When should iron chelation therapy be considered in patients with myelodysplasia and other bone marrow failure syndromes with iron overload?

Despite the absence of a robust evidence base, there is growing consensus that effective treatment of iron overload leads to decreased morbidity and premature mortality in patients with good prognosis myelodysplastic syndromes (MDSs). Furthermore, new treatment modalities, including disease-modifying therapies (lenalidamide and azacytidine) and reduced intensity conditioning therapies for allogeneic blood stem cell transplants, are offering the prospect of longer survival for patients with traditionally less favourable prognosis MDS, who might also benefit from iron chelation. This article proposes assessment of patients with MDS and related bone marrow failure syndromes to determine suitability for iron chelation. Iron chelation therapy options and monitoring are discussed.     

Deferasirox in MDS patients with transfusion-caused iron overload—a phase-II study

Blood transfusions represent a main component of supportive care in myelodysplastic syndromes (MDS). To avoid organ damage caused by transfusion-dependent iron overload, an adequate iron chelation therapy is required. Recently, a new oral iron chelator deferasirox (ICL670, Exjade) has become available. A study was conducted to demonstrate the efficacy and tolerability of deferasirox in transfusion-dependent iron-overloaded patients with MDS. The efficacy of deferasirox was monitored by changes in serum ferritin, bone marrow iron, and liver iron concentration (LIC), as determined by T2*-weighted magnetic resonance imaging. Twelve patients with MDS of different subtypes (median age 76 years, range 53-91) were enrolled. Deferasirox administered in a once-daily dose of 20-30 mg/kg for 12 months was effective in reducing median ferritin concentration from 1,515 microg/L (range 665-6,900) to 413 microg/L (range 105-3,052). Within the first 4 weeks of treatment before the continuous decline of ferritin levels, the values markedly rose in eight of 12 patients. The median LIC declined from 315 to 230 micromol/g (p=0.02) at the end of study, accompanied by a reduction of bone marrow siderosis. The most common adverse events were mild and transient gastrointestinal disturbances, skin rash, nonprogressive transient increases in serum creatinine and urine beta2-microglobulin, and a temporary reduction of the creatinine clearance. The renal parameters normalized after end of treatment. No hematologic toxicities were observed. Deferasirox proved to be effective in transfusion-dependent iron overload in MDS by mobilizing iron deposits in liver and at least stabilizing iron stores in bone marrow.     

Efficacy and safety of deferasirox,an oral iron chelator,in heavily iron-overloaded patients with β-thalassaemia: the ESCALATOR study

Objective: Many patients with transfusional iron overload are at risk for progressive organ dysfunction and early death and poor compliance with older chelation therapies is believed to be a major contributing factor. Phase II/III studies have shown that oral deferasirox 20–30 mg/kg/d reduces iron burden, depending on transfusional iron intake. Methods: The prospective, open-label, 1-yr ESCALATOR study in the Middle East was designed to evaluate once-daily deferasirox in patients ≥2 yr with β-thalassaemia major and iron overload who were previously chelated with deferoxamine and/or deferiprone. Most patients began treatment with deferasirox 20 mg/kg/d; doses were adjusted in response to markers of over- or under-chelation. The primary endpoint was treatment success, defined as a reduction in liver iron concentration (LIC) of ≥3 mg Fe/g dry weight (dw) if baseline LIC was ≥10 mg Fe/g dw, or final LIC of 1–7 mg Fe/g dw for patients with baseline LIC of 2 to <10 mg Fe/g dw. Results: Overall, 233/237 enrolled patients completed 1 yr’s treatment. Mean baseline LIC was 18.0 ± 9.1 mg Fe/g dw, while median serum ferritin was 3356 ng/mL. After 1 yr’s deferasirox treatment, the intent-to-treat population experienced a significant treatment success rate of 57.0% (P = 0.016) and a mean reduction in LIC of 3.4 mg Fe/g dw. Changes in serum ferritin appeared to parallel dose increases at around 24 wk. Most patients (78.1%) underwent dose increases above 20 mg/kg/d, primarily to 30 mg/kg/d. Drug-related adverse events were mostly mild to moderate and resolved without discontinuing treatment. Conclusions: The results of the ESCALATOR study in primarily heavily iron-overloaded patients confirm previous observations in patients with β-thalassaemia, highlighting the importance of timely deferasirox dose adjustments based on serum ferritin levels and transfusional iron intake to ensure patients achieve their therapeutic goal of maintenance or reduction in iron burden.     

Deferasirox effectively decreases iron burden in patients with double heterozygous HbS/β-thalassemia

Iron overload is present in several cases of double heterozygous sickle-cell/beta-thalassemia (HbS/β-thal). Deferasirox is an orally administered iron chelator which is effective on iron overloaded patients with transfusion-dependent anemia. The aim of this study was to investigate the efficacy and safety of deferasirox on HbS/β-thal patients with iron overload. We evaluated 31 adult patients with HbS/β-thal (14M/17F; median age 41 years) who had serum ferritin levels >1,000 ng/mL and who were sporadically transfused. Total iron burden was monitored by measuring serum ferritin levels before and monthly after starting deferasirox, while liver iron concentration and cardiac iron burden were measured by magnetic resonance imaging (MRI) T2 and T2* parameters at baseline and 12 months after deferasirox treatment. Deferasirox managed to reduce the mean serum ferritin levels after 12 months of treatment from 1,989 ± 923 to 1,008 ± 776 ng/mL (P < 0.001). This reduction was accompanied by a significant improvement on MRI T2* of the liver (from 3.9 ± 3.2 to 5.8 ± 3.1 ms; P < 0.01) and by a comparable improvement of biochemical parameters of liver function. Mild nausea and diarrhea of grade 1/2 were reported in 25% of patients within the first month of treatment, but did not re-occur. These data indicate that deferasirox provided effective control of iron levels (mainly of the liver) in minimally transfused patients with HbS/β-thal, without significant adverse events, at similar doses to those studied widely for the treatment of patients with thalassemia syndromes.     

Hepatic iron contents and response to interferon-α in patients with chronic hepatitis C

Recent reports have shown that response to interferon treatment is influenced by hepatic iron contents in patients with chronic hepatitis C. In those reports, however, hepatitis C virus (HCV) genotypes and serum HCV-RNA levels were not examined. The aim of the present study was to investigate whether hepatic iron contents influence the response to interferon in patients with chronic hepatitis C and whether HCV genotypes and serum HCV-RNA levels play a role in this relationship. Among 65 patients with chronic hepatitis C, hepatic iron contents were significantly high in patients with a history of excess drinking of alcohol (more than 80 g/day) compared to those without, and significantly low in female patients before menopause. Having excluded these patients, hepatic iron contents were significantly higher in patients with genotype 1b infection than those with genotype 2a and 2b infection. There was no significant correlation between hepatic iron contents and plasma HCV-RNA levels. Among the patients with genotype 1b infection, hepatic iron contents were significantly lower in the responders to interferon than those in the nonresponders (429 ± 100 vs 875 ± 110 µg/g liver,P<0.05). From these results, it is concluded that response to interferon is mainly influenced by HCV genotypes, while hepatic iron contents may play an important role in response to interferon in patients with genotype 1b infection.     

A new iron free treatment with oral fish cartilage polysaccharide for iron deficiency chronic anemia in inflammatory bowel diseases： A pilot study

AIM:To investigate the effect of a new oral preparation,highly concentrated in fish cartilage,in a group of inflammatory bowel diseases(IBD)patients with chronic iron deficient anemia.METHODS:In an open label pilot study,we supple-mented a group of 25 patients(11 with Crohn's disease and 14 with ulcerative colitis)in stable clinical conditions and chronic anemia with a food supplement which does not contain iron but contains a standardized fraction of fish cartilage glycosaminoglycans and a mixture of antioxidants(Captafer Medestea,Turin,Italy).Patients received 500 mg,twice a day during meals,for at least 4 mo.Patients were suggested to maintain their alimentary habit.At time 0 and after 2 and 4 mo,emocrome,sideremia and ferritin were examined.Paired data were analyzed with Student's t test.RESULTS:Three patients relapsed during the study(2 in the 3rd mo,1 in the 4th mo),two patients were lost to follow up and two patients dropped out(1 for orticaria,1 for gastric burning).Of the remaining 18 patients,levels of serum iron started to rapidly increase within the 2nd mo of treatment,P < 0.05),whereas serum ferritin and hemoglobin needed a longer period to significantly improve their serum levels(mo 4)P < 0.05.The product was safe,easy to administer and well tolerated by patients.CONCLUSION:These data suggest a potential new treatment for IBD patients with iron deficiency chronic anemia and warrant further larger controlled studies.     

Iron status in Danes updated 1994. I: Prevalence of iron deficiency and iron overload in 1332 men aged 40–70 years. Influence of blood donation, alcohol intake, and iron supplementation

 Iron status, S-ferritin, and hemoglobin (Hb) were assessed in a population survey in 1994 (DAN-MONICA 10) comprising 1332 Caucasian Danish men equally distributed in age cohorts of 40, 50, 60 and 70 years. Blood donors (n=186) had lower S-ferritin, median 76 μg/l, than nondonors, median 169 μg/l (p<0.0001). S-ferritin in donors was inversely correlated with the number of phlebotomies (r _s=–0.57, p<0.0001). S-ferritin in nondonors (n=1146) was similar in men 40–60 years of age, median 176 μg/l, and subsequently decreased at 70 years of age to a median of 146 μg/l (p=0.01). In the entire series, the prevalence of small iron stores (S-ferritin 16–32 μg/l) was 2.7%, that of depleted iron stores (S-ferritin <16 μg/l) 0.45%, and that of iron deficiency anemia (S-ferritin <13 μg/l and Hb <129 g/l) 0.15%. Among nondonors, the prevalence of iron overload (S-ferritin >300 μg/l) was 20%. S-ferritin in nondonors correlated with body mass index (r _s=0.19, p=0.0001) and with alcohol intake (r _s=0.26, p=0.0001). In the entire series, 28% of the subjects took supplemental iron (median 14 mg ferrous iron daily). Iron supplements had no influence on iron status. Nondonors (n=170) treated with acetylsalicylic acid had lower S-ferritin, median 136 μg/l, than nontreated, median 169 μg/l (p<0.001) and those treated with H₂-receptor antagonists (n=30) had lower S-ferritin, median 142 μg/l, than nontreated, median 171 μg/l (p<0.04). Compared with the DAN-MONICA 1 iron status survey of Danish men in 1984, the prevalences of iron depletion and iron deficiency anemia are unchanged whereas the prevalence of iron overload has increased significantly. In Denmark, iron fortification of flour was abolished in 1987. This apparently had no negative effect on iron status in men. Received: November 19, 1998 / Accepted: April 25, 1999     

Elevated liver iron concentration is a marker of increased morbidity in patients with β thalassemia intermedia

Background

Patients with β thalassemia intermedia can have substantial iron overload, irrespectively of their transfusion status, secondary to increased intestinal iron absorption. This study evaluates whether iron overload in patients with β thalassemia intermedia is associated with morbidity.

Design and Methods

This was a cross-sectional study of 168 patients with β thalassemia intermedia treated at two centers in Lebanon and Italy. Data on demographics, splenectomy status, transfusion status, and presence of co-morbidities were retrieved. Laboratory values of serum ferritin, fetal and total hemoglobin levels, as well as platelet and nucleated red blood cell counts were also obtained. Iron burden was determined directly by measuring liver iron concentration using magnetic resonance imaging. Patients were subdivided according to transfusion and splenectomy status into groups with phenotypes of different severity.

Results

The mean age of the patients was 35.2±12.6 years and 42.9% of them were male. The mean liver iron concentration was 8.4±6.7 mg Fe/g dry weight. On multivariate logistic regression analysis, after adjusting for age, gender, splenectomy status, transfusion status, and laboratory indices, an increase in 1 mg Fe/g dry weight liver iron concentration was independently and significantly associated with higher odds of thrombosis, pulmonary hypertension, hypothyroidism, osteoporosis, and hypogonadism. A liver iron concentration of at least 7 and at least 6 mg Fe/g dry weight were the best thresholds for discriminating the presence and absence of vascular and endocrine/bone morbidities, respectively (area under the receiver-operating characteristic curve: 0.72, P<0.001). Elevated liver iron concentration was associated with an increased rate of morbidity in patients with phenotypes of all severity, with a steeper increase in the rate of vascular morbidity being attributed to aging, and an earlier appearance of endocrine and bone disease.

Conclusions

Elevated liver iron concentration in patients with β thalassemia intermedia is a marker of increased vascular, endocrine, and bone disease.     

Frequency,pattern, and associations of renal iron accumulation in sickle/β-thalassemia patients

Annals of Hematology - We evaluated frequency, pattern, and associations of renal iron accumulation in sickle/β-thalassemia. Thirty-three sickle/β-thalassemia patients...     

Are we giving too much iron? Low-dose iron therapy is effective in octogenarians

PURPOSE: Elderly patients are vulnerable to the dose-dependent adverse effects of iron replacement therapy. Our study examines whether low-dose iron therapy can efficiently resolve iron-deficiency anemia in patients over the age of 80 years and reduce adverse effects. SUBJECTS AND METHODS: Ninety hospitalized patients with iron-deficiency anemia were randomized to receive elemental iron in daily doses of 15 mg or 50 mg as liquid ferrous gluconate or 150 mg of ferrous calcium citrate tablets for 60 days. Thirty control patients without anemia were given 15 mg of iron for 60 days. A 2-hour iron absorption test was performed after the initial dose. Hemoglobin and ferritin levels were measured on day 1, 30, and 60 after initiating therapy. Each patient completed a weekly questionnaire regarding drug-induced adverse effects. RESULTS: Serum iron rose significantly in the anemic patients beginning 15 minutes after the first dose but not in nonanemic patients. Two months of iron treatment significantly increased hemoglobin and ferritin concentrations similarly in all 3 groups of iron-deficiency anemia patients (for example, hemoglobin levels rose from 10.0 g/dL to 11.3 g/dL with 15 mg/d of iron therapy and from 10.2 g/dL to 11.6 g/dL with 150 mg/d). Abdominal discomfort, nausea, vomiting, changes in bowel movements, and black stools were significantly more common at higher iron doses. CONCLUSIONS: Low-dose iron treatment is effective in elderly patients with iron-deficiency anemia. It can replace the commonly used higher doses and can significantly reduce adverse effects.