Myelodysplastic Syndromes, Red Cell Transfusion Presentation by Pr. David Bowen, St James’s Institute of Oncology, Leeds Teaching Hospitals, UK

1. Myelodysplastic SyndromesMyelodysplastic Syndromes
red cell transfusionred cell transfusion
Pr. David BowenPr. David Bowen
St James’s Institute of OncologySt James’s Institute of Oncology
Leeds Teaching HospitalsLeeds Teaching Hospitals
UKUK

2. MDS - age at diagnosisMDS - age at diagnosis
RegistryRegistry Median age at diagnosis (years)Median age at diagnosis (years)
DusseldorfDusseldorf 69-7369-73
PaviaPavia 65-7165-71
MD AndersonMD Anderson 6666
SW ThamesSW Thames 77 (77-78)77 (77-78)
SEERSEER Mid-late 70sMid-late 70s
≥≥80y – 38%80y – 38%
≥≥70y – 33%70y – 33%
HMRN YorkshireHMRN Yorkshire 7575
ELN MDS RegistryELN MDS Registry 74 (72.5-75)74 (72.5-75)

3. European LeukemiaNet (ELN)European LeukemiaNet (ELN)
low-risk MDS registrylow-risk MDS registry
ProspectiveProspective registry for newly diagnosed IPSSregistry for newly diagnosed IPSS
Low/INT-1Low/INT-1
Recruiting from 11 countries, 107 sitesRecruiting from 11 countries, 107 sites
Data collection at baseline and 6-monthlyData collection at baseline and 6-monthly
– Haematological, MDS therapy (incl. transfusions),Haematological, MDS therapy (incl. transfusions),
concomitant medication, co-morbidity, QoL (EQ-5D),concomitant medication, co-morbidity, QoL (EQ-5D),
serum and urine samples.serum and urine samples.

4. ELN registry: Sorror Score of Co-morbidityELN registry: Sorror Score of Co-morbidity
AU
CZ
FR
GE
GR
ND
RO
SP
SW
UK
0.511.522.533.54
MeanSorrorScore
Mean Score 2.4, range (0 to 11)

5. ELN registry patients at diagnosis:ELN registry patients at diagnosis:
Past Medical History & TreatmentPast Medical History & Treatment
Cardiac DiseaseCardiac Disease 28%28%
Pulmonary DiseasePulmonary Disease 13%13%
Diabetes MellitusDiabetes Mellitus 16%16%
Thyroid DiseaseThyroid Disease 12%12%
Anti –Hypertensive DrugsAnti –Hypertensive Drugs 37%37%
Anti-PlateletAnti-Platelet 16%16%
Cholesterol LoweringCholesterol Lowering 14%14%

6. French MDS Group practice surveyFrench MDS Group practice survey
one week cross sectional study (n= 907 patients)one week cross sectional study (n= 907 patients)
Median age = 74 yearsMedian age = 74 years
Throughout the one week observationalThroughout the one week observational
period:period:
– ~5% patient episodes were in-patient~5% patient episodes were in-patient
admission for transfusionadmission for transfusion
– 31% all episodes were for red cell transfusion31% all episodes were for red cell transfusion
– 61% patients required red cell transfusion61% patients required red cell transfusion
Kelaidi et al, Haematologica 2010, 95, 892

7. French MDS Group practice surveyFrench MDS Group practice survey
one week cross sectional study (n= 907 patients)one week cross sectional study (n= 907 patients)
Kelaidi et al, Haematologica 2010, 95, 892

8. Transfusion frequencyTransfusion frequency
Frequency of transfusion in weeks (n=185)
mean = 2.7
median = 2.0
10.00
8.00
6.00
5.00
4.00
3.00
2.00
1.00
Service evaluation of chronically transfused patients at Leeds General Infirmary, 2006-2007

9. Transfusion totals by year - complete years 1+2
2 3 6 7 8 10 13
0
10
20
30
40
50
60
Yr 1
Yr 2
Patient
Redcellunits/year
Transfusion burdenTransfusion burden

10. Red cell transfusion as aRed cell transfusion as a negative prognostic factornegative prognostic factor::
WHO- based prognostic scoring systemWHO- based prognostic scoring system
Cazzola & Malcovati Hematol/Oncol Clin North Am 2010, 24, 459

11. Complications of red cellComplications of red cell
transfusion in MDStransfusion in MDS
Fluit et al, Transfusion 1990, 30, 532

12. QuestionsQuestions
Optimal transfusion strategy to maximiseOptimal transfusion strategy to maximise
quality of life?quality of life?
Optimal trigger for transfusion forOptimal trigger for transfusion for
individual patients?individual patients?
If, who, when to offer iron chelation?If, who, when to offer iron chelation?

13. Quality of life in transfused MDSQuality of life in transfused MDS
patientspatients

15. ELN Registry: QoL - EQ-5D Health ScoreELN Registry: QoL - EQ-5D Health Score
baselinebaseline
AU
CZ
FR
GE GR
ND
RO
SP
SW UK
0102030405060708090100
MeanHealthState
Median Score 70 , range (4 to 100)

16. Health related quality of life by transfusion dependence /Health related quality of life by transfusion dependence /
independence (EQ-5D)independence (EQ-5D)

17. Iron chelation – if, who, when?Iron chelation – if, who, when?

18. Ferritin concentration influencesFerritin concentration influences
overall survivaloverall survival
A. WHO RA, RARS, 5q-
B. WHO RCMD/RS

19. Transfusion burden influences survivalTransfusion burden influences survival
Malcovati, Haematologica 2006

20. Elevated serum ferritin as adverseElevated serum ferritin as adverse
factor for transplant outcomefactor for transplant outcome
Armand, P. et al. Blood 2007;109:4586-4588

21. French MDS groupFrench MDS group
transfusion / chelation surveytransfusion / chelation survey
18 GFM centres surveyed for transfusion data in 200518 GFM centres surveyed for transfusion data in 2005
– Patients surveyed again in 2007Patients surveyed again in 2007
53/97 patients with IPSS Low/INT-1 received iron chelation therapy (ICT)53/97 patients with IPSS Low/INT-1 received iron chelation therapy (ICT)
for at least 6 months (median duration = 36 mo, and median interval fromfor at least 6 months (median duration = 36 mo, and median interval from
diagnosis to chelation = 23 mo)diagnosis to chelation = 23 mo)
Overall survival from diagnosisOverall survival from diagnosis
– 124 months for chelated patients124 months for chelated patients
– 53 months non-chelated53 months non-chelated
No information re. triggers or barriers for iron chelation (co-morbidity)No information re. triggers or barriers for iron chelation (co-morbidity)
Arms areArms are balancedbalanced forfor
– median ferritin concentrationmedian ferritin concentration
– causes of deathcauses of death
Arms areArms are imbalancedimbalanced for age, IPSS.for age, IPSS.
Rose et al, Leuk Res 2010 Feb 1 online
BUT

22. Prevalence of comorbid conditions among transfused and
nontransfused patients with myelodysplastic syndromes (MDS)
Goldberg S L et al. JCO 2010;28:2847-2852

23. Morbidity and mortality associatedMorbidity and mortality associated
with iron overload in MDS patients?with iron overload in MDS patients?
Cardiac failureCardiac failure
– Malcovati et al, 2005Malcovati et al, 2005
Cause of death in up to 50% low-risk patientsCause of death in up to 50% low-risk patients
Cardiac failure more common cause of deathCardiac failure more common cause of death
in transfused patientsin transfused patients
– Oliva et al, 2005Oliva et al, 2005
Cardiac remodelling (left ventricularCardiac remodelling (left ventricular
hypertrophy)hypertrophy)
– more frequent in transfusion-dependent patientsmore frequent in transfusion-dependent patients
– Correlated with haemoglobin concentrationCorrelated with haemoglobin concentration

24. Cardiac pathologyCardiac pathology
Cardiac failure is associated with anaemia in MDS?Cardiac failure is associated with anaemia in MDS?
– High cardiac output stateHigh cardiac output state
particularly at haemoglobin concentration < 8g/dlparticularly at haemoglobin concentration < 8g/dl
– Stiff vascular bedStiff vascular bed
– ?right heart strain ??pulmonary hypertension?right heart strain ??pulmonary hypertension
– Renal impairment (cardio-renal-anemia syndrome)Renal impairment (cardio-renal-anemia syndrome)
Transfusion practice across Europe varies but manyTransfusion practice across Europe varies but many
countries transfusecountries transfuse only when Hb.<9 g/dl (oronly when Hb.<9 g/dl (or
lower triggers)lower triggers)

25. 20
EPIC trial (β-thal major)
•12 months Deferasirox
•T2* increase from 11.2 ms to 12.9 ms
•No change in LVEF
Pennell et al, Eur H J, 2001, 22, 2171
Mamtani & Kulkarni BJH 2008, 141, 882
•Systematic review and meta-analysis
•Iron chelators reduce myocardial iron content
•No influence on LVEF
Iron chelation therapy and T2* values in thal majorIron chelation therapy and T2* values in thal major

26. MRI T2* studies in MDS suggestMRI T2* studies in MDS suggest
infrequentinfrequent cardiac iron loading:cardiac iron loading:
Ferte et al, ASH 2006Ferte et al, ASH 2006
– 21 MDS patients21 MDS patients
– 3/8 patients with > 100 units3/8 patients with > 100 units
transfused had reduced T2* (transfused had reduced T2* (but 5/8but 5/8
did not!!did not!!))
– 2/3 had clinical cardiac failure2/3 had clinical cardiac failure
– No correlation between T2* andNo correlation between T2* and
serum ferritinserum ferritin

27. Deferasirox reduces serum ferritinDeferasirox reduces serum ferritin
in MDSin MDS
EPIC studyEPIC study
341 low/INT-1 MDS pts341 low/INT-1 MDS pts
12 months DFX: median 19 mg/kg/d12 months DFX: median 19 mg/kg/d
Serum ferritin reduced by median ofSerum ferritin reduced by median of
253 mcg/l (for patients completing 12253 mcg/l (for patients completing 12
months)months)
49% withdrawal (13% drug related)49% withdrawal (13% drug related)
Gattermann et al, Leuk Res 2010 34, 1143Gattermann et al, Leuk Res 2010 34, 1143

28. Deferasirox reduces serum ferritin andDeferasirox reduces serum ferritin and
labile plasma iron in MDS:labile plasma iron in MDS: US03 studyUS03 study
Year 1Year 1 Year 2Year 2
Number ofNumber of
patientspatients
176176 8383
MedianMedian
deferasirox dosedeferasirox dose
20 mg/kg/day20 mg/kg/day 20 mg/kg/day20 mg/kg/day
Serum ferritinSerum ferritin
reductionreduction
3397 to 25013397 to 2501
mcg/l (all)mcg/l (all)
3002 to 20693002 to 2069
mcg/l inmcg/l in 22 yearsyears
(n=50 pts)(n=50 pts)
Withdrawal rateWithdrawal rate 45%45%
(10% drug related)(10% drug related)
42%42%
(~15% drug related)(~15% drug related)
List et al, ASH 2008 & 2009

29. Argument for chelation:Argument for chelation:
Iron mediated organ toxicity is caused byIron mediated organ toxicity is caused by
toxic free irontoxic free iron
– NoNo direct evidence in MDS patientsdirect evidence in MDS patients
– YesYes, there is evidence for oxidative stress in, there is evidence for oxidative stress in
MDS cells but ?bystander or driverMDS cells but ?bystander or driver

30. We need toWe need to ironiron out someout some
misconceptionsmisconceptions

31. Influence of iron chelation therapyInfluence of iron chelation therapy
in MDS patientsin MDS patients
OnlyOnly biochemical improvementsbiochemical improvements
convincingly demonstrated to dateconvincingly demonstrated to date
NoNo clinicalclinical benefit yet proven in MDSbenefit yet proven in MDS
patients (survival, AML transformation)patients (survival, AML transformation)

32. Practical approachPractical approach
My practice now:My practice now:
– chelate younger / fitter patients with RARS,chelate younger / fitter patients with RARS,
5q-, RA5q-, RA
Use Desferrioxamine (Deferiprone) andUse Desferrioxamine (Deferiprone) and
rarely Deferasiroxrarely Deferasirox

33. Trial opportunityTrial opportunity
TELESTO 2302 studyTELESTO 2302 study
– Randomise deferasirox: placeboRandomise deferasirox: placebo
(2:1)(2:1)
– 3-5 year treatment period3-5 year treatment period
– Several UK centresSeveral UK centres
– Open in UKOpen in UK

34. Thank you for your attentionThank you for your attention
Questions?Questions?