Talassemie intermedie:
trattamento
Antonio Piga
Università di Torino Dipartimento di Scienze Cliniche e Biologiche
Scuola di Medicina ed Azienda Ospedaliero-Universitaria S. Luigi Gonzaga - Orbassano
S.C.D.U. Pediatria Centro Microcitemie - Centro SQUID
email: [email protected] tel. 011 9026851
thalassemia AND intermedia AND treatment
thalassemia AND intermedia AND treatment
Elisa F., Thalassemia intermedia ? At 2 years of age: Hb 8.2 g dL
To treat or not to treat ?
Thalassemia Centre University of Torino
Thal Major more likely
Thal Intermediamore likely
ClinicalPresentation (yrs) <2 >2
Hb levels (g/dl) <7 8-10
Liver/spleen enlargement Severe Moderate to severe
HematologicalHbF (%) >50 10-50 (up to 100%)
HbA2 (%) <4 >4
GeneticParents High HbA2 in both High HbF or HbA2<4 in one or both
MolecularType of mutation Severe Mild/Silent
Coinheritance of α-thal No Yes
High HbF production No Yes
Hyperunstable Hb variant No Yes
βThal heterozygous + αααor αααα globin genes
No Yes
KEY POINTS FOR LONG-TERM MANAGEMENT OF THALASSEMIA INTERMEDIA
Thalassemia Centre University of Torino
1. TI phenotype may be poorly predictable 2. TI phenotype has a trend to worsen 3. Long term complications may be severe and
irreversible
Age and clinical complications in Thalassemia Intermedia (584 patients on OPTIMAL CARE study)
Taher AT, Blood, 2010
0
5
10
15
20
25
30
35
40
0-1818-35>35 years
Freq
uenc
y of
Com
plic
atio
ns (%
)
……………………………………………………………………………………………………………………….. Medical Attention
Thalassemia Intermedia Clinical Synopsis
Chronic Anemia
10 years 20 years 40 years 30 years 50 years
Thalassemia Centre University of Torino
Diagnosis
KEY POINTS FOR LONG-TERM MANAGEMENT OF THALASSEMIA INTERMEDIA
Thalassemia Centre University of Torino
1. TI phenotype may be poorly predictable 2. TI phenotype has a trend to worsen 3. Long term complications may be severe and
irreversible 4. Prevention of complications requires:
• regular follow-up focused on preclinical markers
Tanno T, Nature Medicine, September 2007
N = 37 13 12 20 40 17 20 22 55
Musallam KM, et al. Blood Cells Mol Dis. 2011;47:232-4.
GDF15 levels correlate with clinical severity score in β-thalassaemia intermedia
r = 0.830 p < 0.001
Mild Moderate Severe
Musallam KM, et al. Blood Cells Mol Dis. 2011;47:232-4.
GD
F15
(pg/
mL)
Clinical severity score
Treatment
Extramedullary erythropoiesis in Thalassemia Intermedia
Symptomatic case
Ileri T, J Pediatr Hemat Oncol, 2009
Full recovery at 12 months
Radiation therapy
Hydroxyurea at 15 mg/kg/d
Hypertransfusion
Neurosurgery
Extramedullary erythropoiesis in Thalassemia Intermedia
Thalassemia Centre University of Torino
Management
Extramedullary erythropoiesis in Thalassemia Intermedia
Tabesh H, J Medical Case Reports, 2011
Thalassemia Intermedia and ischemic lesions
Taher AT, et al. J Thromb Haemost. 2010;8:54-9.c
Hahalis G, Cardiology, 2011
Endothelial dysfunction and subclinical atherosclerosis in asymptomatic thalassemia
intermedia
Ashjazadeh N, Anemia, 2012
Transcranial Doppler sonography (TCD) shows high arterial blood flow velocity in β-thalassemia intermedia
Transcranial
Doppler
Scanning
Thalassemia Centre University of Torino
Thalassemia Centre University of Torino
β Thalassemia Intermedia
Thalassemia Centre University of Torino
β Thalassemia Intermedia
Thalassemia Centre University of Torino
β Thalassemia Intermedia
Thalassemia Centre University of Torino
β Thalassemia Intermedia
Thalassemia Centre University of Torino
Thalassemia Intermedia
Thalassemia Centre University of Torino
β Thalassemia Intermedia
Thalassemia Centre University of Torino
β Thalassemia Intermedia
Thalassemia Centre University of Torino
β Thalassemia Intermedia
KEY POINTS FOR LONG-TERM MANAGEMENT OF THALASSEMIA INTERMEDIA
Thalassemia Centre University of Torino
1. TI phenotype may be poorly predictable 2. TI phenotype has a trend to worsen 3. Long term complications may be severe and
irreversible 4. Prevention of complications requires:
• regular follow-up focused on preclinical markers • early treatment with blood transfusion
Indications for transfusion therapy in thalassaemia intermedia
➥Hb level < 50 g/l ➥Declining Hb level in parallel with profound enlargement of the spleen ➥Severe bony changes ➥Growth failure or poor performance at school ➥Diminished exercise tolerance ➥ Infection ➥Failure of secondary sexual development in parallel with bone age ➥Pregnancy ➥Other specific complications
➥ (e.g. Heart failure, pulmonary hypertension, thromboembolic disease, leg ulcers, priapism)
Taher AT, Brit J Haematol, 2011
o Thal. minor
o Thal. intermedia “mild”
o Thal. intermedia “severe”
o Thal. major
DEGREE OF ANEMIA
ASYMPTOMATIC
MILD
MODERATE
SEVERE
TRANSFUSION-DEPENDENT
NO TRANSFUSION
TRANSFUSION
Thalassemia Centre University of Torino
THALASSEMIA PHENOTYPES AND TRANSFUSION
o Thal. minor
o Thal. intermedia “mild”
o Thal. intermedia “severe”
o Thal. major
THALASSEMIA PHENOTYPES AND TRANSFUSION
DEGREE OF ANEMIA
ASYMPTOMATIC
MILD
MODERATE
SEVERE
TRANSFUSION-DEPENDENT
NO TRANSFUSION
TRANSFUSION
Thalassemia Centre University of Torino
COMPLICATION
Thalassemic stigmata
Hypersplenism
Autoimmune Hemolitic Anemia
Extramedullary erythropoiesis
Leg ulcers
Thromboembolism
Pulmonary Hypertension
Heart Disease
Endocrinopathies
Osteoporosis
Iron overload
Cholelithiasis
Hyperuricuria and Gout
Pseudoxantoma Elasticum
Infections
Role of Blood Transfusion in Preventing or Treating Thalassemia Intermedia Complications
Thalassemia Centre University of Torino
COMPLICATION ROLE IN PREVENTION ROLE IN TREATMENT
Thalassemic stigmata +++ ++ (during chilhood)
Hypersplenism ++ +-
Autoimmune Hemolitic Anemia +++ (if early) -
Extramedullary erythropoiesis +++ ++ (response requires time)
Leg ulcers +++ ++ (response requires time)
Thromboembolism ++ +-
Pulmonary Hypertension ++ ?
Heart Disease ++ (high output HD) +
Endocrinopathies + +-
Osteoporosis + (?) ?
Iron overload + (↑ hepcidin) / - + (↑ hepcidin) / -
Cholelithiasis + -
Hyperuricuria and Gout +++ ++
Pseudoxantoma Elasticum +++ -
Infections ++ ++
Role of Blood Transfusion in Preventing or Treating Thalassemia Intermedia Complications
Thalassemia Centre University of Torino
Thalassemia Centre University of Torino
Thalassemia Centre University of Torino
deferoxamine (DFO)
deferiprone (DFP)
deferasirox (DFX)
Monotherapy Combination of DFO + DFP Potential use of any combination of any 2 or 3 chelators
Iron chelators
Treatment options for Thalassemia Intermedia
Wait & see
Supportive treatment
Sporadic/occasional Transfusion
Regular Transfusion
Iron chelation therapy
Thalassemia Centre University of Torino
KEY POINTS FOR LONG-TERM MANAGEMENT OF THALASSEMIA INTERMEDIA
Thalassemia Centre University of Torino
1. TI phenotype may be poorly predictable 2. TI phenotype has a trend to worsen 3. Long term complications may be severe and
irreversible 4. Prevention of complications requires:
• regular follow-up focused on preclinical markers • early treatment with blood transfusion
5. Alternatives to blood transfusion are problematic
Treatment options for Thalassemia Intermedia
Wait & see
Supportive treatment
Sporadic/occasional Transfusion
Regular Transfusion
Iron chelation therapy
Hydroxyurea
Thalassemia Centre University of Torino
• Antineoplastic chemotherapeutic agent • Ribonucleotide reductase inhibitor • Mechanisms of action in thalassemia
• Increases Hgb F concentration • Decreases bone marrow hyperplasia • Others
Model of regulation of fetal haemoglobin in adults
Adapted from Stamatoyannopoulos, G. Expt Hematology 33 (2005) 259-271
Killing of cycling cells
F cells
F cells
F cells
Heterocellular HPFH
Hemoglobin changes in Thalassemia Intermedia during Hydroxyurea (HU) treatment
Karimi M, Eur J Hematol, 2010
⬅ HU + carnitine + Mg ⬅ HU + carnitine
⬅ HU + Mg
⬅ HU
Echocardiographic parameters in Thalassemia Intermedia during Hydroxyurea (HU) treatment
Karimi M, Eur J Hematol, 2010
HU + carnitine HU + Mg HU + carnitine + Mg
Treatment options for Thalassemia Intermedia
Wait & see
Supportive treatment
Sporadic/occasional Transfusion
Regular Transfusion
Iron chelation therapy
Hydroxyurea (other cytostatic drugs)
Thalassemia Centre University of Torino
Hb F Synthesis Induction
• Cytotoxic drugs • 5-azacytadine, decitabine
• Hydroxyurea • Gamma globin gene promoters
• butyrates: arginine butyrate, sodium phenylbutyrate, isobutyramide, 2-methyl-hydroxy-cinnamic acid (ST7)
• Erythropoietin • Combination of drugs
Thalassemia Centre University of Torino
Treatment options for Thalassemia Intermedia
Wait & see
Supportive treatment
Sporadic/occasional Transfusion
Regular Transfusion
Iron chelation therapy
Hydroxyurea (other cytostatic drugs)
Splenectomy
Thalassemia Centre University of Torino
The OPTIMAL CARE study splenectomized patients: 325/584
Complication Parameter RR 95% CI p value
EMH Splenectomy 0.44 0.26–0.73 0.001 Transfusion 0.06 0.03–0.09 < 0.001 Hydroxyurea 0.52 0.30–0.91 0.022
Pulmonary hypertension Age > 35 years 2.59 1.08–6.19 0.032 Splenectomy 4.11 1.99–8.47 < 0.001 Transfusion 0.33 0.18–0.58 < 0.001 Hydroxyurea 0.42 0.20–0.90 0.025 Iron chelation 0.53 0.29–0.95 0.032
Heart failure Transfusion 0.06 0.02–0.17 < 0.001 Thrombosis Age > 35 years 2.60 1.39–4.87 0.003
Hb ≥ 9 g/dL 0.41 0.23–0.71 0.001 Serum ferritin ≥ 1,000 µg/L 1.86 1.09–3.16 0.023 Splenectomy 6.59 3.09–14.05 < 0.001 Transfusion 0.28 0.16–0.48 < 0.001
Cholelithiasis Age > 35 years 2.76 1.56–4.87 < 0.001 Female 1.96 1.18–3.25 0.010 Splenectomy 5.19 2.72–9.90 < 0.001 Transfusion 0.36 0.21–0.62 < 0.001 Iron chelation 0.30 0.18–0.51 < 0.001
Abnormal liver function Serum ferritin ≥ 1,000 µg/L 1.74 1.00–3.02 0.049
Taher AT, et al. Blood. 2010;115:1886-92.
Complication Parameter RR 95% CI p value
Leg ulcers Age > 35 years 2.09 1.05–4.16 0.036 Splenectomy 3.98 1.68–9.39 0.002 Transfusion 0.39 0.20–0.76 0.006 Hydroxyurea 0.10 0.02–0.43 0.002
Hypothyroidism Splenectomy 6.04 2.03–17.92 0.001 Hydroxyurea 0.05 0.01–0.45 0.003
Osteoporosis Age > 35 years 3.51 2.06–5.99 < 0.001 Female 1.97 1.19–3.27 0.009 Splenectomy 4.73 2.72–8.24 < 0.001 Transfusion 3.10 1.64–5.85 < 0.001 Hydroxyurea 0.02 0.01–0.09 < 0.001 Iron chelation 0.40 0.24–0.68 0.001
Hypogonadism Female 2.98 1.79–4.96 < 0.001 Serum ferritin ≥ 1,000 µg/L 2.63 1.59–4.36 < 0.001 Transfusion 16.13 4.85–52.63 < 0.001 Hydroxyurea 4.32 2.49–7.49 < 0.001 Iron chelation 2.51 1.48–4.26 0.001
Splenectomy is independently associated with an increased risk of most disease-related complications
Taher AT, et al. Blood. 2010;115:1886-92.
The OPTIMAL CARE study splenectomized patients: 325/584 (cont.)
Proportion of splenectomy-free patients in 4 birth cohorts in 295 patients with thalassemia major from 5 Italian Centres
Piga A, Am J Hematol, 2011
Treatment options for Thalassemia Intermedia
Wait & see
Supportive treatment
Sporadic/occasional Transfusion
Regular Transfusion
Iron chelation therapy
Hydroxyurea (other cytostatic drugs)
Splenectomy
Stem Cell Transplantation Ethical concerns on risks/benefits ratio Individual cases only or where optimal care is missing
Thalassemia Centre University of Torino
Treatment options for Thalassemia Intermedia
Wait & see
Supportive treatment
Sporadic/occasional Transfusion
Regular Transfusion
Iron chelation therapy
Hydroxyurea (other cytostatic drugs)
Splenectomy
Stem Cell Transplantation
Thalassemia Centre University of Torino
Treatment options for Thalassemia Intermedia
Wait & see
Supportive treatment
Sporadic/occasional Transfusion
Regular Transfusion
Iron chelation therapy
Hydroxyurea (other cytostatic drugs)
Splenectomy
Stem Cell Transplantation
Modulation of erythropoiesis Thalassemia Centre University of Torino
Khandros E, Hematol Oncol Clin N Am, 2010
Overloading of degradation systems leads to accumulation of a-globin in b-thalassemia
Khandros E, Hematol Oncol Clin N Am, 2010
Examples of protein aggregation diseases
Ginzburg Y, Blood, 2011
Normal and Ineffective Erythropoiesis
Treatment options for Thalassemia Intermedia
Wait & see
Supportive treatment
Sporadic/occasional Transfusion
Regular Transfusion
Iron chelation therapy
Hydroxyurea (other cytostatic drugs)
Splenectomy
Stem Cell Transplantation
Modulation of erythropoiesis Thalassemia Centre University of Torino
Gestione del paziente con Talassemia Intermedia
Thalassemia Centre University of Torino
Pediatra ospedaliero
Pediatra di base