskaridou et al, 2004). The patient was started on deferasirox, at a dose of 20 mg/ kg/d, without major improvement of her iron overload status. The liver and cardiac MRI T2* were 3Æ33 ms and 10Æ59 ms respectively, after 12 months of treatment (Fig 1A). Thus, deferasirox dose was increased to 30 mg/kg/d and the patient was routinely followed up. Two years later, serum ferritin was persistently high (2080 lg/l; Fig 1B). Liver and cardiac MRI T2* values (7Æ81 and 13Æ76 ms respectively) were still compatible with moderate liver and severe heart siderosis, although there was improvement from the baseline values of 3 years earlier (Fig 1A). Due to the continuously elevated serum ferritin, the persistence of moderate liver and cardiac overload and the presence of a severe episode of atrial fibrillation 3Æ2 years post-deferasirox initiation, it was suggested that the patient started combined chelation therapy with both deferasirox and deferiprone. After giving written consent, the patient received therapy with a combination of the two