Thalassemia: Diagnosis and Treatment. Kittti Torcharus, M.D. Department of Pediatrics Phramongkutklao Hospital

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1 Thalassemia: Diagnosis and Treatment Kittti Torcharus, M.D. Department of Pediatrics Phramongkutklao Hospital

2 Scope of lecture Incidence Diagnosis Blood transfusion Iron chelation Treatment related complications Hematopoietic stem cell transplantation Preimplantation genetic diagnosis (PGD) Survival 11/23/2017 Kitti Torcharus, M.D. 2

3 Prevalence of Thalassemia in The world MARCH OF DIMES GLOBAL REPORT ON BIRTH DEFECTS; /23/2017 Kitti Torcharus, M.D. 3

4 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 Chiangmai 8.0 Northeast Hemoglobin Constant Spring /23/2017 Kitti Torcharus, M.D. 4

5 Prevalence of thalassemia and hemoglobinopathies Wongprachum K, et al. Acta Haematol. 2016;135(2): /23/2017 Kitti Torcharus, M.D. 5

6 Classification: Clinical severity Severity Clinical Hb (g/dl) Type Severe Moderate Age onset of anemia < 2 yrs, Age at first blood transfusion < 4 yrs, Weight & Height lower than normal, Facial bone change, Huge splenomegaly Anemia, jaundice, hepatomegaly, splenomegaly < 7 Homo. b 0 -thal (b 0 /b 0, b 0 /b + ), b 0 -thal/hb E, surviving Hb Bart s hydrops, Non-deletional Hb H 7-9 Homo. b 0 -thal (b 0 /b + ), b 0 -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 11/23/2017 Kitti Torcharus, M.D. 6

7 Transfusion-dependent thalassemia (TDT) Severe type (Clinical severity) Require regular transfusion with iron chelation Maintain Hb level g/dl Thalassemia type: Homo. b 0 -thal (b 0 /b +, b 0 /b + ) b 0 -thal/hb E, Hb Bart s hydrops fetalis (surviving) Non-deletional Hb H 11/23/2017 Kitti Torcharus, M.D. 7

8 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 (b 0 /b +, b + /b + ), b-thalassemia/hb E, (b 0 /b E, b + /b E ) Hb H disease 11/23/2017 Kitti Torcharus, M.D. 8

or after birth Homozygous b 0 -thalassemia Genotype: b 0 -thal/b

9 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 b 0 -thalassemia Genotype: b 0 -thal/b 0 -thal Transfusion dependent 11/23/2017 Kitti Torcharus, M.D. 9

b-thalassemia/ Hb E Genotype: b 0 -thal/b E Hb H with Hb

10 Clinical severity: moderate to severe thalassemia (Anemia, jaundice, occasional require blood transfusion) b-thalassemia/ Hb E Genotype: b 0 -thal/b E Hb H with Hb CS Genotype: a-thal 1/Hb CS 11/23/2017 Kitti Torcharus, M.D. 10

11 Mild thalassemia (Anemia, jaundice, not require blood transfusion) b-thalassemia/ Hb E Genotype: b + -thal/b E Hb H disease Genotype: a-thal 1/a-thal 2 11/23/2017 Kitti Torcharus, M.D. 11

12 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 11/23/2017 Kitti Torcharus, M.D. 12

anisocytosis, poikilocytosis, target cell Reticulocytosis Inclusion bodies Hb H

13 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) Reticulocyte Inclusion bodies 11/23/2017 Kitti Torcharus, M.D. 13

Beta-thalassemia/Hb E Nucleated red cell (NRC) Target cells 23/11/2017

14 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 23/11/2017 Torcharus K 14

15 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. 11/23/2017 Kitti Torcharus, M.D. 15

16 Hb type: Criteria for diagnosis (I) Conditions Hb type Normal A 2 A ( A % ) a-thal 1 trait A 2 A ( A % )* a-thal 2 trait A 2 A ( A % )* b-thal trait A 2 A ( A 2 > 3.5% ) Hb E trait EA ( E= % ) Hb E homozygous EE ( E >85% ) Hb CS trait CS A 2 A ( CS 1-2 % ) Hb CS homozygous CS A 2 A ( CS 3-6% ) *Can not diagnose by Hb type *Diagnose by PCR for a-thal 1 trait and a-thal 2 trait respectively 11/23/2017 Kitti Torcharus, M.D. 16

17 Hb type: Criteria for diagnosis (I) Conditions Hb type Hb Barts hydrops Portland, Barts Hb H disease A 2 A H Barts Hb H with Hb CS CS A 2 A H Barts Hb AEBarts disease A E Barts Homozygous b-thal A 2 F b-thal / Hb E EF Hb CS trait CS A 2 A ( CS 1-2 % ) 11/23/2017 Kitti Torcharus, M.D. 17

18 Molecular Diagnosis (cont.) a-thalassemia:(gap-pcr) a-thal 1 trait (aa/- - SEA, aa/- - Thai ) a-thal 2 trait (aa/ - a 3.7, aa/- a 4.2 ) Hb CS trait (aa/a CS a), Hb Pakse trait (aa/a Ps a) b-thalssemia:(arms-pcr*, RDB**, Gap-PCR, DNA sequencing) b 0 -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 (C>T), CD 19(A>G), -28 (A>G), CD 26, etc. db-thalassemia HPFH: HPFH-6, etc. *Amplification refractory mutation system, **Reverse dot-blot hybridization 11/23/2017 Kitti Torcharus, M.D. 18

19 Screening and diagnostic algorithm for thalassemia and hemoglobinopathies 1. Screening OF+DCIP or MCV+DCIP - /- + /- or - / + or + / + Non-thalassemia, Non clinical significant thalassemia 2. Confirmation Hb typing: A 2 A (A 2 <3.5%) Suspected a-thal trait A 2 A (A 2 >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 3. Confirmation PCR for a-thal 1: a-thal 1 trait Thalassemia disease (NTDT) a-thal: Hb H disease, etc. b-thal: b + -thal/hb E, etc. db-thal: db-thal, HPFH, etc. 11/23/2017 Kitti Torcharus, M.D. 19

20 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 Kitti Torcharus, MD. 20

21 Blood transfusion Recommended: leucoreduced < 1x 10 6 Leucocyte depleted packed red cell (LDPRC) Leucocyte poor packed red cell (LPRC) Before first transfusion: antigen typing: C, c, E, e, Mi a 11/23/2017 Kitti Torcharus, M.D. 21

22 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 Cappellini D, ed. TIF Guidelines : 2007 p Taher A, Blood Cells Mol Dis. 2006;37(1): /11/60 Kitti Torcharus,M.D. 22

23 Immune-mediated transfusionsreactions 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 Delayed frequency Alloimmune 1/100 Hemolytic (extravascular) 1/2,500 Garft vs Host Disease Rare 11/23/2017 Kitti Torcharus, M.D. 23

mg/kg/day, subcutaneous infusion 8-10 hour by infusion

24 Iron chelator Deferoxamine (DFO), 500 mg/vial Deferiprone (L1), 500 mg/tab Iron chelator Administration mg/kg/day, subcutaneous infusion 8-10 hour by infusion pump mg/kg/day Deferasirox (DFX), 500 mg/tab mg/kg/day

25 Indication: Received PRC >10-20 units Iron chelation Serum ferritin > 1,000 ng/ml First line: Deferoxamine (DFO) mg/kg/day, sc. Second line: Deferiprone (L1) mg/kg/day, oral Deferasirox (DFX) mg/kg/day, oral Combination therapy: L1: mg/kg/day + DFO: mg/kg 3-5 days/wk Kontoghiorghes GJ. Hemoglobin. 2009;33(5): /23/2017 Kitti Torcharus, M.D. 25

26 Assessment and thresholds of iron overload Assessment Normal Mild Moderate Severe Ferritin (ng/ml) > 1,000 1,000-2,500 > 2,500 LIC (mg Fe/g dw) 2 < to <7 7 to < 15 > 15 MRI(T2*)mg Fe/g dw 3 < to 7 7 to <15 >15 CMR, T2*(ms) 4 > 20 <20 to 10 < 10-5 < 5 LIC=Liver Iron Concentration MRI = Magnetic resonance imaging CMR =Cardiovascular Magnetic resonance 1 Olivieri NF, N Engl J Med ;331(9): Angelucci E, N Engl J Med. 2000;343(5): CPG, Diagnosis & management.of thalassemia syndromes 2014: Wood JC. Hematology Am Soc Hematol Educ Program. 2011;2011: /23/2017 Kitti Torcharus, M.D. 26

27 Iron Chelator: Properties Property Deferoxamine Deferiprone Deferasirox Usual dose (mg/kg/day) Route Sc, iv (8-12 hr, 5 days/week) Oral 3 times dialy Oral Once daily Half-life 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 nonprogressive creatinine increase, elevated liver enzymes, Ophthalmologic, auditory 11/23/2017 Kitti Torcharus, M.D. 27

28 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 mg/kg/day, iv. dirp 24 hr. 5-6 days per wk 23/11/60 28 Kitti Torcharus,M.D.

29 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 11/23/2017 Kitti Torcharus, M.D. 29

30 Splenectomy Indications: Increased blood requirement ( 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. 11/23/2017 Kitti Torcharus, M.D. 30

31 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 *Mortality rate 50-70%, death occurs within 24 hr 11/23/2017 Kitti Torcharus, M.D. 31

32 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 11/23/2017 Kitti Torcharus, M.D. 32

33 Hematopoietic stem cell transplantation (HSCT) Indication: Thalassemia major (transfusion dependent thalassemia) homozygous b-thalassemia b-thalassemia/ Hb E (severe) 11/23/2017 Kitti Torcharus, M.D. 33

34 Source of hematopoietic stem cell 1. Bone marrow 2. Peripheral blood 3. Cord blood /23/2017 Kitti Torcharus, M.D. 34

35 Hematopoietic stem cell transplantation (HSCT) 1.Conditoning chemo. therapy 2.Transfusion of stem cell 3.During HSCT 4.Post HSCT 11/23/2017 Kitti Torcharus, M.D. 35

36 Overall survival, thalassemia-free survival, non-rejection mortality and rejection for class 1 patients younger than 17 yrs Gaziev J, Lucarelli G. Curr Stem Cell Res Ther. 2011;6(2): /23/2017 Kitti Torcharus, M.D. 36

37 HSCT: Thai ( ) 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) HSCT=Hematopoietic stem cell transplantation 11/23/2017 Kitti Torcharus, M.D. 37

38 HSCT in Department of Pediatrics, PMK Aplastic anemia 4% Nuroblastoma 4% Thalassemia 26% Lymphoma 33% ALL 7% AML 26% 11/23/2017 Kitti Torcharus, M.D. 38

39 HSCT in Department of Pediatrics, PMK 11/23/2017 Kitti Torcharus, M.D. 39

40 Comparison of life expectancy for patients who were alive at the beginning of 1970, 1980, 1990 and 2000 Modell B, et al. J Cardiovasc Magn Reson. 2008;10:42 11/23/2017 Kitti Torcharus, M.D. 40

41 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 11/23/2017 Kitti Torcharus, M.D. 41

42 Proposed schema of gene therapy for β-thalassaemia Yannaki E, et al.expert Rev Mol Med. 2010;12:e31 11/23/2017 Kitti Torcharus, M.D. 42

43 National thalassemia guidelines: Clinical practice guidelines for diagnosis and management of thalassemia syndromes & Care of thalassemia patients 1 st edition: nd edition: st edition: /23/2017 Kitti Torcharus, M.D. 43

44 Summary Thalassemia is public health problems in ASEAN Thailand and LAO PDR (high prevalence, similar genotypephenotype) 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 11/23/2017 Kitti Torcharus, M.D. 44

45 Thank you for your attention 11/23/2017 Kitti Torcharus, M.D. 45

Thalassemia Maria Luz Uy del Rosario, M.D.

Thalassemia Maria Luz Uy del Rosario, M.D. Philippine Society of Hematology and Blood Transfusion Philippine Society of Pediatric Oncology What is Thalassemia Hereditary Hemoglobin disorder Hemolytic anemia