ค ำถำม 1. ควรเร่ิมให้ยาขบัเหล็กแก่ผู้ ป่วยธาลัสซีเมียเม่ือใด

ก. ได้รับเลอืดเป็นประจ ำเป็นระยะเวลำนำนอย่ำงน้อย 1 ปี

ข. ได้รับเลอืดปริมำณมำกกว่ำ 2 unitต่อเดือน

ค. ค่ำ serum ferritin > 2,500 ng/ml

ง. มีภำวะแทรกซ้อนจำกเหลก็เกิน

จ. เร่ิมให้ยำขบัเหลก็ในผู้ ป่วย thalassemia major ทกุรำย ถ้ำไมม่ีข้อห้ำม

2. ผู้ ป่วย thalassemia major มา รพ. ด้วยอาการหอบเหน่ือย นอนราบไม่ได้ ท่านตรวจพบว่ามีภาวะ cardiomyopathy with congestive heart failure ตรวจ serum ferritin ได้ 6,500 ng/ml การให้ ยาขบัเหล็กในข้อใดเหมาะสมที่สุด

ก. Deferoxamine iv. + Deferiprone

ข. Deferoxamine iv. + Deferasirox

ค. Deferoxamine sc. + Deferiprone

ง. Deferoxamine sc. + Deferasirox

จ. Deferiprone + Deferasirox

Clinical practice guidelines for management of

thalassemia syndromes

Surasak Sawatnatee, M.D.

Division of Hematology

Department of Medicine

Sanprasittiprasong Hospital

Outline

• Introduction

• Genotype-phenotype associations

• Screening and labolatory diagnosis

• Transfusion therapy

• Splenectomy

• Iron overload and chelation therapy

• Complications and management

• Thalassemia prevention and genetic counseling

Thalassemia (ธาลสัซเีมยี)

• Inherited disorders of

globin synthesis in which the

production of globin chains is

partially or completely suppressed

Excess -chains

Heme

AHSP

precipitation α-Inclusion

bodies

Hb A

Chromosome 16

α-Gene cluster

Chromosome 11

-Gene cluster

Deletions in the a-globin gene cluster

Deletions cause a – thal2

a1 a2 a1

- a3.7

- a4.2

a1 a2

a1 a2

a1 a2

a1 a2

a1 aCS

a thal 1 trait

a thal 2 trait

Hb H disease with CS

Hb Bart’s hydrops fetalis

Normal

a thal 2 homozygote

Hb H disease

Type Position mutation

- thalassemia Codon 17 AT

IVSI-1 GT

Codon 35 CA

Codon 41 – C

Codon 41/42 – TCTT

Codon 71/72 + A

3.4 kb deletion

+- thalassemia – 87 CG

– 28 AG

– 29 AG

IVSI-5 GC

IVSII-654 CT

Codon 126 TG

• Clinical manifestation

• Screening test

• CBC , MCV

• inclusion bodies

• Hb analysis

• DNA study

Diagnosis of Thalassemia

Extramedullary

hematopoiesis

Screening test in Thalassemia

Osmotic Fragility test

OF test DCIP precipitation test

- False positive 5%

- thal trait 96%

- a thal trait 93%

- false positive in Hypochromic rbc

- HbE 100%

- HbH

Automatic HPLC system: VARIANT®

Normal thal/Hb E disease

Molecular diagnosis by Reverse Dot Blot Hybridization

Amplification Refractory Mutation System

Genotype-phenotype associations in α-thalassemia

Genotype-phenotype associations in β-thalassemia

Objective of transfusions in TDT

Maintenance of pretransfusional hemoglobin 9.5 g/dl

• Correction of anemia

• Suppression of erythroid expansion

• Prevention of hypersplenism

• Reduction of ineffective erythropoiesis

• Reduction GI iron absorbtion

Cazzola M,et al. Transfusion,1997, 37(2):135-40.

Blood transfusion can prevent several complications

Musallam KM, et al. Haematologica. 2013;98:833-844.

60kg thalassemia patient

Transfusion therapy results in iron overload

45 blood units /year

200mg

Overload can occur after 10-20 transfusions

9g iron / year (transfusions)

1g iron / year (digestive absorption)

+

10g iron /year

Current indications for transfusion therapy in NTDT subtypes

NTDT subtype Indications for transfusion

• Hb H disease

• HbE/β-thalassemia

Mild

Moderate

Severe

• β-TI

• Infections exacerbating anaemia

• Growth retardation

• Generally none

• As per β-TI

• Transfusions required for survival, as per β-TM

• Hb < 5 g/dl

• Failure to thrive secondary to anaemia

• Emergency of bone deformities

• Tendency to thrombosis

• Presence of leg ulcers

• Development of pulmonary hypertension

• Poor growth and development

• Splenic enlargement

• Pregnancy

• Infection

• Cardiovascular disease

Evaluation of Iron Overload • Serum ferritin concentration

• Noninvasive

• Accuracy in iron overload questionable

• Liver iron concentration (LIC)

• Liver biopsy

• Reference standard

• SQUID

• Noninvasive, availability limited

• MRI

• Noninvasive, FDA-approved technique

• Others: NTBI and T2*MRI

Olivieri N, Brittenham G. Blood. 1997;89:739.

Measuring and interpreting serum ferritin

Advantages Disadvantages

• Easy to assess

• Inexpensive

• Repeat measures are

useful for monitoring

chelation therapy

• Positive correlation with

morbidity and mortality

• Indirect measurement of iron

burden

• Fluctuates in response to

inflammation, abnormal liver

function, metabolic deficiencies

• Serial measurement required

Measuring LIC by liver biopsy

Advantages Disadvantages

• Direct measurement of LIC

• Validated reference standard

• Quantitative, specific, and sensitive

• Allows for measurement of non-

heme storage iron

• Provides information on liver

histology/pathology

• Positive correlation with morbidity and

mortality

• Invasive, painful procedure

associated with potentially

serious complications

• Risk of sampling error,

especially in patients with

cirrhosis

• Requires skilled physicians

and standardized laboratory

techniques

กำรแปลผลกำรประเมินเหลก็ในหวัใจ ด้วยคำ่ T2*

กำรแปลผลกำรประเมินเหลก็ในตบั ด้วยคำ่ T2*

Benefits of Ferritin Control

• Change in serum ferritin over time reflects change in LIC

• Proportion of ferritin measurements >2500 ng/mL affects cardiac disease-free survival1 (see graph)

• Maintenance of serum ferritin <2500 ng/mL

• Significantly correlates with cardiac disease-free survival2–5

Surv

ival pro

babili

ty

0 5 10 15

0

0.25

0.50

0.75

1.00

Ferritin >2500 ng/mL

on >1/3 of occasions

Years of Follow-Up

.

Maintenance of Lower Ferritin Levels

a Positive Indicator for Survival

at UCLH (unpublished data)

Chelation Therapy (years)

0.00

0.50

0.25

0.75

1.00

0 2 4 6 8 10 14 12 16

Pro

port

ion W

ithout C

ard

iac D

isease

<33% ferritin measures

>2500 ng/mL

33%–67% ferritin

measures

>2500 ng/mL

>67% ferritin

measures

>2500 ng/mL

1. Olivieri NF, et al. N Engl J Med. 1994;331:574. 2. Gabutti V, Piga A. Acta Haematol. 1996;95:26.

3. Telfer PT, et al. Br J Haematol. 2000;110:971. 4. Davis BA, et al. Blood. 2004;104:263.

5. Borgna-Pignatti C, et al. Haematologica. 2004;89:1187.

To treat or Not to treat : Summary

• Without chelation, SF levels continue to rise in transfusion-independent patients with NTDT

• SF levels ≥ 800 ng/ml are associated with a significant increase in long-term morbidity risk; while levels ≤ 300 ng/ml are not associated with any risk

• Such association between SF increase and morbidity in NTDT is independent of confounding factors

DFO DFX DFP

Studies evaluating iron chelation therapy in NTDT patients

Desferrioxamine (Desferal®, DFO)

• was discovered accidentally as a byproduct of antibiotics

• 8-12 hr subcutaneous infusion, 5-7 times/wk by portable infusor

• initial dose 25-35 mg/kg/d should be started

• Maximum dose 50 mg/kg/d

• cumbersome and expensive(0.5 g~200 ฿)

DFO: severe Fe overload & organ damage

• Reversal of Fe-induced organ dysfunction

• Continuous IV infusion

• via Port – a – Cath or Hickman lines

• Dose 50 mg/kg/d

Common Side Effects of Deferoxamine

• Local reactions - Erythema (localized redness) - Induration (localized swelling) - Pruritus (itchiness)

• Ophthalmologic - Reduced visual acuity - Impaired color vision - Night blindness - Increased by presence of diabetes

• Hearing loss

• Zinc deficiency

Challenges of Deferoxamine

• Subcutaneous/Intravenous route of administration

• Expensive

• Cumbersome

• Uncomfortable

• Rapid metabolism (30 minute half-life) necessitates prolong infusion

• Complications due to iron overload still occur due to poor compliance with therapy

Oral Fe chelator: Deferiprone - L1

• Good compliance

• dose 50 - 75 mg/kg/d

• ? Effectiveness

• side effects

Deferiprone

• In a retrospective study on 129 iron-chelated thalassemic patients

• Piga et al. found that long-term therapy with deferiprone provided a greater cardioprotective effect against the toxicity of iron overload > deferoxamine

Long-term trial of Deferiprone in 51 Tx-dependent iron overloaded patients , Blood 1996

Deferiprone Experience in Thailand

• 9 patients with -thal/HbE, transfusion independent

• dose 50 mg/kg/d, duration 17-86 wk

• serum ferritin decreased from 2,168 to 300 ng/ml

• Hepatic iron decreased from 16.3 to 11.8 mg/gDW

• RBC iron disappeared

7th International Conference on Thalassaemia and

the Haemoglobinopathies, Bangkok, 1999

Deferiprone Experience in Thailand

• 9 patients with -thal/Hb E(7) and homzygous -thal(2)

• transfusion independent

• dose 25-50 mg/kg/d, duration 17-86 wk, mean 49 wk

• serum ferritin 2,168 300 ng/ml

• Hepatic iron 16.3 11.8 mg/gDW

• RBC iron 76.2 7.2 mmol/mg

Pootrakul, P et: Br J Haematol 2003

Deferiprone : side effects

• Arthropathy 15 - 40 %

• Agranulocytosis 1 - 2 %

• Neutropenia 2%

• GI symptoms 15 %

• Zn deficiency

• progression of hepatic fibrosis: 1 report

Deferasirox: a novel once-daily oral iron chelator

• Tridentate* iron chelator

• An oral, dispersible tablet

• Administered once daily

• Highly specific for iron

• Chelated iron excreted

mainly in feces (< 10% in urine)

*3 polar interaction sites in the binding pocket

Nick H et al. Curr Med Chem 2003;10:1065–1076

Deferasirox is a once-daily orally active tridentate iron chelator with high

affinity and specificity for iron

Once-daily administration of deferasirox

EXJADE® (deferasirox) Basic Prescribing Information. Novartis Pharma AG. National Prescribing Information should be followed

Deferasirox is administered once daily by dispersing tablets in

water, apple or orange juice and swallowing the suspension

Administration of deferasirox

Combination therapy: Deferasirox should

not be combined with other iron chelation

therapies as the safety of such

combinations has not been established

Exjade® (deferasirox) Prescribing Information. Novartis Pharmaceuticals Corporation, November 2005

• Taken once daily on an empty stomach at least 30 minutes

before food, preferably at the same time each day

• The tablets are dispersed by stirring in a glass of water

or orange juice (100–200 mL) until a fine suspension

is obtained

• The tablets must not be chewed or swallowed whole

• รำคำขำย เมด็ละ 589 บำท (250 mg) (สิทธิจ่ำยตรงสำมำรถเบิกไดถ้ำ้มี indication) • (สิทธิกำรรักษำอ่ืน สำมำรถเขำ้โครงกำร XPAP ได ้โดยซ้ือ 1 กล่อง บริษทัยำแถมให ้3 กล่อง แต่ รพ.สปส.ช่วยจ่ำยให ้75% ของรำคำยำท่ีซ้ือ สรุปคือ ผูป่้วยซ้ือยำ 7 เมด็ รำคำ 4,123 บำท จะไดย้ำ 4 กล่อง (112 เมด็ รำคำจริง 65,968 บำท )

Gmean myocardial T2* in Pts Rx with DFX or DFO for 1 year

Overview of Iron Chelators Property Desferrioxamine1 Deferiprone2 Deferasirox3

Usual dose 25–60 mg/kg/d 75 mg/kg/d 20–30 mg/kg/d

Route SC, IV

8–12 h, 5 d/wk

PO

3 times daily

PO

Once daily

Half-life 20–30 min 3–4 h 8–16 h

Excretion Urinary, faecal Urinary Faecal

Adverse effects Local reactions, ophthalmologic, auditory, growth retardation, allergic

GI disturbances, agranulocytosis/neutropenia, arthralgia, elevated liver enzymes

GI disturbances, rash, mild non-progressive creatinine increase, ophthalmologic, auditory, elevated liver enzymes

Status Licensed Not licensed in the United States or Canada

Licensed

Approved indications

Treatment of chronic iron overload due to transfusion-dependent anaemias

Thalassaemia major Treatment of chronic iron overload due to frequent blood transfusions

1. Desferrioxamine [PI]. Stein, Switzerland: Novartis Pharma Stein AG; 2007. 2. Deferasirox [Summary of Product Characteristics] [PI]. Apotex Europe LTD. 1999. 3. Deferiprone [PI]. West Sussex, UK: Novartis Europharm LT; 2006.

Goal of Iron Chelation • Start treatment when

• serum ferritin >1,000 ng/mL or

• 20 Unit transfusion or 1 yr of regular transfusion

• Keep serum ferritin <2,500 ng/mL or LIC <15 mg/g dry weight

• Monitor serum ferritin q 3 months

• Monitor adverse events

• Monitor cardiac parameters: MRI, Echo

• Patients with heart failure would require intensive and immediate treatment with IV DFO and addition of DFP as soon as possible

• Compliance is a key factor associated with response to a chelation therapy

Olivieri N, Bailliere’s Clinical Haematology 1998, p147-162

TIF Recommendations

Taher A, et al. Guidelines for the Management of Non-Transfusion-Dependent Thalassaemia (NTDT). 2013. Thalassaemia International Federation.

CPG for management TDT

CPG for management NTDT

ข้อบง่ใช้ยำ 1. วินิจฉัยวำ่เป็น Thalassemia major หรือ β thal/HbE 2. ได้รับเลือดมำกกวำ่ 10 ครัง้ต่อปี 3. Surum ferritin > 1,000 ng/ml โดยกำรตรวจเลือด 2 ครัง้ ห่ำงกนัไมน้่อยกวำ่ 1 เดือน

ขอ้บ่งใชย้ำ Deferasirox

• ผู้ ป่วยอำย ุ2-5 ปี ท่ีไมส่ำมำรถให้ DFO ได้ เนื่องจำกมีภำวะ intolerance หรือ poor compliance

• serum ferritin < 8,000 ng/ml แตไ่มส่ำมำรถใช้ยำ DFO หรือ DFP ได้ เนื่องจำก • มีภำวะ agranulocytosis (ANC < 500 /mm3)

• มีภำวะ neutropenia (ANC < 1,000 /mm3) และหลงักำรให้ยำซ ำ้ (rechallange) ยงัคงเกิดภำวะ neutropenia ซ ำ้อีก

• Elevated liver enzyme (SGPT > 2.5 เทำ่ ของ UNL)

• มีกำรแพ้ยำ หรือผลข้ำงเคียงอื่นที่รุนแรง เช่น ข้ออกัเสบรุนแรง อำเจียนรุนแรง เป็นต้น

ขอ้บ่งใชย้ำ Deferasirox

• ไมต่อบสนองตอ่กำรรักษำด้วยยำ DFO หรือ DFP ในขนำดท่ีเหมำะสม • คำ่ Serum ferritin ลดลงน้อยกวำ่ 15% ใน 3 เดือน • ขนำดยำที่เหมำะสม คือ • Deferiprone

• PO : 25 mg/kg 3times/day, up to 100 mg/kg/day • Desferoxamine • IV : 40 mg/kg/day นำน 8-12 ชม. วนัละครัง้

Splenectomy

TDT

• Hypersplenism

• Tx > 225-250 ml/kg/yr or 20 ml/kg/mo

• Compressive symptom

NTDT

• Hb H disease – anemia required Tx, growth retardation

Induction of Fetal Hemoglobin

Observations : Mild phenotype of patient

• thal + HPFH

• homozygous thal with increased HbF

HbF newborn 80 — 90 % adult < 1%

Fetal Hemoglobin stimulating compounds

• 5-Azacytidine

• Butyrate compound

• Erythropoietin

• Hydroxyurea

Thalassemia prevention and genetic counseling

เฉลย 1. ควรเร่ิมให้ยาขบัเหล็กแก่ผู้ ป่วยธาลัสซีเมียเม่ือใด

ก. ได้รับเลอืดเป็นประจ ำเป็นระยะเวลำนำนอย่ำงน้อย 1 ปี

ข. ได้รับเลอืดปริมำณมำกกว่ำ 2 unitต่อเดือน

ค. ค่ำ serum ferritin > 2,500 ng/ml

ง. มีภำวะแทรกซ้อนจำกเหลก็เกิน

จ. เร่ิมให้ยำขบัเหลก็ในผู้ ป่วย thalassemia major ทกุรำย ถ้ำไมม่ีข้อห้ำม

2. ผู้ ป่วย thalassemia major มา รพ. ด้วยอาการหอบเหน่ือย นอนราบไม่ได้ ท่านตรวจพบว่ามีภาวะ cardiomyopathy with congestive heart failure ตรวจ serum ferritin ได้ 6,500 ng/ml การให้ ยาขบัเหล็กในข้อใดเหมาะสมที่สุด

ก. Deferoxamine iv. + Deferiprone

ข. Deferoxamine iv. + Deferasirox

ค. Deferoxamine sc. + Deferiprone

ง. Deferoxamine sc. + Deferasirox

จ. Deferiprone + Deferasirox

Thank you