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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
19/09/2019 Torcharus K 4
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
9/19/2019 Torcharus K, M.D. 10
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
9/19/2019 Torcharus K, M.D. 11
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
9/19/2019 Kitti Torcharus, M.D.
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
9/19/2019 Torcharus K, M.D. 22
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
9/19/2019 Torcharus K, M.D. 23
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
9/19/2019 Torcharus K, M.D. 25
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
9/19/2019 Torcharus K, M.D. 26
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
9/19/2019 Torcharus K, M.D. 27
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
9/19/2019 Torcharus K, M.D. 28
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
9/19/2019 Torcharus K, M.D. 29
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
9/19/2019 Kitti Torcharus, M.D.
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)
9/19/2019 Torcharus K, M.D. 36
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
9/19/2019 Torcharus K, M.D. 37
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
9/19/2019 Torcharus K, M.D. 38
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
9/19/2019 Torcharus K, M.D. 39
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
9/19/2019 Torcharus K, M.D. 42
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