Myelodysplastic SyndromesMyelodysplastic Syndromesred cell transfusionred cell transfusion

Pr. David BowenPr. David BowenSt James’s Institute of OncologySt James’s Institute of Oncology

Leeds Teaching HospitalsLeeds Teaching Hospitals

UKUK

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 75 75

ELN MDS RegistryELN MDS Registry 74 (72.5-75)74 (72.5-75)

European LeukemiaNet (ELN) European LeukemiaNet (ELN) low-risk MDS registrylow-risk MDS registry

ProspectiveProspective registry for newly diagnosed IPSS registry 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.

ELN registry: Sorror Score of Co-morbidityELN registry: Sorror Score of Co-morbidity

AUCZ

FR

GE

GR

ND

RO

SPSW

UK

0.5

11.

52

2.5

33.

54

Mea

n S

orro

r S

core

Mean Score 2.4, range (0 to 11)

ELN registry patients at diagnosis: ELN registry patients at diagnosis: Past Medical History & TreatmentPast Medical History & Treatment

Cardiac Disease Cardiac Disease 28%28%Pulmonary Disease Pulmonary Disease 13%13%Diabetes Mellitus Diabetes Mellitus 16%16%Thyroid Disease Thyroid Disease 12%12%

Anti –Hypertensive Drugs Anti –Hypertensive Drugs 37%37%Anti-Platelet Anti-Platelet 16%16%Cholesterol Lowering Cholesterol Lowering 14%14%

French MDS Group practice surveyFrench MDS Group practice surveyone 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 observational Throughout 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

French MDS Group practice surveyFrench MDS Group practice surveyone week cross sectional study (n= 907 patients)one week cross sectional study (n= 907 patients)

Kelaidi et al, Haematologica 2010, 95, 892

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

3.002.00

1.00

Service evaluation of chronically transfused patients at Leeds General Infirmary, 2006-2007

Transfusion totals by year - complete years 1+2

2 3 6 7 8 10 130

10

20

30

40

50

60Yr 1Yr 2

Patient

Red

cel

l u

nit

s /

year

Transfusion burdenTransfusion burden

Red cell transfusion as a Red 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

Complications of red cell Complications of red cell transfusion in MDStransfusion in MDS

Fluit et al, Transfusion 1990, 30, 532

QuestionsQuestions

Optimal transfusion strategy to maximise Optimal transfusion strategy to maximise quality of life? quality of life?

Optimal trigger for transfusion for Optimal trigger for transfusion for individual patients?individual patients?

If, who, when to offer iron chelation?If, who, when to offer iron chelation?

Quality of life in transfused MDS Quality of life in transfused MDS patientspatients

ELN Registry: QoL - EQ-5D Health ScoreELN Registry: QoL - EQ-5D Health Scorebaselinebaseline

AU

CZ

FR

GE GR

ND

RO

SPSW UK

010

2030

4050

6070

8090

100

Mea

n H

ealth

Sta

te

Median Score 70 , range (4 to 100)

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

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

Ferritin concentration influences Ferritin concentration influences overall survivaloverall survival

A. WHO RA, RARS, 5q-

B. WHO RCMD/RS

Transfusion burden influences survivalTransfusion burden influences survival

Malcovati, Haematologica 2006

Elevated serum ferritin as adverse Elevated serum ferritin as adverse factor for transplant outcomefactor for transplant outcome

Armand, P. et al. Blood 2007;109:4586-4588

French MDS group French 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) for at 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 from diagnosis least 6 months (median duration = 36 mo, and median interval from diagnosis to chelation = 23 mo)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 are Arms are balancedbalanced for for – median ferritin concentrationmedian ferritin concentration– causes of deathcauses of death

Arms are Arms are imbalancedimbalanced for age, IPSS. for age, IPSS.

Rose et al, Leuk Res 2010 Feb 1 online

BUT

Prevalence of comorbid conditions among transfused and nontransfused patients with myelodysplastic syndromes (MDS).

Goldberg S L et al. JCO 2010;28:2847-2852

Morbidity and mortality associated Morbidity 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 patientsCardiac failure more common cause of death Cardiac failure more common cause of death in transfused patientsin transfused patients

– Oliva et al, 2005Oliva et al, 2005Cardiac remodelling (left ventricular Cardiac remodelling (left ventricular hypertrophy) hypertrophy)

– more frequent in transfusion-dependent patientsmore frequent in transfusion-dependent patients– Correlated with haemoglobin concentrationCorrelated with haemoglobin concentration

Cardiac pathologyCardiac pathology

Cardiac failure is associated with anaemia in MDS?Cardiac failure is associated with anaemia in MDS?– High cardiac output state High 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 Transfusion practice across Europe varies but many countries transfuse many countries transfuse only when Hb.<9 g/dl only when Hb.<9 g/dl (or lower triggers) (or lower triggers)

20

EPIC trial (-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

MRI T2* studies in MDS suggest MRI 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 units 3/8 patients with > 100 units

transfused had reduced T2* (transfused had reduced T2* (but 5/8 but 5/8 did not!!did not!!))

– 2/3 had clinical cardiac failure2/3 had clinical cardiac failure– No correlation between T2* and No correlation between T2* and

serum ferritinserum ferritin

Deferasirox reduces serum ferritin Deferasirox reduces serum ferritin in MDSin MDS

EPIC studyEPIC study341 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 of Serum ferritin reduced by median of 253 mcg/l (for patients completing 12 253 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

Deferasirox reduces serum ferritin and Deferasirox reduces serum ferritin and labile plasma iron in MDS: labile plasma iron in MDS: US03 studyUS03 study

Year 1Year 1 Year 2Year 2

Number of Number of patientspatients

176176 8383

Median Median deferasirox dosedeferasirox dose

20 mg/kg/day20 mg/kg/day 20 mg/kg/day20 mg/kg/day

Serum ferritin Serum ferritin reductionreduction

3397 to 2501 3397 to 2501 mcg/l (all)mcg/l (all)

3002 to 2069 3002 to 2069 mcg/l in mcg/l in 2 2 years years (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

Argument for chelation:Argument for chelation:

Iron mediated organ toxicity is caused by Iron mediated organ toxicity is caused by toxic free irontoxic free iron

– NoNo direct evidence in MDS patients direct evidence in MDS patients– YesYes, there is evidence for oxidative stress in , there is evidence for oxidative stress in

MDS cells but ?bystander or driver MDS cells but ?bystander or driver

We need to We need to ironiron out some out some misconceptionsmisconceptions

Influence of iron chelation therapy Influence of iron chelation therapy in MDS patientsin MDS patients

Only Only biochemical improvementsbiochemical improvements convincingly demonstrated to dateconvincingly demonstrated to date

No No clinicalclinical benefit yet proven in MDS benefit yet proven in MDS patients (survival, AML transformation)patients (survival, AML transformation)

Practical approachPractical approach

My practice now: My practice now: – chelate younger / fitter patients with RARS, chelate younger / fitter patients with RARS,

5q-, RA 5q-, RA

Use Desferrioxamine (Deferiprone) and Use Desferrioxamine (Deferiprone) and rarely Deferasiroxrarely Deferasirox

Trial opportunityTrial opportunity

TELESTO 2302 studyTELESTO 2302 study– Randomise deferasirox: placebo Randomise 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

Thank you for your attentionThank you for your attention

Questions?Questions?