thalassemia: diagnosis and treatment - tsh.or.thtsh.or.th/file_upload/files/2 kitti torcharus -...
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Thalassemia: Diagnosis and Treatment
Kittti Torcharus, M.D.
Department of Pediatrics
Phramongkutklao Hospital
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Scope of lecture
Incidence
Diagnosis
Blood transfusion
Iron chelation
Treatment related complications
Hematopoietic stem cell transplantation
Preimplantation genetic diagnosis (PGD)
Survival
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Prevalence of Thalassemia in The world
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MARCH OF DIMES GLOBAL REPORT ON BIRTH DEFECTS; 2006
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Prevalence of thalassemia in Thailand
Alpha-thalassemia (%) a-thalassemia 1 Bangkok 3.5
Chiangmai 12.0 a-thalassemia 2 Bangkok 16.0 Chiangmai 19.0
Beta-thalassemia Bangkok 3.0 Chiangmai 9.0
Northeast 2-6 Hemoglobin E Bangkok 13-19
Chiangmai 8.0 Northeast 32-60
Hemoglobin Constant Spring 2-4
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Prevalence of thalassemia and hemoglobinopathies
11/23/2017 Kitti Torcharus, M.D. 5 Wongprachum K, et al. Acta Haematol. 2016;135(2):65-9.
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Classification: Clinical severity
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Severity Clinical Hb (g/dL)
Type
Severe Age onset of anemia < 2 yrs, Age at first blood transfusion < 4 yrs, Weight & Height lower than normal, Facial bone change, Huge splenomegaly
< 7 Homo. b0-thal (b0/b0, b0/b+), b0-thal/Hb E, surviving Hb Bart’s hydrops, Non-deletional Hb H
Moderate Anemia, jaundice, hepatomegaly, splenomegaly
7-9 Homo. b0-thal (b0/b+), b0-thal/Hb E,
Mild Anemia, jaundice, mild splenomegaly >9 Homo. B+-thal (b+/b+), b+-thal/Hb E, Hb H
Asymptomatic No symptoms normal Thal trait, Hb E trait, Homo Hb E
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Transfusion-dependent thalassemia (TDT)
Severe type (Clinical severity)
Require regular transfusion with iron chelation
Maintain Hb level 9.5-10.5 g/dL
Thalassemia type: Homo. b0-thal (b0/b+, b0/b+)
b0-thal/Hb E,
Hb Bart’s hydrops fetalis (surviving)
Non-deletional Hb H
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Non-transfusion-dependent thalassemia (NTDT)
Moderate-mild type (Clinical severity)
Age onset at diagnosis 2-6 yrs.
Steady-state Hb level 7-10 g/dL
Develop anemia or hemolytic crisis after infection which may require blood transfusion (occasional transfusion)
Thalassemia types: b-thalassemia intermedia (b0/b+, b+/b+),
b-thalassemia/Hb E, (b0/bE, b+/bE) Hb H disease
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Clinical severity: severe thalassemia
Hb Bart’s hydrops fetalis Genotype: a-thal 1/a-thal 1
Hydrops, severe anemia
Dead in utero or after birth
Homozygous b0-thalassemia Genotype: b0-thal/b0-thal
Transfusion dependent
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Clinical severity: moderate to severe thalassemia (Anemia, jaundice, occasional require blood transfusion)
b-thalassemia/ Hb E
Genotype: b0-thal/bE
Hb H with Hb CS
Genotype: a-thal 1/Hb CS
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Mild thalassemia (Anemia, jaundice, not require blood transfusion)
b-thalassemia/ Hb E
Genotype: b+-thal/bE
Hb H disease Genotype: a-thal 1/a-thal 2
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Hemolytic crisis in Hb H
Symptoms Fever, pallor, jaundice
Dark urine
Hepato-splenomegaly
Etiology (infection) Influenza, typhoid,
malaria, Dengue hemorrhagic fever
Treatment Treat infection
PRC transfusion
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Diagnosis: thalassemia disease
CBC : anemia
Red cell indicies
MCV <80 fL, MCH < 27 pg, RDW > 16%
Blood smear: red cell morphology
Hypochromic, microcytic, anisocytosis, poikilocytosis, target cell
Reticulocytosis
Inclusion bodies
Hb H disease
Hb typing (Hb analysis)
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Inclusion bodies Reticulocyte
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Blood Smear of thalassemia disease
Hb H disease Hypochromic
Microcytic
Anisocytosis (varied size RBC)
Poikilocytosis (varied RBC morphology)
Beta-thalassemia/Hb E Anisocytosis (varied size RBC)
Poikilocytosis (varied RBC morphology)
Nucleated red cell (NRC)
Target cells
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Diagnosis: thalassemia trait
Carrier screening:
Complete blood count: red cell indicies
MCV < 80 fL, MCH < 27 pg
One tube osmotic fragility (OF) test
Positive: b-thal trait, a-thal 1 trait, Iron deficiency
Dichlorophenolindophenol (DCIP) precipitation test
Positive: Hb E trait, homo. Hb E
Hb E screen test
Positive: Hb E trait, homo. Hb E
Confirmation tests: Hemoglobin typing (HPLC, LPLC, CE)
b-thal trait, Hb E, CS, Pakse, thal. disease (NTDT), etc.
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Hb type: Criteria for diagnosis (I) Conditions Hb type
Normal A2 A ( A2 2.5-3.5% )
a-thal 1 trait A2 A ( A2 2.5-3.5% )*
a-thal 2 trait A2 A ( A2 2.5-3.5% )*
b-thal trait A2 A ( A2 > 3.5% )
Hb E trait EA ( E= 25- 35 % )
Hb E homozygous EE ( E >85% )
Hb CS trait CS A2 A ( CS 1-2 % )
Hb CS homozygous CS A2 A ( CS 3-6% )
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*Can not diagnose by Hb type
*Diagnose by PCR for a-thal 1 trait and a-thal 2 trait respectively
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Hb type: Criteria for diagnosis (I)
Conditions Hb type
Hb Barts’ hydrops Portland, Barts’
Hb H disease A2 A H Barts’
Hb H with Hb CS CS A2 A H Barts
Hb AEBarts’ disease A E Barts’
Homozygous b-thal A2 F
b-thal / Hb E EF
Hb CS trait CS A2 A ( CS 1-2 % )
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Molecular Diagnosis (cont.) a-thalassemia:(Gap-PCR)
a-thal 1 trait (aa/- -SEA, aa/- -Thai)
a-thal 2 trait (aa/ - a3.7, aa/- a4.2)
Hb CS trait (aa/aCSa), Hb Pakse trait (aa/aPsa)
b-thalssemia:(ARMS-PCR*, RDB**, Gap-PCR, DNA sequencing)
b0-thalassemia:
CD 41/42(A>T), CD 17 (A>T), CD 35(C>A), IVS 1-1 (G>T), CD 71/72(A>T), etc.
b+-thalassemia:
IVS 1-5 (G>C), IVS 2-654 (C>T), CD 19(A>G), -28 (A>G), CD 26, etc.
db-thalassemia
HPFH: HPFH-6, etc.
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*Amplification refractory mutation system, **Reverse dot-blot hybridization
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Screening and diagnostic algorithm for thalassemia and hemoglobinopathies
OF+DCIP or MCV+DCIP
Non-thalassemia, Non clinical significant thalassemia
Hb typing:
A2A (A2<3.5%) Suspected a-thal trait
A2A (A2>3.5%) b-thal trait
EA (E=25-35%) Hb E trait
EA (E < 25%) Hb E trait
With/without a-thal trait
EE (E > 85%) Homo. Hb E
With/without a-thal trait
Thalassemia disease (NTDT) a-thal: Hb H disease, etc. b-thal: b+-thal/Hb E, etc. db-thal: db-thal, HPFH, etc.
PCR for a-thal 1: a-thal 1 trait
- /- + /- or - / + or + / +
1. Screening
2. Confirmation
3. Confirmation
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Management Strategy
Proper treatment of existing patients
Best patient care and management
Blood transfusion: Hyper transfusion regimen
Iron chelation
Treatment of complications Bone marrow transplantation
Prevention of the disease
Genetics counseling
Screening of thalassemia trait Prenatal diagnosis
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Blood transfusion
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Recommended: leucoreduced < 1x 106
Leucocyte depleted packed red cell (LDPRC)
Leucocyte poor packed red cell (LPRC)
• Before first transfusion: antigen typing: C, c, E, e, Mia
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Indication for blood transfusion
Homo. b-thalassemia(TDT)
Definite diagnosis
Hb < 7 g/dL or
Hb > 7 g/dL with Facial change
Poor growth
Fracture
Extramedullary hematopoiesis
NTDT
Growth failure
Poor performance at school
Pregnancy, infection
Symptomatic anemia
Congestive heart failure
Pulmonary hypertension
Leg ulcers
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Taher A, Blood Cells Mol Dis. 2006;37(1):12-20. Cappellini D, ed. TIF Guidelines : 2007 p. 18-30.
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Immune-mediated transfusions-reactions and reported frequencies
Acute Frequency
Febrile non-hemolytic 1/100
Allergic (urticarial) 1/100
Hemolytic (intravascular) 1/25,00
Transfusion –related acute lung injury (TRALI) 1/10,000
Anaphylactic 1/50,000
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Delayed frequency
Alloimmune 1/100
Hemolytic (extravascular) 1/2,500
Garft vs Host Disease Rare
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Iron chelator Iron chelator Administration
Deferoxamine (DFO), 500 mg/vial
40-60 mg/kg/day, subcutaneous infusion 8-10 hour by infusion pump
Deferiprone (L1), 500 mg/tab
75-100 mg/kg/day
Deferasirox (DFX) , 500 mg/tab
20-30 mg/kg/day
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Iron chelation Indication:
Received PRC >10-20 units
Serum ferritin > 1,000 ng/mL
First line:
Deferoxamine (DFO) 40-60 mg/kg/day, sc.
Second line:
Deferiprone (L1) 75-100 mg/kg/day, oral
Deferasirox (DFX) 20-30 mg/kg/day, oral
Combination therapy:
L1: 80-100 mg/kg/day + DFO: 40-60 mg/kg 3-5 days/wk
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Kontoghiorghes GJ. Hemoglobin. 2009;33(5):332-8
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Assessment and thresholds of iron overload
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Assessment Normal Mild Moderate Severe
Ferritin (ng/ml)1 30-300 > 1,000 1,000-2,500 > 2,500
LIC (mg Fe/g dw)2 < 1.2 2 to <7 7 to < 15 > 15
MRI(T2*)mg Fe/g dw3 < 1.8 1.8 to 7 7 to <15 >15
CMR, T2*(ms)4 > 20 <20 to 10 < 10 - 5 < 5
1Olivieri NF, N Engl J Med. 1994 ;331(9):574-8
3CPG, Diagnosis & management.of thalassemia syndromes 2014:26-31
LIC=Liver Iron Concentration MRI = Magnetic resonance imaging CMR =Cardiovascular Magnetic resonance
4Wood JC. Hematology Am Soc Hematol Educ Program. 2011;2011:443-50.
2Angelucci E, N Engl J Med. 2000;343(5):327-31
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Iron Chelator: Properties Property Deferoxamine Deferiprone Deferasirox
Usual dose (mg/kg/day)
25-60 75-100 20-40
Route Sc, iv (8-12 hr, 5 days/week)
Oral 3 times dialy
Oral Once daily
Half-life 20-30 min 3-4 hr 8-16 hr
Excretion Urinary, fecal Urinary fecal
Main adverse effects
Local reaction, Ophthalmologic, auditory, growth retardation, allergy
Gastrointestinal disturbances, agranulocytosis, neutropenia, arthralgia, elevated liver enzymes
Gastrointestinal disturbances, rash, mild non-progressive creatinine increase, elevated liver enzymes, Ophthalmologic, auditory
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Emergency therapy: Intravenous deferoxamine
Indications:
Severe hemosiderosis & vital organ dysfunction
Cardiac arrhythmia, left-ventricular ejection fraction (LVEF) < 56%
LIC > 15 mg/g dw, cardiac T2* < 10 ms
Deferoxamine:
Dose 50-60 mg/kg/day, iv. dirp 24 hr. 5-6 days per wk
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Post-transfusion Hypertension, Convulsion, and Cerebral hemorrhage (HCC syndrome)
HCC syndrome Multiple blood
transfusion
Headache
Hypertension
Convulsion
Cerebral hemorrhage
Prevention: furosemide 1
mg/kg/dose
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Splenectomy
Indications: Increased blood requirement (200-220 ml/kg/yr)
Hypersplenism (cytopenia)
Symptomatic splenomegaly (massive splenomegaly)
Vaccine Pneumococcal vac.: 2 wk. before; 3-5 yr. after Splenectomy
Influenza vac.: annually
Penicillin prophylaxis 125 mg bid (<5 yr); 250 mg bid (>5yr) for 2 yr
ASA: 2-5 mg/kg if platelets > 800,000 /cu.mm.
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Splenectomy adverse events
Peri-operative complications:
Bleeding, atelectasis, subphrenic abscess
Post-operative:
Overwhelming post-splenectomy infection (OPSI)*
Streptococcus pneumoniae, Haemophilus influenzae type b, Neisseria meninggitidisEscherichia coli, Pseudomonas aeruginosa, Salmonella sp., Klebsiella sp.
Thrombosis
Hypercoagulability
Pulmonary hypertension
Iron overload
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*Mortality rate 50-70%, death occurs within 24 hr
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Treatment related complications
Chronic HBV infection
Serum HBsAg (+ve), HBeAg (–ve), anti HBe Ab (+ve)
HBV viral load> 2,000 IU/ml, ALT > 80 IU
Chronic HCV infection
Anti HCV (+ve), HCV-RNA virus, ALT > 80 IU
Diabetes mellitus
Fasting glucose > 126 mg/dl
Oral glucose tolerance test (2 hr) >200 mg/dl
Gall stone (asymptomatic, 60-80%)
Biliary colic, common bile duct stone, ascending cholangitis, acute cholecystitis
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Hematopoietic stem cell transplantation (HSCT)
Indication:
Thalassemia major (transfusion dependent thalassemia)
homozygous b-thalassemia
b-thalassemia/ Hb E (severe)
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Source of hematopoietic stem cell
1. Bone marrow
2. Peripheral blood
3. Cord blood
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1 3
2
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Hematopoietic stem cell transplantation (HSCT)
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2.Transfusion of stem cell
4.Post HSCT 3.During HSCT
1.Conditoning chemo. therapy
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Overall survival, thalassemia-free survival, non-rejection mortality and rejection for class 1 patients younger than 17 yrs
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Gaziev J, Lucarelli G. Curr Stem Cell Res Ther. 2011;6(2):162-9
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HSCT: Thai (1988-2011)
HSCT N (%) Cure (%) Alive with disease
Death
Related 190 (74.5) 165 (88.6) 9(4.7) 16 (8.5)
Unrelated 65 (25.5) 50 (76.9) 6 (9.2) 9 (13.8)
Total 255 (100) 215 (84.3) 15 (5.9) 25 (9.8)
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HSCT=Hematopoietic stem cell transplantation
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HSCT in Department of Pediatrics, PMK
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Lymphoma 33%
AML 26%
ALL 7%
Thalassemia 26%
Aplastic anemia 4%
Nuroblastoma 4%
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HSCT in Department of Pediatrics, PMK
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Comparison of life expectancy for patients who were alive at the beginning of 1970, 1980, 1990 and 2000
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Modell B, et al. J Cardiovasc Magn Reson. 2008;10:42
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Preimplantation genetic diagnosis (PGD)
Selection of unaffected embryos prior to establishment of pregnancy
Start a pregnancy with a disease free baby
Avoid termination of an affected pregnancy
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Proposed schema of gene therapy for β-thalassaemia
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Yannaki E, et al.Expert Rev Mol Med. 2010;12:e31
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National thalassemia guidelines: Clinical practice guidelines for diagnosis and management of
thalassemia syndromes & Care of thalassemia patients
1st edition: 2006
2nd edition: 2014
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1st edition: 2017
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Summary • Thalassemia is public health problems in ASEAN
Thailand and LAO PDR (high prevalence, similar genotype-phenotype)
Definite diagnosis, Clinical Practice Guideline, Standard of care
Management Strategy Proper management of existing patients and prevention of new
cases
Life-long survival Early blood transfusion Efficacy and effectiveness of iron chelation HSCT
New treatment: Preimplantation genetic diagnosis & HLA type Gene therapy: “the beginning of a new era of thalassemia”
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Thank you for your attention
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