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NIH-NHLBI/NIDDK Thalassemia Workshop: Clinical Priorities and Clinical Trials
Fishers Lane Conference Center
May 20-21, 2009
On May 20 and 21, 2009, the National Heart, Lung, and Blood
Institute (NHLBI) and the National Institute of Diabetes and Digestive and
Kidney Diseases (NIDDK) convened a workshop to discuss priorities for
thalassemia research and clinical trials. Thalassemia major affects
approximately 1,000 persons in the U.S., however, increased immigration to the
U.S. is increasing the prevalence and broadening the demographics of
thalassemia. The goal of the workshop was to identify clinical research needs
and trials to reduce the burden of disease.
Investigators, clinicians, and patient advocates identified
priorities for clinical research and discussed study infrastructure and
international collaborative opportunities. Key areas for the successful
completion of clinical trials in thalassemia include:
- Forming international collaborations to increase and expand
- Keeping the goals, protocols and organizational structure as
simple as possible
- Facilitating cooperation among the investigators designing and
conducting the studies and clinical research organizations with expertise in
regulatory issues for each country
- Enhancing protocol design by seeking input from thalassemia
patients and families
- Developing a framework that rewards key investigators for
timely attainment of study milestones
Meeting attendees identified high priority scientific areas
- Studying chelation therapy to determine factors that may
predispose to poor responses to chelation and determining optimal management of
chelation therapy in children to prevent iron overload; preventing iron injury
and identifying factors that modulate iron distribution and toxicity
- Investigating the molecular and cellular mechanisms that
underlie globin gene activation and silencing; developing robust laboratory
drug screening techniques that are applicable to thalassemia
- Determining the optimal period of bisphosphonate treatment to
improve the low bone mass of thalassemia patients and studying the long-term
safety profile of bisphosphonate therapy; investigating the risks and benefits
of vitamin D therapy in children, adolescents and chronically transfused
- Testing the feasibility and efficacy of haplo-identical
transplantation for thalassemia; developing a reduced intensity transplantation
regimen that will permit hematopoietic stem cell transplantation in a broader
range of patients
- Improving the efficiency of stem-cell targeted gene transfer;
determining the degree of myelosuppression required for high-level engraftment
of genetically modified stem cells
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Structure and Content of the
Subcommittees of experts assembled before the workshop to develop
opinions on five topics:
- Iron Overload: Clinical Monitoring and Chelation Therapy
- Fetal Hemoglobin
- Stem Cell Transplantation
- Gene Therapy
- Endocrine Disorders/Bone Disease/Growth and Development
Each subcommittee considered four questions:
- What are the clinical research priorities currently facing the
- What are the most important clinical trials (Phase I, II, and
III) that should be undertaken?
- How can successful study completion and patient recruitment be
- What is the role of international collaborations in thalassemia
The first day of the workshop, representatives from each
subcommittee presented recommendations for clinical research priorities. On the
second day of the workshop, experts in thalassemia clinical trial research
described the current status of clinical trials conducted in the U.S. and
Thailand. The workshop was co-chaired by Drs. Suthat Fucharoen of the
Thalassemia Research Center, Institute of Science and Technology for Research
and Development, Mahidol University, Thailand and Dr. Cheryl Hillery, Professor
of Pediatrics at the Medical College of Wisconsin. The NHLBI Deputy Director,
Dr. Susan Shurin, underscored the need for workshop attendees to address issues
of public health, critical scientific questions and opportunities in
thalassemia globally, such as the state of curative and supportive care, how to
prolong longevity, and priorities for undertaking research activities that
would yield the largest payoff for the most patients. Drs. Griffin Rodgers,
Director, NIDDK, and Dr. W. Keith Hoots, Director, Division of Blood Diseases
and Resources, NHLBI welcomed the participants and endorsed the need for a
global approach to thalassemia clinical research. Information provided at the
workshop will help inform NHLBI and NIDDK in the development of future
thalassemia research initiatives.
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Reports From Subcommittees
Iron Overload: Clinical Monitoring and Chelation Therapy
- Chelation therapy studies should evaluate: combined and/or
serial usage of licensed drugs such as deferasirox and deferoxamine or
deferasirox and deferiprone; novel iron chelators; genetic or other factors
that may predispose to poor chelation response; optimal management of chelation
therapy in young children to prevent iron overload; optimal usage of T2* and
magnetic resonance imaging to guide chelation therapy; and prospective
long-term chelation compliance.
- Studies should determine whether antioxidant therapies are
beneficial in preventing iron injury.
- Studies of hepcidin are needed in thalassemia animal models
and patients to: understand the role of anemia, hypoxia, ineffective
erythropoiesis and iron overload on hepcidin synthesis; determine whether
measurement of plasma hepcidin has prognostic utility; and determine whether
hepcidin agonists modify transfusional iron overload and decrease iron
distribution to the heart and gastrointestinal tract.
- Clinical studies are needed to: identify factors that modulate
iron distribution and toxicity; study variations in distribution of
extra-hepatic iron from patient to patient; determine genetic modifiers that
may affect iron distribution; and examine environmental or treatment-related
differences (other than chelation therapy) such as blood transfusion strategy
that affect iron distribution.
- Non-transferrin bound plasma iron (NTBI) should be studied to:
better determine the mechanisms of cellular uptake; define the nature and
speciation of NTBI; identify the factors determining NTBI levels; and clarify
the relationship between NTBI and speciation with extra-hepatic iron
- Magnetic resonance imaging studies should be conducted to
study the relationship between endocrine iron loading and end-organ
- Molecular and cellular studies are needed to better understand
globin gene activation, switching and silencing. It is important to identify
the drivers of globin activation and silencing to enable therapeutic
interventions that are more locus restricted.
- A central database of all compounds identified as having HbF
induction potential and a central drug development resource should be
- Robust laboratory drug screening techniques need to be
developed that are applicable to thalassemia.
- Clinical trials should be undertaken with DNA
methyl-transferase inhibitors and short-chain fatty acids.
- The Electronic Infrastructure for Thalassemia Research Network
(Ithanet), a Euro-mediterranean network of research centers conducting
molecular and clinical research of thalassemia and related hemoglobinopathies,
should be used for conducting international clinical trials.
Endocrine Disorders/Bone Disease/Growth and Development
- Low bone mass affects approximately two-thirds of thalassemia
patients. Treatment with bisphosphonates improves the low bone mass of
thalassemia patients, however, additional trials are needed, especially in
children and adolescents, to determine the optimal duration, dose and schedule
of treatment and a long-term safety profile of bisphosphonate therapy.
- Trials of anti-resorptives, bone anabolic agents, vitamin D,
physical activity, and combination therapies are needed for patients who fail
to respond to bisphosphonate therapy.
- Vitamin D abnormalities are prevalent in thalassemia. Studies
are needed, particularly in children, adolescents and chronically transfused
patients, to evaluate vitamin D dosage on bone mass, inflammation, immune
responses and cardiac function.
- Studies are needed to determine the effects of iron overload
and chelation on gonadal function and fertility.
- Trace element deficiencies (zinc, copper and selenium) are
more common in thalassemia than healthy cohorts and have been linked to altered
immune function and low bone mass. Deferiprone induces zinc deficiency in
approximately 15 percent of thalassemia patients. Studies are needed to
determine the effects of optimal deferasirox dosage on trace elements and the
effect of micronutrient replacement on chelator efficacy.
- Diabetes occurs in 10 percent of thalassemia patients. Studies
are needed to define the cardiovascular complications of glucose abnormalities
and to identify optimal treatment options for impaired glucose tolerance in
aging thalassemia patients.
Stem Cell Transplantation
- More than 900 thalassemia patients have received
sibling-matched blood or marrow hematopoietic stem cell (HPSC) transplants with
an overall survival rate of 73 percent. Since only 25 percent of patients have
a matched HSPC related donor, there is a vital need for alternative donors and
transplantation strategies. Pilot studies are needed to test the safety and
efficacy of haplo-identical transplantation and reduced intensity conditioning
- Transplantation studies should evaluate the role of
alloimmunization in transplant outcomes and optimal strategies to prevent and
control graft versus host disease.
- Prognostic factors which predict complications and early death
in thalassemia should be refined to better identify transplantation risks.
- For gene therapy to succeed in ß-thalassemia patients,
clinically effective levels of vector-transduced, normal ß-globin gene
expression and HPSC chimerism are necessary. Small scale, pilot clinical
studies and concurrent primate studies are needed to improve the efficiency of
HSPC-targeted gene transfer and to determine the myelosuppression level
required for stable engraftment of genetically modified cells.
- Patients should be carefully screened to identify those who
have residual capacity for red cell production to enhance the efficacy of gene
- Studies are needed to determine the safety and feasibility of
cytokine (Granulocyte-Colony Stimulating Factor and other agents) mobilization
and transduction of peripheral HSPC from thalassemia patients.
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Clinical Trials in Thalassemia
The Thalassemia Clinical Research Network: Accomplishments and
Janet Kwiatkowski, MD, Thalassemia Program, Children's Hospital of
Philadelphia, University of Pennsylvania School of Medicine and Ellis Neufeld,
M.D., Ph.D., Children's Hospital Boston reviewed the accomplishments and
challenges of the Thalassemia Clinical Research Network (TCRN).
The TCRN, funded by the NHLBI (2000-2005 and competitively renewed
2005-2010), consists of six core clinical sites, 26 satellite sites throughout
the United States, Canada, and England, and a Data Coordinating Center (New
England Research Institute). The TCRN's goal is to accelerate research in the
management of thalassemia through multicenter trials.
The TCRN strengths include: the thalassemia experts and
statisticians who develop studies and identify important research goals and
findings; access to a critical mass of patients for studies; a website that
facilitates communication, data analysis and publications; collaborations
between core and satellite sites, and with CDC Surveillance Project, the
Cooley's Anemia Foundation, other countries, other networks, and pharmaceutical
companies; and, support for junior investigators to perform and publish
The TCRN developed a study Registry and the following
- The Longitudinal Cohort Study (TLC) builds baseline data and
other information from the Registry by adding annual data collection to
describe genotype-phenotype variability, the prevalence and incidence of
complications specific to thalassemia and its treatment, assessments of iron
burden and therapeutic adherence, and quality of life.
- Objectives of the Cross Sectional Observational Study of Low
Bone Mass in Thalassemia are to determine the prevalence of low bone mass,
fractures, and bone pain and evaluate the interaction of endocrine, genetic and
environmental factors as well as transfusion and chelation regimens on the
development of low bone mass.
- The Pilot Study of Response of Oxidant-Stress Induced Injury
and Mitochondrial Dysfunction Biomarkers to Treatment with Iron Chelators is an
ancillary study to the Novartis ICL-670 107 study which estimates the magnitude
of iron-induced oxidative stress and inflammation and compares deferoxamine
with deferasirox treatments.
- The Assessment of Pain Survey is a survey to assess the
prevalence of pain in subjects with transfusion and non-transfusion dependent
Five major interventional trials in the TCRN include:
- Safety and efficacy of Peg-interferon and ribavirin for the
treatment of hepatitis C
- Phase 2 randomized, double-blind, placebo controlled trial
comparing the effect of deferoxamine with and without oral deferiprone on left
ventricular function in adults with transfusion-dependent thalassemia
- Phase 2A study of subcutaneous decitabine in patients with
- Pilot study of oral sildenafil for the treatment of pulmonary
hypertension in thalassemia
- Reduced intensity unrelated donor HSPC transplantation
The major challenges for the TCRN include: the slow pace of
protocol development, patient enrollment, data analysis and manuscript
completion; the need to recruit patients from outside the U.S. because of the
small number of thalassemia patients in the U.S.; and, difficulties for
launching international sites (translation of numerous trial forms, differences
in local regulatory authorities, indemnification and insurance requirements in
the European Union).
Facilitating NIH-Funded International Clinical Trials in
Francis P. Crawley, MA, FFPM, Good Clinical Practices Alliance
Europe reviewed the European Directive as it pertains to conducting clinical
trials in the European Union (EU). EudraLex includes the rules governing
medical products in the EU, however, clinical investigators also must also
adhere to local and national rules. The International Good Clinical Practices
(GCP) framework includes: generalInternational Council on Harmonization
Good Clinical Practices and World Health Organization (WHO) Good Clinical
Practices; regional/appliedU.S. Code of Federal Regulations and EU GCP;
and national/appliedGCP guidelines apply to India, China, Russia,
Singapore, Malaysia, Indonesia, South America, South Africa, and Turkey.
The European Directive, implemented in 2001, directs national
governments to implement laws on GCP in the conduct of clinical trials for
medicinal projects for human use. This applies not only to pharmaceutical
companies, but also to investigators conducting clinical trials. It defines the
roles of the investigator, sponsor, competent authority (EU GCP inspections),
and has a review timeline of 60 days from the date of receipt of a valid
application to give its reasoned opinion. The structures and regulations differ
in Member States for IRBs and ethics committees. Many of these countries have
developed their own regulations for implementing the EU Directive. Differences
among member states pose special challenges including:
- Cooperation across member state borders and with third
countries (including U.S.)
- Education programs for Ethics Committee members
- Reviewing Suspected/Unexpected Serious Adverse Reactions
- Reviewing financial matters, including payments to subjects,
investigators, and sites
- Reviewing insurance and indemnity
- Patient representation on Ethics Committees
- Phase I clinical trials
- Pediatric clinical trials
Regulations governing pediatric clinical trials are similar to
U.S. regulations. To undertake pediatric studies in Europe, the European
Medicines Agency requires an early plan for review. The EU has regulations for
orphan drug development.
Major challenges include the lack of consistency across member
- The contents of the Clinical Trials Application
- The definition of an Investigational Medicinal Product
- The definition of substantial amendment
- Good Manufacturing Practices requirements for Investigational
Medicinal Medicinal Products
Clinical Trials in Thalassemia: Imperatives and Insights from the
Gina Cioffi, National Cooley's Anemia Foundation, reviewed the
Cooley's Anemia Foundation (CAF) perspective of clinical trials and provided
recommendations to enhance patient enrollment in studies.
Patient recruitment and enrollment in clinical trials is a major
challenge. Among people who suffer from severe chronic illness, only 6 percent
participate in clinical trials. Almost 50 percent of trial delays result from
patient enrollment problems and 86 percent of all U.S. clinical studies fail to
recruit the required number of subjects on time. Industry wide there is a 20-30
percent patient dropout rate in Phase II/III studies.
The CAF informs patients and families about trials to further the
conversation between the patient and the clinical investigator and the patient
and his/her physician without dispensing medical advice or encouraging consent
to take part in a trial. The CAF maintains a balance in presenting studies
available without overtly promoting an opportunity through a Thalassemia Action
Group newsletter, conferences and an interactive website listing studies and
other relevant information.
Consideration of the patient point of view can enhance an
investigational concept and lead to more rapid enrollment. Enrollment success
depends on a good fit among the protocol design, participant sites, and the
target population. The major challenges for patient are:
- Lack of patient/family role in design
- Participating while working
- Lack of follow up on trial conclusions.
Patients would like trials designed more to their convenience:
- Allow for hospital stays no longer than 3 days
- Conduct studies outside of TCRN sites
- Facilitate transportation.
- Consider motivators such as:
- Financial incentives
- Trials offering "hope"
- More assurance about safety
- More participation from younger adult patients
- More direct benefit to the adult patients
- A report showing academic and career success among
Recommendations for specific areas of study include:
- Effectiveness of L1 in raising T2*
- Quality of Life studies
- Additional study of chelation therapy
- Additional study on noninvasive iron measurements
- Clotting Risks
- Gene therapy
- Patients with low ferritins and abnormal T2*
Thalassemia in Southeast Asia An Overview
Suthat Fucharoen, MD, Thalassemia Research Center, Institute of
Science and Technology for Research and Development, Mahidol University
provided on overview of thalassemia demographics in Southeast Asia.
There is a high prevalence of thalassemia and abnormal hemoglobin
in Southeast Asia with variability of different ethnic-specific mutations in
each country: α-, β-thalassemia and abnormal hemoglobins (Hb) such as
Hb E and Hb Constant Spring are common in Southeast Asia; β-thalassemia
and Hb Constant Spring are scattered throughout the region at 1-8 percent,
however, α-thalassemia and Hb E are focal. In the northeastern part of
Southeast Asia, near Laos and north Thailand, α-thalassemia occurs at
frequencies of 30-40 percent. Hb E is common among the Thai-speaking population
living at the junction of Cambodia, Laos, and Thailand where the prevalence of
Hb E reaches 50-60 percent.
Thalassemia presents an increasingly severe public health burden
for many countries in Southeast Asia.
- It is difficult to diagnose thalassemia at small health care
units because of the heterogeneity of the disease and because carriers have no
- Treatment of severe thalassemia with regular blood transfusions
and iron chelation is expensive. Therapy is usually performed only in large
cities, which requires some patients to travel long distances. Bone marrow
transplantation, the only cure, is less expensive than long-term transfusion
and iron chelation therapy.
- Policies addressing prevention, such as screening for all
pregnant women, would be more cost effective than therapy.
- It is difficult to persuade international health agencies and
governments that thalassemia is a serious public health issue when compared
with communicable diseases that the countries are handling.
A WHO report adopted by the 57th World Health Assembly in 2004,
Genomics and World Health, recommended that local networks should be
established to help member countries evolve services. An Asian Network for
Thalassemia Control was formed to disseminate good practice in the control and
management of thalassemia in Asia and to provide a central forum for
interacting with individual governments and international health agencies to
provide support for the objectives. The objectives are:
- Develop and disseminate adequate screening techniques for
determining the frequency of the different forms of thalassemia in Asian
- Develop education and screening programs for prenatal
diagnosis of thalassemia,
- Develop more adequate approaches to treatment.
Recent Clinical Trials of Chelation Therapy in Thailand
Vip Viprakasit, MD, DPhil, FRCPT, Division of Haematology-Oncology
and WHO Collaborating Centre for the Control of Thalassaemia and
Haemoglobinopathies, Siriraj Hospital, Mahidol University Bangkok, Thailand
reviewed the status of clinical trials of chelation therapy in Thailand.
There are at least 500,000 people with thalassemia in Thailand,
with approximately 12,000 new cases annually, and 48,000 at-risk pregnancies.
More than 20,000 transfusion-dependent patients require regular transfusion and
life-long chelation therapy. An analysis of treatment compliance and related
health and social determining factors in Thai thalassemia patients under
long-term deferrioxamine (DFO) administration at Faculty of Medicine Siriraj
Hospital, Bangkok revealed that 40 percent of 112 pediatric patients with
severe thalassemia (49 percent receiving DFO therapy for 2-7 yrs and 51 percent
receiving DFO therapy for 7-17 yrs) were reported by their parents as having
good compliance with DFO therapy. However, only 14 percent of the cases studied
had an average serum ferritin (assayed during the prior year) of less than
2,500 ng/ml (a surrogate marker for adequate chelation therapy with
well-controlled iron burden).
Thailand is an ideal location for conducting an iron chelation
trial because of its large patient population and its experience with:
operating clinical studies under the GCP standard; thalassemia patient care;
protecting patient safety; and excellent technical and MRI capabilities.
Thailand has four transplant centers and is conducting a multi-center national
study on Thai Government-made oral chelator (GPO-L-ONE or deferiprone, DFP) and
also international studies on oral chelation therapy on Exjade (deferasirox,
Recent clinical studies on iron chelation therapy in Thailand
include ICL670 (Exjade) trials:
- 2409 (EPIC) & Cardiac sub-studies
- 2206 (DFO VS Exjade)
- 2209 (Exjade in Thal Intermediate)
- 2411 (Exjade in young patients; 2-6yrs)
- Exjade in other anemias: myelodysplastic syndrome.; and
Thailand also has undertaken multi-center national studies for
clinical efficacy and adverse effects of GPO-L-ONE (deferiprone). This trial,
which takes place at five centers in Bangkok, expects to enrol 150 patients (75
pediatric/75 adult) and to complete enrolment by the end of May 2009.
Fetal Globin Induction in Beta Thalassemia: Potential and
Pitfalls from Prior TrialsA Model for a Global Health Initiative
Susan Perrine, MD, Hemoglobinopathy Thalassemia Unit, Boston
University School of Medicine reviewed her clinical trial experience with
The hemoglobin switching field was founded decades ago for the
sole purpose of defining the molecular and cellular mechanisms of fetal globin
gene reactivation, with the goal of developing therapeutics to reverse the
natural silencing of the gene as a natural remedy for the beta globin diseases.
Fetal globin gene induction as a therapeutic modality is particularly appealing
- It is endogenous in all living humans.
- Continued expression is safe.
- Adequate expression is effective (thalassemia trait).
- It is integrated in hematopoietic stem cells.
Although there are challenges to reactivating the endogenous fetal
globin genes to therapeutic levels in the diverse thalassemias, the necessary
target level has been accurately identified to induce γ globin expression
enough for non-α globin chains to balance α globin chain synthesis by
65-70 percent (thalassemia trait ratios).
The proof of concept in reducing anemia and eliminating long-term
transfusion dependency in thalassemia has been established with three classes
of therapeutic candidates. These classes of therapeutics have produced
significant hematologic responses with rises in total hemoglobin (of 1-5
gms/dl) in the thalassemias:
- Chemotherapeutic (cytotoxic) agents 5 azacytidine,
- Short chain fatty acids (butyrate, phenylbutyrate, and
- Erythropoietin (EPO) and darbopoietin
The agents have corrected the phenotypes from thalassemia major,
intermedia, and trait. Synergistic activity has been found when combining two
groups of therapeutics: 5 azacytidine (demethylating agent) with butyrate, and
butyrate with EPO.
Therapeutic agents are needed that are more feasible for
widespread, global applicationoral agents that act at lower doses and are
patient friendly, ideally have dual actions of improving red blood cell
survival, not reducing red blood cell proliferation, and are safe for long term
use (not cytotoxic or mutagenic). One agent, HQK -1001, which was developed
entirely with NIH funding, has begun clinical testing in Thailand and Lebanon
for beta thalassemia and in the U.S. for sickle cell disease, supported by the
biotechnology company HemaQuest Pharmaceuticals, Inc.
Factors that influence responses in to Hb F induction and require
attention in clinical trial design include: baseline Hb F levels, baseline EPO
levels, splenectomy status, and iron supplements. Other factors that affect
responses include genetic modifiers and metabolism differences.
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List of Abbreviations
Cooley's Anemia Foundation
Thai government-made oral chelator, deferiprone
Hematopoietic stem cell
Deferiprone, manufactured by Lipomed AG,
Messenger ribonucleic acid
National Heart, Lung, and Blood Institute
National Institute of Diabetes and Digestive and Kidney
Non-transferrin bound plasma iron
Single nucleotide polymorphism
A magnetic resonance imaging technique used to quantify
tissue iron concentration in the heart and liver
Thalassemia Clinical Research Network
Thalassemia Longitudinal Cohort Study
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