Survival of Thalassemia

in the 21 century

Caterina Borgna-Pignatti
University of Ferrara
Italy
 “Wilhelm Meisters Lehrjahre” Goethe

Do you know the land

where the orange tree blooms?

where shines and smiles like a gift from God

an eternal spring under an ever blue sky!
Do you know the land where the lemon
tree blooms?

Where shines and smiles

an eternal spring under an ever blue sky!!

W.Goethe
“Wilhelm Meisters Lehrjahre”
 “Wilhelm Meisters Lehrjahre” Goethe

Do you know the land where the lemon tree blooms?

The land of golden fruit and red roses,
where the breeze is gentler and the bird lighter,
where in every season the bees forage,
where shines and smiles like a gift from God
an eternal spring under an ever blue sky!
Alas, that I may not follow you
toward that happy land from which Fate drove me.
It is there! It is there! That I wish to live,
to love, to love and to die!
Rivista di Clinica Pediatrica 26: 620-640, 1928
 THALASSEMIA MAJOR - SURVIVAL

Adapted from B. Modell and V. Berdoukas, 1984

Blood transfusion
was the answer
 THALASSEMIA MAJOR - SURVIVAL

Adapted from B. Modell and V. Berdoukas, 1984

 Graph 7 Cumulative Proportion Splenectomy free (Kaplan Meier)

1.0

0.9

0.8
Cumulative Proportion of Splenectomy-free

0.7

0.6

0.5
'90-'99 N=67 (2 SPL)
'80-'89 N=229 (32 SPL)
0.4
'70-'79 N=534 (204 SPL)

0.3 '60-'69 N=62 (57 SPL)

0.2

0.1

0.0
0 5 10 15 20 25 30 35 40 45
Age years
 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 censored
• Follow-up performed in 1999
Borgna-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
2. patients born in more recent
years (p<0.00005)
3. females (p=0.0003);

68% of pts were alive at age 35yrs.

 Survival by Cohort of Birth (N=977)

85 - 97
1.00 80 - 84
75 - 79

70 - 74

0.75
Survival Probability

65 - 69

0.50
60 - 64

0.25 P<0.00005

0.00

0 5 10 15 20 25 30
Age (Yr)
Borgna-Pignatti et al. Haematologica, 2004
 Survival by Sex (N=977)

1.00

Females

0.75
Males

0.50

0.25 P=0.0003

0.00

0 5 10 15 20 25 30
Age (Yr)
MEAN SERUM FERRITIN
DIVIDED BY SEX

MALES 2102 ± 1514n.s.

FEMALES 2066 ± 1580
MEAN SERUM FERRITIN LEVELS
DIVIDED BY SEX

MALES Alive 2022 ± 1458

n.s.

FEMALES Alive 1981 ± 1454

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

MALES FEMALES p
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.
Causes of death for the entire population of patients and for those born after 1970
% 0 5 10 15 20 25 30 35 40 45 50 55 60 65

60,2
Heart Failure
50,8
6,8
Arrhythmia
6,6
1,8 All patients (N=1073)
Myocardial infarction
Patients born after 1970 (N=720)
6,8
Infection
14,8
4,1
Cirrhosis

4,1
Thrombosis
3,3
3,6
Malignacy
3,3
3,2
Diabetes
3,3
2,7
Unknown
8,2
6,7 Accident, Renal Failure, HIV/AIDS, Familial autoimmune
Altro
9,7 disorder, Anorexia, Hemolytic Anemia, Thrombocytopenia.
 Causes of Death
70
Italy Hong Kong Cyprus
60
50

40

30
20
10
0
Heart Dis Infection BMT Accident Liver
 Probability of death due to heart disease after age 10 yrs
100

80
Born <1980 ,
Cumulative Deaths (%)

Born 1980-89

60 60 - 64

40 65 - 69
Li et al, Hong Kong Med J, 2002.

20 70 - 74

75 - 79
85 - 97
0 80 - 84
10 15 20 25 30
Age(yrs)
 THYROID 9%
11%

HEART 10%
A: 6% HF 7%

LIVER-CIRRHOSIS 35%/10%
HCV 85% 8%

DIABETES 10%
6%

HYPOGONADISM
35%
55%

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

 3000
P- Value < .0003 .064 .31 .034 .0016 .0011
2751 2763 2743
2500
2472

2000 2197
Ferritin µg/l 1672 1672 1680 1662 1951 1696

1500

1077
1000
DeadAlive
500

Patient N → 563 32 565 30 562 33 526 69 331 42 572 23

0

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ea
et

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ai

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F

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S
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(u
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No Yes
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H
 Cardiac Disease-free Survival Time by Ferritin in 1995 (N=447)

1.00 1001-2500 mcg/L

<1000 mcg/L
P =0 .0043
>2500 mcg/L
0.75
Survival Probability

0.50

0.25

0.00

0 2 4 6 8 10
Years since Study Entry
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 During Chelation Therapy with DFO
in 97 Patients With Thalassemia Major
Olivieri et al, 1994

P=0.008

Survival without Cardiac Disease

in Patients with Thalassemia Major
Treated with DFO (N=43) or DFP (N=44)
Piga et al 2003

“For the full cohort, the estimated survival without cardiac disease was 80 percent after 5
years
Using the large Italian database
we 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
 Study Design
• 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.

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 Deferiprone-switched
Variable (n = 359) (n = 157) 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) <0.001

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

Ferritin level in 1995 (mcg/L) ( <0.001

< 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
Incidence of cardiac events by calendar year
Deferoxamine Deferiprone
Year* Subjects Cardiac Percentage Subjects Cardiac Percentage
at Risk Events (95%CI) at Risk Events (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.
 Distribution of Cardiac Events by
Descriptive Treatment Groups
DFO-only DFP-switched
Cardiac Event P-value
(n = 359) (n = 157)
Death due to
15 0
cardiac cause 0.001

Heart failure 30 0

12 0
Arrhythmia
 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.
 Kaplan-Meier Survival Curves by Treatment

1.00 Deferiprone-switched

Deferoxamine-alone
Survival Probability

0.75

0.50

0.25
P=.082

0.00

0 2 4 6 8 10
Years since Study Entry
 Causes of death
Deferoxamine Deferiprone
• 14 heart failure • 1 accident
• 1 arrhythmias • 1 infection
• 1 accident
• 1 anorexia
• 1 hemolytic anemia
• 1 cirrhosis
• 1 infection
• 4 unknown
• No cardiac event occurred
while on deferiprone
• The earliest event after end of
DFP and switching back to DFO
happened 1 year and 8 mo after
the switch
 Side Effects
Forty-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).
 6,000
Ferritin Levels (ng/mL)
4,000
2,000
0

1995 1996 1997 1998 1999 2000 2001 2002 2003

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
dell et al, Lancet 2000
Kaplan Meier Survival curves-recent
update

Up to 1999 Up2003
Up to to 2004
Kaplan-Meier survival estimates, by cohort

after 1984
85+
1.00
85+
1975-1984
75-84
75-84
0.75
65-74
1965-1974 65-74
0.50
55-64
1955-1964
55-64

0.25
Pre-1955 Pre-1955

before 1955
0.00
0 5 10 15 20 25 30 35 40 45 50 55 60
Age
Survival age
Age
 UK
Disposable DFO infusors
Deferiprone alone and in combination
with DFO
T2* Cardiac MRI
National register
Referral to centres of excellence
Activities of UKTS
Cyprus Thalassaemia Survival Study

539 BTM patients

274 birth cohort born after 1974
Followed 1980-2005
6 BMT
58 deaths (31 cardiac)
12,323 pt years follow-up
 Mortality rates over 5 yr time periods
12
Iron overload
deaths
Mortality per 1000 pt years

10 Deaths other
causes

0
<1960 1960-69 1970-79 1980-89 1990-99 2000-2003
Year
 Combined chelation in Cyprus
0.25

0.2
% with combination therapy

0.15 450 person years

0.1 0 deaths

0.05

0
1999 2000 2001 2002 2003 2004 2005
Date
We have now more sophisticated
ways of studying the heart
 MRI T2*
Lack of Correlation: Liver and Cardiac Iron

Liver Liver
helation Randomised Controlled Tria

Myocardial T2* Ejection Fraction

18 75
Deferiprone Deferiprone
Deferoxamine Deferoxamine
17 73

LV Ejection Fraction (%)

Myocardial T2* (ms)

16
71

15
69
14

67
13
p= p= p= p= p= p=
12 0.77 0.040 0.023 65 0.34 0.074 0.0034
Baseline 6 months 12 months Baseline 6 months 12 months
 Possible explanations
1. 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
Survival of Thalassemia
in the 21 century
in rich countries

Caterina Borgna-Pignatti
University of Ferrara
Italy
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
EUROCORD Related CBT for hemoglobinopathies
Event free survival according to diagnosis
1.0 90% Sickle cell disease
0.8

79% Thalassemia
0.6
EFS
0.4

n events
Thalassemia 33 7
0.2

Sickle cell disease 11 1

P=0.5
0.0

0 500 1000 1500 2000 2500 Days

 Eiection fraction

ap

30%
35%
40%
45%
50%
55%
60%
r-
m 05
ag
-0
gi 5
DFO

u-
0
lu 5
g-

T2* = 13ms
ag 05
o-
0
se 5
t -0
ot 5
t -0
no 5
v-
0
di 5
c-
ge 05
n-
0
DFO+DFP

fe 6
b-
m 06

Tempo
ar
T2* = 17ms

-0
ap 6
r-
m 06
ag
-0
gi 6
u-
0
T2*,EF,Ferritin

lu 6
g-
ag 06
o-
0
DFP

se 6
Ferritin

t -0
EF

ot 6
t-0
6
T2* = 36ms

0
200
400
600
800
1000
1200
1400
1600

Ferritin
 Eiection fraction

ap

30%
35%
40%
45%
50%
55%
60%
r-
m 05
ag
-0
gi 5
DFO

u-
0
lu 5
g-

T2* = 13ms
ag 05
o-
0
se 5
t -0
ot 5
t -0
no 5
v-
0
di 5
c-
ge 05
n-
0
DFO+DFP

fe 6
b-
m 06

Tempo
ar
T2* = 17ms

-0
ap 6
r-
m 06
ag
-0
gi 6
u-
0
T2*,EF,Ferritin

lu 6
g-
ag 06
o-
0
DFP

se 6
Ferritin

t -0
EF

ot 6
t-0
6
T2* = 36ms

0
200
400
600
800
1000
1200
1400
1600

Ferritin
 Eiection fraction

ap

30%
35%
40%
45%
50%
55%
60%
r-
m 05
ag
-0
gi 5
DFO

u-
0
lu 5
g-

T2* = 13ms
ag 05
o-
0
se 5
t -0
ot 5
t -0
no 5
v-
0
di 5
c-
ge 05
n-
0
DFO+DFP

fe 6
b-
m 06

Tempo
ar
T2* = 17ms

-0
ap 6
r-
m 06
ag
-0
gi 6
u-
0
T2*,EF,Ferritin

lu 6
g-
ag 06
o-
0
DFP

se 6
Ferritin

t -0
EF

ot 6
t-0
6
T2* = 36ms

0
200
400
600
800
1000
1200
1400
1600

Ferritin
 Eiection fraction

ap

30%
35%
40%
45%
50%
55%
60%
r-
m 05
ag
-0
gi 5
DFO

u-
0
lu 5
g-

T2* = 13ms
ag 05
o-
0
se 5
t -0
ot 5
t -0
no 5
v-
0
di 5
c-
ge 05
n-
0
DFO+DFP

fe 6
b-
m 06

Tempo
ar
T2* = 17ms

-0
ap 6
r-
m 06
ag
-0
gi 6
u-
0
T2*,EF,Ferritin

lu 6
g-
ag 06
o-
0
DFP

se 6
Ferritin

t -0
EF

ot 6
t-0
6
T2* = 36ms

0
200
400
600
800
1000
1200
1400
1600

Ferritin
 Year of Birth

Iron choice of HCV/HBV

overload chelator
Splenectomy BMT status

Heart
Infection Thrombosis HCC
disease

gender
 Deferoxaminee

Deferoxaminee
 Deferoxaminee

Deferoxaminee