BR J Haematol - 2023 - Hokland - Thalassaemia A Global View PDF

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Received: 25 November 2022 Accepted: 15 January 2023
DOI: 10.1111/bjh.18671
GLOBAL VIEW
Thalassaemia—A global view
Peter Hokland1 | Shahina Daar2 | Wael Khair3 | Sujit Sheth4 | Ali T. Taher5 |

Lorenza Torti6 | Chattree Hantaweepant7 | Deborah Rund8
1
Faculty of Health, Department of Clinical
Medicine, Aarhus University, Aarhus, Summary
Denmark The thalassaemias are a group of genetic disorders of haemoglobin which are en-
2
College of Medicine & Health Sciences, demic in the tropics but are now found worldwide due to migration. Basic stand-
Sultan Qaboos University, Muscat, Oman
3
ard of care therapy includes regular transfusions to maintain a haemoglobin level
Khartoum Oncology Hospital, Khartoum,
Sudan of around 10 g/dL, together with iron chelation therapy to prevent iron overload.
4
Division of Hematology Oncology, Novel therapies, bone marrow transplantation, and gene therapy are treatment op-
Department of Pediatrics, Weill Cornell tions that are unavailable in many countries with stressed economies. This Wider
Medicine, New York City, New York, USA Perspectives article presents the strategies for management of an adolescent refugee
5
Division of Hematology & Oncology, patient with beta thalassaemia, as it would be performed by expert haematologists in
Department of Internal Medicine, American
University of Beirut Medical Centre, Beirut, six countries: Italy, Lebanon, Oman, the Sudan, Thailand and the United States. The
Lebanon experienced clinicians in each country have adapted their practice according to the
6
Hemoglobinopathies Unit, Hematology resources available, which vary greatly. Even in the current modern era, providing
Department, S. Eugenio Hospital, (ASL Roma adequate transfusions and chelation is problematic in many countries. On the other
2), Rome, Italy
7
hand, ensuring adherence to therapy, particularly during adolescence, is a similar
Faculty of Medicine Siriraj Hospital, Division
of Hematology, Department of Medicine, challenge seen in all countries. The concluding section highlights the disparities in
Mahidol University, Bangkok, Thailand available therapies and puts the role of novel therapies into a societal context.
8
Department of Haematology, Hebrew
University-Hadassah Medical Centre, K EY WOR DS
Jerusalem, Israel
diagnosis, global view, refugee, thalassaemia, therapy
Correspondence
Peter Hokland, Faculty of Health, Department
of Clinical Medicine, Aarhus University,
Aarhus, Denmark.
Email: [email protected]
Deborah Rund, Department of Haematology,

Hebrew University-Hadassah Medical Centre
Jerusalem, Israel.
Email: [email protected]
I N T RODUC T ION economic environment. Patients, too, are not the same the
world over. Early presentation is more common in the devel-
Haematologists always seek to follow standardised guide- oped world as is the patient's understanding of the disease
lines for practice and apply the best treatment within their process. This in turn has an impact on the way patients are
means for patients with blood diseases. However, treatment managed, the rigorousness of patient adherence to the treat-
can never follow an exact procedure. Opinions differ as ment schedule and the outcome.
to the best approach; sometimes more than one treatment The thalassaemias constitute a heterogenous group of ge-
approach results in similar outcomes, or treatments differ netic disorders of haemoglobin (Hgb) synthesis with clinical
only by the manner in which they fail. Furthermore, the pictures ranging from practically symptom-free in thalas-
haematologist is faced with constraints relating to the local saemia trait to the debilitating and life-shortening illness
This is an open access article under the terms of the Creative Commons Attribution-NonCommercial License, which permits use, distribution and reproduction in any
medium, provided the original work is properly cited and is not used for commercial purposes.
© 2023 The Authors. British Journal of Haematology published by British Society for Haematology and John Wiley & Sons Ltd.
Br J Haematol. 2023;00:1–16. wileyonlinelibrary.com/journal/bjh | 1

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2 GLOBAL PERSPECTIVES ON THALASSAEMIA
of beta-t halassaemia major1 (for a recent review, see2), while

alpha thalassaemia in its severe form causes intrauterine BOX 1 Case story
death unless sophisticated measures are implemented to
save the fetus. The management of symptomatic patients is As a haematologist caring for adult patients you en-
closely related to the severity of the resulting anaemia, the counter a 15-year old boy at your outpatient-clinic.
extent of iron overload and organ involvement. Given its He is a political refugee who has lost all the informa-
prevalence in countries with strained economies, it is a given tion he had from prior diagnosis and treatment in
that not all patients can benefit from the latest developments his home country. He tells you that his father, but
in care. Further, such problems can be insurmountable in not his mother, has the disease. He has two appar-
today's world, where the refugee problem is on the increase. ently healthy sisters. He also had a brother who died
Finally, even in countries associated with advanced health 5 years ago at the age of 18 due to complications of
care systems, comorbidities, and even mortality, are in- the disease. He tells you that the death of his brother
creased in transfusion-dependent thalassaemia.3,4 was in part ascribed to lack of adherence to advice
For these reasons, given the same starting conditions, from his prior caregivers, including not following
patients will be treated differently according to the coun- suggested dietary advice as well as not taking pre-
try and institution they are in. Therefore, in this review I scribed medications. The brother did receive blood
have tasked experts from around the world to describe their transfusions, but on a very irregular basis, mostly
management plan and rationale for a specific disease pre- due to logistical problems in procuring the blood.
sentation. Herein, they explore the management of thalas- The patient says that while he has tried to follow
saemia within widely varying health systems in six different the advice of his caregivers in his country of origin,
institutions worldwide. We finish with a conclusion from he has not been adhering strictly to their dietary
an expert in the field comparing and contrasting these dif- suggestions. Moreover, his mother, who is accompa-
ferent management styles and considering their merits and nying him, adds that he has received about 40 blood
limitations. We hope that this exercise will demonstrate to transfusions. He is taking no fixed medications, nei-
practicing clinicians that there is more than one “right” way ther oral nor by injection.
to manage patients. In fact, there is much to learn from our Facially, he has a high forehead, prominent max-
colleagues working in strained economies. This teaches us illary bones and small chin, features which are asso-
that we should be nuanced in our perception of how and why ciated with thalassaemia, with a spleen three fingers
treatments differ worldwide. under the curvature. His heart rate is 72 beats
The case history and questions posed to the experts are per minute and you hear a grade 1–2 holosystolic
shown in the Boxes 1 and 2, and the responses are sum- murmur.
marised in Table 1.
Primary contact Thalassemia International Federation (TIF) guidelines.

Serum ferritin values above 1000 ng/dL demonstrate inade-
The perspective from Italy quate iron chelation therapy.5
The diagnostic work- up will comprise first and sec-
In Italy, patients with transfusion dependent thalassae- ond level-examinations. The first level will include a full
mia are recorded in a national database (“Società Italiana blood count (FBC), reticulocytes, peripheral blood (PB)
Talassemie ed Emoglobinopatie”) and referred to specialised film for examining erythrocyte morphology, hepatore-
centres for treatment that are staffed by dedicated experts nal function, haemolysis indices, iron, ferritin, transferrin,
for both adults and children. My regional centre follows 135 high-performance-liquid-chromatography (HPLC) of Hb-
adult patients with transfusion dependent thalassaemia, fractions for the presence of HgbA, quantitation of HgbA2
while paediatric patients are followed in a separate spe- and HgbF and other abnormal haemoglobins.6
cialised centre. All individuals who have obtained recogni- The second level work-up would include a molecular
tion of refugee-status are entitled to registration within the analysis by polymerase chain reaction (PCR)-based or DNA
National Health Service. sequencing determining the alpha and beta globin muta-
Thus, this patient would be offered the most appropri- tions with alpha globin gene copy number analysis, to con-
ate diagnostic evaluation and transfusion as well as iron firm diagnosis and enable genotype/phenotype correlations.
chelation therapy. The most important aspects regarding To evaluate the possible organ impact of the disease we
past personal patient history are the transfusion history would perform blood tests including transaminases, pancre-
and previous treatment reactions. Immunohaematological atic function, thyroid and gonadal hormones, glucose-levels
tests are always required for patients beginning transfusion and oral-glucose-tolerance, parathyroid hormone and elec-
treatment. Extended red-cell antigen-typing of patients, at trolytes. To ascertain the body iron levels and organ dam-
least for D, C, c, E and Kell and, if available, a full red-cell age at baseline, we would perform abdominal ultrasound,
phenotype/genotype should be always performed, following fibroscan, echocardiogram as well as magnetic resonance
HOKLAND et al.
3 |
BOX 2 Questions for the panel
Question 1
Please describe your institution in terms of its ability to care for such patients.
Given that your patient carries no information of his disease history, how would you
1. Diagnose his disease?
2. Evaluate his organ status by clinical biochemistry and imaging analyses?
Question 2
You find that the young man has thalassaemia major with a definite need for both transfusions and iron chelation.
Given the choices of therapies at your disposal at your institution:
1. In what setting and how would you follow the patient?
2. What is your criteria for transfusion and for iron chelation?
3. Please relate how expenditures are dealt with in the health system you function in
4. What categories of caregivers do you have at your disposal, (e.g. for dietary advice and for diagnosing medical
complications)?
5. What first line therapy, if any, would you prefer?
Question 3
During the first months of follow-up, it becomes clear to you that the patient has severe issues with compliance. While
these, to a lesser extent, can be ascribed to his refugee status, they appear to you to be more likely grounded in lack of
understanding of his situation. Thus, he has difficulties keeping appointments (including presenting himself at the
clinic without one); he answers your questions regarding dietary restrictions evasively and at every visit advocates for
transfusions, irrespective of his haematological status. Finally, you are in doubt about his compliance to the chelation
therapy that you find necessary to control his disease.
1. How will you tackle this situation and ensure that he will follow advice in the future?
2. Would the lack of compliance make you shift therapies?
3. If you feel that you are lacking tools to accomplish your goals, please specify them.
Question 4
During the next 24 months, the patient adheres better to your instructions and to treatments. However, based on your
follow-up, you project that he will be experiencing cardiac and hepatic organ damage in the foreseeable future.
1. Are there any potentially curative experimental procedures and/or therapies available at your institution?
2. If the latter includes allogeneic stem cell transplantation (SCT), please state the conditions and donor selection and
where the procedure can be performed.
imaging (MRI T2*). In addition, I am able to consult with transfusion-dependent thalassaemia (TDT; also known as
an endocrinologist, cardiologist, gynaecologist, ophthal- thalassaemia major) and non-transfusion-dependent thalas-
mologist, otolaryngologist, orthopaedist, radiologist, neu- saemia (NTDT).7
rologist, hepatologist, physiatrist and psychologist for As the case in discussion involves a refugee, and know-
multidisciplinary-assistance. ing the current socioeconomic situation in Lebanon, there
Taken together, the combination of haematological and are a lot of factors as to why this case could not fit the ideal
biochemistry work-up, ethnicity, molecular analysis and the care model. Despite having a centre that aims to give the best
above-mentioned tests allow us to obtain a proper diagnosis care to thalassaemia patients, it is unable to offer services
and therapeutic plan.7 to refugees or immigrants due to the economic situation.
Consequently, refugees receive the minimal care and chela-
tion therapy in refugee camps.
The perspective from Lebanon I will, therefore, answer the questions as they relate
to the CCC. However, even that is affected by the cur-
In Lebanon, all thalassaemia patients are followed at a sin- rent socioeconomic situation in our country. We are
gle centre called the Chronic Care Centre (CCC) that was passing through a serious financial crisis, and the recent
established in early 1993, and where all the Lebanese tha- violent explosion that occurred in Beirut affected all as-
lassaemia patients are registered. At that time, around pects of life in the country including economy deterio-
1200 patients were registered and distributed between ration and resources shortages. Besides this, the country
T A B L E 1 Responses country-w ise to questions regarding the diagnosis, therapy and follow-up of a 15-year old boy.
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First line therapy including criteria for Change of therapy defined by Dealing with compliance Allogenic transplant or experimental
4
Country Diagnostic tools at presentationa initiation organ damage issues therapies

Italy FBC+ film Tx initiation: Hgb <7 g/dL on two visits or Modify or intensify iron Psychosocial support Luspatercept to be available shortly for
Hgb EP, iron stores Hgb >7 g/dL with facial or other bony chelation possibly using Support from a cultural patients over 18 years.
Abd USG, liver elastography changes. Tx every 3–4 weeks. combined regimens. mediator HSCT for young patients with HLA
Echo, MRI T2* Target pre-t x Hgb 9.5–10.5. DFP preferred in case of heart compatible donor or MUD or CB from
HPLC of family members Start chelation at either ferritin >1000 ng/mL damage, DFX in case of liver sibling. Pt should have no severe organ
Genetic analysis of alpha and beta or LIC ≥3000 mcg/dw or total tx 10 units damage damage. Refer to accredited BMT
globin genes since age 2 with end-organ iron overload. centres.
1st choice DFX with normal kidney Gene therapy becoming available at
function, or DFP p.o. or DFO s.c. specialised centres
Consider adding HU to reduce tx for severe
iron overload
Lebanon FBC, Hgb EP Tx every 3–4 weeks with a target pre-t x Hgb Combination iron chelation Psychologist for HSCT is available if patient is well chelated.
Molecular studies including alpha- 9–10 to be initiated if Hgb >7 g/dL on therapy DFO/DFP DFO/ psychological support Preferably with HLA-identical siblings.
fetoprotein, endocrinology 2 visits DFX dosaging depending on and assessment of Refugees must pay partial cost.
including fructosamine, Family recruitment of donors needed. the extent of hepatic and/or depression and anxiety Experimental therapies targeting
Echo, BMD, Abd USG, MRI T2* Adequate chelation using oral chelators cardiac hemosiderosis Nurse educator to provide underway:
HPLC of family members deferiprone (DFP), and deferasirox practical information and Ineffective erythropoiesis as Luspatercept
Some of these may be problematic for (DFX) following the guidelines of TIF. patient education. and mitapivat
refugees due to lack of medical Combination with deferoxamine (DFO) Patient advocacy via group Iron regulation as minihepcidins
coverage possible (pregnancy, BMT or heart therapy and regular Gene therapy not available
failure). workshops and meetings
Refugees may self-pay for some medications
Oman FBC + film Transfusion initiated when Hgb <7 gm/dl Follow up according to MRI T2*: Discussion groups with HSCT if matched donor, available at our
HPLC Hgb EP or increasing spleen size or facial bony 3 monthly T2* MRI if cardiac similar age/sex patients. institution.
Echo, Abd USG, Liver elastography changes. T2* is <10 ms. Change chelation Would have high priority in Thalassemia
HPLC of family members Target pre-Tx Hgb >9 gm/dl 6 monthly MRI T2* if cardiac medications if there are wait list, as he is 16 years old. However,
Extended RBC typing Initiate chelation when SF 800–900 ng/mL T2* 10–15 ms remaining options. overall priority is given to patients with
with low dose DFX. MRI T2* performed Yearly if >15 ms And do not stop counselling! malignancies as there are limited beds
as soon as patient can adhere to MRI If already on 24 h DFO chelation for HSCT. Admission for intensive iron
protocol. Chelation tailored according at home, try to get admission chelation prior to procedure.
to SF to start with and then T2* (shortage of beds) and need Luspatercept is expected to be available in
In more severe cases DFX at 28 mg/kg/day for minimum 3 months. 2023.
or combination DFO/DFP. If on DFO with poor compliance Gene therapy is not available, although the
Refugees may need to pay for health care or no effect, switch to DFX department has been approached to
instead of DFO take part in trials
Sudan Family history Tx initiation Hgb <7 g/dL. Switch from PO to SC chelation Get family and other None
CBC + film Target pre-t x Hgb: > 9 g/dL, but blood or vice versa if no compliance caregivers involved Patients referred abroad for HSCT only if
Hgb EP, clinical status supply problematic. Family may need to Consider HU or splenectomy to able to pay
ECG, CXR, Abd USG, Echo recruit blood donors. reduce tx requirement
MRI heart/liver, self-pay only Leukocyte depletion and extended typing
not always available.
Possible HU therapy to reduce Tx need.
Chelation if ferritin >1000 ng/mL
1st choice DFO. Oral chelation is self-pay
Refugees may need to pay for all meds
GLOBAL PERSPECTIVES ON THALASSAEMIA
T A B L E 1 (Continued)
HOKLAND et al.
First line therapy including criteria for Change of therapy defined by Dealing with compliance Allogenic transplant or experimental
Country Diagnostic tools at presentationa initiation organ damage issues therapies
Thailand Family history Tx initiation Hgb <7 g/dL or >7 g/dL with Change to combination regimen Intensify counselling Matched-related donor, MUD, and
FBC + film complications from anaemia if ferritin or MRI for LIC or Appointment with groups haploidentical donor HSCT are
Hgb HPLC or CE Target pre-t x Hgb 9–10.5 g/dL cardiac T2* cannot be kept to of patients with good available at our institution
Molecular testing if HPLC/CE non- Pre-t x Hgb can be reduced to 7 if patient is target levels or development compliance Refugee may have to pay privately.
diagnostic (HPLC and Molecular noncompliant of progressive organ damage Consider decreasing pre -t x Luspatercept and gene therapy not available
testing self-pay for refugees) Chelation If ferritin >1000 ng/mL or Reduce pre-t x Hgb to 7 to reduce Hgb to >7 g/dL
Viral testing MRI for LIC >7 mg/gdw or cardiac number of visits to hospital Switching 3-t imes DFP to
Extended RBC typing. T2* < 20 ms Refugees may be noncompliant once-daily DFX
Serum ferritin. 1st choice DFP or DFO to keep ferritin with chelation due to inability
MRI for LIC and cardiac T2* only 500–1000 ng/mL or LIC 3–7 mg/gdw or to pay for meds
selected pts cardiac T2* > 20 ms
If ferritin >1000: FBS, TFT, calcium
and phosphate, vitamin D level,
morning cortisol, LH, FSH,
estradiol, testosterone, LFT. CXR,
ECG. Echo if symptomatic. Abd
USG if gallstones suspected
USA FBC + film Would continue regular transfusions every Chelation is tailored based on Counselling at every Luspatercept available but pt. ineligible
Laboratory testing including 2–4 weeks to maintain pre-t ransfusion MRI assessments. transfusion visit, setting (<18 y) and not good candidate for
molecular HPLC genetic testing haemoglobin level in the 9.5–10.5 g/dL Initially would start targets based on MRI and clinical trial using one of two possible
and complete endocrine, MRI range monotherapy, increasing the ferritin levels, assistance PK activators, mitapivat, etavopivat,
T2* Chelation after approximately 15 total tx. dose as needed. from social worker, due to poor compliance
1st choice DFX If MRI shows increasing liver family members to Allogeneic transplantation if a sibling is an
iron or cardiac iron, add a ensure compliance. HLA match. Would not recommend
second chelator, DFP If technologically savvy, MUD or mismatched HSCT
could use an assistance Could now be offered gene therapy with
app on his mobile device. Zyntyeglo® or could be enrolled in
Consider splenectomy to clinical trial for autologous SCT with
reduce tx and chelation. gene editing (NCT03745287), but may
Think ahead to HSCT not qualify for either due to high iron
burden
Abbreviations: Abd USG, abdominal ultrasound; BMD, bone mineral density; CB, umbilical cord blood; FBC full blood count; CE, Capillary electrophoresis; CXR, Chest Xray; DFO, deferioxamine (subcutaneous), DFP, deferiprone
(oral), DFX, Derasirox (oral); ECG, electrocardiogram; Echo, Echocardiogram; Elastography, Transient elastography, also called fibroscan (for liver fibrosis); FBC, full blood count; FBS, fasting blood sugar; FSH, follicular stimulating
hormone; Gdw, grams per dry weight (units of LIC, liver iron concentration); Hgb EP, haemoglobin electrophoresis; Hgb, haemoglobin; HPLC, High-performance liquid chromatography; HSCT, allogeneic haematopoietic stem cell
transplantation; HU, hydroxyurea; Iron stores, se-Fe, se-t ransferrin and se-ferritin; LH, luteinizing hormone; MRI’ magnetic resonance imaging; MUD, matched unrelated donor; PK, pyruvate kinsase; Pre-t x, pretransfusion; RBC
typing, Extended RBC phenotyping for minor blood group antigens; s.c., subcutaneous; smear, peripheral blood smear evaluation; TFT, thyroid function tests; TIF, Thalassaemia International Federation; Tx, transfusion; Viral testing,
hepatitis B and C viruses and human immunodeficiency virus testing.
a
All contributors performed clinical biochemistry studies for electrolytes, renal and liver functions.
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5
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is still recovering from the COVID-19 pandemic and its Although we have no definitive diagnosis, we have been
challenges.8 told that he has had multiple transfusions and that his
Our centre is not within an academic institution, but it brother died in his second decade; the history is suggestive of
is affiliated to the American University of Beirut Medical beta thalassaemia major, possibly thalassaemia intermedia.
Centre (AUBMC), where I work.9,10 A first evaluation to establish a baseline and would in-
The way we would diagnose such patient would be by clude a full physical examination, including looking for
taking an extensive family history, performing a good phys- evidence of bone expansion, hepatosplenomegaly and evalu-
ical examination in addition to lab tests such as FBC, iron ation of pubertal status, height and weight. Laboratory tests
studies (ferritin, iron, iron binding capacity and percent should include serum ferritin and blood group and antibody
iron saturation) to rule out iron deficiency that is common status. If he has been transfused recently it would not be pos-
in thalassaemia. In addition, we would perform Hgb elec- sible to do an extended blood group panel and we currently
trophoresis (EP) followed by sequence analysis of the beta do not have the facility at our institution to do this through
globin gene followed by gene-targeted deletion/duplication molecular methods. A full endocrine work-up including an
analysis if only one or no pathogenic variant was found, to oral glucose tolerance test (OGTT) at 0.1 and 2 h with serum
rule out the most common mutations found in our part of insulin at 1 h,12 serum testosterone, luteinising hormone and
the world, the beta thalassemias. Mutation analysis is usu- follicle stimulating hormone, calcium and parathyroid hor-
ally carried out by the amplification refractory mutation sys- mone, thyroid function tests, early morning cortisol, urea
tem PCR (ARMS-PCR) screening for multiple mutations.11 and electrolytes and liver function tests are mandatory as a
In parallel, our patient would be evaluated by clinical baseline as well as screening hepatitis B virus (HBV), hepati-
biochemistry such as liver enzymes, liver function tests, vi- tis C virus (HCV) and HIV.
rology, fructosamine and alpha fetoprotein. Assessment of Imaging studies should prioritise MRI T2*13 to assess car-
organ status would be done using echocardiography, bone diac and liver iron. MRI T2* assessment of the pituitary and
densitometry, ultrasound of the abdomen and MRI T2* of pancreas are not currently available to us. Ultrasound and
the liver and the heart. Some of the tests cannot be done at elastography (fibroscan) of the liver14 should be scheduled
the one-day clinic and patients are referred to the AUBMC and audiometry and referral to ophthalmology can follow.
or these tests. MRI T2* of the liver and the heart are done Our institution does not currently have a reliable normal
for patients who are covered by a secured fund dedicated range for bone densitometry for individuals 20 years age or
for patients of the thalassaemia centre. Before the current under.
situation, a group of students with some physicians would
visit the refugee camps on a regular basis, offering medical
support and counselling. However, with the current chal- The perspective from Sudan
lenges, the support of refugees is restricted to dedicated non-
governmental organisations (NGOs). In Sudan, as in many low-income countries, thalassaemia
major does not get enough attention as a public health prob-
lem. It was not known in Sudan until 1960s, when one case
The perspective from Oman was described in a Sudanese family in which haematological
and family investigations showed the presence of thalassae-
My institution (Sultan Qaboos University Hospital) is a mia major in a child and the trait in the parents.15,16 At pre-
tertiary-care hospital that is a referral centre for beta tha- sent, the incidence of thalassaemia is unknown due to lack of
lassaemia. Laboratory facilities relevant to thalassaemia official statistical reports.
include all routine biochemistry, haematology (including In Sudan, it is mainly paediatricians who treat children
leuco-reduced red cells for transfusion, red cell antibody with thalassaemia. In adulthood, haematologists and inter-
identification), routine pathology and microbiology as well nal medicine specialists take over and follow these patients,
as molecular diagnostic laboratories. Imaging tests available but under resource poor conditions. In my institution,
(other than routine) are liver elastography (fibroscan), MRI the Department of Haematology at Khartoum Oncology
T2*, echocardiography, ECG and bone densitometry. Hospital (KOH), a government sponsored hospital with at-
Given that he has no previously available records, I would tached clinics, we mainly see patients with malignant hae-
start with routine blood count and film and HPLC. The lat- matological diseases, but also patients with different benign
ter would be helpful if his last transfusion was a few weeks disorders such as thalassaemia and sickle cell disease. At
back or he had been poorly transfused; HPLC will also pick outpatient appointments patients are required to pay a sym-
up other abnormal Hgbs, such as E, S, C and D, if present. bolic charge of 500 Sudanese pounds (around 1 USD). I have
Parental samples and blood from his two sisters (if available) been working as a haematologist for the last 6 years, both in
could be concurrently screened for elevated Hgb A2 that KOH and in other hospitals in Sudan. Almost all the institu-
would indicate beta thalassaemia carrier status. In particu- tions where I have worked now have transfusion-dependent
lar, the father's blood film should be carefully examined as thalassaemia patients under follow-up.
we are told that his father ‘has the disease’. In addition, all If a refugee can document his/her status with a valid ID
samples can be stored for molecular diagnostics. card, then the treatment will be the same as for Sudanese
HOKLAND et al. |
7
citizens. The exception can be that refugees need to pay for anti-HCV, and extended red cell phenotypes for multiple-
prescribed medications, but this rule is not strictly followed. transfused patients.
To diagnose thalassaemia major we use Hgb EP, FBC with
red cell indices, PB film, haemolysis markers, family history
and the clinical picture. Genetic testing (e.g., to detect HbA The perspective from USA
gene deletions to confirm alpha thalassaemia) is not avail-
able in our country. My practice is located within an academic medical centre
To evaluate organ status we use renal and liver function in a large city in the United States. My own clinical and re-
tests, hormonal screening, ECG, echocardiography, abdom- search interests are disorders of red blood cells and iron me-
inal ultrasound, chest X-ray, cardiac and liver MRI. MRI is tabolism, both iron deficiency and overload.17
very expensive, but if it is indicated we prescribe it, and pa- The Thalassemia Centre is one of the largest, single-
tients have to pay to have it done in private clinics. centre institutions in the country.b We believe in the com-
prehensive care model, offering all modalities of treatment,
including the possibility of clinical trials, with the availabil-
The perspective from Thailand ity of allogeneic stem cell therapy (SCT) and, more recently,
gene therapy. We also have laboratory support including ge-
I am an adult haematologist and academic staff member at netic testing and MRI facilities to be able to quantify tissue
Siriraj Hospital, the oldest and largest tertiary and university iron accurately.
hospital in Thailand. Many patients with complex thalassae- This patient would be diagnosed based on blood testing,
mia are referred to the hospital from around the country. including DNA-based globin gene analysis, and monitored
The national health care system covers all Thai patients' ex- for liver and cardiac iron by MRI. He would be regularly
penses. Our institution has the budget to support refugees followed by cardiology and endocrinology as well. Over the
only for life-saving treatment. years, we have had individuals who have migrated from other
I would begin to diagnose the patient by assessing his parts of the world, including some refugees. These individu-
clinical presentation. Next, I would send an FBC and ex- als receive care in the same setting as any other patient, with
amine PB film to confirm thalassaemia and exclude other the same facilities being available to them. They would be
congenital haemolytic anaemia. If patients say that the last covered under state sponsored insurance programmes and
blood transfusion was longer than 3–4 months ago, Hgb typ- have a social worker, interpreter, and other support available
ing by capillary electrophoresis (CE) technique can be done. to them.
In-house, HPLC will be used if CE results are indeterminate.
If he received a transfusion recently and the next transfusion
cannot be delayed, I would choose molecular testing, (i.e., Initial therapy
reverse dot blot used for detecting common beta mutations
in Thailand). The perspective from Italy
Thailand is a low-income country and has limited re-
sources. Therefore, some high-cost screenings, as the TIF Once the patient is recognised as a refugee, he would be reg-
guideline suggests, are not routinely done.5 This patient istered into the National Health Service data base and sub-
possibly developed iron overload due to receiving more than sequently be treated as an Italian citizen. The patient would
10–20 units of blood, poor medication adherence and uncon- be followed primarily as an outpatient in the thalassaemia
trolled diet. In that case, serum ferritin would be performed clinic. He would receive transfusion therapy and iron chela-
to evaluate his iron burden. Most patients treated at rural tion regimen on a day hospital inpatient regimen, within my
hospitals have difficulty accessing this. Our institution does institution. Unfortunately, the long bureaucratic procedure
have access to MRI, but we can only employ it in selected of refugee status recognition, may cause a delay in beginning
patients whose serum ferritin does not correlate clinically, therapy.
for example, in patients exhibiting levels less than 1000 ng/ We would assess his cardiac and liver iron by MRI, and
mL despite having haemochromatosis-related organ damage initiate iron chelation immediately, given his history and his
or when following up patients whose ferritin is more than high likelihood of having a significant body iron burden, we
4000 ng/mL.a would initiate deferasirox (DFX) once daily as first-line ther-
If ferritin is more than 1000 ng/mL, organ damage is apy (if his kidney functions are normal), since compliance is
further evaluated including endocrine function as well as already an issue. If he has a very high liver iron concentra-
sex hormones in patients with symptoms, liver function tion or the presence of cardiac iron, I would add deferiprone
tests, ultrasound of the liver in case of suspected symp- (DFP) to his chelation regimen, if he becomes compliant to
tomatic gallstone, if the patient is having ongoing HBV or DFX I may add hydroxyurea (HU) to increase HgbF values
HCV infections. Chest X-ray and ECG are performed to and possibly to reduce transfusion requirements.
screen cardiovascular complications. Echocardiography He would be assessed by the social worker in our centre
is applied in patients with symptoms or abnormal screen- and receive counselling from all of his caregivers. Insurance
ing test. Finally, blood is screened for anti-HIV, HBs Ag, would cover the costs of his therapy with no out of pocket
|
expenses. I would not impose dietary restrictions related but the presence of alloantibodies can cause difficulty as our
to his thalassaemia (since restricting iron intake would not blood bank has limited inventory. Blood is voluntarily donated
make much of a difference given the vastly greater amounts at our institution, and this is supplemented by regular blood
he is receiving through transfusions), other than to take his drives. However, the university hospital is the largest referral
chelation around meals as prescribed. centre for haemoglobinopathies (both beta thalassaemia and
sickle cell disease) and, therefore, the blood bank is continu-
ally under intense pressure to provide blood, but every effort is
The perspective from Lebanon made to have appropriately matched blood available.
Iron chelation for this patient would depend on the re-
We would definitely try to keep a pretransfusion haemoglo- sults of the cardiac and liver MRI T2*. My criteria are as fol-
bin level of 9.5–10 At the same time, one of the problems in lows: if both cardiac and liver iron are in the minimal range
our country is the lack of a central blood bank, so the pa- (cardiac MRI T2* >20 ms, liver <3 mg/gdw), I would advise
tient or the family would need to look for blood to prepare Jadenu (an oral tablet form of DFX, which is preferable to
for the next visit. The blood is cross-matched and filtered patients but costlier than the original formulation). If car-
before being administered to the patient. The criteria for diac iron and liver iron are moderately raised, monotherapy
transfusion and iron chelation will be according to the TIF with Jadenu is the first option, but with close follow-up. DFP
guidelines. I participated in writing these guidelines, which can be added to Jadenu if there is worsening or no improve-
were updated recently for TDT in 2021.c After receiving 10– ment of iron overload. For young children, I prefer to start
20 transfusions, and/or having a serum ferritin above 1000, iron chelation before the serum ferritin reaches 1000 ng/mL;
indicates that the patient needs to be chelated. The iron che- either Jadenu or DFP can be given at a low dose. In all cases,
lators available currently in my country are the oral ones; we monitor at-risk patients closely with MRI T2*, which is
however, combination therapy is being used occasionally, essential, with chelation therapy tailored to the individual
specifically if the patient has very high serum ferritin, in patient. If both organs are heavily iron loaded, my first line
preparation for pregnancy or bone marrow transplantation of treatment is subcutaneous (s.c.) DFO 5–7 days/week, com-
or if the patient has heart failure.18,19 bined with DFP. We have seen excellent results with this
The Chronic Care Centre (Thalassemia centre) in Baabda, combination therapy.20 However, this treatment requires
Lebanon (http://www.chroniccare.org.lb/) is an NGO that long-term commitment on the part of the patient as cardiac
had been the best example in a third world country of how iron is mobilised very slowly and it can take years for the T2*
an NGO can align with the government and private sector to to normalise.21,22 In difficult cases, the patient may have to
provide the best care for our patient. As mentioned above, the be admitted to the hospital long-term or have a port-a-cath
support of the refugees is currently restricted to other dedi- inserted for an infusion pump. The latter involves the patient
cated NGOs. The bulk of our patients depend on the Ministry coming to the day care unit three times a week to change
of Public Health to provide the medications, still keeping in the infusion pump, as we have no personnel to deliver this
mind that the situation that I am referring to existed prior to service outside our institution. Because of possible adverse
our recent economic crisis. Safe blood transfusion and good events, such as neutropenia, renal function and liver func-
chelation therapy are still the first line of therapy at our cen- tion tests are routinely monitored.
tre.6 However, the current economic situation is becoming a Most endocrinopathies are dealt with by the thalassae-
real obstacle in providing the same high-quality services that mia team with input from endocrinologists as required.
were present previously, especially due to the limitations in Endocrinologists on call will come to the Day Care Unit
securing adequate quantities of medications. when a patient is having a transfusion to discuss any prob-
We are really frustrated at being unable to offer the ref- lem. Cardiologists always review echocardiograms, but their
ugees the needed and suitable medical help because of the experience with thalassaemia is very limited. Dietitians are
current circumstances. Better strategies are needed to or- also available but are few. Social workers are very few and do
ganise cooperation between international NGOs and local not go into the community, so all social aspects are dealt with
academic institutions to be able to serve refugees. by the team, particularly the thalassaemia nurse specialist.
We have never treated refugees in our clinic. Health care
is completely free for citizens and for government employ-
The perspective from Oman ees and their families. All others either have to pay out of
pocket or have health insurance. However, many insurance
Once the definitive diagnosis of thalassaemia major has been companies may exclude pre-existing conditions. Emergency
made, I would discuss treatment options with the patient and treatment is free for anyone.
his parents. He would be followed by the thalassaemia team
in the Day Care Unit. All investigations are planned for the
day of appointment whenever possible, so as to cause mini- The perspective from Sudan
mal disruption to school/work. I would administer routinely
packed blood cell transfusions aiming to maintain his pre- Blood transfusion remains the cornerstone of treatment of
transfusion level above 9 gm/dl. Blood is generally available, patients with thalassaemia, but with risk of transmitting
HOKLAND et al. |
9
infections and developing iron overload with subsequent a hepatologist if cirrhosis develops. Iron chelation is inten-
organ damage. In addition, repeated blood exposure can in- sified and any complication is dealt with. We do not have
duce alloimmunisation to erythrocyte-antigens, leading to direct contact with other specialists and when we need their
difficulties in identifying compatible blood. support we give a referral letter to the patients, who must
It is to be anticipated that many patients in Sudan will not find the specialist themselves. This can be a specialist from
follow a programmed transfusion schedule and are trans- the public or private sector. It is easier to get family members
fused only during emergency situations, due to lack of un- of Sudanese patients involved in this process than refugees.
derstanding of the disease by patients and some caregivers,
as well as to logistical issues in providing regular transfu-
sions. There are registered blood donors in Sudan who come The perspective from Thailand
and give blood regularly, so sometimes TDT patients can be
fortunate and receive transfusions without being asked to The patient would be followed up at the thalassaemia outpa-
provide a donor from their relatives. tient clinic. When a doctor prescribes transfusion, generally
Transfusion is usually initiated in early infancy/child- with packed RBC, crossmatching is performed on that day,
hood, as soon as the diagnosis is established and continued and the patient will be scheduled to be transfused the fol-
throughout life to maintain good exercise tolerance and to lowing day. In Thailand, blood products are obtained from
suppress ineffective erythropoiesis. We usually follow pa- voluntary donors. Since the COVID-19 pandemic, there has
tients by outpatient appointments every 3–4 weeks, where been a shortage of blood products throughout the country.
we check FBC prior to transfusion. We usually transfuse In selected patients who have difficulties coming on subse-
if Hgb is less than 9.0 g/dL. This target is advocated by quent days (e.g., patients who live very far from the hospital
studies balancing suppression of extramedullary eryth- or who have poor performance status, which hinders them
ropoiesis and risk of excessive iron overload.23 However, from frequent travelling), we will aim to complete the trans-
it is often difficult to meet this recommendation mainly fusion on the same day. If a refugee has such problems and
because of shortages in blood products. Blood transfusion we still have a slot for him, he can complete a one-day trans-
is free but the patient's family may be asked to refer blood fusion in the same manner as Thai patients.
donors in case of shortages. All donations are tested for We follow the 2021 TIF guidelines for transfusion de-
HBV/HCV and HIV. Some measures, such as extended pendent thalassaemia.d Ideally, patients with thalassaemia
cross matching to prevent alloimmunisation, or leukocyte major who have baseline Hgb less than 7 g/dL or who de-
depletion to reduce febrile nonhemolytic reactions, are not velop complications even with Hgb more than 7 g/dL, need
normally available in Sudan. to be treated with a high transfusion protocol. This patient
Every 3–4 months we will check standard biochemistry, has bone changes consistent with thalassaemia, indicating
(HbA1C and TSH). Heart failure can develop either because chronic anaemia complications. The nurses and I would
of iron overload or because of prolonged severe anaemia/hy- counsel him to understand the benefit of hypertransfusion
poxia as a result of an inadequate transfusion programme, (i.e., promoting normal growth and normal physical activi-
so, optimally, echocardiography is done every 1–2 years or as ties, and reducing the complications of anaemia). However,
indicated by symptoms. Blood transfusions, iron chelation, if he cannot follow this strict treatment, giving fewer trans-
hydroxyurea and folic acid therapy are all government spon- fusions to keep Hgb over 7 g/dL could still improve his qual-
sored and free of charge for Sudanese citizens. As mentioned ity of life (a suggestion from Thai guidelines). Iron chelation
above, refugees can be asked to pay for medications. is started when serum ferritin is more than 1000 ng/mL
Iron chelation is usually initiated after 10 units of trans- or liver iron concentration (LIC) is more than 7 mg/g dry
fused blood or when ferritin is over 1000 mmol/L. This is also weight or cardiac T2* is less than 20 ms. Chelation medica-
paid for by the government. DFO s.c. is the most commonly tion is available to all Thai patients with clinical or labora-
used iron chelator. If a shift to oral chelation is indicated, tory indications.
patients will have to pay for new drugs. Oral folic acid 5 mg Siriraj Hospital provides pre-storage-f iltered blood to all
daily is given to all patients. Luspatercept was found to be patients with thalassaemia because it is the most effective
effective for beta thalassaemia major,24 but is only available in reducing alloimmunisation and febrile non-haemolytic
if the patient can buy it from abroad. Hydroxyurea is used to transfusion reactions, even though the cost is higher than
increase HgbF and possibly enable a decreased transfusion leukocyte-poor blood (LPB). Unfortunately, many second-
requirement. Splenectomy can be considered if increased ary hospitals in Thailand use LPB since they do not have the
blood requirement prevents adequate control with iron che- equipment for pre-storage filtering blood.
lation therapy or if hypersplenism is leading to cytopenias. The Government Pharmaceutical Organisation (GPO)
Patients with complications are usually referred to the is a state enterprise operated under the Ministry of Public
respective specialists: a dietician to guide to iron-poor diet; Health. It was established in Thailand in 1966. One of its
a cardiologist if there are cardiac complications; an endo- aims is to promote the production of quality medicines for
crinologist for growth impairment/delayed puberty, diabe- domestic use, which can reduce the high cost of importing
tes mellitus, thyroid and parathyroid function abnormalities; drugs. For iron chelators, GPO has manufactured DFP and
a rheumatologist if the patient has iron related arthritis and DFX, since 2008 and 2019 respectively, to be used for patients
|
with haemochromatosis throughout the country. DFX is the of continuous subcutaneous chelation with DFO alone, or in
second-line treatment. Patients can access it when they fail combination with other oral chelators, in case of an MRI T2*
or cannot tolerate the side effects of the first-line option. cardiac signal of less than 20 ms, demonstrating iron over-
Importantly, DFX is not covered by Social Security. I prefer load or ferritin values if more than2000 ng/mL.
prescribing DFP for Thai patients or a refugee due to oral While DFO is the gold standard, its parenteral admin-
availability, cost effectiveness and manageable toxicity.25 istration and the burden of a daily infusion pump hin-
Siriraj Hospital has specialists and advanced investigation der optimal compliance. DFP is orally active, but should
techniques for thalassaemia. Screening and diagnosing un- be administered three times daily; periodic monitoring of
complicated complications, checking treatment adherence white-blood-cells is prompted because of the risk of agran-
and dietary advice are performed by physicians and nurses ulocytosis. DFX is active in a single-daily-dose and is well
at the thalassaemia clinic. Patients who require special test- tolerated, but its effective cardiac chelation is lower than
ing will be referred to relevant specialists. that of DFP. On the other hand, DFX is advantageous for
not requiring many hospital visits and being administered
only once a day. I usually seek psychological support for the
The perspective from USA patient's young age, refugee situation and recent communi-
cation of a complex diagnosis.
The patient would be followed primarily as an outpatient in Poor adherence to the recommended therapy is the domi-
the thalassaemia clinic. He would be transfused regularly nant cause for treatment failure in my experience. About half
(every 3–4 weeks), with the goal of maintaining his pre- of my patients have experienced this aspect, especially with
transfusion haemoglobin level in the 9.5–10.5 g/dL range.e the administration of DFO and more often during summer
He would have limited extended phenotyping (c, D, e and months. The causes are varied and need to be approached
Kell) prior to initiation of transfusions and get phenotypi- individually, ranging from psychological issues to difficulty
cally matched blood accordingly.26 of administration. Strategies to improve compliance, such as
We would assess his cardiac and liver iron by MRI T2*, automatic reminders and psychological counselling, should
and initiate iron chelation immediately, given his history and be used. In providing culturally adapted care, physicians
his high likelihood of having a significant body iron burden. should consider poverty, social stigmatisation and language
We would initiate DFX once daily as first-line therapy, since barriers of new immigrants after their arrival. In my experi-
compliance is already an issue. If he has a very high liver iron ence, social and economic conditions are precarious and dif-
concentration or the presence of cardiac iron, I would add ficulties in communication are always present. Psychological
DFP to his chelation regimen, once I had an idea that he was support therapy will be provided as needed.
compliant with the DFX.f From a clinical perspective, the language barrier rep-
He would have a comprehensive endocrine evaluation, resents the major challenge related to medical diagnostic as-
including hormone levels and an oral glucose tolerance test sessment and treatment of refugee patients. A crucial aim is
and bone density evaluation. He would be assessed by the finding a translator capable of translating medical terminol-
social worker in our centre and receive counselling from all ogy. We opt for the presence of a cultural-mediator during
of his caregivers. He would be enrolled in a state sponsored the first and following doctor's visits, who can speak the pa-
medical insurance programme, which would cover the costs tient's native language. If compliance is nevertheless poor, it
of his therapy with no out of pocket expenses. He would also is necessary before any iron-chelation modification to make
be provided transportation and other assistance to be able sure that the patient has correctly understood how and when
to keep his appointments at the hospital. He would not have to take it. There are no direct methods to accurately assess
any dietary restrictions related to his thalassaemia (since re- adherence, but I have found that a significant tool is the dou-
stricting iron intake would not make much of a difference ble checking with the hospital pharmacy to ascertain how
given the vastly greater amounts he is receiving through often the drugs are withdrawn by the patient.
transfusions), other than to take his chelation around meals
as prescribed.
The perspective from Lebanon
Tackling low compliance Since compliance is not only related to the drug itself, but
many times it can be related to the background of the patient
The perspective from Italy (whether religious, or cultural besides mere lack of knowl-
edge), all our patients will be seen by the nurse educator and
Starting a daily regimen of chelation therapy, oral or par- psychologist, who will look for possible reasons of inconsist-
enteral, represents a significant disruption of lifestyle, re- ent compliance. Extensive and regular counselling with the
quiring careful information with education and a support family would have been done since diagnosis to raise aware-
programme. Our aim is to enhance acceptance and compli- ness and explain the importance of adherence to iron chela-
ance. The choice of the specific iron chelator depends on the tion, especially as our patient is a 15-year-old boy and will be
extent of iron overload, because we strongly suggest 24-h use dependent on his family.
HOKLAND et al. |
11
Furthermore, we always try to use advocacy of other pa- of which are due to iron overload. The hope is that explain-
tients through workshops and group therapy, which might ing these consequences may cause the patient to become
help in re-establishing, strengthening and prolonging com- more compliant.
pliance, besides advocating for the rights of the patients in
getting the needed care. The cornerstone of chelation ther-
apy in this case is 24-h continuous DFO that may carry a fi- The perspective from Thailand
nancial burden of a long hospital stay or expenses of frequent
transportation to the hospital. However, should the lack of I think the reason for the patient's poor compliance is his
compliance persist, sometimes patients, who are on i.v. che- unawareness of the morbidity and mortality of thalassae-
lation therapy are shifted to oral therapy. mia and iron overload if left untreated. Special nurses and I
would counsel him and his family about the importance of
strict treatment. Appointments with groups of patients with
The perspective from Oman good compliance and well controlled disease would encour-
age him to adhere to treatment.
Any new patient to the thalassaemia unit gets intensive If the patient cannot strictly adhere to a high transfusion
counselling with the family over the first few months. In protocol, he should at least be transfused to keep his Hgb at
this particular case, his main issues are attendance and more than 7 g/dL. This regimen would make for fewer visits
compliance with chelation. As he is 15 years old, he is de- to the hospital, while retaining an acceptable quality of life.
pendent on his family for transport to the hospital. His In this situation, I would also switch from DFP three times
non-attendance on his appointment date could be due a day to a once-daily dose of DFX in a further attempt to
to parents being unaware of appointment date or due to improve his compliance.
lack of transport. In these cases, we call the parents a few Apart from poor compliance, the cost of treatment is of
days before the appointment and then the day before to concern. The patient would have to pay £135–270/month for
check that they are coming. Non-compliance with medica- a blood transfusion of 1–2 units plus DFX 20–40 mg/kg/day.
tion is a major problem. We would add him to the patient For Thai patients, the national health insurance covers the
WhatsApp group chats, so he could get support from his cost of blood products but does not cover DFX if used be-
peers. In addition, we would try to make sure that he comes cause of poor compliance with DFP.
for appointments on the same day as well, compliant pa-
tients of the same sex and age group so he could talk with
them. With his history, the only remaining option would The perspective from USA
be admission for chelation. Unfortunately, my experience
with non-compliant patients has been that no intervention This is not an uncommon situation for patients who arrive
on our part works unless the patient is committed to it. from low-income countries. There is a lack of understanding
Ideally, providing 24 h DFO chelation with a Baxter de- of the disease, many preconceived notions that are not based
vice is the best option in this case. However, we cannot do on facts, while compliance is often an issue in their home
home delivery and there is a massive burden on the family in country because of unavailability of resources for transfu-
terms of coming to the hospital every 48–72 h to change the sions and chelation.
infuser. Patients are unwilling to commit for the long-term Our team would provide education about the disease—
admission required, as they would miss school and, not sur- both in person with a translator and with materials trans-
prisingly, find the length of stay in hospital to be untenable. lated in his preferred language, if possible—and this would
be done at every visit, reinforcing the need for compliance to
prevent complications. We would try and put him in contact
The perspective from Sudan with other patients/families from similar sociocultural back-
grounds and have him join one of our teenage peer groups.
Most of the time, young patients have issues with compli- His transfusions would be on a specific schedule based on
ance to chelation therapy. If this happens, we encourage his pre-transfusion haemoglobin levels, and he would be
family members to help explain to the patient and family the made to understand that this is different from the way he
importance of adherence to programmed blood transfusions may have been treated in his native country. We have had
and to chelation therapy. good results with these interventions in the past and would
Sometimes it is necessary to switch from infusional to hope to have success with him as well.
oral chelation to improve compliance. Other members of the He is likely to need combination chelation, which would
health-care team who are involved in managing iron over- be started once he had demonstrated compliance with a
load complications can contribute to improving the patients single agent. Ongoing reinforcement of this at every visit,
understanding of the importance of chelation therapy. In with targets and maintenance of a diary, should help as
Sudan, hypogonadism is the most common complication well. We might consider a splenectomy to reduce transfu-
seen in more than 50% of thalassaemia patients, and heart sion requirements and thus reduce iron loading, if there is
complications are the most common cause of death,27 both evidence of hypersplenism and an increasing transfusion
|
burden. In my experience, this can reduce transfusion re- for patients without elevated thrombotic risk or extramed-
quirements by 20%–30%. We do hesitate, however, because ullary haematopoiesis, who express rare erythrocyte pheno-
post-splenectomy there is concern about infection risk and types, thereby reducing the need to find matched blood for
also the development of vascular disease such as pulmonary transfusion.
hypertension. The patient and his siblings, and possibly his
mother if his parents are consanguineous, will be HLA-
typed to see if there is a matched family donor available for a The perspective from Lebanon
haematopoietic stem cell transplant. This would not be per-
formed while he was very iron overloaded, but he would be Initially, I would like to stress that a good number of my pa-
counselled that this might be a possibility once his iron levels tients are on clinical trials. We currently have eight clinical
come down. trials for our thalassaemia patients. Most of these are related
to iron chelation and novel therapies that are targeted at cor-
recting globin chain imbalance and improving ineffective
Possibilities for advanced therapy erythropoiesis. For novel therapies, some of the clinical tri-
als work on increasing the haemoglobin level via targeting
The perspective from Italy ineffective erythropoiesis,37 while others focus on the ma-
nipulation of iron regulation mechanisms.38 Gene therapy
My first attempt is always to optimise iron chelation therapy, and editing are still not available.
to prevent or reverse severe organ damage, possibly by start- The potentially curative option of SCT is available
ing combined therapy. Cardiac function improvement and in Lebanon at AUBMC for patients, who have an HLA-
reversal of heart failure were noted in trials of DFP mono- identical donor. As mentioned, given the present economic
therapy or with combination DFP-DFO.28 Following the constraints and the high expenses incurred, the procedure
guidelines of the American Heart Association consensus was initially not fully covered by the government and the
statement, patients with heart failure due to hemosiderosis degree of coverage is currently reduced. In the end, the
must be followed at a tertiary centre to allow for a closely costs of SCT will be beyond what this patient could afford,
integrated cardiology/haematology care.29 so I would not consider this an option for him. On the
Because cardiomyopathy causes more than 70% of the other hand, if all logistics are resolved, we follow the in-
causes of thalassaemia deaths, decompensated heart-failure ternational guidelines for SCT, meaning that the patients
is a medical-emergency we manage by continuous infusion are chosen based on young age, adequacy of chelation, ab-
of high-dose intravenous DFO, augmented by oral DFP.30 sence of liver fibrosis and hepatomegaly. Ideal donors are
Provided that his renal functions remained normal, I would compatible siblings, who are fortunately mostly available
opt for DFX treatment, since it is currently the only chelator for thalassaemia patients in Lebanon due to the prevalence
to demonstrate activity in this situation.31 of large families.
Several other therapies are available for patients with
β-t halassaemia.32,33 To date, allogeneic SCT is the only
available curative option, and there have been recent im- The perspective from Oman
provements of both prophylaxis against graft-versus-host-
disease as well as treatment of cytomegalovirus infection.34 If the patient has not improved in compliance over 2 years,
Consequently, I would explain this option in detail to this we could consider other therapies. SCT is an option. Criteria
patient at an early stage of therapy, or at least before compli- for transplantation in thalassaemia are having a suitable
cations due to iron overload become apparent. Normally, I matched donor and patient aged up to 16 years. However,
would look for an HLA-identical sibling, but since this is un- this is the only unit in the country providing allogeneic
likely in this refugee patient, I would opt for either unrelated transplantation, so the waiting list for patients with haemo-
bone marrow or cord blood from an HLA-identical sibling globinopathies is extremely long. In theory, there are spots
that could be used.35 allocated to thalassaemia patients, but generally malignan-
Gene-therapy to replace the defective β-globin gene has cies take priority. In many cases, the Ministry of Health will
shown promising results in reducing or eliminating the provide financial support for the SCT to be done abroad,
transfusion requirement in a transfusion dependent pa- generally in India.
tient.36 At my centre we do not have therapeutic options for Luspatercept, which has very recently become now avail-
SCT or gene therapy available, so we send patients to the able, but in limited amounts, could be an option. Gene ther-
Joint Accreditation Committee ISCT- Europe- accredited apy is not available.
transplant centres in Italy.
I would also consider using the novel activin II receptor
ligand luspatercept, (which is becoming available for patients The perspective from Sudan
over the age of 18), since it has been shown to be useful in
decreasing the transfusion requirement.24 Here, we are in Unfortunately, no curative therapies are available in Sudan.
the process of initiating luspatercept in our clinical practice Thus, no gene therapy and no SCT could be offered to this
HOKLAND et al. |
13
young patient. Patients can be advised to travel abroad to with our experience with thalassaemia, we will be one of
seek such options, if they are wealthy and able to do so. those centres.
The perspective from Thailand DISC US SION
Stem cell transplantation is the only curative treatment for The thalassemias are the world's most common genetic
patients with thalassaemia major in Thailand. Six university diseases, with 1.5% of the world's population carrying a
hospitals and one tertiary hospital in Northeast Thailand thalassaemia gene.42 Thalassaemia is endemic in the “ma-
perform this procedure. The outcome of SCT of all types, laria belt”, however in modern times, the disease is found
including matched related, haploidentical or matched unre- worldwide due to migration.43 Thalassaemia is an increasing
lated donor (MUD), is excellent in our country.39,40 Neither global health problem, as the prescient Sir David Weatherall
gene therapy nor luspatercept is available in Thailand. and Professor JB Clegg wrote in 1996.44 Due to improved
In Thailand, matched related donor (MRD), MUD and health care, sanitation and infection control, childhood
haploidentical donor SCT (haplo-SCT) have commenced. mortality has decreased in countries in which thalassaemia
Performing MRD or MUD SCT in patients younger than is endemic, leading to increased numbers of children surviv-
10 years of age is covered by the National Health System. ing to require therapy.
Older children with an MRD or haploidentical donor have to The number of patients with thalassaemia worldwide is
pay privately. The present patient, who is clinically a thalas- not known. In 2008, about 100,000 transfusion dependent
saemia major, would ideally proceed to SCT after having a patients were estimated worldwide, most of whom were not
high transfusion protocol and adequate chelation. However, getting adequate therapy.45 The voluntary organisation TIF
his poor socioeconomic status would most likely prohibit published a global report in 2021 with data from many coun-
him from this curative treatment. tries.g In parts of the Middle East, the Mediterranean region,
the Indian subcontinent and China, there are estimated to be
tens of thousands (or more) transfusion-dependent thalas-
The perspective from USA saemia patients, but accurate records are lacking in many
countries. Carrier screening with prenatal diagnosis in the
If the patient is on combination iron chelation and he is com- first trimester is highly accurate and cost effective,46 but is
pliant, we would anticipate bringing down his cardiac and not implemented in many countries for financial or social
liver iron which would prevent progression of organ dysfunc- reasons.
tion. Chelation compliance is key to maintaining him in iron The diagnosis of thalassaemia can be made using basic
balance and preventing cardiac, hepatic and endocrine com- tools, such as physical examination, FBC with peripheral
plications. Once iron levels have come down, and if his organ film and reticulocyte count. Geographic origin, family his-
function is normal, especially hepatic and renal, we would tory (in particular, consanguinity) and blood counts of fam-
offer a therapy with curative intent. If he has a matched family members are valuable, demonstrating carrier status of
ily member, this could be an allo-SCT, or he might be of- both parents. Hgb EP (or other methods, CE EP, HPLC) is
fered a clinical trial for gene therapy, either gene addition informative with elevated HgbA2 and HgbF and absence of
or gene editing. These trials (NCT03207009, NCT03655678) other haemoglobinopathies. All of the contributing authors
are conducted at our sister institution, Columbia University use these methods, which are available and relatively inex-
Medical Centre, also in New York. Given his age and risk for pensive. DNA-based diagnosis is the most accurate and can
morbidity based on his iron levels, we would not offer him a give important prognostic information, but it is not available
mismatched or unrelated donor transplant.41 If feasible, we in all countries and may only be used selectively for diagnos-
can perform the transplant at our centre, whether it be an al- tically uncertain cases.
logeneic transplant from a family member, or an autologous Baseline evaluation of iron status and the quantitation
transplant on a gene therapy protocol. Given that he is not el- of iron overload varies greatly in different countries. In
igible for luspatercept24 (approved for adults >18 years only) some, the routine evaluation includes many blood tests and
and given his poor compliance history, I personally would costly radiological examinations, such as MRI or fibroscan,
not offer him a clinical trial for a pyruvate kinase activator whereas in some countries these are virtually unavailable.
(NCT04987489). MRI is used sparingly in some countries, for example, only
With the recent Food and Drug Administration approval if the degree of iron overload or response to chelation is un-
of gene therapy as a curative option,36 this could also be con- clear. Looking back to the 1980s and even the 1990s, patients
sidered, but I would only consider it once his iron overload with transfusion- dependent thalassaemia were managed
had been well controlled. I believe that having comorbidi- using ferritin alone before cardiac MRI T2* was widely avail-
ties, including a high iron burden, would make this therapy able.47 Cardiac MRI enables greater accuracy regarding the
more complicated. This therapy will be available only at a adequacy of iron chelation and its precision has contributed
select few Qualified Treatment Centres in the United States, to increasing the lifespan of patients, where it is available.48
and those have yet to be established; however, it is likely that, Other imaging modalities such as fibroscan, bone density
|
and even abdominal ultrasound, can provide important in- available in all countries. It can reduce strain on blood
formation regarding complications of the disease, but these transfusion supplies and may reduce iron loading.24 That,
also may be difficult to obtain in countries with strained or other similar drugs, offer hope for improving the future
economic situations. It is possible to manage patients with- situation of thalassaemia patients. It will be a number of
out all of these tests at baseline, but depending on symptoms, decades until the cost of such novel patented drugs makes
at least some of them will be necessary at some point. them available to the many patients living in countries
Beta thalassaemia patients must have regular blood with strained economies. The same can be said for hepci-
transfusions starting early in life in order to survive. din mimetics or stimulators, which can potentially reduce
The contributing authors have a similar approach to the the need for high-dose chelation. 38 Such novel drugs are
threshold for transfusion. If the patient has a consistently potentially very valuable, but will only offer some relief to
low Hgb (7 g/dL or less), or evidence of end-organ damage the global issues in the distant future, due to their current
from chronic anaemia, then regularly scheduled transfu- high cost.
sions are initiated. As seen from Table 1, all contributors Stem cell transplantation is used in practice in many
aim to maintain pre-t ransfusion Hgb of 9–9.5, though this countries and can offer substantial improvements to the
could be higher in patients with cardiac complications quality of life for thalassaemia patients. There is much ex-
(TIF guidelines). 5 Unfortunately, this goal is not easily perience with MRD, and even MUD or haploidentical trans-
achieved in some countries, due to inadequate blood do- plants. In regions where thalassaemia is prevalent, there
nations.49 Several contributors note that the patient's fam- are likely to be matched donors, due to large families (as in
ily may be requested to bring a donor for transfusion. The Lebanon), but as seen from the contributions, the facilities
global issue of blood donation shortages is discussed in the for HSCT are scarce and costly, preventing its widespread
TIF Global Report. 5 Sufficient quantities of donor units utilisation. Furthermore, it should, ideally, be implemented
free of pathogens are essential but lacking. Phenotypic early in life in a patient who has been well chelated, making
matching and pre-storage filtration may not be feasible or this problematic for the patient discussed here.
available in many countries where thalassaemia is preva- Gene therapy using genetically altered autologous stem
lent. Splenectomy is not well proven in beta thalassaemia cells is being implemented36,38 and is, in theory, an ideal
and raises risks of increased infections; but it can be per- therapy for this disease, despite the checkered history of
formed for certain patients who may benefit, with result- this interventional treatment modality in other diseases.
ing reduction of transfusion requirement. 50 Downsides of Autologous stem cells may be corrected ex vivo by gene
the procedure include infections, even years after splenec- therapy using viral vectors. This has been performed for a
tomy, and thrombotic events postoperatively (both imme- number of years in small clinical trials with increasingly
diate and late). In addition, splenectomised patients may to sophisticated, safer vectors with differing rates of beneficial
be at risk for thrombosis on luspatercept, which may be a outcomes.36,38,56 The CRISPR/Cas9 technology, however,
relative contraindication in the current era. 51 has yielded surprisingly positive results with high efficiency
Hydroxyurea has been used in regions where blood sup- targeted integration in haematopoietic stem cells using elec-
ply is inadequate and has been reported to be cost effective,52 troporation,57 disrupting GATA-1 binding at +58 of the
and genetic determinants may be associated with response erythroid specific enhance of BCL11A. Genetic therapies
to hydroxyurea.53,54 Hydroxyurea is indeed safe from the hold the promise of providing a “one-and-done” approach,
point of view of infections, especially in the prevalent HgbE where one genetic therapy procedure could result in life-
form of the disease.55 However, especially in countries with long independence of the laborious treatment measures laid
good blood services, most practitioners prefer to transfuse out here (for a recent review of pros and cons as well as the
and chelate rather than give a cytotoxic drug for a hereditary more technological angles of this, see58). Recently, a phase
anaemia. 1/2 trial of gene editing was performed in China,59 using
Transfusion dependency results in iron overload, which the same type of CRISPR/Cas9 approach as Frangoul et al.57
will be fatal without chelation. Chelation is absolutely re- Two patients with the most severe genotype of beta thalas-
quired. The cost of chelation agents is an important issue saemia achieved high level HgbF production, with normali-
and in countries where chelators may not be guaranteed at sation of Hb levels, transfusion independence and cessation
low or no cost, it is obvious that patients will suffer end- of chelation.59 As has been stated, we are now in the era of
organ damage and, possibly, early death. Chelator treatment “a plethora of gene therapies for haemoglobinopathies”.60
options are still not ideal, as all three chelators, even oral Counteracting these positive trends are the daunting issues
ones, are not pleasant to use and compliance is still problem- of reagent costs, the necessity for having specialised labo-
atic worldwide, particularly in adolescents, as exemplified by ratories and, as such, the overall inaccessibility of the regi-
this case. Strategies to overcome this are varied and differ by mens. As could be expected, only one contributor has direct
country, according to institutional resources, and family and access to gene therapy, and he rightly points out the fact that
peer relationships. this particular patient, at the time he was presented to him,
What is the place of advanced medical therapies in was not an ideal candidate to be included in such trials.
thalassaemia therapy? Luspatercept can reduce transfu- This article demonstrates that practitioners in different
sion requirement, although it is parenteral and not yet parts of the world have successfully adapted the treatment
HOKLAND et al. |
15
of thalassaemia to the resources available to them. Many R EFER ENCES

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2008;86(6):480–7.

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13652141, 0, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/bjh.18671 by Texas A&M University Library, Wiley Online Library on [21/03/2023].

Thalassaemia—A global view

Peter Hokland1 | Shahina Daar2 | Wael Khair3 | Sujit Sheth4 | Ali T. Taher5 |

Deborah Rund, Department of Haematology,

Br J Haematol. 2023;00:1–16. wileyonlinelibrary.com/journal/bjh | 1

of beta-t halassaemia major1 (for a recent review, see2), while

Primary contact Thalassemia International Federation (TIF) guidelines.

BOX 2 Questions for the panel

Country Diagnostic tools at presentationa initiation organ damage issues therapies

The perspective from Thailand DISC US SION

of thalassaemia to the resources available to them. Many R EFER ENCES

You might also like

BR J Haematol - 2023 - Hokland - Thalassaemia A Global View PDF

Uploaded by

Copyright:

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BR J Haematol - 2023 - Hokland - Thalassaemia A Global View PDF

Uploaded by

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Original Title

Copyright

Available Formats

Share this document

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Sharing Options

Did you find this document useful?

Is this content inappropriate?

Copyright:

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BR J Haematol - 2023 - Hokland - Thalassaemia A Global View PDF

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Copyright:

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13652141, 0, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/bjh.18671 by Texas A&M University Library, Wiley Online Library on [21/03/2023].

Thalassaemia—­A global view

Peter Hokland1 | Shahina Daar2 | Wael Khair3 | Sujit Sheth4 | Ali T. Taher5 |

Deborah Rund, Department of Haematology,

Br J Haematol. 2023;00:1–16. ﻿ wileyonlinelibrary.com/journal/bjh | 1

of beta-­t halassaemia major1 (for a recent review, see2), while

Primary contact Thalassemia International Federation (TIF) guidelines.

BOX 2 Questions for the panel

Country Diagnostic tools at presentationa initiation organ damage issues therapies

The perspective from Thailand DISC US SION

of thalassaemia to the resources available to them. Many R EFER ENCES

You might also like

Thalassaemia—A global view

Br J Haematol. 2023;00:1–16. wileyonlinelibrary.com/journal/bjh | 1

of beta-t halassaemia major1 (for a recent review, see2), while