Q&A with Dr. Richard Ward: Non-Transfusion-Dependent Thalassemia

January 13, 2015 Below, Dr. Richard Ward answers some commonly-asked questions regarding non-transfusion-dependent thalassemia and its treatment.


Non-transfusion-dependent thalassemia (NTDT) is the term given to individuals with thalassemia that do not require regular blood transfusion but who still have some complications. This differentiates you from both thalassemia major and thalassemia trait/minor, respectively. There are three main genetic groups that encompass NTDT: beta thalassemia intermedia, E beta thalassemia, and hemoglobin H disease. However, the diagnosis is a clinical one, based on the presence of a spectrum of medical complications, and can vary quite a bit between individuals.

Our knowledge of NTDT has changed dramatically over the past decade, in large part due to research and clinical experience from the Middle East and Mediterranean. In addition, as patients with NTDT have aged, it has become apparent that they often have suffered more than those with thalassemia major who are transfused. As there is so much heterogeneity, it is important for you to have a personalized management plan in place with your healthcare team. This will be based on how you feel, what you want to achieve through any medication or treatments, and any possible side effects of treatment. As the field is maturing quickly, the decisions you make today may not be the same in a few years’ time, so it is worth re-evaluating your care plan annually.

1. What are the most important things for a person with NTDT to know?

NTDT is a spectrum, meaning there can be a wide variability in the problems patients may encounter. It is therefore important to ensure that you have been fully evaluated for all the possible complications. These include: blood clots in the arteries (stroke) and veins of the leg (deep vein thrombosis, DVT) or lungs (pulmonary embolism, PE); enlarged spleen; gallstones; severe anemia; low bone density/strength; lumps of blood forming tissue that press on other organs or nerves (extramedullary hematopoiesis, EMH) or causing changes to the bone shape and bone pain (medullary expansion); high pressure in the lung vessels (pulmonary hypertension); and leg sores (ulcers). We also know that even if you do not receive blood transfusions, you can often develop iron overload by taking in too much iron from your diet. Patients with NTDT can even have very high liver iron concentrations, comparable to thalassemia major.

RWardNTDT1Although this is a long and scary list, many people with NTDT do not have most of these issues, though an unfortunate minority may have developed many of them. It can be difficult to assess for all these problems clinically, and therefore it is recommended that tests are ordered to screen for them. These include: ECHO (ultrasound of the heart), liver MRI for iron concentration, bone mineral density DEXA scan, and other tests that may be suggested by your physician. Of note, the ferritin values we use to monitor for iron overload in thalassemia major are not the same as those we use in NTDT, where a much lower ferritin may be significantly abnormal. It is also important not to blame the hemoglobin (Hb) value and anemia for all your symptoms. For example, there are many causes of tiredness including an underactive thyroid gland, depression, lack of physical exercise, et. If all other causes have been ruled out, and you feel it is a struggle to get through a regular day, then you may wish to consider treatment options for your anemia. For all of these reasons, if you have or suspect you have NTDT, it is reasonable to request a consultation with a thalassemia specialist.

2. Some complications – pulmonary hypertension, gallstones, leg ulcers, etc. – are associated with beta thalassemia intermedia; are they also a concern for other forms of non-transfused thalassemia? Are there complications with these other forms of non-transfused thalassemia that are NOT typically associated with beta thalassemia intermedia?

All forms of NTDT have in common a mild anemia from breakdown (hemolysis) of the red blood cells and poor quality production (ineffective erythropoiesis) of new red blood cells. However, in general, hemoglobin H disease is a fairly mild form of NTDT and with some exceptions (non-deletional forms) often causes no or very few problems. In my own practice, we see patients with hemoglobin H disease annually, but often there is nothing of concern or that needs to be done for them. E beta thalassemia and beta thalassemia intermedia are often associated with some complications, but there is a lot of variability between individuals. In my practice, we would review such patients every 3-6 months depending on severity. There is a small group of milder thalassemia intermedia where fewer problems are seen. A common theme in NTDT is the variable spectrum of complications and their severity, which makes generalizations difficult.

3. Some non-transfusion-dependent thalassemics eventually reach a point where they require a level of transfusion that is similar to that of beta thalassemia major. Does beginning regular transfusions at a much later stage create any special considerations or issues?

RWardNTDT2The traditional reason for not transfusing an individual with NTDT was the fear of iron overload complications from the transfusions. This is nowadays much less of an issue with three chelators available and more in development, as well as MRI evaluation of the iron levels. This combined with our growing understanding of the complications of NTDT has somewhat tipped the balance in favor of more liberally transfusing people with NTDT who have complications. The main concern is the risk of developing antibodies to the transfused blood (alloimmunization). Infants with thalassemia major start transfusion at a very young age whilst their immune system has not fully developed. As a consequence they will be more tolerant to any minor differences in the blood group of the transfused blood and their own, and so less likely to develop antibodies to the red blood cells. However, patients with NTDT often begin transfusions later in life when their immune system is fully functioning, and there is a concern that this may increase the risk of developing antibodies to the blood. If this were to occur, there is a chance that it would become harder to obtain the correctly matched units of blood for you subsequently. If you were to have a transfusion reaction to an antibody this may also make you more anemic. Although chelation these days is much easier with the use of oral drugs, the fact that patients with NTDT have not had to take them lifelong may raise challenges with adherence and this should be discussed openly with your healthcare team prior to starting transfusions.

4. Bone health can be a concern for people with NTDT. What steps are appropriate for preventing/delaying bone issues from developing?

We are not certain as to the exact cause for low bone density in NTDT and we believe it is a little different from what we see in thalassemia major. However, the same general principles for prevention and treatment apply and I refer you to a previous Q&A session on this topic [Click here for that earlier article]. There have been far fewer studies in NTDT looking at specific bone building medications such as bisphosphonates. However, as there are many more individuals with NTDT than thalassemia major who are beyond menopausal age, the recommendations that apply to the general older population should also be considered.

5. What is the proper dose range for beta thalassemia intermedia patients using Zometa for osteoporosis?

Specific drugs and their doses should be discussed with your healthcare providers, as there are factors that come into play beyond the thalassemia, such as kidney function. As mentioned previously, there is very little data or research to inform us whether standard doses recommended in the general population are equally applicable in NTDT, and even which types of drugs are effective. If your hematologist is unsure, consideration can be given to seeing an osteoporosis specialist or endocrinologist.

6. Under what circumstances is hydroxyurea beneficial to a person with NTDT?

RWardNTDT3This is an excellent question and very hard to give a straightforward answer. Hydroxyurea, and other fetal hemoglobin-inducing medications, have been tried in various forms of thalassemia, including also thalassemia major. The data is not conclusive and wildly differing results have been reported from different countries and using different prescribing regimens. One trend that has emerged is that there is a group of patients in Iran who seem to have an excellent response. Individuals with hemoglobin Lepore or delta-beta forms of thalassemia may also be more likely to respond to the medication. Unlike in sickle cell disease, where high doses of the medication generally give better results, a lower dose is probably more suitable in thalassemia.

At the present time the main consideration I would recommend is to ask yourself whether you need any form of treatment for your NTDT. If the answer is yes, then the next question to discuss with your provider is whether medication or transfusion/chelation is most suitable. If you decide you want to avoid transfusion, it would then be reasonable to consider trying hydroxyurea for 6-9 months to see if you respond. If there is no improvement after this time, it is unlikely to be beneficial to keep taking it. Other drug treatments are being actively developed and researched for NTDT, so recommendations may change in the next few years.

Occasionally, both transfusion and hydroxyurea will be recommended. One scenario for this is when there is compression of the spinal cord by extramedullary hematopoiesis. In this case, the hydroxyurea is thought to soften the masses whilst the transfusions reduce their size (somewhat more slowly). Due to the risk of paralysis we tend to be very aggressive in our management of this particular complication. (Fortunately, compression of the spinal cord is a very rare occurrence in thalassemia. If you do, however, notice any weakness or tingling in the legs or arms, you should inform your provider immediately, as this can be a sign of possible compression.)

7. What else would you like to say?

Thalassaemia International Federation has recently published guidance on the management of NTDT; it is a very well written and easy to read reference: https://www.thalassemia.org/wp-content/uploads/2011/09/Guidelines-for-Mgmt-of-NTDT-TIF-2017.pdf

RWardNTDT4However, due to the wide variability in symptoms and problems that individuals with NTDT may face it is important to make an individualized care plan with your healthcare team that takes into account YOUR complications, quality of life and life goals, and your view on various treatment options. This is even more important than with individuals with thalassemia major. As our understanding of NTDT is growing rapidly and there are now several different drug and treatment strategies being developed, it is sensible to re-evaluate your care plan on a regular basis, say every year, as the risk-benefit ratio for intervention may have changed.

CAF thanks Dr. Ward for sharing his expertise with the thalassemia community.

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