ค ำถำม ล็กแก่ผู้ป่วย€¦ · clinical practice guidelines for...
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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
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