The era of comparable life expectancy between thalassaemia major and intermedia: Is it time to revisit the major-intermedia dichotomy?

In the last few decades, the life expectancy of regularly transfused ß-thalassaemia major (TM) patients has dramatically improved following the introduction of safe transfusion practices, iron chelation therapy, aggressive treatment of infections and improved management of cardiac complications. How such changes, especially those attributed to the introduction of iron chelation therapy, improved the survival of TM patients to approach those with ß-thalassaemia intermedia (TI) remains unknown. Three hundred and seventy-nine patients with TM (n = 284, dead 40) and TI (n = 95, dead 13) were followed retrospectively since birth until 30 June 2015 or death. Kaplan-Meir curves showed statistically significant differences in TM and TI survival (P < 0·0001) before the introduction of iron chelation in 1965, which were no longer apparent after that date (P = 0·086), reducing the Hazard Ratio of death in TM compared to TI from 6·8 [95% confidence interval (CI) 2·6-17·5] before 1965 to 2·8 (95% CI 0·8-9·2). These findings suggest that, in the era of iron chelation therapy and improved survival for TM, the major-intermedia dichotomy needs to be revisited alongside future directions in general management and prevention for both conditions.

Extramedullary haematopoiesis correlates with genotype and absence of cardiac iron overload in polytransfused adults with thalassaemia.

BACKGROUND: The mechanisms responsible for the sporadic occurrence of extramedullary haematopoiesis in polytransfused thalassaemic patients have not yet been clarified. In this study we tried to elucidate the influence of genotype and other factors on the presence of extramedullary haematopoiesis. MATERIALS AND METHODS: We performed a retrospective database review of our polytransfused thalassaemic patients between January 2006 and December 2011. Demographic, transfusional, genetic, radiological and biochemical data were collected and statistically analysed. RESULTS: Extramedullary haematopoiesis was found in 18 out of 67 patients (27%). All of them were splenectomised, had a higher nucleated red blood cell count and higher levels of the soluble form of transferrin receptor with respect to patients without extramedullary haematopoiesis; furthermore, patients with EMH had a lower transfusional iron intake and a higher pre-transfusion haemoglobin level as compared with those without extramedullary haematopoiesis. Ten out of the 18 patients with extramedullary haematopoiesis were compound heterozygotes for IVS 1-6/codon 39. A high frequency of thrombotic events was also recorded among all patients followed at our centre with this genetic profile. DISCUSSION: Among our cohort of thalassaemic polytransfused patients, extramedullary haematopoiesis was not such a rare event. Furthermore, we identified a group of patients, most of whom were compound heterozygotes for IVS 1-6/codon 39, with increased soluble transferrin receptor levels and excessive expansion of erythroid marrow probably responsible for the tendency to develop extramedullary haematopoiesis.

Long-term treatment with deferiprone enhances left ventricular ejection function when compared to deferoxamine in patients with thalassemia major.

Transfusion and iron chelation treatment have significantly reduced morbidity and improved survival of patients with thalassemia major. However, cardiac disease continues to be the most common cause of death. We report the left-ventricular ejection fraction, determined by echocardiography, in one hundred sixty-eight patients with thalassemia major followed for at least 5years who received continuous monotherapy with deferoxamine (N=108) or deferiprone (N=60). The statistical analysis, using the generalized estimating equations model, indicated that the group treated with deferiprone had a significantly better left-ventricular ejection fraction than did those treated with deferoxamine (coefficient 0.97; 95% CI 0.37; 1.6, p=0.002). The heart may be particularly sensitive to iron-induced mitochondrial damage because of the large number of mitochondria and its low level of antioxidants. Deferiprone, because of its lower molecular weight, might cross into heart mitochondria more efficiently, improving their activity and, thereby, myocardial cell function. Our findings indicate that the long-term administration of deferiprone significantly enhances left-ventricular function over time in comparison with deferoxamine treatment. However, because of limitations related to the design of this study, these findings should be confirmed in a prospective, randomized clinical trial.

Effect of splenectomy on iron balance in patients with ß-thalassemia major: a long-term follow-up.

OBJECTIVE: A retrospective study was performed to explore the effect of splenectomy on iron balance in thalassemia major (TM). METHODS: Twenty two TM patients treated with splenectomy were compared with a control group (non-splenectomized patients) matched for sex, age, pretransfusional Hb, chelation therapy, and duration of follow-up in a retrospective study to evaluate blood consumption, iron intake, and serum ferritin during an overall observation period of 6 yrs before and 10 yrs after splenectomy. RESULTS: Splenectomy improved parameters of iron balance, determining a significant reduction in blood consumption (P < 0.01), iron intake (P < 0.01), and serum ferritin (P < 0.01). Comparing the two groups, blood consumption and iron intake were similar in presplenectomy period (P > 0.05), but serum ferritin was significantly higher in splenectomized patients (P < 0.01). After splenectomy, blood consumption and iron intake were significantly lower (P < 0.01) in splenectomized group while serum ferritin did not differ significantly (P > 0.05) between two groups, except for the first year (P < 0.05). CONCLUSION: Splenectomy determines immediate drop in blood consumption and iron intake but slow downtrend of ferritin; direct measurements of iron overload, such as magnetic resonance studies, are needed to better understand the effect of splenectomy on iron balance parameters. Tailoring chelation therapy and eventually its intensification seem more efficient measures to manage iron accumulation in TM and to lower iron level to safety threshold.

Serial echocardiographic left ventricular ejection fraction measurements: a tool for detecting thalassemia major patients at risk of cardiac death.

Cardiac damage remains a major cause of mortality among patients with thalassemia major. The detection of a lower cardiac magnetic resonance T2* (CMR-T2*) signal has been suggested as a powerful predictor of the subsequent development of heart failure. However, the lack of worldwide availability of CMR-T2* facilities prevents its widespread use for follow-up evaluations of cardiac function in thalassemia major patients, warranting the need to assess the utility of other possible procedures. In this setting, the determination of left ventricular ejection fraction (LVEF) offers an accurate and reproducible method for heart function evaluation. These findings suggest a reduction in LVEF≥7%, over time, determined by 2-D echocardiography, may be considered a strong predictive tool for the detection of thalassemia major patients with increased risk of cardiac death. The reduction of LVEF≥7% had higher (84.76%) predictive value. Finally, Kaplan-Meier survival curves of thalassemia major patients with LVEF≥7% showed a statistically significant decreased probability of survival for heart disease (p=0.0022). However, because of limitations related to the study design, such findings should be confirmed in a large long-term prospective clinical trial.

Splenectomy is a risk factor for developing hyperuricemia and nephrolithiasis in patients with thalassemia intermedia: a retrospective study.

Few data are available on the prevalence and the risk factors for the presence of kidney stones and hyperuricemia in patients with thalassemia intermedia. We retrospectively reviewed the charts and radiological studies of 89 patients with thalassemia intermedia followed at our clinic with routine biochemical examination and radiological imaging of the urinary tract. Renal calculi were identified in 11 patients (12%) and 22 patients (25%) were under uricosuric treatment for hyperucemia. The prevalence of nephrolithiasis increased with age but not in a statistically significant manner. Major risk factors for renal stone formation were splenectomy (in 91% of the cases) and higher number of erythroblasts. Patients with renal stones had higher mean creatinine level and lower GFR value with respect to those observed in patients not affected. Our data suggest that splenectomy, by further increasing erythrocyte turnover and number, may be directly involved in the pathogenesis of hyperuricemia and nephrolithiasis observed in thalassemia intermedia patients.

Long-term use of deferiprone significantly enhances left-ventricular ejection function in thalassemia major patients.

A multicenter randomized open-label long-term sequential deferiprone­deferoxamine (DFP-DFO) versus DFP alone trial (sequential DFP-DFO) performed in patients with thalassemia major (TM) was retrospectively reanalyzed to assess the variation in the left ventricular ejection fraction (LVEF) [1].

A useful relationship between the presence of extramedullary erythropoeisis and the level of the soluble form of the transferrin receptor in a large cohort of adult patients with thalassemia intermedia: a prospective study.

In thalassemia intermedia (TI), the increase in bone marrow hemopoietic activity frequently leads to extramedullary erythropoeisis (EMH), but its relationship with the soluble form of transferrin receptor (sTfR) which fully reflects the marrow erythropoietic activity, has not yet been explored. From January 2007 to December 2010, all TI patients attending at our center were prospectively enrolled to undergo sTfR assay and MRI or CT (if claustrophobic) scan evaluation for the presence of paraspinal EMH. A total of 59 patients with TI were studied; EMH involved 23 (39%) patients; overall, the concentration of sTfR varied from 2.6 to 20.6 (mean = 8.7) mg/L, but in splenectomized group and in unsplenectomized group, it varied from 4.2 to 17.8 (mean ± SD = 9.86 ± 3.33) mg/L and from 2.6 to 20.6 (mean ± SD = 7.25 ± 3.9) mg/L, respectively with a statistically significant intergroup difference (p < 0.01). The cutoff point at 8.6 mg/L using the ROC curve showed a sensitivity of 78.3% and a specificity of 72.2%, in predicting EMH but, in unsplenectomized subgroup, they raised to 100% and 90.9%, respectively. These data showed that in TI the level of sTfR could represent a predictive factor of EMH particularly in patients with spleen.

Iron chelation therapy in thalassemia major: a systematic review with meta-analyses of 1520 patients included on randomized clinical trials.

The effectiveness of deferoxamine (DFO), deferiprone (DFP), or deferasirox (DFX) in thalassemia major was assessed. Outcomes were reported as means±SD, mean differences with 95% CI, or standardized mean differences. Statistical heterogeneity was tested using χ2 (Q) and I2. Sources of bias and Grading of Recommendations Assessment, Development and Evaluation system (GRADE) were considered. Overall, 1520 patients were included. Only 7.4% of trials were free of bias. Overall measurements suggest low trial quality (GRADE). The meta-analysis suggests lower final liver iron concentrations during associated versus monotherapy treatment (p<0.0001), increases in serum ferritin levels during DFX 5, 10, and 20 mg/kg versus DFO-treated groups (p<0.00001, p<0.00001, and p=0.002, respectively), but no statistically significant difference during DFX 30 mg/kg versus DFO (p=0.70), no statistically significant variations in heart T2* signal during associated or sequential versus mono-therapy treatment (p=0.46 and p=0.14, respectively), increases in urinary iron excretion during associated or sequential versus monotherapy treatment (p=0.008 and p=0.02, respectively), and improved ejection fraction during associated or sequential versus monotherapy treatment (p=0.01 and p<0.00001, respectively). These findings do not support any specific chelation treatment. The literature shows risks of bias, and additional larger and longer trials are needed.

Sequential alternating deferiprone and deferoxamine treatment compared to deferiprone monotherapy: main findings and clinical follow-up of a large multicenter randomized clinical trial in -thalassemia major patients.

In ß-thalassemia major (ß-TM) patients, iron chelation therapy is mandatory to reduce iron overload secondary to transfusions. Recommended first line treatment is deferoxamine (DFO) from the age of 2 and second line treatment after the age of 6 is deferiprone (L1). A multicenter randomized open-label trial was designed to assess the effectiveness of long-term alternating sequential L1-DFO vs. L1 alone iron chelation therapy in ß-TM patients. Deferiprone 75 mg/kg 4 days/week and DFO 50 mg/kg/day for 3 days/week was compared with L1 alone 75 mg/kg 7 days/week during a 5-year follow-up. A total of 213 thalassemia patients were randomized and underwent intention-to-treat analysis. Statistically, a decrease of serum ferritin level was significantly higher in alternating sequential L1-DFO patients compared with L1 alone patients (p = 0.005). Kaplan-Meier survival analysis for the two chelation treatments did not show statistically significant differences (log-rank test, p = 0.3145). Adverse events and costs were comparable between the groups. Alternating sequential L1-DFO treatment decreased serum ferritin concentration during a 5-year treatment by comparison to L1 alone, without significant differences of survival, adverse events or costs. These findings were confirmed in a further 21-month follow-up. These data suggest that alternating sequential L1-DFO treatment may be useful for some ß-TM patients who may not be able to receive other forms of chelation treatment.

A case of well-tolerated and safe deferasirox administration during the first trimester of a spontaneous pregnancy in an advanced maternal age thalassemic patient.

In this report, we present a case of a spontaneous pregnancy in a 42-year-old thalassemic woman referred to our Microcythemic Unit while she was on deferasirox (DFX) therapy. The patient had been on treatment with DFX since March 2008 and in March 2009 realized that she was pregnant at 12 weeks of gestation. The conception was spontaneous and the baby was born at full term without complications or malformations.

Deferasirox, deferiprone and desferrioxamine treatment in thalassemia major patients: cardiac iron and function comparison determined by quantitative magnetic resonance imaging.

BACKGROUND: Oral deferiprone was suggested to be more effective than subcutaneous desferrioxamine for removing heart iron. Oral once-daily chelator deferasirox has recently been made commercially available but its long-term efficacy on cardiac iron and function has not yet been established. Our study aimed to compare the effectiveness of deferasirox, deferiprone and desferrioxamine on myocardial and liver iron concentrations and bi-ventricular function in thalassemia major patients by means of quantitative magnetic resonance imaging. DESIGN AND METHODS: From the first 550 thalassemia subjects enrolled in the Myocardial Iron Overload in Thalassemia network, we retrospectively selected thalassemia major patients who had been receiving one chelator alone for longer than one year. We identified three groups of patients: 24 treated with deferasirox, 42 treated with deferiprone and 89 treated with desferrioxamine. Myocardial iron concentrations were measured by T2* multislice multiecho technique. Biventricular function parameters were quantitatively evaluated by cine images. Liver iron concentrations were measured by T2* multiecho technique. RESULTS: The global heart T2* value was significantly higher in the deferiprone (34 ± 11 ms) than in the deferasirox (21 ± 12 ms) and the desferrioxamine groups (27 ± 11 ms) (P = 0.0001). We found higher left ventricular ejection fractions in the deferiprone and the desferrioxamine versus the deferasirox group (P = 0.010). Liver iron concentration, measured as T2* signal, was significantly lower in the desferrioxamine versus the deferiprone and the deferasirox group (P = 0.004). CONCLUSIONS: The cohort of patients treated with oral deferiprone showed less myocardial iron burden and better global systolic ventricular function compared to the patients treated with oral deferasirox or subcutaneous desferrioxamine.

The impact of previous or concomitant IFN therapy on deferiprone-induced agranulocytosis and neutropenia: a retrospective study.

OBJECTIVE: Although IFN therapy is known to cause neutropenia, data on the risk of deferiprone (DFP)-induced haematological complications in patients receiving IFN are lacking. RESEARCH DESIGN AND METHODS: This was a retrospective single-centre study to assess the association between exposure to IFN for hepatitis C virus treatment and haematological side effects of DFP therapy in patients with thalassemia major and intermedia using a large database spanning 2001 ­ 2008. During observation time, a total of 66 patients, including 63 affected by thalassemia major and 3 by thalassemia intermedia, were treated with chelation DFP-based regimens. A subset of 25 patients was treated at least for 3 months also with IFN (6 were cotreated and 19 were pretreated). RESULTS: Overall, the incidence of neutropenia and agranulocytosis was 9.83 and 1.14/100 patient/year, respectively. Receipt of IFN was significantly associated with increased risk of haematological complications of DFP therapy: among patients receiving IFN, 48 and 12% experienced at least one episode of neutropenia and agranulocytosis, respectively. CONCLUSIONS: These results suggest that IFN therapy may increase the risk of complications of DFP-based iron chelation therapy in patients with thalassemia. Further research is needed to assess whether the association observed in this retrospective single-centre observational study is due to IFN or other factors.

Combined chelation therapy in thalassemia major with deferiprone and desferrioxamine: a retrospective study.

OBJECTIVES: The benefits of combined chelation therapy with daily deferiprone (DFP) and subcutaneous desferrioxamine (DFO) have been widely reported in literature. We retrospectively evaluated the efficacy of different schedules of combined chelation therapy and the incidence of adverse events. METHODS: We evaluated 36 patients affected by thalassemia major treated with combined chelation therapy. Patients were subdivided into four treatment arms according to severity of iron overload and previous onset of adverse events to DFP therapy: Group 1 (13 pts) DFP 75 mg/kg per d plus DFO (25-35 mg/kg per d for 5 d); Group 2 (6 pts) DFP 50 mg/kg per d plus DFO (25-35 mg/kg for 5 d), Group 3 (10 pts) DFP 75 mg/kg per d plus DFO (25-35 mg/kg for 3 d), and Group 4 (7 pts) DFP 50 mg/kg per d plus DFO (25-35 mg/kg for 3 d). Change in serum ferritin level was evaluated in all patients. RESULTS: Overall, ferritin decreased from 2592 +/- 1701 to 899 +/- 833 ng/mL (P < 0.001). All treatments were able to reduce ferritin levels, but in patients of group 1 and group 2 the highest mean decrease in serum ferritin level and the greatest improvement in liver iron concentration (LIC) and in T2* values were observed. CONCLUSIONS: This study showed that the administration of DFO for 5 d a wk in combination with daily administration of DFP at 75 mg/Kg seemed to be the most efficacy and rapid method for reducing iron overload at liver and heart level. Furthermore, the use of different schedules of combined DFO and DFP administration was not associated with different incidence of adverse effects between the groups.

Paradoxically increased ferritin level in a beta-thalassemia major patient following the start of deferasirox chelation therapy.

In this report we present a 37-year-old thalassemia patient with hyperferritinemia referred to our Microcytemia Centerat the beginning of deferasirox (DFX) therapy. Treatment with subcutaneous infusions of desferrioxamine (DFO) had started when he was 10 years old. During the 6-month DFX treatment, serum ferritin levels progressively increased from 600 to 2,700 ng/ml despite progressive DFX dose adjustments.This paradoxically abnormal ferritin levels required drug discontinuation but were not paralleled by a similar iron burden in T2 * magnetic resonance imaging. In this clinical case, ferritin levels were inappropriately increased following initiation of DFX treatment, but in the presence of an almost unmodified pattern of organ iron overload. Excluding the diagnostic dilemma of an improbable failure of DFX chelation, the pathogenesis of this phenomenon remains to be clarified, thus further complicating the problem of ferritin specificity and its role in monitoring chelation efficacy and in adapting DFX dosage in a limited period of treatment.

Long-term sequential deferiprone-deferoxamine versus deferiprone alone for thalassaemia major patients: a randomized clinical trial.

A multicentre randomized open-label trial was designed to assess the effectiveness of long-term sequential deferiprone-deferoxamine (DFO-DFP) versus DFP alone to treat thalassaemia major (TM). DFP at 75 mg/kg, divided into three oral daily doses, for 4 d/week and DFO by subcutaneous infusion (8-12 h) at 50 mg/kg per day for the remaining 3 d/week was compared with DFP alone at 75 mg/kg, administered 7 d/week during a 5-year follow-up. The main outcome measures were differences between multiple observations of serum ferritin concentrations. Secondary outcomes were survival analysis, adverse events, and costs. Consecutive thalassaemia patients (275) were assessed for eligibility; 213 of these were randomized and underwent intention-to-treat analysis. The decrease of serum ferritin levels during the treatment period was statistically significant higher in sequential DFP-DFO patients compared with DFP-alone patients (P = 0.005). Kaplan-Meier survival analysis for the two chelation treatments did not show any statistically significant differences (long-rank test, P = 0.3145). Adverse events and costs were comparable between the groups. The trial results show that sequential DFP-DFO treatment compared with DFP alone significantly decreased serum ferritin concentration during treatment for 5 years without significant differences regarding survival, adverse events, or costs.

Improving survival with deferiprone treatment in patients with thalassemia major: a prospective multicenter randomised clinical trial under the auspices of the Italian Society for Thalassemia and Hemoglobinopathies.

The prognosis for thalassemia major has dramatically improved in the last two decades. However, many transfusion-dependent patients continue to develop progressive accumulation of iron. This can lead to tissue damage and eventually death, particularly from cardiac disease. Previous studies that investigated iron chelation treatments, including retrospective and prospective non-randomised clinical trials, suggested that mortality, due mainly to cardiac damage, was reduced or completely absent in patients treated with deferiprone (DFP) alone or a combined deferiprone-deferoxamine (DFP-DFO) chelation treatment. However, no survival analysis has been reported for a long-term randomised control trial. Here, we performed a multicenter, long-term, randomised control trial that compared deferoxamine (DFO) versus DFP alone, sequential DFP-DFO, or combined DFP-DFO iron chelation treatments. The trial included 265 patients with thalassemia major, with 128 (48.3%) females and 137 (51.7%) males. No deaths occurred with the DFP-alone or the combined DFP-DFO treatments. One death occurred due to graft versus host disease (GVHD) in a patient that had undergone bone marrow transplantation; this patient was censored at the time of transplant. Only one death occurred with the DFP-DFO sequential treatment in a patient that had experienced an episode of heart failure one year earlier. Ten deaths occurred with the deferoxamine treatment. The main factors that correlated with an increase in the hazard ratio for death were: cirrhosis, arrhythmia, previous episode of heart failure, diabetes, hypogonadism, and hypothyroidism. In a Cox regression model, the interaction effect of sex and age was statistically significant (p-value<0.013). For each increasing year of age, the hazard ratio for males was 1.03 higher than that for females (p-value<0.013). In conclusion, the results of this study show that the risk factors for predicting mortality in patients with thalassemia major are deferoxamine-treatment, complications, and the interaction effect of sex and age.

Hypocholesterolemia in adult patients with thalassemia: a link with the severity of genotype in thalassemia intermedia patients.

OBJECTIVES: Hypocholesterolemia has been previously described in patients affected by thalassemia. In this study we retrospectively evaluated the cholesterol level in two groups of patients affected by either thalassemia major (TM) or thalassemia intermedia (TI), with the aim of establishing factors correlated to hypocholesterolemia within both populations. METHODS: All patients referring to our Unit of Thalassemia were considered. Observation time, defined as the interval between the first and last set of laboratory test, was 2 yr (January 2005-December 2006). RESULTS: We found that patients with TI had significantly lower cholesterol and hemoglobin level as compared with TM patients. In addition there was no correlation between groups with identical genotype and cholesterol levels in both populations. However, within the TI group, lower values of cholesterol were found in patients with more severe genotype and lower body mass index. CONCLUSIONS: Our data support the hypothesis that, independently from single genotype involved, the reduced level of cholesterol in patients with TI are sustained by active erythropoiesis which increases cholesterol requirement.