1. Overview of the Management of Thalassemia
Prof. Manzur Morshed FCPS, MRCP
Adviser, BTF
Overview of the Management of Thalassemia

2. “Patients with optimally treated thalassemia can now enjoy a near- normal life and lifestyle, and experience regular physical and emotional development from childhood to adulthood”.
– TIF guidelines for TDT; 3rd edition (2014) p 224

3. Goal of treatment
To maintain the best possible quality of life with minimum intervention
Regular monitoring/follow up is the key to maintain a good quality life
Treatment of a thalassemia patient – whether TDT or NTDT - needs a serious commitment from treating doctor

4. Management of b thalassemia
General care and nutrition
Blood transfusion
Iron chelation: s/c Desferioxamine, oral deferasirox/ deferiprone
Drugs aiming at increment of Hb
Splenectomy – indications and precautions
Management of thrombosis, Pul HTN and leg ulcer
Management of endocrine, hepatic and cardiac complications
Management of fertility and pregnancy
Curative treatment
Stem cell transplantation
Gene therapy

5. Management of b thalassemia
General care and nutrition
Blood transfusion
Iron chelation: s/c Desferioxamine, oral deferasirox/ deferiprone
Drugs aiming at increment of Hb
Splenectomy – indications and precautions
Management of thrombosis, Pul HTN and leg ulcer
Management of endocrine, hepatic and cardiac complications
Management of fertility and pregnancy
Curative treatment
Stem cell transplantation
Gene therapy

6. Management of b thalassemia
General care and nutrition
Blood transfusion
Iron chelation: s/c Desferioxamine, oral deferasirox/ deferiprone
Drugs aiming at increment of Hb
Splenectomy – indications and precautions
Management of thrombosis, Pul HTN and leg ulcer
Management of endocrine, hepatic and cardiac complications
Management of fertility and pregnancy
Curative treatment
Stem cell transplantation
Gene therapy
Monitoring and follow up plan

7. General Care and Nutrition
Growth and QoL : Observation and supportive care
appetite
activity, schooling, employment and social life
Diet: Poor growth can be due to nutritional factors such as caloric intake and micronutrient deficiencies.
Iron restriction myth
A diet high in calcium is also recommended (milk, fish, cheese etc.).
A diet rich in high Vitamin E content, ie; eggs and vegetable oils, nuts.

8. General Care and Nutrition
Calcium & Vitamin D: Recommended for all thalassemics, along with measurements of vitamin D levels every few months.
Folic acid: Apart from Hb synthesis, risk of thrombosis is also reduced.
Vitamin C: 2-3 mg/kg/day, with DFO infusions, or if deficiency is proven.
L-carnitine: May be beneficial (50mg/kg/day).
Silymarin: In case of liver involvement. Dose is 140mg 3 times daily.
Zinc: Not recommended as routine.
Wheat grass: Insufficient evidence for any long term benefits.

9. General Care and Nutrition
Alcohol, tobacco and substance abuse should be avoided
Physical activity should be encouraged.
Co-morbidities need appropriate evaluation.
Routine dental care: Maxillary deformities may occur in absence of adequate blood transfusions from an early age. Orthodontic interventions may become necessary.

10. Management of Fever Two major risks during fever
Worsening of anemia
Serious sepsis
During the clinic or ER visits
Check hemoglobin, reticulocyte count and bilirubin
Admit for observation or transfusion if the hemoglobin low
Antibiotic treatment may be needed
Splenectomized patients with a fever
Should be seen on the same day
Given a dose of intravenous antibiotic, admission recommended

11. Drugs to reduce the need for transfusion in beta thalassemia

12. Ways to increase Hb production
Induction of Fetal Hb (α2γ2)
Hydroxyurea (DNA-binding drug)
Thalidomide
histone deacetylase inhibitors (azacitidine, decitabine)
mTOR pathway inhibitors : Everolimus
Metformin
Targeting IE (ineffective erythropoesis)
JAK2 inhibitors
Activin receptor trap ligands
Iron restriction erythropoisis
α-globin synthesis reduction

13. Induction of HbF (α2γ2)
Increased production of γ-globin leads to decreased imbalance between β & α-chains resulting in haemolysis reduction.
Also - inherited persistent high levels of HbF have a milder clinical course than other patients with Thalassemia.
Therefore, therapeutic approaches reactivating and increasing HbF concentration, are attractive.
Accordingly, several studies were done with potential inducers of HbF – particularly with hydroxyurea.

14. Hydroxyurea Experience from Iran and India
many patients were reported to have become transfusion-independent
in patients who were not transfused, the Hb concentration increased
the combination of hydroxyurea with L-carnitine or magnesium could be more effective in improving hematologic parameters and cardiac status in patients with TI than hydroxyurea alone
Experience from Europe
constant increase of the RBC volume and in HbF, but only a modest effect on total Hb concentration
Karimi M, et al. J Pediatr Hematol Oncol. 2005;27:380-5.
Dixit A, et al. Ann Hematol. 2005;84:441-6.
Karimi M, et al. Eur J Haematol. 2010;84:52-8.

15. Hydroxyurea (Cont’d) Predictive of good response:
Co-inheritance of α-thalassemia,
the Xmn-1 HBG2 polymorphism, and
the underlying β-globin genotype
Hb E/β-thalassemia patients
Treatment with hydroxyurea has also shown promising results in decreasing plasma markers of thrombin generation
Singer ST, et al. Br J Haematol. 2005;131:
Panigrahi I, et al. Hematology. 2005;10:61-3.
Ataga KI, et al. Br J Haematol. 2007;139:3-13.

16. In the OPTIMAL CARE study Patients on hydroxyurea: 202/584
Complication
Parameter RR
95% CI
p-value
Leg Ulcers
Age > 35 yrs
2.09
0.036
Splenectomy
3.98
0.002
Transfusion
0.39
0.006
Hydroxyurea
0.10
Hypothyroidism
6.04
0.001
0.05
0.003
Osteoporosis
3.51
<0.001
Female
1.97
0.009
4.73
3.10
0.02
Iron chelation
0.40
Hypogonadism
2.98
Ferritin ≥ 1000 ng/ml
2.63
16.13
4.32
2.51
Hydroxyurea treatment was protective for EMH, PHT, leg ulcers, hypothyroidism, and osteoporosis.
Taher AT, et al. Blood ;115:

17. Hydroxyurea side effects
However, side effects include -
cytopenia,
hyperpigmentation,
weight gain,
opportunistic infections,
azoospermia in approximately 80% of men (even years after the end of treatment), and
marked hypomagnesemia.
Teratogenicity.

18. Safety measures to reduce harm from Hydroxyurea
> Not be used in pregnant women or patients with hepatic or renal failure
> CBC, Hepatic and renal function studies, q2 weeks for the first 3 months & then monthly
> History and physical examination evaluating for GI, neurologic, or dermatologic side-effects, monthly
Gonadal function follow-up
Restrict use in the following groups of NTDT patients:
Patients for which a transfusion course is required but are alloimmunized
Patients with following morbidities – Pulmonary HTN, EMH pseudotumors, Leg ulcers.

19. Hydroxyurea
Dose: Start at 10 mg/kg/day with escalation q8 wks to maximal tolerated dose, but not exceeding 20 mg/kg/day.
Response evaluation:
At 3 and 6 months of therapy - Hb increase of >1 g/dl.
Discontinue in patients not showing response.
Re-evaluate at 12, 18, and 24 months to ensure maintenance of response.
Though baseline HbF level and it’s response to HU is dependent on genetic factors, criteria for treatment should not be based on genetic characteristics.

20. Thalidomide
A synthetic glutamic acid derivative, was used as a sedative as well as an anti-emetic. Because of serious teratogenic effects in pregnant women, it was withdrawn.
Relaunched for its anti-angiogenic properties and is now used in various inflammatory disorders and certain malignancies such as MPN, MDS, Multiple Myeloma.
Mechanism of action:
HbF production: It is postulated that thalidomide might have effect on the γ-globin gene through ROS-p38 MAPK signaling pathway as other HbF stimulating drugs. Therefore Thalidomide causes an increase in Hb through raising HbF.
Downregulation of alpha chain production, thereby reducing alpha:beta ratio.

21. Are we ready for thalidomide as a routine drug in thalassemia?
The answer is a clear “No”!
Not yet undergone adequate trials for its routine use in thalassemia.
Has significant adverse events including serious life-threatening ones. Thrombosis has already been reported even with a single course of thalidomide in a patient of thalassemia major.
Only anecdotal reports of its use in those patients, in whom transfusions were near impossible due to alloimmunisation and other immunomodulators failed to improve the situation.
It is mandatory to explain to the patients and their families the need for use of a non-approved drug with its inherent life-threatening adverse effects. Only if they then consent, should it be used.
……….. Presently, therefore, it has no role in routine management of thalassemia syndromes.
Management of ß-thalassemia – Consensus and controversies!
Mamta V Manglani et al; Pediatric Hematology Oncology Journal 2;4, 2017, 94-97

22. SPLENECTOMY

23. Splenectomy Less common than in the past because –
proper transfusion regimen and chelation has brought the disease very well controlled and reduced the incidence of splenomegaly and iron overload
the high disease burden (complications) associated with it.
Main indications include -
growth retardation or poor health with increased transfusion demand (to reduce excessive blood consumption and consequent severe iron overload)
Leukopenia/thrombocytopenia (Hypersplenism)
symptomatic splenomegaly
less transfusion requirement

24. Splenectomy: adverse events
Splenectomy was independently associated with an increased risk of most disease-related complications.
Thromboembolic events-
Venous thrombosis
Silent brain infarctions
Pulmonary hypertension
Infection - sepsis
10-year follow-up of 221 splenectomized patients, 6 of whom died of sepsis
no need to “wait & see” in such patients with fever
Cappellini MD, et al. Br J Haematol. 2000;111:
Atichartakarn V, et al. Int J Hematol. 2003; 78: Pinna AD, et al. Surg Gynecol Obstet. 1988;167:

25. Splenectomy vs. hypercoagulability
150
120 90 60 30 10
Time (seconds)
Thrombin generation (nM)
Splenectomized TI patients
Non-splenectomized TI patients
Normal controls
Splenectomized controls
Higher rates of prcoagulant RBCs and activated platelets in splenectomized patients.
Taher A, et al. Blood Rev. 2008;22:
Splenectomized TI had the highest
Representative examples of time course of thrombin generation in the presence of erythroid thalassemic cells as source of phospholipids
Cappellini MD, et al. Br J Hematol. 2000;111:467–73. Reprinted with permission.

26. Splenectomy care Should be avoided in patients <5 years
If splenectomy is indicated, patients should receive the following vaccines (2 weeks prior to and then 3 to 5 years later):
Pneumococcal 23-valent polysaccharide vaccine – (s/c or i/m)
H influenzae vaccine - If not administered as childhood immunizations
Meningococcal polysaccharide vaccine
Influenza vaccine annually
Patients who underwent splenectomy without being given the vaccine may still benefit from vaccination postsplenectomy
Post-splenectomy sepsis remains a risk; therefore, febrile splenectomized patients should undergo rapid evaluation and treatment.

27. Post-splenectomy prophylaxis
Compliance with prophylactic abx should be stressed while explaining that it does not entirely prevent postsplenectomy sepsis.
Splenectomized patients should receive prophylactic abx for > 2 years following splenectomy (for children until >5 years of age)
P.O. penicillin, 125 mg bid for age <2 yrs, & 250 mg bid for >2 yrs
Alternatives include amoxicillin, TMP-SMZ, and erythromycin
The GB should be inspected and removed during splenectomy if there is evidence of gallstones. Liver biopsy may be considered.

28. Thrombotic disease

29. Thrombotic disease
The following subgroups of NTDT patients should be considered at higher risk of thrombosis or CVD, :
Adult patients
Splenectomized patients
Never or previously minimally transfused patients
Patients with elevated platelet counts (≥500 x 109/l)
Patients with elevated nucleated RBCs (≥300 x 106/l)
Patients with a Hb level <9 g/dl
Patients with a history of pulmonary hypertension
Patients with iron overload
Pregnant patients
Patients with a personal or family history of thrombosis
Patients with other conventional risk factors for thrombosis or CVD
Patients developing thrombotic or CVD should be treated as per standard guidelines
In high-risk patients prophylactic anticoagulants/antiaggregants should be given.
Aspirin should be given in splenectomized NTDT patients with platelets ≥500 x 109/l.
Transfusion should be considered for prevention of thrombotic or CVD in high-risk patients.

30. Pulmonary HTN
NTDT patients should undergo yearly echocardiogram for the assessment of Pulmonary HTN
Patients ‘likely’ to have pulmonary HTN on echo should undergo right heart catheterization to confirm the diagnosis.
Ventilation/perfusion lung scan is also recommended to rule out pulmonary thromboembolic disease
Patients with ‘possible’, ‘likely’, or confirmed pulmonary hypertension may benefit from the following interventions -
> Blood transfusion & adequate control of iron overload status
> hydroxyurea
> Sildeanfil citrate
> Anticoagulant therapy

31. CONCLUSION

32. The initial clinic visit
Review laboratory results
Hematological
Electrophoresis
DNA tests
Establish baseline evaluation
Counseling
Discuss probable outcome and uncertainties
Stress that close follow up is essential to make informed decisions
Introduce the care team
Physician, Nurse, Social Worker etc
Provide support

33. Montioring/Follow up Frequency of visits Growth and development
Initially every month, then 2 months, then 3-12 months
Growth and development
Height and weight, pubertal development
Nutrition
Folate, vitamin D, avoiding supplemental iron
Endocrine, cardiac, iron status
Counseling for risk during infections
Building relationship
Accessibility, social work assessment.

34. Laboratory monitoring/follow up
Assessment
Ages
Frequency
Comments
Bone mineral density
≥10
Yearly
DEXA scan or quantitative CT
Tanner stage
10–20
start at 10 y & continue till breast or gonadal T. Stage 5 or age 20.
Liver iron content
All
MRI method (R2, T2*) or liver biopsy
Cardiac T2*
≥ 10
To be performed at evidence of iron overload or age > 10 yrs
Cardiac studies
Echo or cardiac function by MRI; assess for pulmonary HTN (echo)
CBC plus differential
3m(min)
If transfused, preceding each transfusion
Blood chemistries 3m
BUN, creatinine, calcium, magnesium, phosphorus, and zinc
LFTs 6m
ALT, AST, total bilirubin, albumin
Ferritin
Yearly(min)
HIV
Only for transfused participants starting at the first transfusion
Hepatitis testing
For txed patients starting at 1st tx. HBV, HCV serology and PCR
Serum glucose
12 h fast
Endocrine panel I ≥6
TSH, free T4, PTH, 25-OH and 1,25 dihydroxy vitD levels
Endocrine panel II
Testosterone (males), FSH, LH (both sex), estradiol (females)
Ophthalmology and Audiology
All undergoing chelation. Auditory testing for those on dfxamine

35. Challenges for Quality treatment
Noncompliance to treatment
Financial
Education
Lack of support
Intolerance and Complications of drugs
Lack of availability of appropriate blood products and drugs

36. Last word
Protocol based but individualized plan is needed for appropriate management.
The protocol should be made by a coordinated effort by the dedicated “thalassemia care givers” keeping the real scenario of our patients in mind.
Co-operation and coordination among different specialties (Adult and Pediatric Physicians, Cardiologists, Gynecologists, Endocrinologists, Gastroenterologists etc) is very much needed to manage these patients appropriately.