Field News

Hemoglobinopathy and Iron Overload Research Program Registry
Specific Aim: to intensify our comprehension of Hemoglobinopathies and Iron Overload disorders and consequently improve the management, treatment, and clinical outcomes for patients affected by these illnesses. This study is two-fold, firstly a registry will be created that will describe the prevalence of different types of Hemoglobinopathies and iron overload disorders. Secondly, the frequency of specific complications related to these disorders in a sample of patients attending the University Health Network (UHN) Red Cell Disorders Clinic will be examined.

Background and Rationale: Given the potential for life-threatening consequences of Hemoglobinopathies and iron overload disorders, an enhanced understanding of the occurrence and the clinical course of these complications is crucial to optimize their management, treatment, and clinical prognosis. This study aims to enroll approximately 150 consenting patients with hemoglobin and iron overload disorders, with the purpose of creating a comprehensive registry of clinical care baseline data (including type of diagnosis and complications related to these disorders). The registry will contain data for an assembly of patients being treated at the UHN Red Cell Disorders Clinic (Toronto, Ontario), collected by review of medical records and brief patient interviews (non-structured interviews will be used only if information is not contained within medical records).

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Sexual Maturation and Hepatic Iron Study
Specific Aim: to examine the relationship between sexual maturation/gonadal function and hepatic iron concentration (HIC) in a sample of transfused individuals with β -Thalassemia Major, furthering the effort to better understand and manage some of the serious consequences of iron overload. Specifically, this study will attempt to (a) identify a threshold of hepatic (liver) iron concentration, above which sexual maturation/gonadal function is impeded, and (b) to determine if iron toxicity is a function of cumulative iron exposure or short-term exposure to high iron concentrations.

Background and Rationale: Hepatic iron concentration directly correlates with body iron burden, both of which can lead to serious health issues and premature death. Liver iron concentrations associated with excess mortality from cardiac disease and liver disease are generally well known. Despite the established link between iron burden, delayed sexual maturation and impaired gonadal function, the relationship between liver iron concentration and the presentation of gonadal function is still relatively unfamiliar.

Consenting patients with β- thalassemia major and transfusional iron overload will be enlisted for this retrospective chart-based review. Medical records will be used to obtain an accurate assessment of patients' past medical history (including HIC, serum ferritin concentrations, sexual function, history of hormone replacement therapy medications, and history of other diseases/illnesses). No direct contact with patients will be necessary for this study, as medical records are the only required source of data.

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Investigating the Factors Promoting Increased Rate and Success of Pregnancy in Thalassemia Patients in Toronto
Specific Aim: a) to investigate potential factors affecting the rate and success of pregnancy in patients with Thalassemia Major in Toronto, Ontario, Canada. b) to analyze patients with Thalassemia who have fathered children

Background and Rationale: Due to the enhancements in treatment over the past 40 years, patients with Beta-Thalassemia in North America now have a life expectancy up to the fifth and sixth decades of life. As a result, a therapy regarding fertility and childbearing has become a growing concern. While reports regarding the achievement of conception, management and outcome of pregnancy in beta-thalassemic patients have been described from clinics worldwide, information regarding the North American population remains incomplete. As life expectancy increases and overall health improves, clear data on fertility, pregnancy complications, and the maternal health of patients with Thalassemia is required to ensure optimal patient care and quality of life.

Data regarding potential factors affecting pregnancy will be collected using the medical charts of a sample of consenting patients who are participating in the Thalassemia Program (ideally an unique population of women with Thalassemia who have been studied over the past 20 years). Information concerning transfusion and chelation history, achievement of menarche or sexual maturation, methods involved in conception, management of pregnancy, possible risks and complications of pregnancy, and delivery and post-partum outcomes will be collected. Patients will only be interviewed if there is insufficient information or details within their medical reports.

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Thalassemia Longitudinal Cohort (TLC) Study
Specific Aim: to enhance the clinical understanding, management and treatment of thalassemia by closely examining many central aspects of the chronic disease. These central features include: the prevalence and incidence of complications, fertility and pregnancy outcomes, causes of mortality and changes in mortality risk (depending on methods of diagnosis and treatment), variations in Thalassemia diagnoses and presentations, body iron burdens, the adherence and quality of life among a population of patients with the disease. This study will also determine the availability of potential participants for other Thalassemia Clinical Research Network (TCRN) studies.

Background and Rationale: This study will collect clinical care data at the beginning of study (baseline) and annually for patients with Thalassemia. Not only will thorough and standardized annual assessments ensure well-tailored and optimal care for the participants of this study, but findings will also help improve the understanding, management, treatment, and quality of life of Thalassemia patients as a whole.

This prospective study will require consenting patients from the Red Cell Disorders clinic at UHN to attend the study clinic annually after their initial visit for data collection. Specifically, patients will be asked questions regarding their medical history (i.e. patient health, family history, complications related to Thalassemia, chelation therapy, reproductive health, cigarette and alcohol use, and medications) and will be administered quality of life, nutritional status and adherence questionnaires. A blood sample will also be required for genetic testing, to determine the type of Thalassemia and the specific genes causing the disease. Patients' medical charts will be reviewed to collect information regarding blood transfusions and additional information on medical history (i.e. major diagnoses).

Participants enrolling as successful stem cell transplant (SCT) recipients will have a pre- and post-SCT evaluation, which will include all of the above data collection barring the blood test and questionnaires. A single follow-up visit is required approximately one year following participation which will require a review of medical and reproductive history and details of the SCT and phlebotomy (collection of blood) or chelation performed following the SCT.

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Complications of Iron Overload (CIO): A Longitudinal Study of Thalassemia in Canada
Specific Aim: to characterize the development of complications in 200 Thalassemia patients from centers across Canada over an extended period of time.

Background and Rationale: With the development of improved transfusion and iron-chelating therapy programs, life expectancy in patients with Beta-Thalassemia has greatly improved in North America. Therefore, a longitudinal study monitoring complications of Thalassemia in Canada over time will be an invaluable tool for the development of more coherent and comprehensive management standards in treating Thalassemia.

This study will employ a retros pective chart review for consenting patients in participating centers across Canada. Data will be collected from medical records that correspond to the period of time in which the patients were followed in the clinic, and will include: demographic information, age of diagnosis, longitudinal profile of iron burden, a profile of adherence, effectiveness and toxicities regarding iron-chelaton treatment, and a profile of complications relating to Thalassemia. Only in rare circumstances, where patient information is incomplete or absent from their medical records, will patients be interviewed. Also, if a patient was managed outside of the study clinic they too may be contacted to obtain relevant information pertaining to the study. Standardized quality of life questionnaires (SF36v2/CHQ) will also be administered. Note: This will be the first effort to systematically characterize quality of life status among Thalassemia patients with a standardized instrument that is globally available and in many validated languages.

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Multi-Center Study of Iron Overload (MCISO) -Survey Study: Examining Mechanisms of Iron Trafficking
Specific Aim: to assess the risk of cardiac and pituitary iron deposition among patients with Sickle Cell Disease (SCD), Thalassemia Major (TM), and Diamond-Blackfan Anemia (DBA) who share a common need in requiring blood transfusions.

Background and Rationale: While not yet systematically examined, preliminary findings suggest that iron distribution resulting from transfusional iron overload may differ between SCD and TM. With the introduction of MRI techniques to estimate iron concentrations in tissues, the possibility now exists to compare iron distribution outside the liver in multi-transfused patients with SCD, TM, and DBA and better understand the molecular mechanisms controlling iron. Investigating the mechanisms behind iron loading is of extreme importance given the detrimental consequences of surplus iron in the body (i.e. heart failure, liver damage, endocrine gland damage, delayed/stunted growth, delayed or lack of sexual maturation, diabetes and premature death).

Data collection will be done by the review of consenting patients' medical charts and laboratory measurements for the past two years. Collected information will pertain to patients': general medical history, iron burden (liver iron biopsy and average annual ferritin values), transfusion history, and chelation history. No direct contact with participants is necessary for this study.

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Bisphosphonate Analysis
Specific Aim: to assess the risk of cardiac and pituitary iron deposition among patients with Sickle Cell Disease (SCD), Thalassemia Major (TM), and Diamond-Blackfan Anemia (DBA) who share a common need in requiring blood transfusions.

Background and Rationale: Bisphosphonates are effective anti-resorptive agents reported to reduce the risk of bone fractures, but there have been recent concerns about a potential link between bisphosphonate therapy and atrial fibrillation. Moreover, limited clinical information currently exists regarding the possible risks associated with long-term bisphosphonate therapy. It is vital to determine the effectiveness and potential harms of this treatment, particularly in a population of Thalassemia patients, who are prone to osteoporosis and have an increased risk of atrial fibrillation due to cardiac iron overload.

This study will collect data both retrospectively (collected from past records) and prospectively (continuously over time). Information to be obtained retrospectively will include: history of chelation, history of alcohol and caffeine use, the most recent results of a variety of cardiac tests and Holter-monitoring, history of bisphosphonate use, iron burden, and patient's height and weight. Data to be prospectively include: 24-hour Holter monitoring, ECG, blood test to determine if there are other clinical predictors of atrial fibrillation that may be missed during the Holter monitoring, DEXA scan, and a Lifestyle Questionnaire to screen for confounding factors that may increase risk.

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A Pilot Study of Subcutaneous 5-aza-2i Deoxycytidine (Decitabine) in Patients with Thalassemia
Specific Aim: to assess the safety and ability of low-dose Decitabine to increase the total hemoglobin concentration in patients with Beta-Thalassemia Intermedia.

Background and Rationale: Thalassemia intermedia is a serious condition that can lead to bone abnormalities, endocrine failure, cardiac dysfunction, iron overload and pulmonary hypertension. These complications progress over the years and can lead to transfusion dependence in adolescence or young adulthood. Decitabine has demonstrated the ability for a considerable sustained increase in hemoglobin F and total hemoglobin in patients with sickle cell disease (SCD) and may have similar effect in those with thalassemia. Assessing the efficacy and risks associated with this drug will in add to the scientific evidence regarding this treatment and could substantially benefit Thalassemia patients if uptake is deemed safe and effective.

Approximately 8 Beta-Thalassemia Intermedia patients will be recruited for this study and will be injected with Decitabine twice a week for a total of 12 weeks. Baseline data to be collected include: average hemoglobin concentration over 8 weeks, folic acid status, detailed medical history, past transfusion requirement, measures of hemolysis and erythropoiesis status, and special red blood cell (RBC) biology test results. Increased total hemoglobin among our sample will be measured by the proportion of participants achieving a peak increase in hemoglobin of 1.5 g/dL or more. Changes in total hemoglobin established on percentage of weeks, changes in mean total hemoglobin concentration, and changes in percentage hemoglobin F will also be determined; as will the changes in hemolysis, erthropiesis, and RBC characteristics compared with baseline.

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Pilot Study of Oral Sildenafil for the Treatment of Pulmonary Hypertension (PHT) in Thalassemia Patients
Specific Aim: to investigate Sildenafil as a potential treatment for pulmonary hypertension (high blood pressure originating in the arteries of the lungs) in patients with Thalassemia.

Background and Rationale: Currently, there is no standard therapy to treat PHT in patients with Thalassemia, which when left untreated can lead to additional complications (such as shortness of breath and decreased ability to tolerate exercise). While there exist various medications for pulmonary hypertension (i.e Sildenafil), none have been investigated in patients with both Thalassemia and PHT.

Consenting Thalassemic patients will be tested for PHT using an echocardiogram (ultrasound of the heart and lungs). Those with confirmed PHT will be placed on Sildenafil treatment, while patients without PHT will act as “controls” for the duration of the study (12 weeks). These controls will not be given Sildenafil or any other study treatment. Approximately 4 to 5 clinic visits will be required, comprised of a(n): medical history (obtained through patient interviews and medical records), physical exam (similar to those conducted for a Thalassemia clinic visit), 6 minute walk test , echocardiogram, blood test (for regular blood counts, kidney and liver function tests, hemoglobin and iron burden tests), urine tests, pulmonary function testing (to assess lung function), chest MRI, and chest CAT scan (to observe lung structure and search for signs of pulmonary hypertension).

Pain Occurrence and Management in Thalassemia Patients
1. Assessment of Pain Survey
2. Assessment of Pain in Transfusion Dependent Thalassemia Patients during Transfusion
Specific Aim:
Assessment of Pain Survey
This study aims to increase the awareness and understanding of pain and Thalassemia. Its primary goals are to (a) assess the prevalence of pain in subjects with transfusion and non-transfusion dependent Thalassemia, (b) identify the most common sites of pain (by age, gender and diagnosis), and determine if there is a relationship between these variables and severity of pain, (c) assess the impact of pain on participant functioning and well-being, and (d) determine if the relationship between participant's reports of pain and the effectiveness of treatment/medication varies over time.

Assessment of Pain in Transfusion Dependent Thalassemia Patients during Transfusion
This study aims to assess whether (a) reports of pain vary over the transfusion cycle, (b) the length of the transfusion cycle affects pain level and (c) pain varies by pre-transfusion hemoglobin and reticulocyte (immature blood cells) levels. Both of these elements are important in determining factors related to pain and ways in which pain can be understood, anticipated, and minimized.

Background and Rationale:
Because chronic pain and its appropriate management have been identified by patients and providers as an emerging issue, this study will evaluate if and when pain becomes a concern. Moreover, this study will determine possible sources of pain, which have not yet been described in the literature due to the lack of studies in this particular area. Understanding and managing triggers of pain may lead to improvements in clinical care and to increased quality of life for patients with Thalassemia.

Assessment of Pain Survey
Pain will be assessed using the Brief Pain Inventory, administered four times over the course of nine months in three patient populations: Transfused patients (individuals who received eight or more transfusions in the last year), intermittently transfused patients (individuals who received fewer than eight transfusions in the last year), and non-transfused patients (individuals who were not transfused in the last year). Patients between 12 and 18 years old will also be given the Adolescent Pediatric Pain Tool to assess the correlation between the two questionnaires.

Assessment of Pain in Transfusion Dependent Thalassemia Patients during Transfusion:
Consenting patients will complete a daily pain assessment during three separate transfusion cycles, separated by at least three months. Data collection will begin on the first day of transfusion and continue until the day before the next transfusion. Pre-transfusion (done immediately before scheduled transfusion) CBC with hemoglobin and reticulocyte levels will be recorded by chart review for each transfusion cycle during which pain data is collected.

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Peer Mentoring Study Summary
Specific Aim: to investigate and facilitate change towards patient adherence in iron-chelation therapy in adolescents with Thalassemia Major.

Background and Rationale: From the population of patients with Thalassemia Major, adolescents show decreased adherence, which leads to iron overload, resulting in morbidity and premature death. The exploratory project is a proof‐of‐concept investigation of a complex contextual intervention in a group of young adult thalassemia patients needing chronic blood transfusions and iron chelation therapy.

Our approach is innovative, and is designed to create a situated learning environment that alters an individual's cognitive understanding of their clinical situation, enables them to practice self‐management, and reference their efforts within a patient community that should lead to changes in their self‐management decision pathway. We accomplish this through a system that provides personalized health information, peer mentoring where patients receive active feedback on self‐management approach and practice, and a new context that gives this information and changed behaviours meaning. The intervention should improve patient adherence with iron‐chelation therapy.

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Asian Thalassemia Network
Specific Aim: to permit every country especially across Asia to benefit from expertise to improve the health and lives of children with Thalassemia.

Background and Rationale: Despite the severe health burden of Thalassemia in Asia, it has been difficult to persuade international health agencies and governments that, compared with infectious diseases, thalassemia is a problem of genuine public health importance. In 2004 however, a World Health Organization report Genomics and World Health used hemoglobin disorders to demonstrate the importance of developing genetic services and recommended that local network be established to help member countries develop these services.

Currently, expertise in the diagnosis, control and management of thalassemia varies from country to country. A network would establish a working group to best determine how every country could benefit most from shared expertise. In practice, this would entail regular meetings about advances in current practice, the establishment of workshops for training in topics like genetic screening, counselling, laboratory diagnosis, control, and management.

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