Talassemie intermedie: trattamento...Talassemie intermedie: trattamento Antonio Piga Università di Torino Dipartimento di Scienze Cliniche e Biologiche Scuola di Medicina ed Azienda

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


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


Diagnosis




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



Management


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



β Thalassemia Intermedia








Thalassemia Intermedia











• 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 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


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


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




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






• regular follow-up focused on preclinical markers • early treatment with blood transfusion

5. Alternatives to blood transfusion are problematic


Wait & see



Regular Transfusion


Hydroxyurea


• 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


Wait & see



Regular Transfusion


Hydroxyurea (other cytostatic drugs)


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



Wait & see



Regular Transfusion



Splenectomy


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


Wait & see



Regular Transfusion



Splenectomy

Stem Cell Transplantation Ethical concerns on risks/benefits ratio Individual cases only or where optimal care is missing



Wait & see



Regular Transfusion



Splenectomy

Stem Cell Transplantation



Wait & see



Regular Transfusion



Splenectomy


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


Wait & see



Regular Transfusion



Splenectomy


Modulation of erythropoiesis Thalassemia Centre University of Torino

Gestione del paziente con Talassemia Intermedia


Pediatra ospedaliero

Pediatra di base

Documents

Talassemie intermedie: trattamento...Talassemie intermedie: trattamento Antonio Piga Università di Torino Dipartimento di Scienze Cliniche e Biologiche Scuola di Medicina ed Azienda