Thalassemia management Kitti torcharus, M.D. Department of Pediatrics, Phramongkutkloa Hospital and College of Medicine
Thalassemia management
Kitti torcharus, M.D.
Department of Pediatrics,
Phramongkutkloa Hospital and College of Medicine
Scope of presentation
1. TDT & NTDT
2. Blood transfusion & Iron chelation
3. Splenectomy
4. Treatment related complications
5. Thalassemia survival
6. Hematopoietic stem cell transplantation
7. Alternative treatment
29/19/2019 Kitti Torcharus, M.D.
19/09/2019 Torcharus K 3
CBC Result Reference
Hb (g/dL) 6.5 12.0-16.0
Hct (%) 15.2 36.0-47.0
MCV (fL) 57 80.0-97.0
MCH (pg) 18.8 27.0-32.0
MCHC (g/dL) 32.5 32.0-34.0
RDW (%) 25.8 12.3-15.1
WBC (x109/L) 17.9 4.5-10.0
Plt (x109/L) 480 150-450
◼ เด็กชายอายุ 9 เดือนตรวจทีค่ลินิกสุขภาพเด็กดีพบ ซีด
◼ พอ่แม่เป็น couple at risk for thalassemia ปฏิเสธ PND
◼ Cord blood Hb type: Hb F = 100%
◼ PE: pale, no jaundice, liver & spleen just palpable
Case 1
Hb Typing of Family
• พ่อ beta-thalassemia trait
• แม่ beta-thalassemia trait
• พ่ีชาย beta-thalassemia trait
• ผูป่้วย Homozygous beta-thalassemia
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Hb(g/dL)
Hct(%)
MCV(fL)
MCH(pg)
Hb type A2
(%)F
(%)A
(%)พ่อ 14.0 42.0 69.0 21.0 A2 A 5.7 1.6 92.7แม่ 12.2 34.0 68.0 23.0 A2 A 4.5 1.5 94.0พีช่าย 13.0 39.0 67.0 22.0 A2 A 5.0 2.0 93.0ผู้ป่วย 6.1 35.0 56.0 18.8 A2 F 3.0 87.3 -
Clinical course of Homozygous beta-thalassemia
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10 11 12 13 14 15 16 17 18 19 20 21
PCR 1 1 1 1 1 1 1 1 1 1 1 1
PRC_SUM 1 2 3 4 5 6 7 8 9 10 11 12
Hb 6.5 5.9 7.1 8.5 8.8 7.6 8.1 10.1 9 9.8 9.3 8
0
5
10
15
20
25
Age (months)
PRC transfusion and base line Hb
PCR
PRC_SUM
Hb
Bas
e li
ne
Hb
(g/
dL)
Classification: Clinical severity
6
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
Musallam KM, et al.Haematologica 2013;98(6):833-44.9/19/2019 Kitti Torcharus, M.D.
Transfusion-dependent thalassemia (TDT)
• Clinical severity: Severe type • Age onset, first blood transfusion, Hb < 7g/dL, etc.
• Require regular transfusion with iron chelation• maintain Hb level 9.5-10.5 g/dL
• Thalassemia type (genotype):• Homo. b0-thal (b0/b+, b0/b+)• b0-thal/Hb E (b0/bE)• Surviving Hb Bart’s hydrops fetalis (- -SEA/- -SEA)• Non-deletional Hb H (- -SEA/aCS a)• Hb AEBart’s disease (- -SEA/- a, b/bE)
7
Musallam KM, et al.Haematologica 2013;98(6):833-44.9/19/2019 Kitti Torcharus, M.D.
Non-transfusion-dependent thalassemia (NTDT)
• Clinical severity: Mild to moderate type • Age onset at diagnosis 2-6 yrs. • Steady-state Hb level 7-10 g/dL• Non/occasional transfusion requirement
• Develop anemia or hemolytic crisis after infection• may require blood transfusion (occasional transfusion)
• Thalassemia types (genotype):• Hb H disease (- -SEA/- a)
• b-thalassemia/Hb E (b+/bE, b0/bE)• b-thalassemia intermedia (b0/b+, b+/b+)• db-thalassemia • HPFH (hereditary persistence of fetal hemoglobin)
8Musallam KM, et al.Haematologica 2013;98(6):833-44.
9/19/2019 Kitti Torcharus, M.D.
Management Strategy
• Prevention of the disease
• Genetics counseling• Screening of thalassemia trait/hemoglobinopathies• Prenatal diagnosis
• Proper treatment of existing patients
• Best patient care and management• Folic acid, nutrition and health education, vaccine, etc.
• Blood transfusion: High transfusion VS. Occasional transfusion regimen• Iron chelation
• Treatment of complications• Hematopoietic stem cell transplantation• Alternative treatment (Hb F stimulation, Gene therapy, etc.)
99/19/2019 Kitti Torcharus, M.D.
Indications for regular transfusion
Age < 15 yrs
• Hb < 8 g/dL
• Hb > 8 g/dL with• Facial bone change
• Poor growth
• Fracture
• Extramedullary hematopoiesis
Age >15 yrs
• Hb < 7 g/dL
• Hb > 7 g/dL with• Chronic anemia
• Fracture
• Pulmonary artery hypertension
• Chronic leg ulcer
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Transfusion regimen
Transfusion dependent thalassemia (TDT)
• High transfusion:
• Children: • Pre-transfusion Hb 9-10.5 g/dL,
10-15 mL/kg, 2-4 wks. interval
• Adult TDT if high transfusion can’t available• Pre-transfusion Hb < 7 g/dL,
received 1-2 units/visit
Non-transfusion dependent thalassemia (NTDT)
• Occasional transfusion:• Indication:
• acute hemolysis after infection e.g. Hb H disease with hemolytic crisis
• Pre-transfusion Hb < 7 g/dL, in children
• Pre-transfusion Hb < 5 g/dL, in adult with vital sign change
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Standard of Packed red cell
• Preparation: from healthy and voluntary donner• Screening for infectious: Syphilis, HIV, Hepatitis A, B, and C• Leukocyte-poor packed red cells (LPRC), wbc < 1.2 x 109 cells/unit
• Leukocyte-depleted packed red cells (LDPRC), wbc < 1 x 106 cells/unit • Decrease antibody to wbc (anti-HLA), patient plan for HSCT • Prestorage filter: preparation < 24 hr., decrease prevalence of febrile non-hemolytic
transfusion reaction (FNHTR)• Poststorage filter preparation > 24 hr., e.g. bedside filter
• Apheresis technique (single donor red cell, SDR) • 2 units, 250-350 mL each, wbc < 1 x 106 cells/unit • decrease prevalence of transfusion transmitted disease• For patients which antibody to rbc Ag or rare blood group
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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
13
Delayed frequency
Alloimmune 1/100
Hemolytic (extravascular) 1/2,500
Garft vs Host Disease Rare
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Red cell alloimmunization:Phramongkutkloa Hospital (N=83)
Gender N (%)-Male 49 (59.04)-Female 34 (40.96)Age-Median 12-Range 2-28Blood gr-A 16 (19.28)-B 32 (38.55)-O 34 (40.96)-AB 1 (1.20)PCR type-LPRC 21 (25.30)-LDPRC 62 (74.70)
Red Cell Alloantibodies N (%)
▪ NO 75 (90.36)
▪ Yes 8 (9.64)
▪ ant-E,-Mia 1 (1.20)
▪ anti-c,-E,-Mia 1 (1.20)
▪ anti-E 3 (3.61)
▪ anti-Mia 1 (1.20)
▪ anti-c,-E,-Mia, -Fyb 1 (1.20)
▪ autoantibody 1 (1.20)
9/19/2019 Kitti Torcharus, M.D. 14
Fyb=Duffy
Case 2
15
• เด็กชาย อาย ุ6 ปี ภูมิล าเนา นนทบุรี Refer มารับเลือด (20 ต.ค.59)• 4 ปี PTA (อาย ุ2 ปี) มีไขแ้ละซีลง ไดว้นิิจฉยัเป็น b-thal/Hb E และไดรั้บ LPRC ติดตามการรักษาท่ีคลินิกโรคเลือดได ้LPCR เม่ือเวลาซีดทุก 4-6 เดือน
• ตรวจร่างกาย: T 370C, PR 100/ min, R 30 / min, weight 16.6 kg, height 110 cm., marked pallor, no jaundice, tachycardia, systolic murmur gr. III/VI, liver 4 cm. spleen 7 cm.<LCM
• ตรวจทางหอ้งปฏิบติัการ• CBC: Hb 5.2 g/dL, Hct 16.0%, wbc 1.3x109/L, N 49, L 43, M 7, E 1%, MCV 69.0 fL, MCH
19 pg, MCHC 30 g/dL, platelets 160x109/L• PBS: hypochromia 1+, microcytosis 2+, anisocytosis 1+, poikilocytosis 1+, target cells 1+
• การรักษาท่ีคลินิกโรคเลือดระหวา่ง 20 ต.ค.59-6 ก.พ.61• ไดรั้บเลือด LDPRC 200 mL ทุก 4 สัปดาห์ ยา Deferiprone (500 mg) 1x3• ภาวะซีดไม่ดีข้ึน, spleen 12 cm.<LCM (huge splenomegaly) , Hb 6 g/dL• ปรึกษาศลัยกรรมเพือ่ Splenectomy
• After splenectomy:• Day 30: Hb 8.1 g/dL, Plt 1,070X109/L
• Pen V (125 mg) 1x2, ASA 3mg/kg/day
9/19/2019 Torcharus K, M.D. 16
Splenectomy
• Before splenectomy:• Ultrasound abdomen: gall stone
• Pneumococcal conjugated vaccine
Splenectomy in NTDT: indication
• Worsening anemia leading to poor growth and development • when transfusion therapy is not possible or iron chelation therapy is
unavailable
• Hypersplenism leading to worsening anemia, leukopenia, or thrombocytopenia • resulting in recurrent bacterial infection or bleeding
• Splenomegaly accompanied by symptoms such as left upper quadrant pain or early satiety or massive splenomegaly • largest dimension >20 cm with concern about possible splenic rupture
Haematologica. 2013;98(6):833-44.
9/19/2019 Torcharus K, M.D. 17
Splenectomy in TDT: indication
• Increase blood transfusion requirement > 225-250 mL/kg/year
• Hypersplenism
• At the current time, according the Guidelines for the Management, splenectomy is not recommended as a standard procedure in TDT subjects
Mediterr J Hematol Infect Dis 2015;7(1):e2015057
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Overwhelming post-splenectomy infection (OPSI)
• Medical emergency, symptoms:• fever, shivering, vomiting, headache, septic shock, DIC, • progress to multiorgan failure and death occurs within the first 24 hours
• Risks of OPSI and associated death are highest in the first year after splenectomy
• Organism: • Streptococcus pneumoniae, Haemophilus influenzae type B, Neisseria meningitides, • Klebsiella pneumoniae, Pseudomonas aeruginosa
• Treatment: • empirical antibiotics, third generation cephalosporin, combined with gentamicin or
ciprofloxacin or vancomycin
Mediterr J Hematol Infect Dis 2015;7(1):e2015057
9/19/2019 Torcharus K, M.D. 19
Before and after splenectomy
• Avoid splenectomy before 5 years of age
• Education of the patient and parents:• seek early care when fever develops
• keep an emergency supply of antibiotics for the event of febrile illness
• Vaccination: • Pneumococcal vaccine 2 weeks before splenectomy and then in 3-5 years
• Antibiotic prophylaxis:• oral penicillin for at least two years after splenectomy
• alternative antibiotic (if penicillin allergy): trimethoprim-sulfamethoxazole or erythromycin
Mediterr J Hematol Infect Dis 2015;7(1):e20150579/19/2019 Torcharus K, M.D. 20
Iron chelation in TDT: indication
• Received PRC >10-20 units
• Ferritin > 1,000 ng/mL measure 2 times 1-3 months
• Liver iron concentration (LIC) by liver biopsy or MRI (T2*) > 7 mg/g dry weight of liver
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Iron chelation: administration
• First line: • Deferoxamine (DFO) 40-60 mg/kg/day, sc.
• Deferasirox (DFX) 20-30 mg/kg/day, oral (age 2-6 yrs)
• Second line:• Deferiprone (L1, DFP) 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
*Kontoghiorghes GJ. Hemoglobin. 2009;33(5):332-8
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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 (DFP), 500 mg/tab
75-100 mg/kg/day
Deferasirox (DFX) ,250 mg/tab
20-30 mg/kg/day
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Assessment of iron overload and therapeutic gold of iron chelations
Assessment Normal Mild Moderate Severe
Ferritin (ng/ml)1 30-300 < 1,000 1,000-2,500 > 2,500
MRI(T2*)mg Fe/g dw2 < 1.8 1.8 to 7 7 to <15 >15
CMR, T2*(ms)3 > 20 <20 to 10 < 10 - 5 < 5
Iron chelations No treatment
Target of iron chelation
Risk of iron complications
Risk of cardiac complication
1Olivieri NF, N Engl J Med. 1994 ;331(9):574-8
2CPG, Diagnosis & management.of thalassemia syndromes 2014:26-31
MRI = Magnetic resonance imaging, CMR =Cardiovascular Magnetic resonance
3Wood JC. Hematology Am Soc Hematol Educ Program. 2011;2011:443-50.9/19/2019 Torcharus K, M.D. 24
Iron Chelator: PropertiesProperty Deferoxamine (DFO) Deferiprone (DFP) Deferasirox (DFX)
Usual dose (mg/kg/day)
25-60 75-100 20-40
Route Sc, iv (8-12 hr, 5 days/week)
Oral 3 times dialy
OralOnce daily
Half-life 20-30 min 3-4 hr 12-16 hr
Excretion Urinary, fecal Urinary fecal
Main adverse effects
-local reaction-allergy-auditory (SNHL)1
-ophthalmologic-growth retardation
-gastrointestinal (vomiting)-arthralgia-elevated liver enzymes (ALT, AST)-neutropenia(ANC<1,500/10-6/L)-agranulocytosis(ANC<500/10-6/L)
-gastrointestinal (abdominal pain, nausea, vomiting)-rash-increase creatinine-increase liver enzymes (ALT, AST)
1SNHL=sensorineural hearing loss, 2ANC= absolute neutrophil count
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Iron Chelator: monitor and safetyMonitor Deferoxamine(DFO) Deferiprone (DFP) Deferasirox (DFX)
CBC (ANC) - 1-2 wk (first 3 months) then monthly or when fever/infection occur
-
Ferritin Every 3-6 months
Proteinuria - - Every month
BUN/Creatinine Every 3 months 1-3 month or dose adjustment
Liver function (AST, ALT)
Every 3 months -monthly for the first 3 months, then very 3 months
-adjust dose or stop if AST, ALT > 2.5 x normal
Ophthalmic evaluation
Before start treatment then every year
Audiometry Before start treatment then every year
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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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TDT 2-6 yearsDFO1 20-40 mg/kg/day SC, 5-7 days/week orDFX2 20-40 mg/kg/day od
TDT*: hypertransfusion > 1 year, received transfusion > 10 times, SF > 1000 ng/mL, LIC > 7 mg Fe/g DW
TDT > 6 yearsDFO 20-40 mg/kg/day SC 8-12 hr., 5-7 days/week orDFP3 50-100 mg/kg/day tid
Adverse effect of DFP: 1.Systemic allergic reaction2.ALT, AST > 2.5 ULN3.Neutropenia (ANC < 1,000/µL)4.Severe neutropenia (ANC < 500/µL)5.Severe arthropathy6.DFP intolerance: nausea, vomiting
Failure of DFP:1.DFP maximum dose 100 mg/kg/day2.SF > 2500 ng/mL-SF > 2500 ng/mL for 1 year or
-SF decrease < 15% from start for 2 years
Second line: DFX start 20 mg/kg/day od, adjust 5-10 mg (max. 40 mg/kg/day)
Not response: try combination therapy Deferiprone + Desferoxamine or Deferiprone + Deferaxirox
Response to therapy -Continue treatment -Target SF < 500 ng/mL
No adverse effect
Diagram of iron chelation therapy
Indication
Drug
*TDT = Transfusion dependent thalassemia1DFO = Deferrioxamine, 2DFX = Deferasirox ,3DFP = Deferiprone
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Iron chelation in NTDT:
• Assessment: • serum ferritin every 3-6 month or LIC every 1-2 years
• Indication• age > 10 years, serum ferritin > 800 ng/mL or LIC 5 mg/g dry weight
• Drugs• Deferiprone 50 mg/kg/day (max. 100 mg/kg/day)• Deferasirox 10-20 mg/kg/day (max. 30 mg/kg/day)
• Adjust dose • if Serum ferritin < 500 ng/mL, stop if < 300 ng/mL or • LIC < 3 mg/g dry weight
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Deferasirox: drug-related adverse events(N=472)
Adverse event Frequency, N (%)
Abdominal pain 62 (13.1)
Nausea 55 (11.7)
Diarrhea 40 (8.5)
Vomiting 32 (6.8)
Rash 23 (4.9)
30Taher A, Ther Clin Risk Manag 2009;5:857-68
9/19/2019 Kitti Torcharus, M.D.
Deferiprone (GPO-L-ONE@R ) monotherapy(phase III, 1-year results from a multicenter (Siriraj, Rama, Chula and PMK)
• 73 of severe b-thalassemia (TDT), age 3.2–19 yrs• 64 patients (87.6%) completed the study
• average dose 79.1 + 64.3 mg/kg/day• good compliance (94%)
• Response group(SF reduced >15%), 45% of patients• median reduction of SF = 1,065 ng/ml• reduce LIC and normalize levels of ALT at 1 year
• Baseline SF>3,500 ng/ml, significant fall of SF at 1 year• Drug-related adverse events (AEs)
• gastrointestinal irritation 20.5% • transaminitis 16.4% • neutropenia 6.8%
31
Viprakasit V, et al. Am J Hematol. 2013;88(4):251-60
9/19/2019 Kitti Torcharus, M.D.
Survival of b-thalassemia major in UK
32
Weidlich D, et al. Transfusion 2016 May;56(5):1038-45
0.63
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Expected probability of health outcomes at 50 years
33
Weidlich D, et al. Transfusion 2016 May;56(5):1038-45
9/19/2019 Kitti Torcharus, M.D.
Treatment related complications
Major complication* Prevalence (per 1,000 admissions)
Heart failure 11.9
Cholelithiasis 5.6
Pulmonary hypertension 3.37
Hypothyroidism 1.56
Spinal cord compression 0.25
34
Teawtrakul N, et al. J Med Assoc Thai. 2012 Jul;95 Suppl 7:S211-6
*A cross-sectional study. Data included inpatients and outpatients, fiscal year 2010 (October1, 2009 to September 30, 2010), Faculty of Medicine, Khon Kaen University.
9/19/2019 Kitti Torcharus, M.D.
Treatment related complications
Symptom and laboratory diagnosis:
• Gall stone (asymptomatic, 60-80%)
• Biliary colic, common bile duct stone, ascending cholangitis, acute cholecystitis
• 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
359/19/2019 Kitti Torcharus, M.D.
Hematopoietic Stem Cell Transplantation( HSCT)
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Hematopoietic Stem Cell Transplantation( HSCT)
• Indication: severe thalassemia• homozygous β-thalassemia (β0/β 0, β0/β+)
• severe β-thalassemia/HbE disease
• surviving Hb Bart’s hydrops fetalis syndrome
• severe non-deletional Hb H diseases
• Donor• match-related donor (MRD): Human Leukocyte Antigen (HLA) compatible
• match-unrelated donor (MRD)
• haploidentical donor
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Hematopoietic stem cell transplantation (HSCT): in Thailand (1987-2018)*
HSCT N (%) Cure (%) Alive with disease
Death
Related 213 (65.5) 178 (83.6) 16 (7.5) 19 (8.9)
Unrelated 77 (23.7) 62 (80.5) 7 (9.1) 8 (10.4)
Haploid 35 (10.8) 30 (85.7) 2 (5.7) 3 (8.6)
Total 325 (100) 270 (83.1) 25 (7.7) 30 (9.2)
*Data from CPG working group, Red cell subcommittee, Thai Society of Hematology
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Alternative treatment
• Hb F stimulation: Hydroxyurea• transfusion-dependent thalassemia
• extramedullary hematopoiesis
• red cell alloimmunization
• dose 10 mg/kg/day
• Gene therapy1
• 12 cases: homo. b-thal and b-thal/Hb E
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1Biffi A. N Engl J Med 2018;378(16):1551-2
Thank you for your attention
9/19/2019 Torcharus K, M.D. 40
Gene therapy procedures: Cells were collected from the bone marrow of a patient with β-
thalassemia (Cavazzano-Calvo et al. 2010).
Arthur W. Nienhuis, and Derek A. Persons Cold Spring Harb
Perspect Med 2012;2:a011833
©2012 by Cold Spring Harbor Laboratory Press9/19/2019 Torcharus K, M.D. 41
Summary
• Clinical severity of TDT & NTDT
• Blood transfusion & Iron chelation
• Splenectomy
• Treatment related complications
• Hematopoietic stem cell transplantation
• Alternative treatment
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