Evidence-Based Approach to Managing Non-Transfusion ... Hepatic fibrosis, cirrhosis and cancer Hepatic

  • View
    0

  • Download
    0

Embed Size (px)

Text of Evidence-Based Approach to Managing Non-Transfusion ... Hepatic fibrosis, cirrhosis and cancer...

  • Evidence-Based Approach to Managing

    Non-Transfusion-Dependent

    Thalassemias (NTDT)

    Ali T. Taher, MD, PhD, FRCP

    Professor of Medicine, Hematology & Oncology

    American University of Beirut Medical Center

    Beirut – Lebanon

    Professor of Hematology & Medical Oncology (Adj.)

    Emory School of Medicine

    Atlanta – USA

  •  Non-transfusion-dependent thalassemia (NTDT)

     Morbidity in NTDT – Clinical complications profile

    – Ineffective erythropoiesis and anemia

    – Iron overload and target organ damage

    – Hypercoagulability and vascular disease

     Management of NTDT – Splenectomy

    – Transfusions

    – Fetal hemoglobin induction

    – Iron chelation

    – Novel agents

    Agenda

  •  Non-transfusion-dependent thalassemia (NTDT)

     Morbidity in NTDT – Clinical complications profile

    – Ineffective erythropoiesis and anemia

    – Iron overload and target organ damage

    – Hypercoagulability and vascular disease

     Management of NTDT – Splenectomy

    – Transfusions

    – Fetal hemoglobin induction

    – Iron chelation

    – Novel agents

    Agenda

  • HbE, haemoglobin E; HbH, haemoglobin H.

    1. Taher AT, et al. Br J Haematol. 2011;152:512-23.

    2. Galanello R, Origa R. Orphanet J Rare Dis. 2010;5:11.

    3. Vichinsky E. Hematology Am Soc Hematol Educ Program. 2007;79-83. 4

    4. Muncie HL Jr, Campbell J. Am Fam Physician. 2009;80:339-44.

    5. Figure adapted from Musallam KM, et al. Haematologica. 2013;98:833-44.

    Occasional transfusions

    required (e.g. surgery,

    pregnancy, infection)

    Intermittent transfusions required

    (e.g. poor growth and development,

    specific morbidities)

    Regular, lifelong

    transfusions

    required for survival

    Transfusions

    seldom required

    Transfusions not required

     α-thalassaemia trait

     β-thalassaemia minor

    Non transfusion dependent thalassaemia (NTDT)

     β-thalassaemia intermedia

     Mild/moderate HbE/β-thalassaemia

     HbH disease (α-thalassaemia)

     HbS β-thalassaemia

     HbC thalassaemia

    Transfusion dependent thalassaemia (TDT)

     β-thalassaemia major

     Severe HbE/β-thalassaemia

     Hb Barts hydrops (α-thalassaemia major)

    NTDT patients do not require regular transfusions, although they may require

    occasional transfusions for growth failure, pregnancy, infections, and other

    specific situations1–4

    NTDT: a designation based on transfusion

    requirement

  • 1Weatherall DJ. Blood Rev 2012;26 Suppl 1:S3–S6; 2Available from: http://emedicine.medscape.com/article/959122-overview#a0156; 3Harteveld CL and Higgs DR. Orphanet J Rare Dis 2010;5:13; 4Weatherall DJ. Blood 2010;115:4331–4336.

    3

    Prevalence of Hb H disease

    in Europe and North

    America increasing due

    to migration3

    β thalassemia intermedia

    – most common in

    Africa, Mediterranean,

    India and East Europe1,2

    Hb H – most common in

    Southeast Asia, Middle East

    and Mediterranean3

    Approx. 9500 annual births4

    Hb E/β thalassemia – most common in

    East India, Bangladesh and Southeast Asia1

    Approx. 19,000 annual births4

    The increased migration flow expands the reach of these diseases

    World distribution of hemoglobinopathies3

    The prevalence of NTDT is increasing

    worldwide due to migration

  •  Non-transfusion-dependent thalassemia (NTDT)

     Morbidity in NTDT – Clinical complications profile

    – Ineffective erythropoiesis and anemia

    – Iron overload and target organ damage

    – Hypercoagulability and vascular disease

     Management of NTDT – Splenectomy

    – Transfusions

    – Fetal hemoglobin induction

    – Iron chelation

    – Novel agents

    Agenda

  • HCV, hepatitis C virus. Taher A, et al. Blood Cells Mol Dis. 2006;37:12-20.

    Complication (% of patients affected)

    β-TI β-TM

    Lebanon (n = 37)

    Italy (n = 63)

    Lebanon (n = 40)

    Italy (n = 60)

    Splenectomy 90 67 95 83

    Cholecystectomy 85 68 15 7

    Gallstones 55 63 10 23

    Extramedullary haemopoiesis

    20 24 0 0

    Leg ulcers 20 33 0 0

    Thrombotic events 28 22 0 0

    Cardiopathya 3 5 10 25

    PHTb 50 17 10 11

    Abnormal liver enzymes 20 22 55 68

    HCV infection 7 33 7 98

    Hypogonadism 5 3 80 93

    Diabetes mellitus 3 2 12.5 10

    Hypothyroidism 3 2 15 11

    aFractional shortening < 35%. bDefined as pulmonary artery systolic pressure > 30 mmHg; a well-enveloped

    tricuspid regurgitant jet velocity could be detected in only 20 patients, so frequency

    was assessed in these patients only.

    How it all started: realizing morbidity is

    highly prevalent and different from TDT in

    our clinics

  • Musallam KM et al. Haematologica. 2013;98:833–844.

    Non-Transfusion-Dependent

    Thalassemias (NTDT)

    β-Thalassemia Major

    (Regularly transfused)

    Silent cerebral ischemia

    Pulmonary hypertension

    Right-sided heart failure

    Cardiac siderosis

    Left-sided heart failure

    Splenomegaly

    Gall stones

    Hepatic fibrosis, cirrhosis

    and cancer Hepatic failure

    Viral hepatitis

    Diabetes mellitus

    Hypogonadism

    Facies

    Bone deformity

    (Hair on end)

    Extramedullary

    hematopoietic

    psuedotumors

    Venous thrombosis

    Osteoporosis

    Hypothyroidism

    Hypoparathyroidism

    Osteoporosis

    Leg ulcers

    Musallam KM, et al. Haematologica. 2013;98:833-4.

    Observations were similar in reported literature

  •  Cross-sectional study of 584 patients with β-TI from 6 comprehensive

    care centres in the Middle East and Italy

    β-TI, β-thalassaemia intermedia. Taher AT, et al. Blood. 2010;115:1886-92.

    n = 12 S. Daar

    n = 127 A.T. Taher

    K.M. Musallam

    n = 200 M. Karimi

    n = 51 A. El-Beshlawy

    n = 153 M.D. Cappellini

    n = 41 K. Belhoul

    M. Saned

    The OPTIMAL CARE study Overview on Practices in β-Thalassaemia Intermedia Management Aiming for Lowering Complication rates

    Across a Region of Endemicity:

    http://upload.wikimedia.org/wikipedia/commons/0/03/Flag_of_Italy.svg

  • Taher AT, et al. Blood. 2010;115:1886-92.

    Parameter Frequency

    n (%)

    Age (years)

    < 18 172 (29.5 )

    18–35 288 (49.3)

    > 35 124 (21.2)

    Male:female 291 (49.8) : 293 (50.2)

    Splenectomized 325 (55.7)

    Serum ferritin (µg/L)

    < 1,000 376 (64.4)

    1,000–2,500 179 (30.6)

    > 2,500 29 (5)

    Complications

    Osteoporosis

    EMH

    Hypogonadism

    Cholelithiasis

    Thrombosis

    Pulmonary hypertension

    Abnormal liver function

    Leg ulcers

    Hypothyroidism

    Heart failure

    Diabetes mellitus

    134 (22.9)

    124 (21.2)

    101 (17.3)

    100 (17.1)

    82 (14)

    64 (11)

    57 (9.8)

    46 (7.9)

    33 (5.7)

    25 (4.3)

    10 (1.7)

    Treatment Frequency

    n (%)

    Hydroxyurea 202 (34.6)

    Transfusion

    Never

    Occasional

    Regular

    139 (23.8)

    143 (24.5)

    302 (51.7)

    Iron chelation

    None

    Deferoxamine

    Deferiprone

    Deferiprone +

    deferoxamine

    Deferasirox

    248 (42.5)

    300 (51.4)

    12 (2.1)

    3 (0.5)

    21 (3.6)

    High morbidity rates were confirmed

  • ALF, abnormal liver function; DM, diabetes

    mellitus; HF, heart failure. Taher AT, et al. Br J Haematol. 2010;150:486-9.

    F re

    q u

    e n

    c y (

    % )

    ≤ 10 years 11–20 years 21–32 years > 32 years

    0

    5

    10

    15

    20

    25

    30

    35

    40

    45

    0

    *Statistically significant trend.

    6.7

    13.3

    16.7

    40.0

    26.7

    3.3

    6.7

    16.7

    26.7

    3.3

    13.3

    20.0 20.0

    3.3

    6.7

    10.0 10.0

    3.3

    6.7

    33.3

    13.3

    10.0

    20.0

    13.3

    3.3

    6.7

    10.0

    13.3

    0 0

    3.3

    16.7

    0

    3.3

    10.0

    30.0

    6.7

    16.7

    23.3

    20.0

    0

    16.7

    23.3

    *

    * *

    * *

    *

    120 treatment-naive patients

    Morbidities seemed to increase with

    advancing age

  • • Leg ulcers

    • Thrombotic events

    • Pulmonary

    hypertension

    • Bone deformities

    • Osteoporosis

    Impaired α:β

    globin ratio

    • Diabetes mellitus

    • Growth deficiency

    • Hypothyroidism

    • Hypoparathyroidism

    • Hypogonadism

    • Hepatic cancer

    • Renal disease

    Ineffective erythropoiesis haemolysis

    Anaemia