Non-transfusion dependent thalassemia (NTDT) refers to thalassemia phenotypes that do not require regular blood transfusions to survive. NTDT includes conditions like beta-thalassemia intermedia and hemoglobin E/beta-thalassemia. Patients with NTDT present later in childhood with milder anemia than transfusion-dependent patients. While they do not require lifelong transfusions, NTDT patients are still at risk for complications from iron overload, ineffective erythropoiesis, and hemolytic anemia. Management of NTDT focuses on treating symptoms and may include transfusions, iron chelation, hydroxyurea, or splenectomy.

1. ,
Non Transfusion Dependent Thalassemia
(NTDT)
Thalassemia from genetic disease to clinical diagnosis
Anwer Ghani
FIBMS
iRAQ

2. .
Non-transfusion-dependent thalassemia (NTDT) is a term used to
describe thalassemia phenotypes that do not depend on regular
blood transfusions for survival and daily function.

3. NTDT phenotypes include patients with β-thalassemia
intermedia, hemoglobin E/β-thalassemia, and Hemoglobin H
disease (α-thalassemia intermedia) but also those with
structural variant of hemoglobin associated with “α” or “β”
thalassemia in heterozygous condition which often have
analogous characteristics.

4. Non-transfusion-dependent thalassemia (NTDT) is a broad term
encompassing patients who do not require lifelong transfusion
therapy for survival.

5. NTDT patients commonly, present to medical care later in
childhood and with milder anemia and clinical symptoms compared
to patients with transfusion-dependent forms.

6. In NTDT, iron overload is likely mediated by a variety of factors,
including increased erythropoiesis, hypoxia and the contribution of
factors such as erythroferrone, which suppresses hepcidin synthesis
in the liver.

7. Because hepcidin functionally inhibits iron egress from cells by
binding and internalizing the iron transporter ferroportin in
enterocytes, iron absorption is increased under conditions of
reduced hepcidin synthesis.

8. In hypoxic conditions, synthesis of molecules responsible for
mediating iron absorption (including ferroportin) are increased in
the duodenum, further contributing to the iron overload in NTDT.

9. Presentation of NTDT may include mild to severe anaemia,
enlarged spleen and/or liver, skeletal deformities, growth
retardation, elevated serum ferritin and iron overload.

10. The contributing factors to disease progression are ineffective
erythropoiesis and increased haemolysis, which lead to chronic
anaemia.

11. The body's attempts to correct the anaemia result in constantly
activated erythropoiesis, leading to marrow expansion and
extramedullary haematopoiesis.

12. Diagnosis of NTDT is largely clinical.

13. NTDT patients are at risk of developing a wide variety of clinical
complications including gallstones, leg ulcers, growth retardation,
pulmonary hypertension (PHT), splenomegaly, liver disease and
thromboembolic events.

14. Many of the clinical complications common in NTDT can be
prevented by early intervention strategies.

15. A diagnosis of NTDT before the onset of clinical
complications is therefore a valuable investment in the
future health of patients.

16. NTDT patients with moderately severe phenotype can
develop a haemolytic crisis during an acute pathogenic
infection or high fever.

17. The Hb levels of NTDT patients experiencing a
haemolytic crisis rapidly decline and as a result they
can be mistaken for having TDT and erroneously
entered into a management programme of lifelong,
regular transfusions.

18. Clinical symptoms such as clinical anaemia, fatigue,
lethargy, poor feeding, poor weight gain, intercurrent
infection, liver and spleen size and development of
bone deformities. These parameters will be carefully
considered to categorize patients into either TDT or
NTDT phenotypes.

19. However, even though NTDT can be defined by
genotype, the diagnosis is mainly clinical and it is
based on the severity of the patient's condition.

20. Taher et al. have suggested raising baseline Hb for
NTDT patients to over 9 μg/dL in order to prevent
future complications as a prophylactic measure.

21. It is known that NTDT patients develop extensive liver
iron loading although their serum ferritin levels are
relatively low compared with the serum ferritin levels
indicative of liver iron loading in transfusion-
dependent patients .This complicates the monitoring
of physiological iron loads in NTDT, because the
current thresholds for serum ferritin used to guide
chelation therapy in transfusion-dependent patients
cannot be extrapolated to NTDT patients.

22. Management of NTDT is based on managing
symptoms.

23. Management of NTDT includes blood transfusions,
hydroxyurea treatment, iron chelation and sometimes
splenectomy.

24. Minihepcidins or agents that induce hepcidin
expression in Hbbth3/+ mice decreased transferrin
saturation, heme synthesis, hemichrome formation,
and improved RBC lifespan, anemia, and
splenomegaly.

25. Prognosis for well managed patients is good, with
most patients living a normal life.

26. In NTDT, effective iron chelation can keep serum
ferritin levels relatively low, thereby preventing the
development of clinical complications due to iron
overload.

27. “In conclusion, luspatercept treatment) Reblozyl)
improved quality of life and RBC transfusion burden
compared with placebo in patients with NTDT in the
BEYOND trial,” Dr Kattamis said in a presentation
accompanying his research team’s poster.

28. Reference
1-Published: 30 Vip Viprakasit, Paul Tyan, Sarayuth Rodmai & Ali T Taher; Identification and key management of non-transfusion-dependent
thalassaemia patients: not a rare but potentially under-recognised condition. September 2014. Orphanet Journal of Rare Diseases volume 9,
Article number: 131 (2014).
2- Paolo Ricchi,1 Aldo Filosa,1 Aurelio Maggio,2 and Suthat Fucharoen3; Non-Transfusion-Dependent Thalassemia: A Complex Mix of Genetic
Entities Yet to Be Fully Discovered. Hindawi; Volume 2015 |Article ID 161434.
3- Khaled M. Musallam et al; Survival and causes of death in 2,033 patients with non-transfusion-dependent β-thalassemia. Haematologica. 2021
Sep 1; 106(9): 2489–2492.
4- Vicki Moore; Outcomes in Non transfusion-Dependent β-Thalassemia With Luspatercept or Placebo. HematologyAdvisor; December 14,
2021.