Consequences to Patients, Clinicians, and Manufacturers When Very Serious Adverse Drug Reactions Are Identified (1997-2019): A Qualitative Analysis from the Southern Network on Adverse Reactions (SONAR).

Adverse drug/device reactions (ADRs) serious enough to lead to box warnings on drug labels or drug withdrawals occur in about one fifth of all new molecular entities.

Leg Ulcers: A Report in Patients with Hemoglobin E Beta Thalassemia and Review of the Literature in Severe Beta Thalassemia.

BACKGROUND: Leg ulcers are a frequent complication in patients with the inherited hemoglobin disorders. In thalassemia, the literature is limited, and factors associated with the development of leg ulcers in hemoglobin E (HbE) beta thalassemia, the most common form of severe beta-thalassemia worldwide, have not previously been reported. METHODS: We reviewed all available medical records of patients with HbE beta thalassemia to document the onset of leg ulcers at the 2 largest treatment centers in Sri Lanka. We reviewed the literature to identify studies reporting outcomes of interventions for ulcers in severe thalassemia. RESULTS: Of a total of 255 actively registered patients with HbE thalassemia in the 2 centers, 196 patient charts were evaluable. A leg ulcer with a documented date of onset was recorded in 45 (22%) of 196 evaluable patients, aged (mean ± SEM) 22.2 ± 1.4 years. Most had been irregularly transfused; steady-state hemoglobin was 6.4 ± 0.2 g/dL. Treatment achieving healing in 17 patients included transfusions, antibiotics, oral zinc, wound toileting, and skin grafting. CONCLUSION: Leg ulcers may be more common in HbE beta thalassemia than in other forms of thalassemia. A systematic approach to treatment will be needed to document the prevalence and factors placing such patients at risk for leg ulcers. Controlled trials to evaluate the optimal treatment of this common complication are indicated.

Survival and complications in patients with haemoglobin E thalassaemia in Sri Lanka: a prospective, longitudinal cohort study.

BACKGROUND: Worldwide, haemoglobin E ß-thalassaemia is the most common genotype of severe ß-thalassaemia. The paucity of long-term data for this form of thalassaemia makes evidence-based management challenging. We did a long-term observational study to define factors associated with survival and complications in patients with haemoglobin E thalassaemia. METHODS: In this prospective, longitudinal cohort study, we included all patients with haemoglobin E thalassaemia who attended the National Thalassaemia Centre in Kurunegala, Sri Lanka, between Jan 1, 1997, and Dec 31, 2001. Patients were assessed up to three times a year. Approaches to blood transfusions, splenectomy, and chelation therapy shifted during this period. Survival rates between groups were evaluated using Kaplan-Meier survival function estimate curves and Cox proportional hazards models were used to identify risk factors for mortality. FINDINGS: 109 patients (54 [50%] male; 55 [50%] female) were recruited and followed up for a median of 18 years (IQR 14-20). Median age at recruitment was 13 years (range 8-21). 32 (29%) patients died during follow-up. Median survival in all patients was 49 years (95% CI 45-not reached). Median survival was worse among male patients (hazard ratio [HR] 2·51, 95% CI 1·16-5·43), patients with a history of serious infections (adjusted HR 8·49, 2·90-24·84), and those with higher estimated body iron burdens as estimated by serum ferritin concentration (adjusted HR 1·03, 1·01-1·06 per 100 units). Splenectomy, while not associated with statistically significant increases in the risks of death or serious infections, ultimately did not eliminate a requirement for scheduled transfusions in 42 (58%) of 73 patients. Haemoglobin concentration less than or equal to 4·5 g/dL (vs concentration >4·5 g/dL), serum ferritin concentration more than 1300 µg/L (vs concentration ≤1300 µg/L), and liver iron concentration more than 5 mg/g dry weight of liver (vs concentration ≤5 mg/g) were associated with poorer survival. INTERPRETATION: Patients with haemoglobin E thalassaemia often had complications and shortened survival compared with that reported in high-resource countries for thalassaemia major and for thalassaemia intermedia not involving an allele for haemoglobin E. Approaches to management in this disorder remain uncertain and prospective studies should evaluate if altered transfusion regimens, with improved control of body iron, can improve survival. FUNDING: Wellcome Trust, Medical Research Council, US March of Dimes, Anthony Cerami and Ann Dunne Foundation for World Health, and Hemoglobal.

Single-center retrospective study of the effectiveness and toxicity of the oral iron chelating drugs deferiprone and deferasirox.

BACKGROUND: Iron overload, resulting from blood transfusions in patients with chronic anemias, has historically been controlled with regular deferoxamine, but its parenteral requirement encouraged studies of orally-active agents, including deferasirox and deferiprone. Deferasirox, licensed by the US Food and Drug Administration in 2005 based upon the results of randomized controlled trials, is now first-line therapy worldwide. In contrast, early investigator-initiated trials of deferiprone were prematurely terminated after investigators raised safety concerns. The FDA declined market approval of deferiprone; years later, it licensed the drug as "last resort" therapy, to be prescribed only if first-line drugs had failed. We undertook to evaluate the long-term effectiveness and toxicities of deferiprone and deferasirox in one transfusion clinic. METHODS AND FINDINGS: Under an IRB-approved study, we retrospectively inspected the electronic medical records of consented iron-loaded patients managed between 2009 and 2015 at The University Health Network (UHN), Toronto. We compared changes in liver and heart iron, adverse effects and other outcomes, in patients treated with deferiprone or deferasirox. RESULTS: Although deferiprone was unlicensed in Canada, one-third (n = 41) of locally-transfused patients had been switched from first-line, licensed therapies (deferoxamine or deferasirox) to regimens of unlicensed deferiprone. The primary endpoint of monitoring in iron overload, hepatic iron concentration (HIC), increased (worsened) during deferiprone monotherapy (mean 10±2-18±2 mg/g; p < 0.0003), exceeding the threshold for life-threatening complications (15 mg iron/g liver) in 50% patients. During deferasirox monotherapy, mean HIC decreased (improved) (11±1-6±1 mg/g; p < 0.0001). Follow-up HICs were significantly different following deferiprone and deferasirox monotherapies (p < 0.0000002). Addition of low-dose deferoxamine (<40 mg/kg/day) to deferiprone did not result in reductions of HIC to <15 mg/g (baseline 20±4 mg/g; follow-up, 18±4 mg/g; p < 0.2) or in reduction in the proportion of patients with HIC exceeding 15 mg/g (p < 0.2). During deferiprone exposure, new diabetes mellitus, a recognized consequence of inadequate iron control, was diagnosed in 17% patients, most of whom had sustained HICs exceeding 15 mg/g for years; one woman died after 13 months of a regimen of deferiprone and low-dose deferasirox. During deferiprone exposure, serum ALT increased over baseline in 65% patients. Mean serum ALT increased 6.6-fold (p < 0.001) often persisting for years. During deferasirox exposure, mean ALT was unchanged (p < 0.84). No significant differences between treatment groups were observed in the proportions of patients estimated to have elevated cardiac iron. CONCLUSIONS: Deferiprone showed ineffectiveness and significant toxicity in most patients. Combination with low doses of first-line therapies did not improve the effectiveness of deferiprone. Exposure to deferiprone, over six years while the drug was unlicensed, in the face of ineffectiveness and serious toxicities, demands review of the standards of local medical practice. The limited scope of regulatory approval of deferiprone, worldwide, should restrict its exposure to the few patients genuinely unable to tolerate the two effective, first-line therapies.

Dysregulated arginine metabolism and cardiopulmonary dysfunction in patients with thalassaemia.

Pulmonary hypertension (PH) commonly develops in thalassaemia syndromes, but is poorly characterized. The goal of this study was to provide a comprehensive description of the cardiopulmonary and biological profile of patients with thalassaemia at risk for PH. A case-control study of thalassaemia patients at high versus low PH-risk was performed. A single cross-sectional measurement for variables reflecting cardiopulmonary status and biological pathophysiology were obtained, including Doppler-echocardiography, 6-min-walk-test, Borg Dyspnoea Score, New York Heart Association functional class, cardiac magnetic resonance imaging (MRI), chest-computerized tomography, pulmonary function testing and laboratory analyses targeting mechanisms of coagulation, inflammation, haemolysis, adhesion and the arginine-nitric oxide pathway. Twenty-seven thalassaemia patients were evaluated, 14 with an elevated tricuspid-regurgitant-jet-velocity (TRV) ≥ 2·5 m/s. Patients with increased TRV had a higher frequency of splenectomy, and significantly larger right atrial size, left atrial volume and left septal-wall thickness on echocardiography and/or MRI, with elevated biomarkers of abnormal coagulation, lactate dehydrogenase (LDH) levels and arginase concentration, and lower arginine-bioavailability compared to low-risk patients. Arginase concentration correlated significantly to several echocardiography/MRI parameters of cardiovascular function in addition to global-arginine-bioavailability and biomarkers of haemolytic rate, including LDH, haemoglobin and bilirubin. Thalassaemia patients with a TRV ≥ 2·5 m/s have additional echocardiography and cardiac-MRI parameters suggestive of right and left-sided cardiac dysfunction. In addition, low arginine bioavailability may contribute to cardiopulmonary dysfunction in ß-thalassaemia.

Hepcidin is suppressed by erythropoiesis in hemoglobin E ß-thalassemia and ß-thalassemia trait.

Hemoglobin E (HbE) ß-thalassemia is the most common severe thalassemia syndrome across Asia, and millions of people are carriers. Clinical heterogeneity in HbE ß-thalassemia is incompletely explained by genotype, and the interaction of phenotypic variation with hepcidin is unknown. The effect of thalassemia carriage on hepcidin is also unknown, but it could be relevant for iron supplementation programs aimed at combating anemia. In 62 of 69 Sri Lankan patients with HbE ß-thalassemia with moderate or severe phenotype, hepcidin was suppressed, and overall hepcidin inversely correlated with iron accumulation. On segregating by phenotype, there were no differences in hepcidin, erythropoiesis, or hemoglobin between severe or moderate disease, but multiple linear regression showed that erythropoiesis inversely correlated with hepcidin only in severe phenotypes. In moderate disease, no independent predictors of hepcidin were identifiable; nevertheless, the low hepcidin levels indicate a significant risk for iron overload. In a population survey of Sri Lankan schoolchildren, ß-thalassemia (but not HbE) trait was associated with increased erythropoiesis and mildly suppressed hepcidin, suggesting an enhanced propensity to accumulate iron. In summary, the influence of erythropoiesis on hepcidin suppression associates with phenotypic disease variation and pathogenesis in HbE ß-thalassemia and indicates that the epidemiology of ß-thalassemia trait requires consideration when planning public health iron interventions.

Management of the thalassemias.

During the last 30 years, in addition to the considerable progress made in control and prevention of thalassemias(3), there have also been major advances in their symptomatic management, at least in wealthier countries where appropriate facilities are available. Remarkable improvements in survival in the severe forms of thalassemia have followed the more judicious use of blood transfusion and, in particular, the ability to manage the iron accumulation resulting from transfusion with its severe and ultimately lethal effects on endocrine and cardiac function.

Sildenafil therapy in thalassemia patients with Doppler-defined risk of pulmonary hypertension.

Pulmonary hypertension is a common but often overlooked complication associated with thalassemia syndromes. There are limited data on the safety and efficacy of selective pulmonary vasodilators in this at-risk population. We, therefore, designed a 12-week, open-label, phase 1/2, pilot-scale, proof-of-principle trial of sildenafil therapy in 10 patients with ß-thalassemia and at increased risk of pulmonary hypertension based on an elevated tricuspid regurgitant jet velocity >2.5 m/s on Doppler-echocardiography. Variables compared at baseline and after 12 weeks of sildenafil treatment included Doppler-echocardiographic parameters, 6-minute walked distance, Borg Dyspnea Score, New York Heart Association functional class, pulmonary function, and laboratory parameters. Treatment with sildenafil resulted in a significant decrease in tricuspid regurgitant jet velocity by 13.3% (3.0±0.7 versus 2.6±0.5 m/s, P=0.04), improved left ventricular end systolic/diastolic volume, and a trend towards a improved New York Heart Association functional class. No significant change in 6-minute walked distance was noted. Sildenafil was well tolerated, although minor expected adverse events were commonly reported. The total dose of sildenafil (mg) was strongly correlated with percent change in nitric oxide metabolite concentration in the plasma (ρ=0.80, P=0.01). There were also significant increases in plasma and erythrocyte arginine concentrations. Our study suggests that sildenafil is safe and may improve pulmonary hemodynamics in patients at risk of pulmonary hypertension; however, it was not demonstrated to improve the distance walked in 6 minutes. Clinical trials are needed to identify the best treatment strategy for pulmonary hypertension in patients with ß-thalassemia. (clinicaltrials.gov identifier: NCT00872170).

Treatment strategies for hemoglobin E beta-thalassemia.

Hemoglobin E beta (ß)-thalassemia (HbE thalassemia) is a very common form of ß-thalassemia that exhibits a heterogeneous clinical presentation and variable clinical course. The reasons for this extraordinary clinical heterogeneity are not completely understood. A number of factors, both genetic and environmental, appear to modify the severity of HbE thalassemia. There is also an emerging understanding that the HbE thalassemia phenotype may be unstable, which may reflect changes in adaptation to anemia and, possibly, attenuation of the erythropoietin response over time. These factors make it difficult to develop broad treatment guidelines. It is now generally appreciated that steady-state hemoglobin concentration may be of limited value to determine which patients need regular transfusions. Therefore, periodic reassessment of the need for transfusion therapy is recommended, and intermittent transfusion therapy may now be explored as an approach in this disorder.

Chelation use and iron burden in North American and British thalassemia patients: a report from the Thalassemia Longitudinal Cohort.

Morbidity and mortality in thalassemia are associated with iron burden. Recent advances in organ-specific iron imaging and the availability of oral deferasirox are expected to improve clinical care, but the extent of use of these resources and current chelation practices have not been well described. In the present study, we studied chelation use and the change in iron measurements in 327 subjects with transfusion-dependent thalassemia (mean entry age, 22.1 ± 2.5 years) from 2002-2011, with a mean follow-up of 8.0 years (range, 4.4-9.0 years). The predominant chelator currently used is deferasirox, followed by deferoxamine and then combination therapies. The use of both hepatic and cardiac magnetic resonance imaging increased more than 5-fold (P < .001) during the study period, leading to an 80% increase in the number of subjects undergoing liver iron concentration (LIC) measurements. Overall, LIC significantly improved (median, 10.7 to 5.1 mg/g dry weight, P < .001) with a nonsignificant improvement in cardiac T2* (median, 23.55 to 34.50 ms, P = .23). The percentage of patients with markers of inadequate chelation (ferritin > 2500 ng/mL, LIC > 15 mg/g dry weight, and/or cardiac T2* < 10 ms) also declined from 33% to 26%. In summary, increasing use of magnetic resonance imaging and oral chelation in thalassemia management has likely contributed to improved iron burden.

Hb E/beta-thalassaemia: a common & clinically diverse disorder.

Haemoglobin E-beta thalassaemia (Hb E/ß-thalassaemia) is the genotype responsible for approximately one-half of all severe beta-thalassaemia worldwide. The disorder is characterized by marked clinical variability, ranging from a mild and asymptomatic anaemia to a life-threatening disorder requiring transfusions from infancy. The phenotypic variability of Hb E/ß-thalassaemia and the paucity of long-term clinical data, present challenges in providing definitive recommendations for the optimal management of patients. Genetic factors influencing the severity of this disorder include the type of beta-thalassaemia mutation, the co-inheritance of alpha-thalassaemia, and polymorphisms associated with increased production of foetal haemoglobin. Other factors, including a variable increase in serum erythropoietin in response to anaemia, previous or ongoing infection with malaria, previous splenectomy and other environmental influences, may be involved. The remarkable variation, and the instability, of the clinical phenotype of Hb E beta-thalassaemia suggests that careful tailoring of treatment is required for each patient, and that therapeutic approaches should be re-assessed over-time.

Risk factors and mortality associated with an elevated tricuspid regurgitant jet velocity measured by Doppler-echocardiography in thalassemia: a Thalassemia Clinical Research Network report.

An elevated tricuspid regurgitant jet velocity (TRV) is associated with hemolysis and early mortality in sickle cell disease, yet risk factors, clinical parameters, and mortality associated with this biomarker in thalassemia are poorly defined. This report summarizes the prevalence of an elevated TRV in 325 patients screened by Doppler echocardiography in the Thalassemia Clinical Research Network. A documented TRV was reported in 148 of 325 (46%) of patients. Average age was 25.9 years (range, 5-56 years) and 97% were transfusion-dependent. Mean TRV was 2.3 ± 0.4 m/s (range, 0.2-3.5 m/s). An abnormal TRV ≥ 2.5 m/s was identified in 49 of 148 (33%) of patients with a documented TRV, 5% (8/148), with a TRV ≥ 3.0 m/s, suggesting significant PH risk. Older age was strongly associated with a high TRV; however, 16% of children had a TRV ≥ 2.5 m/s. A history of splenectomy, hepatitis C, smoking, or high white blood cell count was associated with TRV elevation. In summary, an elevated TRV is noted in one-third of transfusion-dependent thalassemia patients with a documented value and develops in both children and adults. Age, splenectomy, hepatitis C, and smoking are significant univariate risk factors, with splenectomy surfacing as the dominant risk factor over time. Mortality was low in this cohort. Prospective longitudinal studies are needed. This study is registered at http://www.clinicaltrials.gov as NCT00661804.

A pilot study of subcutaneous decitabine in ß-thalassemia intermedia.

Ineffective erythropoiesis, the hallmark of ß-thalassemia, is a result of α/non-α globin chain imbalance. One strategy to redress globin-chain imbalance is to induce γ-globin gene (HBG) expression. Repression of HBG in adult erythroid cells involves DNA methylation and other epigenetic changes. Therefore, the cytosine analog decitabine, which can deplete DNA methyltransferase 1 (DNMT1), can potentially activate HBG. In 5 patients with ß-thalassemia intermedia, a dose and schedule of decitabine intended to deplete DNMT1 without causing significant cytotoxicity (0.2 mg/kg subcutaneous 2 times per week for 12 weeks) increased total hemoglobin from 7.88 ± 0.88 g/dL to 9.04 ± 0.77 g/dL (P = .004) and absolute fetal hemoglobin from 3.64 ± 1.13 g/dL to 4.29 ± 1.13 g/dL (P = .003). Significant favorable changes also occurred in indices of hemolysis and red blood cell densitometry. Consistent with a noncytotoxic, differentiation altering mechanism of action, the major side effect was an asymptomatic increase in platelet counts without erythrocyte micronucleus or VDJ recombination assay evidence of genotoxicity. This study was registered at www.clinicaltrials.gov as #NCT00661726.

HbE/ß-thalassemia: basis of marked clinical diversity.

Hemoglobin E thalassemia accounts for about one-half of all cases of severe beta thalassemia. There is marked variability in its clinical severity ranging from an asymptomatic to a transfusion-dependent phenotype. The phenotypic variability and inadequate longitudinal data present challenges in determining the optimal management of patients. This article summarizes findings on the natural history of Hemoglobin E thalassemia and some factors responsible for its clinical heterogeneity. Major genetic factors include the type of beta thalassemia mutation, the co-inheritance of alpha thalassemia, and polymorphisms associated with increased synthesis of fetal hemoglobin. Other factors, including response to anemia, and the influence of infection with malaria and other environmental influences, may be important. The remarkable variation and instability of clinical phenotypes in Hemoglobin E thalassemia require individual management plans for each patient, which should be reassessed over time.

Emerging insights in the management of hemoglobin E beta thalassemia.

Globally, hemoglobin (Hb) E beta thalassemia accounts for approximately half the severe forms of beta thalassemia. Because of its wide clinical diversity and the ability of patients with this condition to adapt unusually well to low hemoglobin levels, the management of Hb E beta thalassemia, particularly the decision to instigate regular blood transfusion, is particularly difficult. Here, we present a summary of our work in patients with this condition, which attempts to define clinical, adaptive, and genetic factors of possible value in determining the early management of this condition.

Interaction of malaria with a common form of severe thalassemia in an Asian population.

In many Asian populations, the commonest form of severe thalassemia results from the coinheritance of HbE and beta thalassemia. The management of this disease is particularly difficult because of its extreme clinical diversity; although some genetic and adaptive factors have been identified as phenotypic modifiers, the reasons remain unclear. Because the role of the environment in the course of severe thalassemia has been neglected completely and because malaria due to both Plasmodium falciparum and Plasmodium vivax has been prevalent in Sri Lanka, we carried out a pilot study of patients with HbE beta thalassemia that showed high frequencies of antibodies to both parasite species and that 28.6% of the children had DNA-based evidence of current infection with P. vivax. Malarial antibodies then were assessed in patients with HbE beta thalassemia compared with those in age-matched controls. There was a significant increase in the frequency of antibodies in the thalassemic patients, particularly against P. vivax and in young children. There was also a higher frequency in those who had been splenectomized compared with those with intact spleens, although in the latter it was still higher than that in the controls. The thalassemic patients showed significant correlations between malaria antibody status and phenotype. Patients with HbE beta thalassemia may be more prone to malaria, particularly P. vivax, which is reflected in their clinical severity. Because P. vivax malaria is widespread in Asia, further studies of its interaction with HbE beta thalassemia and related diseases are required urgently as a part of ongoing thalassemia control programs.

Disparity in the management of iron overload between patients with sickle cell disease and thalassemia who received transfusions.

BACKGROUND: Transfusion therapy is frequently used to prevent morbidity in sickle cell disease (SCD), and subsequent iron overload is common. The objective of this study was to evaluate the current standard of care in monitoring iron overload and related complications in patients with SCD compared to thalassemia (Thal). STUDY DESIGN AND METHODS: A cross-sectional study was conducted at 31 hematology clinics in the United States, Canada, or the United Kingdom. Patients who received transfusions with a mean serum ferritin level of least 2000 ng per mL were eligible. A total of 199 patients with SCD (113 female; 24.9 +/- 13.2 years) and 142 with Thal (66 female; 25.8 +/- 8.1 years) were recruited, and data were collected between 2001 and 2003 by interview and medical record review. RESULTS: Although both groups were recruited on the basis of significant iron overload, the likelihood of performing a liver biopsy for routine iron monitoring was significantly higher (odds ratio [OR], 3.4; 95% confidence interval [CI], 2.2-5.3) in Thal than SCD. Thal patients were also more likely to be screened for iron-related organ injury including an echocardiograph for cardiomyopathy (OR, 2.6; p < 0.001; 95% CI, 1.6-4.2), alanine aminotransferase for liver function (OR, 8.3; CI, 1.05-64.4), and thyroid-stimulating hormone for hypothyroidism (OR, 12.3; CI, 7.0-21.5). For adult SCD patients, those maintained on simple transfusion with a serum ferritin level of greater than 2500 ng per mL were the least likely to have a liver biopsy (p < 0.03). CONCLUSIONS: These data highlight the unsystematic monitoring of iron and related organ injury in SCD. Until the relationship between iron and related comorbidities is better understood, routine monitoring of iron overload in SCD patients who receive transfusions should be considered a standard part of clinical care.