Caterina Borgna-PignattiUniversity of Ferrara

Italy

Survival of Thalassemiain the 21 century

W.Goethe“Wilhelm Meisters Lehrjahre”

Do you know the land where the lemon tree blooms?

Where shines and smiles an eternal spring under an ever blue sky!!

Rivista di Clinica Pediatrica 26: 620-640, 1928

Adapted from B. Modell and V. Berdoukas, 1984

THALASSEMIA MAJOR - SURVIVAL

Adapted from B. Modell and V. Berdoukas, 1984

THALASSEMIA MAJOR - SURVIVAL

Survival

In 1966 no patient treated at the Thalassemia Center in Ferrara had reached age 13 yrs

• Median survival for patients treated at Cornell Medical Center between 1960-1976 was 17 yrs

Italian Study on Survival

• Study started in 1983• Treatment included transfusion and DFO• BMT, DFP censoredBMT, DFP censored • Follow-up performed in 1999Follow-up performed in 1999 Borgna-Pignatti et al. Haematologica, 2004;89:1187Borgna-Pignatti et al. Haematologica, 2004;89:1187

C. Borgna-Pignatti: University of Ferrara

A. Piga: University of Torino

P. De Stefano: University of Pavia

R. Gamberini : Ospedale Ferrara

G.Forni: Ospedale Galliera, Genova

M.A. Romeo: University of Catania

G.C. DelVecchio:University of Bari

M.D. Cappellini: University of Milano

Statistical analysis

Huaqing Zhao, Avital Cnaan: CHOP Philadelphia

Italian Study on Survival

• Study started in 1983• Treatment included transfusion and DFO• BMT, DFP censored • Follow-up performed in 1999 Borgna-Pignatti et al. Haematologica, 2004;89:1187

DESIGN AND METHODS

• survival after the first decade was studied for 977 patients born since 1960

• survival since birth was studied for 720 patients born after 1970.

We investigated the interactions between • gender, birth cohort,

complications, and ferritin

Results

Better survival demonstrated for 1. patients born in more recent

years (p<0.00005) 2. females (p=0.0003);

68% of pts were alive at age 35yrs.

Survival by Cohort of Birth (N=977)S

urv

ival

Pro

bab

ilit

y

Age (Yr)0 5 10 15 20 25 30

0.00

0.25

0.50

0.75

1.00

60 - 64

65 -69

70 -74

75 -7980 - 8485 -97

P<0.00005

Borgna-Pignatti et al. Haematologica, 2004

Survival by Sex (N=977)

Age (Yr)0 5 10 15 20 25 30

0.00

0.25

0.50

0.75

1.00

Males

Females

P=0.0003

MEAN SERUM FERRITIN DIVIDED BY SEX

MALES 2102 ± 1514FEMALES 2066 ± 1580

n.s.

MEAN SERUM FERRITIN LEVELS DIVIDED BY SEX

MALES Dead 3379 ± 1850

FEMALES Dead 4102 ± 2808

p<0.001

MEAN SERUM FERRITIN LEVELS DIVIDED BY SEX

MALESMALES FEMALESFEMALES pp

HEART FAILURE 2541 ± 1976 3254 ± 2297 = 0,02

HYPOTHYROIDISM 2249 ± 1776 2020 ± 1300 N.S.

DIABETES 2294 ± 1586 2212 ± 1857 N.S.

HYPOGONADISM 2138 ± 1606 2079 ± 1662 N.S.

60,2

6,8

1,8

6,8

4,1

4,1

3,6

3,2

2,7

6,7

50,8

6,6

14,8

3,3

3,3

3,3

8,2

9,7

0 5 10 15 20 25 30 35 40 45 50 55 60 65

Heart Failure

Arrhythmia

Myocardial infarction

Infection

Cirrhosis

Thrombosis

Malignacy

Diabetes

Unknown

Altro

All patients (N=1073)Patients born after 1970 (N=720)

Causes of death for the entire population of patients and for those born after 1970

Accident, Renal Failure, HIV/AIDS, Familial autoimmune disorder, Anorexia, Hemolytic Anemia, Thrombocytopenia.

%

Causes of Death

0

10

20

30

40

50

60

70

Heart Dis Infection BMT Accident Liver

Italy Hong Kong Cyprus

,

Probability of death due to heart disease after age 10 yrsC

um

ula

tive

De

ath

s(%

)

Age(yrs)10 15 20 25 30

0

20

40

60

80

100

85 - 9780 - 84

75 - 79

70 - 74

65 - 69

60 - 64

Li et al, Hong Kong Med J, 2002.

Born <1980

Born 1980-89

HF 7%A: 6%

HEART

8%HCV 85%

LIVER-CIRRHOSIS

HYPOGONADISM55%

11%

THYROID

6%

DIABETES

9%

10%

35%/10%

10%

35%

Borgna-Pignatti et al,2004 Cunningham et al.2004

1672 1672 1680 1662 1696

1077

2197

1951

2472

27432751 2763

0

500

1000

1500

2000

2500

3000

No Yes

P- Value < .0003 .064 .31 .034 .0016 .0011

DeadAlive

Ferritin µg/lPatient N 563 32 565 30 562 33 526 69 331 42 572 23

Cardiac Disease-free Survival Time by Ferritin in 1995 (N=447)Surv

ival Pro

babili

ty

Years since Study Entry0 2 4 6 8 10

0.00

0.25

0.50

0.75

1.00

<1000 mcg/L

1001-2500 mcg/L

>2500 mcg/LP =0 .0043

Heart disease is by far the main cause of death

Several recent studies have found deferiprone to be more effective than deferoxamine in removal of

myocardial iron

Survival without Cardiac Disease in Patients with Thalassemia Major

Treated with DFO (N=43) or DFP (N=44)Piga et al 2003

Survival Without Cardiac Disease During Chelation Therapy with DFO in 97 Patients With Thalassemia Major

Olivieri et al, 1994

“For the full cohort, the estimated survival without cardiac disease was 80 percent after 5 years of chelation therapy, 65 percent after 10 years, and 55 percent after 15 years.”

P=0.008

Using the large Italian databasewe tried to verify the effect of deferiprone on the prevalence

of heart disease

Objective of the study

To evaluate the effects of deferiprone vs deferoxamine in terms of:

1.cardiac event incidence 2.survival

in thalassemia major patients in seven Italian centers

• Natural history study

• Pts born after Jan 1, 1970 who did not die or have cardiac event prior to Jan /31/ 1995

• Last follow-up Dec/31/ 03.

Study Design

Deferoxamine-only group

359 patients treated with DFO before Jan 1995 and during the

entire study period

(3610 person-years)

Deferiprone-switched group

pts treated with DFO at least until Jan 1995 and switched to deferiprone at

some point after Jan 1995

157 pts on deferiprone (750 person-years)

median deferiprone treatment duration 4yr

Baseline Characteristics

Deferoxamine-only

(n = 359)

Deferiprone-switched(n = 157) Variable

P-value

Age at study entry (years) 0.56

Mean (SD) 16.48 (5.94) 17.00 (4.61)

Serum ferritin in 1995 (mcg/L) <0.00

1

Mean (SD) 1461 (1271) 1870 (1543)

Ferritin level in 1995 (mcg/L) (<0.00

1

< 1,000 87 (28%) 19 (14%)

1,000-2,500 164 (51%) 74 (55%)

>2,500 66 (21%) 42(31%)

Cox modeling analysis – time to event analysis

• The number of pts who had a cardiac event was summarized by treatment group by calendar yr

• The risk group for each yr was made by all pts alive and w/o cardiac event that were on one of the drugs on Jan 1 of that yr

• The incidence for each yr was calculated as the % of pts experiencing a cardiac event during that yr from the pts at risk during that yr

Year*

Deferoxamine Deferiprone

Subjects

at Risk

Cardiac Events

Percentage(95%CI)

Subjectsat Risk

Cardiac Events

Percentage(95%CI)**

1995 516 3 0.58 (0.12, 1.69) 0 0 -

1996 444 11 2.48 (1.24, 4.39) 63 0 0 (0, 5.69)

1997 420 4 0.95 (0.26, 2.42) 75 0 0 (0, 4.80)

1998 398 5 1.26 (0.41, 2.91) 93 0 0 (0, 3.85)

1999 396 3 0.76 (0.16, 2.20) 89 0 0 (0, 4.06)

2000 393 4 1.02 (0.28, 2.59) 87 0 0 (0, 4.15)

2001 387 6 1.55 (0.57, 3.34) 89 0 0 (0, 4.06)

2002 374 4 1.07 (0.29, 2.72) 88 0 0 (0, 4.30)

2003 358 12 3.35 (1.74, 5.78) 92 0 0 (0, 3.93)

*Each subjects is included once in each year, based on the treatment received on January 1 of that year.

**One-sided 97.5% confidence interval.

Incidence of cardiac events by calendar year

Distribution of Cardiac Events by Descriptive Treatment Groups

Cardiac EventDFO-only(n = 359)

DFP-switched

(n = 157) P-

value

Death due to cardiac cause

15 00.001

Heart failure 30 0

Arrhythmia 12 0

Two additional analyses

• The odds-ratio of a cardiac event on DFO rather than on deferiprone is estimated > 10.5

• A person-years analysis found the hazard of an event on deferiprone < 1/10 of the hazard of an event on DFO.

Causes of death

Deferoxamine• 14 heart failure• 1 arrhythmias• 1 accident• 1 anorexia• 1 hemolytic

anemia• 1 cirrhosis• 1 infection• 4 unknown

Deferiprone• 1 accident• 1 infection

Side EffectsForty-six (31%) patients d/c deferiprone

• increase in ferritin levels or LIC (21), • arthropathy or arthralgia (10), • neutropenia (8) or agranulocytosis (1), • increased ALT (2),• gastric discomfort (2) • worsening of renal failure (1) • worsening of hepatic insufficiency in a

cirrhotic, HCV positive patient (1).

02,

000

4,00

06,

000

1995 1996 1997 1998 1999 2000 2001 2002 2003

Fe

rriti

n Le

vels

(ng

/mL)

Calendar Year

Deferoxamine Deferiprone

Risk Factors

• Ferritin >2,500 µg/L was associated with a HR of 3.71 as compared to ferritin <2,500 µg per liter (P<0.001)

• Age at entry was a predictive risk factor.– Each increasing year of age was

associated with a HR 1.17 (P<0.001).

Confirming previous data

Males were 2.5 times more likely to have a cardiac

event than females (P=0.009).

Conclusion

Our large series confirms that Deferiprone is more

cardioprotective than DFO

Decreased mortality has been observed also in UK and Cyprus

since 1999

Modell et al, Lancet 2000

Kaplan Meier Survival curves-recent update

Up to 2003

55-64

65-74

75-84

85+

Pre-1955

Age

Up to 2004Kaplan-Meier survival estimates, by cohort

Survival age

0 5 10 15 20 25 30 35 40 45 50 55 60

0.00

0.25

0.50

0.75

1.00

before 1955

1955-1964

1965-1974

1975-1984

after 1984

Up to 1999

55-64

Pre-1955

65-74

Age

75-84

85+

UK

Disposable DFO infusorsDeferiprone alone and in

combination with DFOT2* Cardiac MRINational registerReferral to centres of excellenceActivities of UKTS

Cyprus Thalassaemia Survival Study

539 BTM patients274 birth cohort born after 1974Followed 1980-20056 BMT58 deaths (31 cardiac)12,323 pt years follow-up

Mortality rates over 5 yr time periods

0

2

4

6

8

10

12

<1960 1960-69 1970-79 1980-89 1990-99 2000-2003Year

Mort

ality

per

1000 p

t years

I ron overloaddeaths

Deaths othercauses

0

0.05

0.1

0.15

0.2

0.25

1999 2000 2001 2002 2003 2004 2005

Date

% w

ith c

ombi

natio

n th

erap

y

Combined chelation in Cyprus

450 person years

0 deaths

We have now more sophisticated ways of studying

the heart

MRI T2*MRI T2*Lack of Correlation: Liver and Cardiac IronLack of Correlation: Liver and Cardiac Iron

LiverLiverLiverLiver

12

13

14

15

16

17

18

Baseline 6 months 12 months

Myo

card

ial T

2* (

ms)

Deferiprone

Deferoxamine

p= 0.77

p= 0.040

p= 0.023

Myocardial T2*

65

67

69

71

73

75

Baseline 6 months 12 months

LV

Eje

ctio

n F

ract

ion

(%

)

Deferiprone

Deferoxamine

p= 0.34

p= 0.074

p= 0.0034

Ejection Fraction

Chelation Randomised Controlled TrialChelation Randomised Controlled Trial

Possible explanations1. DFP more efficient in entering the

myocytes, to bind iron and remove it from the cell molecule smaller and more lipophilic than DFO

2. Greater daily drug exposure 3. Suppression of free radical activity generated from

excess iron within the myocyte 4. Better compliance could contribute, but the lack of

change of the mean ferritin levels does not point to improved compliance as the mechanism for cardioprotection.

Correlazione tra morte e fattori di rischio

Conclusion

The available therapy, transfusion & chelation, possibly

tailored for the need of each patient, will increase further the chances of

thalassemia patients for a long life free of complications

Caterina Borgna-PignattiUniversity of Ferrara

Italy

Survival of Thalassemiain the 21 centuryin rich countries

Price for one year of treatment

• 14,000 € per patient.• chelation therapy (57%)• transfusions (36%), • surgical procedures (4%), • laboratory tests (3%).

Therefore

• worldwide, 87% of children born with thal major die untreated,

• at least 60% of those transfused have no access to chelation

therapy

new waves of immigration have increased the Hbpathies where they were previously rare

Need for pan-European collaboration to benefit from experience of others, to share methodologies, and to develop standardized preventive and therapeutic approaches.

. Bernadette Modell

Days

EF

S

0 500 1000 1500 2000 2500

0.0

0.2

0.4

0.6

0.8

1.0

90%

79%

n events

Thalassemia 33 7

Sickle cell disease 11 1

P=0.5

Thalassemia

Sickle cell disease

Sickle cell disease

Related CBT for hemoglobinopathiesEvent free survival according to diagnosis

EUROCORDEUROCORD

30%

35%

40%

45%

50%

55%

60%

apr-0

5

mag

-05

giu-0

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lug-0

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mar

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ract

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0

200

400

600

800

1000

1200

1400

1600

Fer

riti

n

DFO DFO+DFP DFP

T2* = 13ms

T2* = 36ms

T2* = 17ms

EF

Ferritin

T2*,EF,Ferritin

30%

35%

40%

45%

50%

55%

60%

apr-0

5

mag

-05

giu-0

5

lug-0

5

ago-

05

set-0

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n f

ract

ion

0

200

400

600

800

1000

1200

1400

1600

Fer

riti

n

DFO DFO+DFP DFP

T2* = 13ms

T2* = 36ms

T2* = 17ms

EF

Ferritin

T2*,EF,Ferritin

30%

35%

40%

45%

50%

55%

60%

apr-0

5

mag

-05

giu-0

5

lug-0

5

ago-

05

set-0

5ot

t-05

nov-

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gen-

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mar

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Tempo

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ctio

n f

ract

ion

0

200

400

600

800

1000

1200

1400

1600

Fer

riti

n

DFO DFO+DFP DFP

T2* = 13ms

T2* = 36ms

T2* = 17ms

EF

Ferritin

T2*,EF,Ferritin

30%

35%

40%

45%

50%

55%

60%

apr-0

5

mag

-05

giu-0

5

lug-0

5

ago-

05

set-0

5ot

t-05

nov-

05

dic-0

5

gen-

06

feb-

06

mar

-06

apr-0

6

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Tempo

Eie

ctio

n f

ract

ion

0

200

400

600

800

1000

1200

1400

1600

Fer

riti

n

DFO DFO+DFP DFP

T2* = 13ms

T2* = 36ms

T2* = 17ms

EF

Ferritin

T2*,EF,Ferritin

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