Impact of Co-Morbidities and Treatment on newly diagnosed lower risk MDS patients from the EU MDS Registry

Theo de Witte, Louise de Swart#, Alex Smith, Pierre Fenaux, Raphael Itzykson*, Guillermo Sanz, Eva Hellström-Lindberg, Argyris Symeonidis, Jaroslav Cermak, Ulrich Germing, Reinhard Stauder, Otilia Georgescu, Marius MacKenzie, Luca

Malcovati, Mette Skov Holm, Krzysztof Mądry, Sophie Park, Odile Beyne-Rauzy, Jackie Droste, and David Bowen

#: Poster #3830 Monday 10-12-12

*: Oral #700 Monday 10-12-12

Background of Low-risk MDS

• Elderly population (75 years!)

• Reluctance to complete diagnostic work-up, such as cytogenetics and marrow biopsy/aspirate

• Main problem: cytopenias, especially anemia

• Therapeutic guidelines based on eminence (experts?) rather than evidence

• Lack of prospective interventional studies

• Solution: Longitudinal observational studies linked with translational studies

Study Design EU-MDS Registry I

• Newly diagnosed MDS patients (<3 months after diagnosis): no selection!

• IPSS low- and intermediate-1

• Total 1000 patients in 14 countries, 118 sites

• Primary objective: to analyze the impact of various disease and patient related factors, including co-morbidity and the impact of disease-management on the outcome

Study design EU-MDS Registry II

Secondary objectives

Investigate correlation between:

• Clinical characteristics at inclusion

• Secondary iron overload due to transfusions

• Administered treatment

and

• Overall survival & progression-free survival

• Performance status, quality of life

Number of Patients by Country

0 100 200 300

PLPODNIT

RONDAUGECZ

SWSPGRUKFR

Males Females

• 14 Countries

• 118 Centres

• Recruited:

• Jan 2008-Dec 2010

• Number of days from diagnosis to inclusion: – 42 median (0 to 98)

Age at Diagnosis 20

4060

8010

0A

ge a

t Dia

gnos

is (Y

ears

)

(total) SP FR GR PO UK SW PL DN IT AU RO GE CZ ND

Median age: 74 (19-95)

MDS Classification WHO 2001 MDS Classification Total Female Median Age (years)

N 1000 (100%) 40% 74

RA 176 (18%) 36% 75

RARS 182 (18%) 45% 76

RCMD 358 (36%) 35% 74

RCMD-RS 71 (7%) 37% 76

RAEB-1 116 (12%) 35% 72

RAEB-2 4 (0.4%) 50% 74

MDS-U 31 (3%) 39% 73

Del(5q) 62 (6%) 81% 74

IPSS & Cytogenetics IPSS Score Total

N 1000 (100%)

0 488 (49%)

0.5 312 (31%)

1 135 (14%)

Not Known 65 (7%)

Cytogenetics Total

N 1000 (100%)

Good 777 (78%)

Intermediate 145 (15%)

Poor 13 (1%)

Not Done 65 (7%)

Cause of Death Cause of Death N % Total 198 100 Infection 42 21.2 AML 37 18.7 Cardiovascular 19 9.6 Other 19 9.6 Other Malignancy 13 6.6 Pulmonary 12 6.1 Haemorrhage 10 5.1 Myelodysplastic 5 2.5 Hepatic 4 2.0 Accidental 3 1.5 Renal Failure 2 1.0 Not Known 32 16.2

Outcome

Overall Survival

0.00

0.25

0.50

0.75

1.00

surv

ival

0 1 2 3 4Time - years

Kaplan-Meier survival estimate

Progression Free survival

0.00

0.25

0.50

0.75

1.00

surv

ival

0 1 2 3 4Time - years

Kaplan-Meier survival estimate

Died n=198 Progression to AML/High Risk MDS n=82

Overall Survival

IPSS WPSS

0.00

0.25

0.50

0.75

1.00

surv

ival

0 1 2 3 4Time - years

0 0.51

p<0.0001

Kaplan-Meier survival estimates

0.00

0.25

0.50

0.75

1.00

surv

ival

0 1 2 3 4Time - years

Very Low LowIntermediate High

p<0.0001

Kaplan-Meier survival estimates

Transfusions: Section Completed

Pre-transfusion Hb per Country Country Hb (g/dL)

Austria 8.3

Czech Republic 7.8

France 7.5

Germany 7.5

Greece 7.8

Italy 8.4

Netherlands 8.4

Poland 7.9

Rumania 7.0

Spain & Portugal 8.1

Sweden & Denmark 8.8

UK 8.0

Transfusion Status

Baseline

020

4060

8010

0pe

rcen

t

PO RO GR FR AU IT UK ND GE CZ DN SP SW PL

Yes No

Over Time

0.1

.2.3

Pro

porti

on T

rans

fuse

d

V1 V2 V3 V4 V5 V6 V7

Overall Survival Impact of transfusion dependency

Overall Survival at 18 Months Cox Model

Total Died Overall Survival HR (95% CI) P-value

N 1000 11%

Transfusions:

No 580 4% 1 P<0.0001

Yes 420 19% 4.1 (2.6-6.5)

IPSS score:

0 488 7% 1 P<0.0001

0.5 312 12% 2.4 (1.2-4.7)

1 135 19% 4.1 (1.6-11.0)

WPSS score:

Very low 315 5% 1 P<0.0001

Low 374 12% 2.4 (1.3-4.4)

Intermediate 194 13% 2.2 (0.9-5.3)

High 37 30% 6.5 (1.9-22.0)

Overall Survival with or without progression percentage of blasts

Impact of transfusion dependency

MDS Treatment

Impact of Response to ESA treatment in transfusion naive MDS patients

Time to first post-ESA transfusion for all ESA-treated patients that had received no transfusions prior to ESA treatment stratified by the presence of a Response to ESA treatment.

p=0.052

Iron Chelation

N Percent

Total 74 100

Deferasirox 64 86.49

Deferoxamine 9 12.16

Deferiprone 1 1.35

• Days from Transfusion to start of chelation – 280.4 (6 -1087)

• Mean Ferritin Values – 1829.7 µg/L

Iron Chelation Therapy Planned analyses

• Control-group with:

- Transfusion-dependent patients

- Ferritin >1000

- No iron chelation therapy

• Compare two groups (iron chelation vs. control-group):

- Look at progression-free survival, overall survival at 12/18 months of follow-up

- Compare total units transfused between the two groups at each visit

adjusted for: age at diagnosis, sex, country, WHO Category, cytogenetics, number of cytopenia,% blasts, number of transfusions, ferritin levels (at registration or start of chelation)

Iron Chelation Therapy - Overall Survival at 18 Months by Chelation Status

Nr Median Ferritin Levels

HR (95% CI)

Adjusted HR (95% CI)

Chelation: No Yes

945 55

281

1779

1

2.05 (1.15-3.64)

1

0.36 (0.15-0.88) Mean number of units

Total No Chelation Chelation

5.9 4.6

28.9

- - -

- - -

- - -

Chelation & Transfusion Status (any visit)

No Transfusion / No Chelation Transfusion / No Chelation Transfusion / Chelation No Transfusion / Chelation Transfusion & Ferritin > 1000 No Chelation Chelation

570 375 52 3

134 94 40

345 377

1838 1224

- -

1 4.71 (3.01-7.36)

5.27 (2.71-10.26) -

1 0.75 (0.38-1.51)

1 3.61 (1.96-6.66) 1.47(0.50-4.31)

-

1 0.51 (0.19-1.32)

*

*

Prognostic relevance of the kinetics of worsening of cytopenias in lower-risk

MDS: a study from the European Leukemia Net low risk MDS registry

ASH Annual Meeting, Dec 10th 2012, Atlanta Abstract #700

Raphael Itzykson, Alex Smith, Theo de Witte, Jackie Droste, Reinhard Stauder, Argyris Symeonidis, Eva Hellstrom-Lindberg, Guillermo Sanz, Jaroslav Cermak, Otilia Georgescu, Mette Skov-Holm, Ulrich Germing, Marius MacKenzie, Odile Beyne-Rauzy, Luca Malcovati, David Bowen, and Pierre Fenaux.

Survival influenced by worsening of cytopenias

ELN registry n=1000

Study Cohort n=530

< 3 visits n=316

LEN, G-CSF, HMA or HY n=154

THb TANC TPLT ≥ 3 measurements: n= 508 495 509

Stable or declining (slope ≤0): n= 250 258 301

Median follow-up (months) 21.8 21.8 21.7

Median time to lose… (months) 1 g/dL 1.0 x109/L 50 x109/L

23.5 28.7 26.9

TANC below median: Loss of 1.0 x109/L in < 28.7 months

Equivalent to: Loss of > 0.42 x109/L in 12 months

TPLT below median: Loss of 50 x109/L in < 26.9 months

Equivalent to: Loss of > 22 x109/L in 12 months

120 3624 48

0%20

%40

%10

0%60

%80

%

Time (months)

Ove

rall

Surv

ival

(%)

120 3624 48

0%20

%40

%10

0%60

%80

%Time (months)

Ove

rall

Surv

ival

(%)

TANC TPLT

above median below median

above median below median

HR=5.5 [2.3-13.4] P<10-4 HR=3.3 [1.7-6.4] P<10-4

Sorror Score of Co-morbidity

Mean Score 2.4, range (0 to 11)

AU

CZ

DN

FR

GE

GR

IT

ND

PL

PORO

SP

SW UK

0.5

11.

52

2.5

33.

54

4.5

Mea

n S

orro

r Sco

re

EQ-5D: Completeness of Data (First Visit)

Quality of Life by Transfusion Status

EQ-5D Dimension N (%)

Transfusion No Yes

P-value

Total 861 (100%) 608 (71%) 253 (29%)

Mobility No Problems 63% 44%

Problems 37% 56% P<0.0001

Self-Care No Problems 90% 79%

Problems 10% 21% P<0.0001

Usual activities No Problems 70% 53%

Problems 30% 47% P<0.0001

Pain/Discomfort No Problems 53% 41%

Problems 47% 59% P=0.002

Anxiety/Depression No Problems 62% 54%

Problems 38% 46% P=0.080

Mobility Self-care

EQ-5D Dimensions and Survival

Quality of Life by Transfusion Status

Blue: transfusion independent Red: transfusion dependent (any time)

Conclusions

• Transfusion-dependent patients have a worse overall survival, specially in patients without progression to leukemia

• Responding patients to ESA treatment have a longer transfusion-free period which may translate in a better survival

• Rapid decline of cytopenias predicts shortened survival

• Transfusion dependency is associated with decreased quality of life and a faster decline of quality of life

• The EU-MDS registry contains a unique data base in low risk MDS patients

Biobanking

The steering committee of the EU-MDS Registry agreed ( EHA; June 15th, 2012) :

• To focus our new studies within the ELN EUMDS registry on biobanking.

• To collect DNA prospectively in the patients still alive (>1,000 patients) and to collect retrospectively on the stored material: smears, biopsies (available in 50% of the patients), locally stored DNA samples

• To focus molecular studies on prognostic markers in a limited set of genes (32) with known relevant mutations

• Additional interesting set of genes might be genes involved in epigenetics, iron metabolism and hematopoiesis

• A grant application has been submitted to the 7th Framework Program of the EU (September 2012): 2-step procedure (first stage: outcome 12th December 2012)