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Assoc Prof Antonis Kattamis Division of Hematology-Oncology, Head First Department of Pediatrics, University of Athens, Greece

Assoc Prof Antonis Kattamis

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Assoc Prof Antonis Kattamis Division of Hematology-Oncology, Head First Department of Pediatrics, University of Athens, Greece. Goals in Chelation Therapy. Progression of Iron Overload. Newly-diagnosed Chelation-naïve Patients with Transfusion-dependent Anemias N=9. - PowerPoint PPT Presentation

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Page 1: Assoc Prof   Antonis Kattamis

● Assoc Prof Antonis Kattamis Division of Hematology-Oncology, Head First Department of Pediatrics, University of Athens, Greece

Page 2: Assoc Prof   Antonis Kattamis

Goals in Chelation Therapy

Page 3: Assoc Prof   Antonis Kattamis

0 20 40 60 80 100 120 1400

2

4

6

8

10

12

14

Transferrin Saturation (%)

Num

ber o

f tra

nsfu

sions

Progression of Iron OverloadNewly-diagnosed Chelation-naïve Patients with Transfusion-dependent Anemias N=9

Delaporta et al; Blood Suppl 2013

0 2 4 6 8 10 12 140

200

400

600

800

1000

1200

1400

1600

1800

Number of transfusions

Ferr

itiin

(ng/

ml)

Page 4: Assoc Prof   Antonis Kattamis

MRI in young patients <10 y.o

Berdoukas V et al, Amer J Hematol; in press 2013

LIVER IRON CONCENTRATION vs AGE

Page 5: Assoc Prof   Antonis Kattamis

Cardiac iron in β-thalassaemia major

Cardiac T2* is negatively correlated with transfusion duration in patients with β-thalassaemia major

Plot of first cardiac T2* as a function of age in 77 patients from Cagliari and Los AngelesCircles indicate patients with normal cardiac function (LVEF 56%) and squares indicate left-ventricular dysfunction

0

10

20

30

40

50

60

0 2 4 6 8 10 12 14 16 18 20

Car

diac

T2*

(ms)

Age (years)

Cagliari CH Los Angeles

Circles LVEF 56%Squares LVEF < 56%

Wood JC, et al. Haematologica. 2008;93:917-20.CH = Children’s Hospital.

Page 6: Assoc Prof   Antonis Kattamis

MRI in young patients <10 y.o

Berdoukas V et al, Amer J Hematol; in press 2013

CARDIAC IRON (R2*) vs AGE

Page 7: Assoc Prof   Antonis Kattamis

Cardiac T2*

Αu W et al; Hemoglobin 2013 in press

Car

diac

MR

I – T

2* (m

s)

Age (years)

Page 8: Assoc Prof   Antonis Kattamis

Cardiac T2* in 23 Transfusion-Dependent patients

Fernandes JL, et al, Haematologica 94(12); 1776, 2009

Page 9: Assoc Prof   Antonis Kattamis

MRI in young patients <10 y.o

Berdoukas V et al, Amer J Hematol; in press 2013

PANCREAS IRON (R2*) vs AGE

Page 10: Assoc Prof   Antonis Kattamis

Noetzli LJ et al. Am J Hematol 2012;87:167–171;

Correlation between pituitary and pancreas / cardiac iron load

r2= 0.49, p<0.0005 r2= 0.52, p<0.0005

Iron Loading Parallels in between Endocrine Glands and Heart

Page 11: Assoc Prof   Antonis Kattamis

Iron Loading Parallels in Different Organs

Αu W et al; Hemoglobin 2013 in press

Page 12: Assoc Prof   Antonis Kattamis

Goals in Chelation Therapy

Page 13: Assoc Prof   Antonis Kattamis

Kattamis C, 2004 unpublished data

hypogo

nadism

short s

tature

IGGT

diabetes

hypopara

thyroidism

hypothyro

idismNorm

al05

1015202530354045

4231 30

5 5 5

27

305 patients 12-25 years

Sequelae of Iron Overload:Prevalence of Endocrinopathies

Page 14: Assoc Prof   Antonis Kattamis

Vogiatzi MG, et al; British Journal of Haematology, 146, 546–556,2009

Height versus calendar age () and bone age ( )

femalemale

Page 15: Assoc Prof   Antonis Kattamis

Vogiatzi MG, et al; British Journal of Haematology, 146, 546–556,2009

Weight versus calendar age () and bone age ( )

femalemale

Page 16: Assoc Prof   Antonis Kattamis

Chatterjee R et al: Ann. N.Y. Acad. Sci. 1202 (2010) 100–114

<10 yrs

11-12yrs

<16 yrs

<18 yrs

Ant Pituitary Mass

Sequelae of Iron Overload:H-P-G dysfunction

Page 17: Assoc Prof   Antonis Kattamis

Noetzli LJ et al. Am J Hematol 2012;87:155–160;

Iron load and Volume of Anterior Pituitary

Pituitary iron overload develops as early as 4 years

Page 18: Assoc Prof   Antonis Kattamis

Goals in Chelation Therapy

Page 19: Assoc Prof   Antonis Kattamis

• Established long-term efficacy • Prevention of endocrine/cardiac

disturbances is suboptimal• Unpleasant, cumbersome treatment

-Needs parental education -May be perceived as punishment by the child

• Introducing a more difficult (parenteral) treatment may later improve adherence with an oral therapy

Mednick LM et al. Pediatr Blood Cancer 2010;55:603–605

Desferrioxamine (DFO) – Good Old Friend

Page 20: Assoc Prof   Antonis Kattamis

DFO – Good Old Friend

Manageable toxicityRisks of over-chelation• Risks of starting too early

-effects on growth-effects on bones, especially < 3 y.o.1,2

• Risks at low iron loads-effects on growth: patients had mean ferritin of 1,300 µg/L3

-otoxicity: with serum ferritin < 2,000 µg/L or when ratio dose/ferritin too high5

1. Olivieri NF, et al. Am J Pediatr Hematol Oncol. 1992;14:48-56. 2. Brill PW, et al. Am.J.Roentgenol. 1991;156:561-5. 3. Piga A, et al. Eur J Haematol . 1998;40:380-1.

4. Olivieri NF, et al. N Engl J Med. 1986;314:869-73. 5. Porter JB, et al. Br J Haematol. 1989;73:403-9.

Page 21: Assoc Prof   Antonis Kattamis

Many young patients have been using deferiprone either as monotherapy or combination therapy with DFO

Aydinok Y et al , 1999; Ha S-Y et al., 2006; Daar S & Pathare AV, 2006; El-Beshlawy A et al, 2008;

Deferiprone in pediatric patients

Page 22: Assoc Prof   Antonis Kattamis

Deferiprone in pediatric patients

Elalfy M et al. J Pediatr Hematol Oncol 2010;32:601–605

Ferriprox oral solution 6-month prospective study in 100 children, mean age 5.1 years Dose 50-100mg/kg/day:3

Serum ferritin levels were reduced from 2532 ± 1463 ng/mL at baseline to 2176 ± 1144 ng/mL after treatment (P<0.0005). Changes differ according to previous chelation treament

Page 23: Assoc Prof   Antonis Kattamis

Deferiprone oral solution in pediatric patients

Elalfy M et al. J Pediatr Hematol Oncol 2010;32:601–605

02468

101214

11 12

46

2

Observed Side Effects (%)

16

AN

C (x

109 /L

)

Non-splenectomized Splenectomized

Time (months)0 3 62 51 4

141210

86420

Mean absolute neutrophil count over time:Non-splenectomized patients had lowest counts

Page 24: Assoc Prof   Antonis Kattamis

Chelation in Pediatric Patients

Amal El-Beshlawy et al. Ann Hematol (2008) 87:545–550* calculated based on LIC changes

Mean age 11 (5-20) 10.8 (5-26) 13.1 (5.5-24) yrs

Iron excretion * 0.45±0.26 0.38±0.23 0.18±0.10 mg/kg/d

Combination therapy (DFO+DFP) have been studied in few small series (in some studies mixed adult/pediatric)

Results showed enhanced efficacy and no additional safety issues

Page 25: Assoc Prof   Antonis Kattamis

1-5 years old: 61 6-11 years old: 8112-15 years old: 80

ApoPharma Pooled Clinical Studies on Ferriprox

16-17 years old: 5118 years old: 369

Kindly provided by F. Tricta, 2012

Page 26: Assoc Prof   Antonis Kattamis

Adverse Drug Reactions during Ferriprox therapy in Pooled Clinical Studies Occurring in 5% of Pts

Kindly provided by F. Tricta, 2012

Neutropenia

Abd. Pain Nausea Vomiting ALT increase

Arhtralgia0

2

4

6

8

10

12

14

16

18

20

12

2

0

7

16

12

4

9 9

45

8

667

18

12

7

111-5 yrs N:616-11 yrs N:8112-15 yrs N:80>16yrs N:420

Page 27: Assoc Prof   Antonis Kattamis

Deferasirox is effective in children as young as 2 years old

DFO, all doses (n = 145)

* vs baseline

Deferasirox, all doses (n = 154)

Age (years)

LIC

-14

-12

-10

-8

-6

-4

-2

0

Cha

nge

in L

IC (m

g Fe

/g d

w)

Age (years)

*P = 0.385

2– < 6 2– < 6

*P < 0.001

6–11 6–11

*P = 0.024

12–15 12–15

Serum ferritin

-2000

-1500

-1000

-500

0

500

1000

1500

Cha

nge

in s

erum

fe

rriti

n (μ

g/L)

Study 107Kattamis C et al. Presented at ASH 2005 [Blood 2005;106(11):abst 2692]

Page 28: Assoc Prof   Antonis Kattamis

Change in serum ferritin levels in pediatric patients with β-thalassemia on treatment with

deferasirox over 4.7 years

Studies 107 and 108Piga A et al. Presented at ASH 2008 [Blood 2008;112(11):abst 3883]

-1000

-800

-600

-400

-200

0

200

BL 3 6 9 12 15 18 21 24 30 33 36 39 42 45 48 51 54

Time (months)

Med

ian

chan

ge in

ser

um fe

rriti

n (n

g/m

L)

27

Dose adjustments allowed from this point

0

5

10

15

20

25

30

35

40

Mean deferasirox dose (m

g/kg/day)

–947

Deferasirox dose (mg/kg/day)Serum ferritin (ng/mL)

Page 29: Assoc Prof   Antonis Kattamis

0.7

AEs decrease in frequency over long term deferasirox treatment in pediatric patients

*Includes abdominal pain, abdominal pain upper and lower

Piga A et al. Presented at ASH 2008 [Blood 2008;112(11):abst 3883]

Year 1 (n=168) Year 2 (n=152) Year 3 (n=137) Year 4 (n=128) Year 5 (n=122)

0.70.80.70

5

10

Abdominal pain* Vomiting Nausea Rash

Freq

uenc

y (%

)

3.6

1.6

3.03.9

1.6

3.63.1

5.4

1.8 2.2

0.7

2.5

7.5

Page 30: Assoc Prof   Antonis Kattamis

• Reversible creatinine increase similar to adults • Renal tubular toxicity (Fanconi syndrome reported)

Creatinine clearance remains stable over long term deferasirox treatment in pediatric patients

Cappellini MD et al. Blood 2011;118:884–893; Rheault MN et al. Pediatr Blood Cancer 2011;56:674–676.

Time (months)

Cre

atin

ine

clea

ranc

e (m

L/m

in)

400

200

0

300

100

BL 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48 51 54 57 60

Core Extension

ULN = upper limit of normal

37 (6.7%) patients with a normal serum creatinine at baseline had 2 consecutive values > 33% and > ULN

Page 31: Assoc Prof   Antonis Kattamis

Concerns with Renal Toxicity

Dubourg L, et al; Pediatr Nephrol (2012) 27:2115–2122

Parameter Baseline (N=10) After DFX (N=10) P

iGFR (ml/min per 1.73m2) 125 ± 15 (103-155) 99 ± 13 (6-124) 0.005

eGFR (ml/min per 1.73m2) 149 ± 33 (95-216) 124 ± 35 (72-180) 0.01

Pcr (μmol/L) 36 ± 9 (25-57) 47 ± 18 (31-85) 0.008

Ca/Ucr (mmol/mmol) 0.4 ± 0.2 (0.1–0.7) 0.8 ± 0.4 (0.3–1.6) 0.03

Magnesemia(mmol/L) 0.83 ± 0.09 (0.67–0.95) 0.94 ± 0.09 (0.83–1.09) 0.005

Plasma uric acid (μmol/L) 251 ± 52 (176-358) 187 ± 73 (96-336) 0.007

Uric acid clearance (ml/min per 1.73m2) 11.1± 3.8 (8.4-20.2) 20.4 ± 11.6 (10.1-49.4) 0.007

Fractional excretion of uric acid (%) 9.2 ± 3.8 (5.8-18.1) 20.4 ± 10.1 (10.6-44.0) 0.005

Page 32: Assoc Prof   Antonis Kattamis

Treatment Allocation in Patients <18 years old

Group 1 Group 2 Group 30.00%

10.00%

20.00%

30.00%

40.00%

50.00%

60.00%

70.00%

80.00%

90.00%

100.00%96.49%

55.32%

3.57%3.50%10.64%

21.42%

0.00%

21.27%

67.85%

0.00%

12.76%7.14%

DFO DFP

2001 2006 2011

% o

f Pat

ient

s

Kattamis et al, ESPHI 2011

1998 20080.00%

10.00%20.00%30.00%40.00%50.00%60.00%70.00%80.00%90.00%

100.00%100.00%

34.40%

0.00%

19.70%

0.00%8.70%

0.00%

36.00%

DFO DFP

Elalfy MS et al; Hematol Oncol Stem Cell Ther 2010; 3(4)-174-8

Page 33: Assoc Prof   Antonis Kattamis

Summary

• Iron overload and toxicity develop early• Timely initiation of chelation therapy• Choose iron chelator judiciously and adjust therapy accordingly

– Growing / Developing body– Events may affect the rest of his/her life– Make treatment less painful

• Desferioxamine is effective but cumbersome a low therapeutic index and especially in young patients

• Deferasirox is effective, but close follow up of renal function necessary

• Data on deferiprone in pediatric patients parallel data on adults• DEEP project underway

Page 34: Assoc Prof   Antonis Kattamis

شكراΕυχαριστώ Thank you