A complication risk score to evaluate clinical severity of thalassaemia syndromes.

The thalassaemia syndromes (TS) show different phenotype severity. Developing a reliable, practical and global tool to determine disease severity and tailor treatment would be of great value. Overall, 7910 patients were analysed with the aim of constructing a complication risk score (CoRS) to evaluate the probability of developing one or more complications. Nine independent variables were included in the investigation as predictors. Logistic regression models were used for Group A [transfusion-dependent thalassaemia (TDT)], Group B [transfused non-TDT (NTDT)] and Group C (non-transfused NTDT). Statistically significant predictors included age (years), haemoglobin levels, hepatic transaminases [alanine aminotransferase (ALT) and aspartate aminotransferase] and left-ventricular ejection fraction (LVEF) for Group A; age (years), age at first chelation (months), ALT and LVEF for Group B; and age (years), mean serum ferritin (SF) levels and LVEF for Group C. The area under the receiver operating characteristic curve was 84·5%, 82·1% and 80·0% for Groups A, Group B and Group C respectively, suggesting the models had good discrimination. Finally, the CoRS for each group was categorised into four risk classes (low, intermediate, high, and very high) using the centiles of its distribution. In conclusion, we have developed a CoRS for TS that can assist physicians in prospectively tailoring patients' treatment.

Evaluation of the efficacy and safety of deferiprone compared with deferasirox in paediatric patients with transfusion-dependent haemoglobinopathies (DEEP-2): a multicentre, randomised, open-label, non-inferiority, phase 3 trial.

BACKGROUND: Transfusion-dependent haemoglobinopathies require lifelong iron chelation therapy with one of the three iron chelators (deferiprone, deferasirox, or deferoxamine). Deferasirox and deferiprone are the only two oral chelators used in adult patients with transfusion-dependent haemoglobinopathies. To our knowledge, there are no randomised clinical trials comparing deferiprone, a less expensive iron chelator, with deferasirox in paediatric patients. We aimed to show the non-inferiority of deferiprone versus deferasirox. METHODS: DEEP-2 was a phase 3, multicentre, randomised trial in paediatric patients (aged 1 month to 18 years) with transfusion-dependent haemoglobinopathies. The study was done in 21 research hospitals and universities in Italy, Egypt, Greece, Albania, Cyprus, Tunisia, and the UK. Participants were receiving at least 150 mL/kg per year of red blood cells for the past 2 years at the time of enrolment, and were receiving deferoxamine (<100 mg/kg per day) or deferasirox (<40 mg/kg per day; deferasirox is not registered for use in children aged <2 years so only deferoxamine was being used in these patients). Any previous chelation treatment was permitted with a 7-day washout period. Patients were randomly assigned 1:1 to receive orally administered daily deferiprone (75-100 mg/kg per day) or daily deferasirox (20-40 mg/kg per day) administered as dispersible tablets, both with dose adjustment for 12 months, stratified by age (<10 years and ≥10 years) and balanced by country. The primary efficacy endpoint was based on predefined success criteria for changes in serum ferritin concentration (all patients) and cardiac MRI T2-star (T2*; patients aged >10 years) to show non-inferiority of deferiprone versus deferasirox in the per-protocol population, defined as all randomly assigned patients who received the study drugs and had available data for both variables at baseline and after 1 year of treatment, without major protocol violations. Non-inferiority was based on the two-sided 95% CI of the difference in the proportion of patients with treatment success between the two groups and was shown if the lower limit of the two-sided 95% CI was greater than -12·5%. Safety was assessed in all patients who received at least one dose of study drug. This study is registered with EudraCT, 2012-000353-31, and ClinicalTrials.gov, NCT01825512. FINDINGS: 435 patients were enrolled between March 17, 2014, and June 16, 2016, 393 of whom were randomly assigned to a treatment group (194 to the deferiprone group; 199 to the deferasirox group). 352 (90%) of 390 patients had ß-thalassaemia major, 27 (7%) had sickle cell disease, five (1%) had thalassodrepanocytosis, and six (2%) had other haemoglobinopathies. Median follow-up was 379 days (IQR 294-392) for deferiprone and 381 days (350-392) for deferasirox. Non-inferiority of deferiprone versus deferasirox was established (treatment success in 69 [55·2%] of 125 patients assigned deferiprone with primary composite efficacy endpoint data available at baseline and 1 year vs 80 [54·8%] of 146 assigned deferasirox, difference 0·4%; 95% CI -11·9 to 12·6). No significant difference between the groups was shown in the occurrence of serious and drug-related adverse events. Three (2%) cases of reversible agranulocytosis occurred in the 193 patients in the safety analysis in the deferiprone group and two (1%) cases of reversible renal and urinary disorders (one case of each) occurred in the 197 patients in the deferasirox group. Compliance was similar between treatment groups: 183 (95%) of 193 patients in the deferiprone group versus 192 (97%) of 197 patients in the deferisirox group. INTERPRETATION: In paediatric patients with transfusion-dependent haemoglobinopathies, deferiprone was effective and safe in inducing control of iron overload during 12 months of treatment. Considering the need for availability of more chelation treatments in paediatric populations, deferiprone offers a valuable treatment option for this age group. FUNDING: EU Seventh Framework Programme.

Failures to further developing orphan medicinal products after designation granted in Europe: an analysis of marketing authorisation failures and abandoned drugs.

OBJECTIVES: The research and development process in the field of rare diseases is characterised by many well-known difficulties, and a large percentage of orphan medicinal products do not reach the marketing approval.This work aims at identifying orphan medicinal products that failed the developmental process and investigating reasons for and possible factors influencing failures. DESIGN: Drugs designated in Europe under Regulation (European Commission) 141/2000 in the period 2000-2012 were investigated in terms of the following failures: (1) marketing authorisation failures (refused or withdrawn) and (2) drugs abandoned by sponsors during development.Possible risk factors for failure were analysed using statistically validated methods. RESULTS: This study points out that 437 out of 788 designations are still under development, while 219 failed the developmental process. Among the latter, 34 failed the marketing authorisation process and 185 were abandoned during the developmental process. In the first group of drugs (marketing authorisation failures), 50% reached phase II, 47% reached phase III and 3% reached phase I, while in the second group (abandoned drugs), the majority of orphan medicinal products apparently never started the development process, since no data on 48.1% of them were published and the 3.2% did not progress beyond the non-clinical stage.The reasons for failures of marketing authorisation were: efficacy/safety issues (26), insufficient data (12), quality issues (7), regulatory issues on trials (4) and commercial reasons (1). The main causes for abandoned drugs were efficacy/safety issues (reported in 54 cases), inactive companies (25.4%), change of company strategy (8.1%) and drug competition (10.8%). No information concerning reasons for failure was available for 23.2% of the analysed products. CONCLUSIONS: This analysis shows that failures occurred in 27.8% of all designations granted in Europe, the main reasons being safety and efficacy issues. Moreover, the stage of development reached by drugs represents a specific risk factor for failures.

Pattern of complications and burden of disease in patients affected by beta thalassemia major.

OBJECTIVES: Despite the correct application of blood transfusions and chelation treatments, beta thalassemia patients have many complications. Systematic population analyses on types and frequency of these complications are very few. The aim of this study is to characterize the complications, their risk factors and their clinical and economic impact. METHODS: Complications at baseline and events occurring during one observational year were analyzed in 272 patients aged >12 years. Risk factors were analyzed through chi-squared and unpaired t tests. Logistic regression was applied to perform the risk factors multivariate analysis. RESULTS: A total of 554 complications (1-6 per patient) affected 82.3% of patients. Cardiac complications were less represented than expected. Musculoskeletal diseases were the most represented complications followed by hepatic, sexual and endocrine diseases. Splenectomized patients, born before 1970 and aged >40 years, starting iron chelation therapy when aged >4 years or after receiving more than 20 blood transfusions, presented a significantly higher number of complications. A total of 885 adverse events requiring 34125 additional medical services occurred in 1 year. Of these, 34.9% were related to treatments and 65.1% to other causes. Event numbers, additional medical interventions and cost increased progressively in patients affected by one or more complication compared to patients with no complications. CONCLUSIONS: The pattern of complications changes according to birth cohort and differentiates older from younger patients. The burden of the disease and its costs increase after the onset of the first complication, therefore prevention of complications is fundamental in these patients.

The Italian multiregional thalassemia registry: Centers characteristics, services, and patients' population.

OBJECTIVES: The prognosis of beta-Thalassemia major and other congenital hemoglobinopathies has profoundly changed over the last decades. Moreover, only few countries in Europe provide dedicated services and the description of the measures for patients monitoring and treatment is overall very scarce. The HTA-Thal project is aimed to identify the services available in Italy and to collect epidemiological and clinical data on the thalassemic population (HTA-Thal Registry). METHODS: A map of the existing centers was created and two electronic questionnaires were completed with information on the services and patients. RESULTS: On 182 centers identified, 60 completed the two questionnaires. Centers resulted to be extremely heterogeneous in terms of size, age of patients in care, and services availability. The transition of pediatric patients to adult centers was not guaranteed. Thousand eight hundred and seventy-three beta-Thalassemia major patients (of which 259 pediatrics), regularly transfused, were registered. Deferasirox is the most used chelator as monotherapy (616 patients) and its use prevails in younger patients. A higher number of patients (847 patients) use Deferoxamine, either alone (448 patients) or in combination with DFP (399 patients), while 782 patients use Deferiprone alone (383 patients) or in combination (399 patients). 31.6 and 66.6% of centers were not equipped for specialized visits or local MRI, respectively. Centers with 30-80 patients show the high percentage of patients appropriately monitored when compared to smaller or bigger centers. CONCLUSIONS: This analysis confirms the importance of patients' registries for the collection of large datasets and the need for dedicated 'specialized centers' equipped to provide the best standard treatment to patients.

Safety Profile of Oral Iron Chelator Deferiprone in Chinese Children with Transfusion-Dependent Thalassaemia.

UNLABELLED: There is a lack of knowledge regarding the incidence of serious adverse drug reactions (ADR) to the oral iron chelator deferiprone in Chinese children with transfusion-dependent thalassaemia. In this retrospective population-based cohort study, paediatric thalassaemia patients in Hong Kong were screened for serious and medically important adverse events related to deferiprone therapy using diagnosis codes, laboratory data and hospital admissions. Potential ADRs were assessed by reviewing concomitant medications, diagnoses and laboratory data and evaluated using standardised causality assessment. Eighty-seven patients contributing 169.8 person-years were included. Thirty ADRs were identified in 21 patients. Most ADRs (56.0%) occurred in the first three months of therapy. Neutropenia occurred in 11 patients (12.6%; incidence rate 6.5 per 100 patient-years) and severe neutropenia (agranulocytosis) was observed in 5 patients (5.7%, incidence rate 2.9 per 100 patient-years). Other identified ADRs involve severe arthropathy, elevated liver enzymes and mild thrombocytopenia. In conclusion, the safety profile of DFP therapy in Chinese children suffering from transfusion-dependent thalassaemia is in line with previous studies of non-Chinese children. However, unlike previous studies, we observed a relatively high incidence of agranulocytosis and neutropenia in patients with simultaneous combined therapy. Hence close monitoring for white blood cell counts is advised in Chinese children under combined iron chelation therapy. Further prospective clinical and pharmacogenetic studies are required to better evaluate this important safety signal. KEY POINTS: • Half of the identified ADRs related to deferiprone therapy occurred during the first three months of treatment. • A relatively high incidence of agranulocytosis and neutropenia. Hence close monitoring for white blood cell counts is advised in Chinese children under combined iron chelation therapy.

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.

The management of iron chelation therapy: preliminary data from a national registry of thalassaemic patients.

Thalassaemia and other haemoglobinopathies constitute an important health problem in Mediterranean countries, placing a tremendous emotional, psychological, and economic burden on their National Health systems. The development of new chelators in the most recent years had a major impact on the treatment of thalassaemia and on the quality of life of thalassaemic patients. A new initiative was promoted by the Italian Ministry of Health, establishing a Registry for thalassaemic patients to serve as a tool for the development of cost-effective diagnostic and therapeutic approaches and for the definition of guidelines supporting the most appropriate management of the iron-chelating therapy and a correct use of the available iron-chelating agents. This study represents the analysis of the preliminary data collected for the evaluation of current status of the iron chelation practice in the Italian thalassaemic population and describes how therapeutic interventions can widely differ in the different patients' age groups.

Risk factors for death in patients with beta-thalassemia major: results of a case-control study.

This retrospective one to one matched case-control study was aimed at evaluating risk factors for death in beta-thalassemic patients followed in Italian centers between 1997 and 2001. The mortality risk was lower in patients with good compliance to iron chelation therapy and in those treated with deferiprone.

Pharmacotherapy of iron overload in thalassaemic patients.

The recommended treatment for thalassaemia major is regular blood transfusions, although these lead to the harmful accumulation of iron in the body. If untreated, iron overload is responsible for heart, liver and endocrine diseases. The only two iron chelating agents available for the treatment of iron overload are deferoxamine and deferiprone. The standard iron chelation therapy is based on the use of deferoxamine. Although this drug was introduced in the 1970s, it still remains the treatment of choice. Recently, another iron chelator, deferiprone, became available for clinical use in the European Community. Deferiprone is indicated as second-line treatment in patients with thalassaemia major, for whom deferoxamine therapy is contraindicated or in patients who present with serious toxicity to deferoxamine therapy. This paper examines this chelating agent and compares it with deferoxamine in order to ascertain the current and potential contribution of deferiprone to the treatment of thalassaemic patients.