Transcript Slide 1

Overview of recommended
Blood Transfusion Therapy
in Thalassaemia Major
Professor John Porter
Red Cell Disorders Unit
University College London Hospitals and UCL
[email protected]
Outline
• Goals of transfusion
• Basic requirements
–
–
–
–
Blood products for transfusion
Blood storage
Donor selection and sample testing
Compatibility testing
• Adverse reactions
– Alloimunisation and other adverse reactions
– Minimising infection and non-infection risks
– Future approaches to reducing infection risk
• Recommended transfusion regime
– Optimise
• Oxygen carriage
• Supression of IE
– Minimise - Iron loading
Goals of transfusion
• Maintenance of red cell viability and function
during storage, to ensure sufficient transport of
oxygen
• Use of donor erythrocytes with a normal recovery
and half-life in the recipient
• Achievement of appropriate haemoglobin level
– To minimise effects of anaemia and ineffective
erythropiesis while minimising iron overload
• Avoidance of adverse reactions, including
transmission of infectious agents.
Outline
• Goals of transfusion
• Basic requirements
–
–
–
–
Blood products for transfusion
Blood storage
Donor selection and sample testing
Compatibility testing
• Adverse reactions
– Alloimunisation and other adverse reactions
– Minimising infection and non-infection risks
– Future approaches to reducing infection risk
• Recommended transfusion regime
– Optimise
• Oxygen carriage
• Supression of IE
– Minimise - Iron loading
Blood Products for Transfusion
•
Leuco-reduced packed red cells recommended
• reduction of leucocytes to 5 X 106
• critical threshold for eliminating adverse reactions attributed to contaminating white cells
and for preventing platelet alloimmunisation [Sprogoe-Jakobsen 1995]
•
Methods for leucoreduction include:
– Pre-storage filtration of whole blood
• carried out with an in-line filter within eight hours after blood collection.
• the delay in filtration may allow some phagocytosis of bacteria (e.g. Yersinia enterocolitica)
[Buchholz 1992].
• high efficiency filtration , consistently low residual leucocytes in the processed RBC
• high red cell recovery
• ‘Packed’ red cells are obtained by centrifugation of the leucoreduced whole blood
– Pre-transfusion, laboratory filtration:
• Packed RBC prepared from donor whole blood then filtered prior to release from blood bank
– Bedside filtration:
• packed red cell unit is filtered at the bedside.
• may not allow optimal quality control
Blood products for special patient populations
• Washed red cells
– may be beneficial for repeated severe allergic transfusion reactions.
– Saline washing removes plasma proteins in the donor product that are the
target for antibodies in the recipient.
– Other clinical states that may require washed red cell products include
immunoglobulin A (IgA) deficiency, in which the recipient’s preformed
antibody to IgA may result in an anaphylactic reaction.
– Washing usually does not result in adequate leucocyte reduction and
therefore should be used in conjunction with filtration.
• Frozen red cells
– used to maintain a supply of rare donor units for certain patients who have
unusual red cell antibodies of who are missing common red cell antigens.
– The Council of Europe is promoting an international network of rare blood
donor units
• Neocyte or young red cell transfusion
– may modestly reduce blood requirements. However, patients are exposed to a
higher number of donors
Storage of donor red cell units
• Nutrient additives AS-1 & AS-3 has permitted storage of red
cells for up to 42 days
• Post-transfusion recovery is 73-83% after maximal storage.
• High levels of ATP are maintained up to the 28th day of storage
• 2,3-DPG levels and P50 values may not be fully maintained.
• Little is known about the red cell half-life in the recipient after
prolonged storage of donor blood.
• Decreased recovery and a shortened half-life may increase
transfusion requirements and the rate of iron loading.
• So …….. the current recommended practice is to use red cells
stored in additive solutions for <2 weeks.
Are the guidleines about age of transfused red
cells in line with the evidence?
• Effectiveness and survival of RBC
– Neocyte transfusion reduces blood requirement in Thal Major
– Effect of storage on RBC function and survival
• Safety
– Increased risk of alloimunisation ? (hendrickson)
– Increased bacterial infection risk in stored blood? (Hogman,
1999)(McDonald, 1996)
– Increased toxic iron formation and inflammation (hod)
– Indirect evidence about morbidity and mortality for major operations
Dzik, W. (2008). "Fresh blood for everyone?.
Almac, E. and C. Ince (2007). "The impact of storage on red cell function in blood transfusion." Best practice & research. Clinical
anaesthesiology 21(2): 195-208.
By how much does the transfusion
of young red cells (neocytes) reduce
blood transfusion requirement in Thal Major?
•
Marcus, R. E., B. Wonke, et al. (1985). "A prospective trial of young red cells in 48 patients
with transfusion-dependent thalassaemia." British journal of haematology 60(1): 153-159.
A minor but statistically significant decrease in blood consumption was observed
in the group receiving YRBC.
•
Berdoukas, V. A., Y. L. Kwan, et al. (1986). "A study on the value of red cell exchange
transfusion in transfusion dependent anaemias." Clinical and laboratory haematology
8(3): 209-220. Using RC Ex, red cell transfusion requirement was reduced by 30%,
reducing the iron load, and the transfusion interval was increased by 43%.
•
Collins, A. F., C. Goncalves-Dias, et al. (1994). "Comparison of a transfusion preparation of
newly formed red cells and standard washed red cell transfusions in patients with
homozygous beta-thalassemia." Transfusion 34(6): 517-520. Significant extension of
transfusion interval in 16 patients receiving neocyte transfusions (38.7 +/- 34
days; vs 32.9 +/- 2.5 days). Mean reduction in transfused iron of 15 percent/y
per patient. Substantial increases in donor exposure and in component
preparation costs.
Effects of storage on RBC function
• Morphology, Deformability, and Viability
– Depletion of ATP
– Sodium Potassium Pump
– Vesicle formation
– Loss of CD47
– Recovery of RBC
• Depletion of 2,3-DPG on O2 delivery
• Vasodilatory Capacity
1. Almac,. & Ince (2007) Best practice & Res. Clin anaesth 21(2): 195-208
Morphology, Deformability,
and Viability on storage
• In vivo natural ageing
– RBC lose area, volume, Hb through vesiculation of 50–200 nm particles [29].
• 10–14% of membrane area is lost during reticulocyte maturation
• 16–17% during the remaining lifespan [30, 31].
– PS/Annexin V found on 30–70% of the microvesicles
– 50% are coated with Ig with prompt removal by Kupffer cells
• On Storage
– Micro-vesiculation occurs in particular of the younger cells [37],
– Echinocytes form because of ATP depletion, initially reversible [38]
– Loss of CD47
• a 50-kDa surface transmembrane glycoprotein reduces by 10–65% [41, 42].
• when expression falls < 50%, RBCs susceptible to phagocytosis [41, 43].
Effect of storage on
RBC survival after transfusion
• RBC 20–30% are non-viable, removed from the circulation
within a few h
– If survive 24 h, normal lifespan, irrespective of storage duration
• Luten, et al. (2008). Transfusion 48(7): 1478-1485
– 24h post-transfusion RBC recovery
• higher after short storage (0-10d)
• than long storage (25-35d)
– RBC, survival of remaining cells are similar
.
Effect of blood storage age
on anaemia in thalassaemia patients
• Difference in pre-transfusion Hb
when using fresh blood vs standard issue blood ?
– 9 adult patients, 2 x 6 month periods
• 2009 (period 1) – standard issue Mean 18 days old
• 2010 (period 2)- ‘fresh’ blood (<14days old) mean 9.5d
– Mean pre-transfusion Hb higher by (0.5g/dl) in period 2
– Transfusion interval and number of units not different
Priddee, et al. (2011) Transfusion medicine 21(6): 417-420.
Depletion of 2,3-DPG
– After 14d storage 2,3-DPG virtually depleted
– Left shifter O2 dissociation- poor O2 delivery
– 1hour after transfusion,
• 25–30% of 2,3-DPG was[15]
• after 24 h recovery it is 50%,
• full restoration may take up to 3 days [16]
– Animal studies suggest that levels are not key to
O2 delivery however
Vasodilatory Capacity
of stored blood
•
•
•
•
Blood flow in microcirculation is regulated by NO
NO is produced by endothelial cells
RBC act as sink for NO
In RBC low O2 is sensed by Hb & NO is released rapidly causing
vasodilatation
• INOBA hypothesis for stored blood
release from damaged RBC scavenges NO
– inappropriate vasoconstriction occurs
– leading to reduced blood flow and insufficient O(2) delivery to
end organs
– Hb
Roback, . (2011). ASH Education Program 2011: 475-479.
Safety of stored RBC
Storage of RBC and iron
• Ozment, Biochimica et biophysica acta 1790(7), 694-701. (2009)
• Progressive release of iron from RBC associated
with storage time
• suggests that morbidity following acute
transfusion, like that seen in chronic
transfusion, may be due in part to elevated
levels of NTBI.
Safety of stored RBC
Storage of RBC and iron
• Hod et al, Blood 2010,118, 4284-92
– a murine RBC storage and transfusion model
– transfusion of stored RBCs, or washed stored RBCs
but not fresh RBC or supernatant
•
•
•
•
•
•
increase (NTBI)
produces acute tissue iron deposition
initiates inflammation.
synergizes with subclinical endotoxinemia
producing clinically overt signs and symptoms.
increased plasma NTBI also enhances bacterial growth
in vitro.
Safety of stored blood
Complications in patients
receiving cardiac intervention
• Age of RBC storage (< or > 14d) associated with outcome after
cardiac surgery (prospective randomised, n= 6,002)1
– Significant difference in: hospital mortality, intubation period, renal failure , sepsis
• Age of RBC storage (< or > 14d) is not associated with outcome after
cardiac surgery (retrospective, n=1153) 2
– No difference in; early mortality, postoperative ventilation , renal failure, pulmonary
and infectious complications, length of intensive care stay, and postoperative
ventilation time
• Higher mortality after percutaneous coronary intervention in
patients given older RBC (>28d) (HR 2.49) 3
1.
2.
3.
Koch, C. G., L. Li, et al. (2008). NEJM 358(12): 1229-1239.
McKenny, M., T. Ryan, et al. (2011) British journal of anaesthesia 106(5): 643-649.
Robinson & Jesnsen AHJ, 2010
Safety in other conditions
old vs fresh blood
• Storage RBC age and 1y mortality
– all transfused Leiden patients retrospective over 5y
– < or > 17 days storage- no difference
– 2-fold increase < 10d vs >24d. Worse with fresh ! (Middleberg,
Transfusion medicine 2012)
• Reduction of myocardial infarct size with fresh blood Hu, H., A. Xenocostas, et
al. (2012). Critical care medicine 40(3): 740-74
• Blood storage duration and cancer recurrence after prostatectomy Cata, et
al. (2011) Mayo Clinic Proc. 86(2): 120-127
• Deep vein thrombosis. Spinella,, et al. (2009) Critical care 13(5): R151
• No difference in pulmonary effects, or coagulation <5d vs ‘standard issue’
(randomised, n=50) Cornet, et al. (2010). Transfusion medicine 20(4)
• No effect on outcome of stem cell transplantation. Kekre, et al. (2011).
Transfusion 51(11): 2488-2494
Conclusions about blood storage
and age in Thal Major
• Young cell decrease transfusion requirement
• A proportion of stored cells are destroyed
within 24h after transfusion
• Older stored red cells may increased may have
small effect on transfusion requirement in TM
• Conflicting data on survival in transfused nonthalassaemics, may relate to volume of blood
transfused in different studies
• Safety unlikely to be an issue <14 days old
with ≤4 units transfed
Compatibility Testing
•
Before embarking on transfusion therapy
– patients should have extended red cell antigen typing
– at least C, c, E, e, and Kell
•
Blood selection
– transfused with ABO and Rh(D) compatible blood.
– Some clinicians recommend the use of blood that is also matched for at least the C, E
and Kell antigens in order to avoid alloimmunisation against these antigens.
– Some centres use even more extended antigen matching.
•
Before each transfusion
–
•
•
it is necessary to perform a full crossmatch and screen for new antibodies
If new antibodies appear, they must be identified so that blood missing the
corresponding antigen(s) can be used
A complete record of
– antigen typing,
– red cell antibodies and transfusion reactions
– should be readily available if the patient is transfused at a different centre.
•
Transfusion of blood from first-degree relatives should be avoided because of the
risk of developing antibodies that might adversely affect the outcome of a later
bone marrow transplant
Adverse reactions
•
•
•
•
•
Acute haemolytic reactions
Delayed transfusion reactions
Autoimmune haemolytic anaemia
Non-haemolytic febrile transfusion reactions
Allergic reactions
• Transfusion-related acute lung injury (TRALI)
• Graft versus host disease (GVHD)
Alloimunisation
• Development of one or more specific red cell
antibodies (alloimmunisation) is a common
complication of chronic transfusion therapy [Spanos
1990].
• Important to monitor patients carefully for the
development of new antibodies
• Eliminate donors with the corresponding antigens.
• Anti-E, anti-C and anti-Kell alloantibodies are most
common.
• 5-10% of patients present with alloantibodies against
rare erythrocyte antigens or with warm or cold
antibodies of unidentified specificity.
Red Cell Allominisation and
autoimmunisation in thalassaemia
• Alloantibodies
– 14 /64 thalassaemia patients (22%) became alloimmunized
– Mis- matched RBC phenotype between the donor population and Asian recipients
for K, c, S, and Fy accounting for 38% of alloantibodies in Asian patients
– Splenectomised - higher alloimmunization than non-splenectomised (36% vs 12.8% P= 0 .06)
• Auto- antibodies (Coomb’s +ve)
– 16 of the 64 ( 25% )
– Causing severe hemolytic anemia in 3 of 16 patients.
– Of these 16, 11 antibodies were typed immu- noglobulin G [IgG], and 5 were typed IgM.
– Autoimmunization associated with alloimmunization (44% ) and splenectomy ( 56 %)
• Prevention
– More effective if phenotypic matching for Rh and Kell
– Vs phenotypically matched for the standard ABO-D system
- alloimunisation - 2.8%
- alloimunisation -33%; P = .0005
Singer et al (Blood. 2000; 96:3369-3373)
Red Blood Cell Allo- and Autoantibodies
in the Thalassemia Clinical Research Network
•
Overall Rates
–
–
–
–
•
Of 502 regularly transfused TM
Alloimmunization were reported 104 - (21%)
Autoantibodies were reported in 46 - (9.2%)
Allo + autoantibodies in 26 (5.2%)
Date of Initiation of transfusion
– Alloantobodies
• before1990 - 27% (mean age 25.8 +/- 8.4 yrs )
• after 1990 - 12.5% (p<.001) (mean age 9.3 +/- 6.8 yrs)
– Autoantobodies
•
•
•
Splenectomy
–
Alloantibodies greater in spelectomised patients post 1990 cohort
•
•
•
•
Splenectomized
14/49 (29%) of subjects who started transfusion after 1990,
Nonsplenectomized
12/159 (7.6%) in subjects (p<.001)
No differences in the pre -1990 cohort,
Race
–
•
before 1990 32/285 (11.2%)
after 1990 - 13/208 (6.3%) (p=.08)
Rates of alloimmunization did not differ among races after controlling for age.
Centre effects
–
Rates of alloimmunization between the cohorts varied among treatment centers, possibly related to
varying procedures for phenotypic antigen matching of RBCs.
M. J. Cunningham1, Eric A. Macklin et al Blood 2005 106: Abstract 1890
Adverse reactions
Transmission of infectious agents
• Including viruses, bacteria and parasites, are a
major risk in blood transfusion.
• New problems continue to emerge, such as the
new variant of Creutzfeldt-Jakob Disease and
West Nile virus.
• Continued transmission of hepatitis B, hepatitis C
and HIV underscore the importance of voluntary
blood donations, careful donor screening,
thorough donor testing, and, in the case of
hepatitis B, immunisation.
Minimising infection risk
Donor Selection & Product screening
• Blood should be obtained from carefully selected
healthy voluntary donors who have undergone
extensive questioning and laboratory screening for:
• Hepatitis B, hepatitis C, HIV, syphilis and other
infectious diseases.
• Specific strategies for donor selection and product
screening will be influenced by the prevalence of
infectious agents in the donor population.
(See TIF Blood Kit)
Adverse reactions
Minimising infection risk
Future strategies
• Pre-Treatment of blood product
• Use of donor independent blood products
Pathogen reduction
of blood components
Approaches
plasma
platelets
RBC
• Methylene blue
+
• Riboflavin light treatment (mirasol) +
+^
• Nucleic Acid targeting (s303) Intercept +^
+^
• Solvent detergent treatment
-
?+
(+)*
-
•Neoantigen formation
•^ce mark EU
+^
Production of red cells from ES cells or from
somatic stem cells?
• Human erythropoiesis - a complex multistep process
involving the differentiation of early erythroid
progenitors to mature erythrocytes
• Human Embryonic Stem Cells (HES)
– 2 recent papers show that viable mature functional
enucleated RBCs can be produced in vitro from ES cells in
numbers - suitable for up-scaling
– Large recent investment by research bodies to develop
these techniques
• HLA-haplotype banking and iPS cells?
– Induced pluripotent stem cells (iPS) from human somatic
stem cells such as skin fibroblasts recently reported
Lu et al Blood. 2008; 112(12): 4475–4484.
Nature Biotchnology 26 (7) 2008
Biologic properties and enucleation of red
blood cells from human embryonic stem cells
•
•
•
•
Feasible to differentiate and to mature human
embryonic stem cells (hESCs) into functional
oxygen-carrying erythrocytes on a large scale
(1010-1011 cells/6-well plate hESCs).
Oxygen equilibrium curves of the hESCderived cells are comparable with normal red
blood cells and respond to changes in pH and
2,3-diphosphoglyerate.
Cells mainly expressed fetal and embryonic
globins, but they also possessed the capacity
to express the adult β-globin chain on further
maturation in vitro.
.
• Cells
underwent maturation events- progressive
decrease in size, increase in glycophorin A , and
chromatin and nuclear condensation.
• Process resulted in extrusion of the pycnotic
nuclei (> 60% of the cells) generating RBCs
approximately 6 - 8 μm.
Lu et al Blood. 2008 December 1; 112(12): 4475–4484.
Outline
• Goals of transfusion
• Basic requirements
–
–
–
–
Blood products for transfusion
Blood storage
Donor selection and sample testing
Compatibility testing
• Adverse reactions
– Alloimunisation and other adverse reactions
– Minimising infection and non-infection risks
– Future approaches to reducing infection risk
• Recommended transfusion regime in TM
– Optimise
• Oxygen carriage
• Supression of IE
– Minimise - Iron loading
Standard Transfusion Regimen for
Thalassaemia Major
• Regular blood transfusions administered every 2-5 weeks
• Maintain the pre-transfusion Hb > 9-10.5g/dl
• Rationale
–
–
–
–
promotes normal growth
allows normal physical activities
adequately suppresses bone marrow activity in most patients
minimises transfusional iron accumulation [Cazzola 1995,1997]
• Modifications
– A higher target 11-12 g/dl may be appropriate for patients with heart
disease or other medical conditions and for those patients who do not
achieve adequate suppression of bone marrow activity at the lower
haemoglobin level.
– Although shorter intervals between transfusions may reduce overall
blood requirements, the choice of interval must take into account
other factors such as the patient’s work or school schedule
Relationship between transfusion regimen and
suppression of erythropoiesis
•
•
52 patients with thalassaemia major whose
mean pre-transfusion haemoglobin levels
ranged from 8.6 to 10*9g/dl
Multiple regression analysis showed that
serum transferrin receptor was the
parameter more closely related to mean
pretransfusion haemoglobin (r = -0.77, P <
0.001)
Pretransfusion Hb 10-11g/dl- 1-2x normal
•
Pretransfusion Hb 9-10 g/dl- 1-4x normal
•
Pretransfusion Hb 8-9 g/dl- 2-6 x normal
•
{Cazzola, 1995 #906}
•
When to start ?
• Should be based on a definitive diagnosis of severe thalassaemia
• Diagnosis should take into account the molecular defect, the
severity of anaemia on repeated measurement
• The level of ineffective erythropoiesis, and clinical criteria such as
failure to thrive or bone changes
• Regular transfusion therapy for severe thalassaemia usually
occurs in the first two years of life
• Some patients with milder forms of thalassaemia who only need
sporadic transfusions in the first two decades of life may later
need regular transfusions because of a falling haemoglobin level
or the development of serious complications
Proportion of lifetime on transfusion (%)
by disease and region
1,744 patients with a variety of transfusion-dependent anaemias
across 23 countries, 3 geographic regions
Thal Intermedia
% of patients
Thal Major
% Receiving
% Not receiving
Aplastic Anaemia
Sickle Cell Disease
% of patients
MDS
Viprakasit et al, Blood Transfusion 2012
Guidelines for choosing how much blood
to transfuse
Thalassaemia International Federation Guidelines
The post-transfusion Hb
• Should not be > 14-15 g/dl
• Regular measurement of the post-transfusion
haemoglobin level is unnecessary
• Occasional determinations allow assessment of
the rate of fall in the haemoglobin level between
transfusions and may be useful in evaluating the
effects of changes in the transfusion regimen, the
degree of hypersplenism, or unexplained changes
in response to transfusion
Hemoglobin Level and Blood
Requirements?
• Evidence that maintenance of higher hemoglobin levels does
not require more blood
• 166 splenectomized and non-splenectomized patients,
transfusion requirements remained constant at mean
transfusion Hb 10-14 g/dL (equivalent to pre-transfusion
hemoglobin levels of approximately 8 to 12 g/dL) (Gabutti 1980)
• 392 patients from three Italian centers confirmed the earlier
findings and concluded that the maintenance of higher
hemoglobin levels in transfusion programs for TM did not
require a higher blood requirement (Gabutti 1982).
• Additional supportive evidence came from a study of
“supertransfusion” where maintenance of pre-transfusion
hematocrits of 27% and 35% required similar amounts of
blood (Propper Blood 1980)
Hemoglobin Level and Blood
Requirements ?
Evidence that maintenance of higher hemoglobin
levels does require more blood
– transfusion requirements of 14 French patients
were directly proportional to mean Hb and nearly
doubled between 9.6 and 13.4 g/dL (Brunengo 1986 )
– 3468 patients in Greece and Italy, transfusion
requirements proportional to mean Hb (Rebulla 1991)
– Only one study was the annual transfusion
requirement measured repeatedly in the same
patients under two different transfusion regimens
(Cazzola 1997)
Effect of target Hb on transfusion (Tfn)
requirements in thalassaemia
Years
Pre-Tfn Hb Tfn given Ferritin
(g/dl)
mean ±S
1981-86
11.3
1987-92
9.4 ± 0.4
± 0.5
(ml/kg/y)
mean ±SD
(µg/L)
median
137± 26
2280
104 ± 23
1004
Blood requirements
iron accumulation and chelation therapy
• Although it is self evident that the greater the
blood transfusion, the greater the iron
accumulation rate and the greater the need
for chelation- this has not been studied until
recently
• Recent studies show that taking into account
the transfusion rate is important:
– To decide an initial chelation dose
– To identify potential ‘non-responders’
Iron accumulation
• A careful record of
transfused blood should be
maintained for each patient.
• Volume or weight of the
administered units
• The haematocrit of the units
or the average haematocrit
of units with similar
anticoagulant-preservative
solutions,
• the patient’s weight.
Thalassaemia International Federation Guidelines
Iron loading from transfusion
• 200mg iron in 1 blood unit (from 420ml of donor)
– 0.47mg iron/ml of whole blood
– 1.08mg iron/ml of ‘pure’ red cells
• In Thal Major (spelenctomised) if mean Hb 12g/dl
–
–
=
–
–
–
300mls blood/kg body wt per annum
More if not splenectomised
average 0.4 mg iron / kg body wt/ day from transfusion
Add 1-4 mg/day from gut absorption
In practice wide range 0.3 to 0.7 mg/kg/day
4 to 10 g of iron per year
Porter JB. Br J Haematol. 2001;115:239-252.
Andrews NC. N Engl J Med. 1999;341:1986-1995
Cohen, A. R. et al. Blood 2008;111:583-587
Highly variable iron excretion is required
to balance transfusional iron loading
in Thalassaemia Major
• Iron accumulation from transfusion
in TM (n = 586)
• 233mls/kg/y blood (if Hct 0.6)
• about 40 units/year for a 70 kg person
• 0.4 ± 0.11 mg/kg/day (mean) of iron
• < 0.3mg /kg day
19% of patients
• 0.3-0.5 mg/kg/day
61%
• > 0.5 mg/kg/day
20%
Cohen,Glimm and Porter. Blood 2008;111:583-7
Deferoxamine dose required for
iron balance given s.c. x5/week
100%
Initial DFO dose (mg/kg/day)
< 25
25–< 35
 50
35–< 50
Increase
0%
Decrease
100%
< 0.3
Decrease in LIC,
67
17
76
> 0.5
0.3–0.5
Iron intake (mg/kg/day)
100
33
43
75
86
17
52
89
% of patients
Cohen AR, et al. Blood. 2008;111:583-7.
Change in LIC by deferasirox dose and
ongoing transfusion burden
Deferasirox dose (mg/kg/day)
5
10
20
30
100
Increase (%)
0
Decrease (%)
< 0.3
0.3–0.5
> 0.5
Iron intake (mg/kg/day)
Decrease LIC (% patients) 0
Phase III: Study 107
29
75
96
9
14
55
83
0
0
47
82
Cohen AR, et al. Blood. 2008;111:583-7.
Dosing to balance iron transfusional
rate
Studies 107 and 108
Mean total body iron excretion
± SD (mg Fe/kg/day)
0.8
Deferasirox
Deferoxamine
0.7
0.6
0.5
Average transfusion iron intake
thalassaemia
0.4
0.3
Average transfusion iron intake SCD
0.2
0.1
Actual doses (mg/kg/day)
0
0
5
10
15
20
25
30
Deferasirox
0
10
20
30
40
50
60
Deferoxamine (5 days/week)
Cohen AR, et al. Blood. 2008;111:583-7.
Conclusions
• Clear Guidelines available for minimising risks
from alloiminisation, other transfusion reactions,
infection risks
• Future developments may reduce infection risks
• Optimal Hb still debated- may vary with patient
population
• Large variability in iron content of a ‘unit’ –
important to understand because impacts on
response to chelation therapy