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Iron chelation therapy (ICT) is the mainstay of treatment in patients with thalassemia requiring blood transfusions. This phase 2 JUPITER study evaluated patient preference between film-coated tablet (FCT) and dispersible tablet (DT) in transfusion-dependent thalassemia (TDT) or non-TDT (NTDT) patients treated with both formulations in a sequential manner. The primary endpoint was patient-reported preference for FCT over DT, while secondary outcomes included patient reported outcomes (PROs) evaluated by overall preference, and by age, thalassemia transfusion status, and previous ICT status. Out of 183 patients screened, 140 and 136 patients completed the treatment periods 1 and 2 of the core study, respectively. At week 48, the majority of patients preferred FCT over DT (90.3 vs. 7.5%; difference of percentage: 0.83 [95% confidence interval (CI), 0.75-0.89; P < 0.0001]). FCT scored better on secondary PROs and showed less severe gastrointestinal symptoms than DT, except in the change of modified Satisfaction with Iron Chelation Therapy (mSICT) preference scores, which were similar for both the formulations. Patients with TDT had stable ferritin levels, while it showed a downward trend up to week 48 in patients with NTDT on deferasirox treatment. Overall, 89.9% of patients reported ≥ 1 adverse event (AE), of which 20.3% experienced ≥ 1 serious AE. The most common treatment-emergent AEs were proteinuria, pyrexia, urine protein/creatinine ratio increase, diarrhea, upper respiratory tract infections, transaminase increase, and pharyngitis. Overall, this study reinforced the observations from the previous study by showing a distinct patient preference for FCT over DT formulation and further supported the potential benefits of life-long compliance with ICT., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

We prospectively assessed by magnetic resonance imaging (MRI) the advantages of desferrioxamine (DFO) with respect to the absence of chelation therapy in non transfusion-dependent thalassaemia (NTDT) patients. We considered 18 patients non-chelated and 33 patients who received DFO alone between the two MRI scans. Iron overload was assessed by the T2* technique. Biventricular function parameters were quantified by cine sequences. No patient treated with DFO had cardiac iron. At baseline, only one non-chelated patient showed a pathological heart T2* value (< 20 ms) and he recovered at the follow-up. The percentage of patients who maintained a normal heart T2* value was 100% in both groups. A significant increase in the right ventricular ejection fraction was detected in DFO patients (3.48 ± 7.22%; P = 0.024). The changes in cardiac T2* values and in the biventricular function were comparable between the two groups. In patients with hepatic iron at baseline (MRI liver iron concentration (LIC) ≥ 3 mg/g/dw), the reduction in MRI LIC values was significant only in the DFO group (- 2.20 ± 4.84 mg/g/dw; P = 0.050). The decrease in MRI LIC was comparable between the groups. In conclusion, in NTDT patients, DFO therapy showed no advantage in terms of cardiac iron but its administration allowed an improvement in right ventricular function. Moreover, DFO reduced hepatic iron in patients with significant iron burden at baseline.

Patients with non-transfusion-dependent thalassemia (NTDT) often develop iron overload that requires chelation to levels below the threshold associated with complications. This can take several years in patients with high iron burden, highlighting the value of long-term chelation data. Here, we report the 1-year extension of the THALASSA trial assessing deferasirox in NTDT; patients continued with deferasirox or crossed from placebo to deferasirox. Of 133 patients entering extension, 130 completed. Liver iron concentration (LIC) continued to decrease with deferasirox over 2 years; mean change was -7.14 mg Fe/g dry weight (dw) (mean dose 9.8 ± 3.6 mg/kg/day). In patients originally randomized to placebo, whose LIC had increased by the end of the core study, LIC decreased in the extension with deferasirox with a mean change of -6.66 mg Fe/g dw (baseline to month 24; mean dose in extension 13.7 ± 4.6 mg/kg/day). Of 166 patients enrolled, 64 (38.6 %) and 24 (14.5 %) patients achieved LIC <5 and <3 mg Fe/g dw by the end of the study, respectively. Mean LIC reduction was greatest in patients with the highest pretreatment LIC. Deferasirox progressively decreases iron overload over 2 years in NTDT patients with both low and high LIC. Safety profile of deferasirox over 2 years was consistent with that in the core study.

Patients with thalassemia major requiring regular blood transfusions accumulate iron that is toxic to the heart, liver, and endocrine systems. The following prospective, randomized trial was carried out to determine the effectiveness, in children and young adults, of combined deferiprone (DFP) and deferoxamine (DFO) in reducing transfusional iron overload compared to either drug alone and to assess the safety and tolerability of DFP. Sixty-six patients were randomized into three treatment arms: daily DFP combined with DFO twice weekly; daily DFP only; and DFO only 5 days/week. Fifty-six patients completed the 54 weeks and were assessed by different indices. A significant reduction of liver iron concentration and serum ferritin was observed in all three arms while significant reduction of liver iron score was observed in patients on combination therapy only. Cardiac function did not significantly change in any arm. Compliance improved in patients who received combined therapy. Toxicity of DFP was mild to moderate and acceptable; most commonly, transient arthropathy and nausea/vomiting were observed. Thus, combination therapy has shown to be effective in reducing iron overload in thalassemia patients.

Osteoporosis is an important cause of morbidity in beta-thalassemia patients. Bisphosphonates have been recently used for the treatment of osteoporosis in beta-thalassemia. This study is a prospective quasi-experimental study to assess the efficacy and safety of zoledronic acid in thalassemics with osteoporosis. Eighteen thalassemia patients with osteoporosis were given zoledronic acid 4 mg intravenously every 3 months over a period of 12 months. The efficacy of treatment was assessed by measuring (BMD) at the lumbar spine, femoral neck, and hip at baseline, 6, and 12 months. Z-score was used to measure the BMD. Other medical assessments included markers of bone formation and resorption (bone alkaline phosphatase (BAP), osteocalcin (OC), and urinary deoxypyridinoline), and the assessment of pain score, analgesic score, and performance score. Ten thalassemic osteoporotic patients were followed up only with serial BMDs as controls. Both groups had no significant difference with respect to age, gender, and baseline BMD. Patients taking zoledronic acid had a significant increase in their lumbar spine, femoral neck, trochanter, and total hip BMD measurements over the 12-month period. Patients in the control group did not have any significant change in BMD measurements. There was a significant change in the levels of OC and BAP over the 12-month follow-up period. There was also a significant decrease in the number of painful sites experienced by the patients. Treatment of thalassemic osteoporotic patients with zoledronic acid is very effective in increasing BMD at the lumbar spine and hip and in reducing pain; it is also well-tolerated.

We evaluated sera from 58 thalassemic patients for the presence of antierythropoietin antibodies to investigate whether these autoantibodies may relate with modest response to treatment with recombinant human erythropoietin (rhEpo). Thirty-seven patients had beta-thalassemia major, 9 patients had beta-thalassemia intermedia, and 12 patients had sickle/beta(+)-thalassemia. Of 58 patients, 24 were on rhEpo treatment in order to increase the intervals between transfusions or the hemoglobin (Hb) values. The study population was divided into three groups according to rhEpo treatment. Group A consisted of 15 patients who were on rhEpo treatment (400-600 IU/kg three times per week, subcutaneously) showing an increase of Hb values or reduction of transfusion requirements. Group B included 9 patients who did not respond to rhEpo and group C consisted of 34 patients who did not receive rhEpo. Laboratory studies included a complete blood count, measurement of serum erythropoietin, immunological evaluation, and determination of antierythropoietin antibodies using enzyme-linked immunosorbent assay (ELISA). There were no significant differences among groups A, B, and C concerning age, Hb, and endogenous erythropoietin values. Fifteen patients had positive antinuclear antibodies and three patients had positive rheumatoid factor. Antierythropoietin antibodies were detected in the sera of seven patients (five men and two women) who received rhEpo. The male patients and one female patient had no response to rhEpo while the other female patient showed response when the dose increased. Other autoantibodies seem to have no clinical significance. In the present study, we detected for the first time in thalassemia patients the presence of antierythropoietin antibodies, which may contribute to rhEpo resistance. Thalassemia patients with low response rates to rhEpo should be evaluated for the presence of antierythropoietin antibodies.

Some patients affected by thalassemia major and treated with an iron-chelating drug such as deferioxamine can suffer from severe osteochondrodystrophic lesions of the long bones. These lesions were radiologically and clinically evident in 2.8% of the patients we examined over the last 10 years. The aim of our research was to evaluate the morphology and morphometry of five tibial biopsy specimens taken from thalassemic patients with bone lesions and two bone biopsy specimens taken from thalassemic patients with no alteration of the long bones. All the bone samples showed a similar morphostructure. Abnormal chondrocytes, alteration of cartilage staining pattern, irregular columnar cartilage, and lacunae in the cartilaginous tissue were revealed histologically. Osteoid thickness was either normal or slightly increased. Some bone trabeculae had microfractures and some had cartilagineous oases. In five cases, iron deposition was detectable by Perls' Prussian Blue staining. It can be concluded that even in patients without radiographic signs of lesions, seriously damaged columnar cartilage, altered bone mineralization, and microfractures are common.

Osteochondrodystrophic lesions, mainly affecting long bone metaphyses, can be radiologically evident in homozygotic thalassemic patients treated with deferoxamine, and their incidence rate varies among authors. The clinical and radiological appearance of these lesions is described in the literature, but microstructural data are still lacking. The aim of our research was to evaluate the microstructure of five tibial biopsy specimens from thalassemic patients with bone lesions (5 cases out of 180 patients followed for the last 10 years, i.e., 2.8%) and two bone biopsy specimens from thalassemic patients with no radiological alteration of the long bones. As control, bone tissue taken from autoptic tibiae of two subjects with no skeletal pathology was used. Using microradiography and X-ray diffraction (XRD), we found a reduced and irregular mineralization of the bone (compared with controls) in thalassemic subjects. Bone tissue microhardness was also significantly reduced. Nevertheless, bone apatite lattice was unaltered and no 'foreign' crystallographic phase was recorded by XRD. In conclusion, all the patients shared a similar picture of abnormal bone, even with no radiological evidence of lesion.

Since intensive chelating therapy for thalassaemic children was introduced, growth rates appear to have diminished. To investigate what factors were responsible we compared velocities of growth in length over a period of 1 year between groups distinguished by different strategies of treatment. Forty-two thalassaemic patients, 30 males aged 4-12 years, and 12 females, 4-10 years old, were assigned from their current treatment into subgroups based upon blood ferritin levels, daily dose of desferrioxamine and urinary zinc levels. CONCLUSION The results confirm that a reduction in desferrioxamine results in greater growth. If blood ferritin is low, the change effect may be greater. Secondly, any zinc deficiency should be treated. The changes in treatment convert a growth velocity of -2 to -3 SDS to a velocity of about -1 SDS.

This study on serum ferritin levels in urinary iron excretion after 12h subcutaneous infusion of desferrioxamine in 10 thalassemia intermedia patients shows that even nontransfusion-dependent patients may have positive iron balance resulting in iron overload from 5 years of age. However, the iron overload found in these patients appears to be much lower than in age matched patients with transfusion-dependent thalassemia major. Iron overload increases with advancing age, as shown by increasing serum ferritin levels and desferrioxamine-induced urinary iron elimination. After a six month trial of 12h continuous subcutaneous desferrioxamine administration there was a significant decline in serum ferritin levels. From this study it seems that iron chelation is indicated in thalassemia intermedia patients over 5 years of age in order to prevent iron accumulation. However, the appropriate treatment schedule should be tailored to the individual needs of each patients, established by close monitoring of serum ferritin levels and desferrioxamine-induced urinary iron elimination.

Heterozygous beta thalassaemia with microcytic anaemia (hemoglobin concentration 77 g/l) has been recognized in a 49 year-old woman of Alsatian extraction. A long history of microcytic anaemia had led to inadequate oral iron treatment before the patient was referred to us because of the persisting microcytic anaemia and iron loading. Indeed the patient also had haemosiderosis with a high transferrin saturation (73%) and markedly elevated ferritinaemia (1,114 micrograms/ml). Ferrokinetic data showed increased plasma iron turnover, early transfer of iron to the liver and evidence of ineffective erythropoiesis. She was treated with desferrioxamine (3 g every three days subcutaneously) and serum ferritin levels gradually decreased together with transferrin saturation. After 15 months serum ferritin and transferrin saturation were within the normal range. Several hypotheses are discussed to explain why this patient had haemosiderosis associated with heterozygous beta thalassaemia. The propositus was found to be HLA-A3, which is strongly associated with idiopathic haemochromatosis. Her sister also carries HLA-A3 with heterozygous beta thalassaemia but she has neither anaemia nor iron overload. Thus double heterozygotism is unlikely in our patient.