PROF. ALAN COHEN

Serve on the DSMB for clinical trials for ApoPharma.

Consultant to Novartis

Scientific Advisor for Roche

Disclosures

• No one can discuss beta thalassemia in 20 minutes.

• I will address current status in (1) transfusion therapy, (2) assessing iron overload and (3) managing chelation therapy.

A DIFFICULT TASK

Sisyphys (1548-49) by Titian

• Optimal transfusion practices

• Assessment of iron overload

• Iron chelators

OUTLINE

Cazzola M, et al. Haematologica. 1997;37:135-40.Wolman IJ. Ann NY Acad Sci. 1964;119:736-47.

Transfusion programs in β-thalassemia major

Hypertransfusion (Hb > 9-10

g/dL) to relieve anemia and

decrease ineffective

erythropoiesis

Improved growth

Less organomegaly

Fewer fractures

Less facial deformity

Less impairment of

normal activity

• Old rule: if at all possible, see if you can get by without transfusion

• New rule: unless the disease is very mild or there is a major concernabout blood safety or availability, offer transfusion. The burden of proof is now on the withholding of transfusion

• New rule: Choose a pre-transfusion hemoglobin level (usually 9-10.5) based on the patient’s quality of life and suppression of ineffective

erythropoiesis

1. Taher AT, et al. Blood. 2010;115:1886-92.

A change in transfusion strategy for thalassemia

“Although current recommendations suggest initiating transfusion therapy after complications have manifested, it may be worthwhile considering earlier initiation as a

preventive approach.”1

• Confirmed diagnosis of severe anemia1

• Laboratory criteria1

• Hb < 7 g/dL on 2 occasions, > 2 weeks apart (excluding all other contributory causes, such as infections)

OR

• Laboratory and clinical criteria,1 including Hb > 7 g/dL with• facial changes• poor growth• impairment of activity• fractures• severe EMH

• All guidelines recommend that in addition to anemia, clinical symptoms and complications should be carefully monitored to determine the need for regular transfusions2

1. Trompeter S, Cohen A. In: Cappellini MD, et al. Guidelines for the management of transfusion dependent thalassaemia (TDT). 3rd ed. Nicosia, Cyprus: Thalassaemia International Federation; 2014. Available from: http://www.resonancehealth.com/images/files/clinician-information/patient-management-guidelines/TIF%20Guidelines

%20for%20the%20Management%20of%20Transfusion%20Dependent%20Thalassaemia.pdf. 2. Musallam KM, et al. Acta Haematol. 2013;130:64-73.

Whom to transfuse

Iron parameters and circulating non–transferrin-bound iron levels increase after transfusions of older RBCs in healthy volunteers.

©2011 by American Society of Hematology

Hod EA et al, Blood 2011

• Optimal transfusion practices• better understanding of the optimal hemoglobin level

• better understanding of storage effects on blood requirements

• pathogen inactivation

• blood substitutes

WHAT IS LEFT TO DO?

• Optimal transfusion practices

• Assessment of iron overload

• Iron chelators

OUTLINE

IRON BALANCE

15–30 mg/day

Desquamation

Blood loss

Stool loss

1–2 mg/day

1–2 mg/day

Transfusion

Diet

Urinary loss

Serum ferritin (SF)

– SF levels inconsistently reflect liver iron concentration (LIC)and poorly predict cardiac iron concentration1,2

– ferritin levels underestimate iron load in non-transfusedpatients

Cardiac and liver MRI3,4

– assessments of liver iron and cardiac iron by T2* and R2 arecalibrated and reproducible

– however, LIC may be a poor predictor of cardiac ironconcentration

KEY POINTS IN MONITORING

IRON OVERLOAD

1. Brittenham GM, et al. N Engl J Med. 1982;307:1671-5.

2. Karam LB, et al. Pediatr Blood Cancer. 2008;50:62-5.

3. St Pierre TG, et al. Blood. 2005;105:855-61.

4. Anderson LJ, et al. Eur Heart J. 2001;22:2171-9

• Assessment is not needed to decide to begin chelation therapy inyoung children. Just determine the cumulative RBC load and beginafter 10-20 transfusions.

• Assessment is needed to monitor organ iron function and managechelation therapy. Begin MRI measurements of liver and cardiac iron at

5-10 years of age.

When to assess for iron overload

Liver R2 images and distributions

Timothy G. St. Pierre et al. Blood 2005;105:855-861©2005 by American Society of Hematology

Kirk P, et al. J Cardiovasc Magn Reson. 2009;11 Suppl 1:O2.

Cardiac T2* predicts cardiac failure in β-thalassaemia major

> 10 ms0

0.10

0.20

0.30

0.40

0.50

0.60

0 30 60 90 120 150 180 210 240 270 300 330 360

Follow-up time (days)

Pro

po

rtio

n o

f p

atie

nts

wit

hh

ear

t fa

ilure

< 6 ms

6–8 ms

8–10 ms

Kaplan–Meier curve showing the proportion of patients who developed overt cardiac failure over a 12-month period according to their baseline cardiac T2* value if no

changes were made to their chelation regimen

World map showing the distribution of the prevalence of severe myocardial iron loading at first CMR scan.

John-Paul Carpenter et al. Haematologica 2013;98:1368-1374

©2013 by Ferrata Storti Foundation

• Assessment of iron overload• dissemination of available technology

WHAT IS LEFT TO DO?

• Optimal transfusion practices

• Assessment of iron overload

• Iron chelators

OUTLINE

Property Deferoxamine Deferiprone Deferasirox

Usual Dose

For TDT

25 – 50 mg/kg/day 75 – 99 mg/kg/day 20 – 40

mg/kg/day

14 – 28

mg/kg/day

Route SC or IV Oral tablet or oral

solution

Dispersible

tablet

Film-coated

tablet or

sprinkles

Dosing frequency Over 8 to 24 hours 3 times daily Once daily

Adverse Effects Local reactions

Audiologic

Ophthalmologic

Bone abnormalities

Pulmonary disease

Gastrointestinal

Neutropenia

Agranulocytosis

Arthralgia

Hepatic

Gastrointestinal

Hepatic

Renal

Rash

Availability Licensed worldwide

1st line agent

Licensed in Europe,

U.S. as 2nd line

Licensed in

Europe- 6y+

(2 - 5y as 2nd line)

U.S.- 2y+

Challenges Adherence with

parenteral

Weekly blood count

monitoring

GI side effects may limit

optimal dosing

Properties of Iron Chelators

Adapted from Kwiatkowski, Hematology, 2011

Iron locationDeferoxamine

(Desferal)

Deferiprone

(Ferriprox)

Deferasirox

(Exjade, Jadenu)

Liver +++ ++ +++

Heart ++* +++ ++

Endocrine + ++ +

Efficacy of Chelators:

Organ-Specific Iron Removal

*Enhanced with higher dose, continuous infusion

• When LIC is very elevated, consider a regimen containing DFX or DFO

• When cardiac T2* is low, consider a regimen containing DFP

• When cardiac dysfunction present, include intensive DFO

• For endocrinopathies, consider a regimen with DFP

• Organ-specific iron loading (cardiac, liver, endocrine)

• Ongoing transfusional iron intake (Cohen, Blood 2008;111:583)

• Higher iron intake requires higher chelator dosing

• If acceptable iron burden, dose chelator to balance ongoing iron intake

• Adherence (Trachtenberg, Am J Hem, 2011;86:433; Piga, Haematologica,

2003;88:489)

• Generally better with oral chelation

• No drug works if patient doesn’t take it

• Adverse effects• Some are dose-related

Adjusting Chelation: Factors to Consider

Improved Chelation RegimensCombination Therapy

• Additive patterns of iron excretion suggest chelation of different pools.

• Adjust ratio of chelators to maximize excretion while minimizing toxicity.

Kattamis et al, 2006

COMBINATION ORAL AND PARENTERALCHELATION THERAPY

DEFEROXAMINE AND

DEFERIPRONE

DEFEROXAMINE AND

DEFERASIROX

Lai et al, 2013

Ferritin

ng/mL

LIC

mg/g dw

Cardiac

T2* (ms)

LVEF

(%)

Baseline 581 ± 346 1.6 ± 1.1 34.1 ± 5.8 61 ± 6

12 –24 mo 103 ± 60 1.0 ± 0.2 36.9 ± 5.6 65 ± 7.6

p-value 0.0001 0.0019 0.0012 0.0014

N = 16; mean age 35 ± 7.5 years

Deferiprone (75 - 100 mg/kg/day)

Deferasirox (20 – 25 mg/kg/day)

• Reversal of cardiac dysfunction

in 2/4 patients

• Improvement in 2h glucose in

2/8 with impaired glucose

tolerance

Farmaki, Blood Cells, Mol, Dis, 2011;47:33

COMBINATION ORAL CHELATION IN THALASSEMIA:

DEFERIPRONE AND DEFERASIROX

Adherence to treatment with different chelation therapies

• Adherence was assessed in 120 patients

• A statistically significant difference was noted among the 3 groups (P<0.001)

Forget their

treatmentAlways adhere

Pa

tie

nts

(%

)

Adherence

Deferoxamine (n=33)

Deferasirox (n=70)

Deferoxamine + deferiprone (n=17)

Goulas V et al. ISRN Hematol 2012;2012:139862.

0

10

20

30

40

50

60

• Iron chelators• Improving adherence

• increasing experience with combination therapy

• resolution of optimal chelation goal

WHAT IS LEFT TO DO?

HAVE WE CHANGED THE

PROGNOSIS IN THALASSEMIA?

Survival by Cohort of Birth (N=977)Su

rviv

al P

rob

abili

ty

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 - 84

85 - 97

P<0.00005

Borgna-Pignatti et al, 2004

Decline in Cardiac Mortality Over 10 Years at Thalassemia Unit Cagliari

Death Rate

(Per 1000

Patient-years)

1998-2000

0

p = 0.012 p = 0.014

8

10

14

12

6

4

2

2001-2003 2004-2006 2007-2009 2010

Modell et al: J Cardiovasc Magn Reson, 2008

Comparison of life expectancy for patients alive at the beginning of 1970, 1980, 1990 and 2000. The calculation shows an average life-expectancy of 17 years in 1970, 27 years in 1980 and 37 years in 1990. Since 2000 over 80% of patients have a life expectancy of more than 40 years. It is still not possible to estimate ultimate life-expectancy, and the prognosis for older patients remains "open-ended".

CHANGING LIFE EXPECTANCY IN THALASSEMIA MAJOR

KAPLAN-MEYER ANALYSIS OF THE SURVIVAL OF 257

PATIENTS WITH TRANSFUSION DEPENDENT THALASSEMIA

V.Gabutti & A.Piga, Acta Haematol 1996; 95:26-36

YEARS

CU

MU

LA

TIV

E P

ER

CE

NT

SU

RV

IVA

L

0

10

20

30

40

50

60

70

80

90

100

0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 38 40

well chelated=149

badly chelated=108