Non Transfusion Dependent Thalassemia

1. Non Transfusion Dependent Thalassemia (NTDT) Thalassemia from genetic disease to clinical Syndrome 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.