CABANG DEPARTEMEN

DI YOGYAKARTA ILMU KESEHATAN ANAK

Dr.dr. Sri Mulatsih., MPH., Sp.AK

Afiliasi/ Institusi
Winaya Waidya Anarawata (WWA) 8 Rumah sakit
Univeristas Asal
Pendidikan Kedokteran Berkelanjutan
IDAI DI Yogyakarta – Departemen IKA FK UGM
Periode Juli 2016
 OUT LINE

1. Classification of Thalassemia – Transfusions perspective

2. Complication of Thalassemia –Iron Overload
3. Transfusion in Thalassemia
4. Iron Chelation
5. Patient adherence
6. Conclusions
PHENOTYPIC CLASSIFICATION OF THALASSAEMIA SYNDROMES BASED ON
CLINICAL SEVERITY AND TRANSFUSION REQUIREMENT
PATHOPHYSIOLOGY: Effects of excess production of free α-globin
chains in β-thalassaemia.
 CELLULAR MECHANISMS BY WHICH DECREASED IRON UPTAKE
INTO ERYTHROID PRECURSORS MAY PROMOTE SURVIVAL AND
DIFFERENTIATION.

Ginzburg & rivella, blood, 20 october 2011 􏰈 volume 118, number 16

 PATHOPHYSIOLOGICAL SEQUELAE OF UNTREATED THALASSAEMIA AND
CORRESPONDING CLINICAL MANIFESTATIONS

Capellini et al. Iron2009_cap.12(286-309)

 Effect of iron overload on survival in β-thalassemia
major patients

Ladis V, et al. Ann N Y Acad Sci. 2005;1054:445-50

Common complication
TDT and NTDT
• Extramedullary erythropoeisis*
• Splenomegaly*
• Leg ulcers (rare)*
• Growth retardation*
• Skeletal abnormalities*
• Renal abnormalities†
• Iron overload complications
• Jaundice
*Preventable by blood transfusion
Additional complication in NTDT
• Ineffective erythropoiesis*
• Thrombosis*
• Pulmonary hypertension*
• Right heart failure*
• Gallstones*
• Infections*
• Hepatocellular carcinoma
• Folic acid deficiency
• Acute hemolytic episodes
Taher et al, Vox Sanguinis (2014)
Musallam & Taher. J Am Soc Nephrol 23: 1299–1302, 2012
Mallat et al: Jnephrol 2013; 26(5): 821-828
.
Mallat et al: Jnephrol 2013; 26(5): 821-828
.
 DEFERASIROX EFFECT ON RENAL HAEMODYNAMIC PARAMETERS
IN PATIENTS WITH TRANSFUSION-DEPENDENT B THALASSAEMIA

Effects of deferasirox on renal haemodynamics were mild and

reversible for up to 2 years of treatment, with no progressive
worsening of renal function over time.

Piga et al. British Journal of Haematology, 2015, 168, 882–890

 STUDY OF THE EFFECT OF IRON OVERLOAD ON THE
FUNCTION OF ENDOCRINE GLANDS IN MALE THALASSEMIA
PATIENTS

Abdulzahra et al. Asian J Transfus Sci. 2011 Jul-Dec; 5(2): 127–131

 BETA-THALASSEMIA MAJOR AND FEMALE FERTILITY: THE ROLE OF
IRON AND IRON-INDUCED OXIDATIVE STRESS

Roussou et al. Hindawi Publishing Corporation Anemia Volume 2013, Article ID

617204, 9 pages http://dx.doi.org/10.1155/2013/617204
TRANSFUSION IN
THALASSEMIA
EFFICIENCY OF ERYTHROPOIESIS AND EFFECT OF
TRANSFUSION IN 􏰈-THALASSEMIA

Ginzburg & Rivella, Blood. 2011;118(16):4321-4330

 EFFICIENCY OF ERYTHROPOIESIS AND EFFECT OF
TRANSFUSION IN 􏰈-THALASSEMIA

Ginzburg & Rivella, Blood. 2011;118(16):4321-4330

IRON CHELATION
 • rate at which the chelator depletes
storage iron
Removal of • the rate of continued iron
excess iron accumulation

• Iron ions have six electrochemical

Neutralization of coordination sites
"free" iron • a chelator molecule that binds to all six
sites completely inactivates the "free" iron
De Domenico I, et al. Blood. 2009;114(20):4546-4551.
Aims of chelation therapy for systemic versus regional siderosis.

Cabantchik, Frontiers in Pharmacology, March 2014 | Volume 5

 RCT OF IRON CHELATORS FOR THE TREATMENT OF CARDIAC SIDEROSIS IN
THALASSEMIA MAJOR

Repeat Abnormal iron

transfusion metabolism

Cardiac Effective & well tolerated

Cardiac T2*
Tx
siderosis

Heart failure RCT

Deferoxamin
Deferiprone
Early mortality
Deferasirox
Review of
Quality ?
Baksi &Pennell, Frontier & Pharmacology;September 2014: Volume 5: Article 217 :1
 RCT OF IRON CHELATORS FOR THE TREATMENT OF CARDIAC SIDEROSIS IN
THALASSEMIA MAJOR

RCT I :
– Deferipone (92mg/kgbb/day) vs deferoxamin (43mg/kgbb/day) for
5,7 day/week
– Result:
• Improvement:
– T2* Deferiprone > deferoxamin (27% vs 13%, P =0,023)
– LVEF Deferipron > deferoxamin (3,1%:0,3% absolut unit, P
=0,003)
– This RCT established that deferiprone was superior to deferoxamine
over 1 year for the removal of cardiac iron, and the improvement
of LV EF in patients with asymptomatic myocardial siderosis

Baksi &Pennell, Frontier & Pharmacology;September 2014: Volume 5: Article 217 :1

RCT OF IRON CHELATORS FOR THE TREATMENT OF CARDIAC SIDEROSIS IN
THALASSEMIA MAJOR

RCT II:
– (Deferiprone+deferoxamine) vs deferoxamine
– 65 patients with myocardial T2∗ from 8 to 20 ms
•Results:
– Improvement T2* (Deferiprone+deferoxamine) > deferoxamine
(ratio of change in geometric means +50% versus +24%; P = 0.02).
– The combined group also showed significantly great improvement in
absolute LV EF (2.6% versus 0.6%; P = 0.05), and absolute
endothelial function (8.8% versus 3.3%; P = 0.02)

Baksi &Pennell, Frontier & Pharmacology;September 2014: Volume 5: Article 217 :1

RCT OF IRON CHELATORS FOR THE TREATMENT OF CARDIAC SIDEROSIS IN
THALASSEMIA MAJOR

RCT II:
– (Deferiprone+deferoxamine) vs deferoxamine
– 65 patients with myocardial T2∗ from 8 to 20 ms
•Results:
– Improvement T2* (Deferiprone+deferoxamine) > deferoxamine
(ratio of change in geometric means +50% versus +24%; P = 0.02).
– The combined group also showed significantly great improvement in
absolute LV EF (2.6% versus 0.6%; P = 0.05), and absolute
endothelial function (8.8% versus 3.3%; P = 0.02)
Baksi &Pennell, Frontier & Pharmacology;September 2014: Volume 5: Article 217 :1
 RCT OF IRON CHELATORS FOR THE TREATMENT OF CARDIAC SIDEROSIS IN
THALASSEMIA MAJOR

RCT III:
•Deferasirox (target dose 40 mg/kg per day) vs deferoxamine (50– 60 mg/kg per day for 5–7
days/week)
•Aprospective, randomized in myocardiac patients (T2∗ 6–20 ms) and no signs of cardiac
dysfunction.
•Result:

– Improvement myocardial T2∗:

• deferasirox (11.2 ms to 12.6 ms at 1 year (+12%) and with deferoxamine from 11.6
ms to 12.3 ms (+7%) with 95% CI : 0.998 - 1.133.
• Mean LVEF remained stable and within the normal range after 1 year of treatment
with deferasirox (66.9– 66.3%) and deferoxamine (66.4–66.4%). The change in mean
LVEF after 1 year was not different between the two treatments (P = 0.54)

Baksi &Pennell, Frontier & Pharmacology;September 2014: Volume 5: Article 217 :1

with equal number of age- and sex-matched controls. All the patients in whom MRI T2* of liver wa

TABLE I SERUM FERRITIN VALUES AT THE START, AT 6 MONTHS AND AT 12 MONTHS IN STUDY PARTICIPANTS

Serum Ferritin levels Geometric Mean (95% CI of GM) (ng/mL)

Deferiprone monotherapy Deferasirox monotherapy Combination therapy*
Time Points (n=17) (n=17) (n=15)

At start 3140.5 (2617.5-3767.9) 3859.2 (3168.8-4700.0) 3696.5 (3079.6-4438.1)

At 6 months 3010.9 (2548.5-3557.1) 3671.1 (3098.1-4350.1) 2977.1 (2384.5-3717.1)
At 12 months 2910.0 (2220.7-3812.4) 3417.4 (2734.6-4270.7) 2572.1 (2138.9-3093.1)
P=0.008
Gomberfors, comparison by ANOVA;
et al. Volume Multiple15,comparison
53__march 2016 (using Tukey’s Test) found no pairs of two time points to be significant in bot
monotheraphy groups; however, baseline S. ferritin was significantly different with 6 month and 12 month S. ferritin value.

__
Bhandari & Galanello,2012; European Journal of Haematology 89 (187--197)
 ADHERENCE TO CHELATORS

Drug Disease Adherence References

Delea et al
Deferoxamine thalassemia 59-78%
2007
Delea et al
Deferiprone thalassemia 79-96%
2007

88%
Kwiatkowski
thalassemia reported by
Deferasirox et al 2012
patients
 FACTORS INFLUENCING PATIENT ADHERENCE

1. Poor patient understanding:

• disease
• benefits of treatment
2. medication is not efficacious or "not working“ ?
3. medication safety or tolerability ?
4. Poor patient understanding of proper administration
5. Poor access to appointments and medications
6. Poor HCP-patient communication
7. High medication costs
8. Dosing frequency
 CONCLUSIONS
• NTDT:
– Morbidity in NTDT patients is more common and serious.
– NTDT patients should be carefully followed for early diagnosis and
management of complications.
• TDT:
– Iron chelation therapies appear to be effective if given in high enough
doses with patient compliance.
– From the available evidence, deferiprone appears to have superior
efficacy compared to deferoxamine, and the effect of deferoxamine is
superior when combined with deferiprone compared to deferoxamine
alone.
– Deferasirox appears to have equivalent efficacy to deferoxamine.