Current Treatment Options in MDS
Dick Wells MD, DPhil, FRCPC
Director, Crashley Myelodysplastic Syndrome Research Laboratory
Odette Cancer Centre
Tale of Two Patients
Mr. Blue
• Low Hb, WBC, platelets
Ms. Green
• Anaemia only
• >90% chance of
developing leukaemia
within 2 years
• ~10% chance of
developing leukaemia
ever
• Life expectancy about
18 months
• Life expectancy more
than 10 years
They both have MDS, but do they both
have the same disease?
MDS is at least two diseases
• Some patients (“high risk”) have a
severe disease that rapidly evolves into
acute leukaemia
• Others (“low risk”) have a chronic
disease that makes them anaemic
Different situations, different goals
Low Risk MDS
To alleviate anaemia and
to minimize the harm
caused by transfusion
High Risk MDS
To prevent the
development of
leukaemia and to
extend lifespan
Treatment Options for High Risk MDS
-prevent leukaemia, extend lifespan
• Supportive/palliative care
• Allogeneic bone marrow transplantation
– Donor not always available
– High risk, high relapse rate
Is that all there is?
Other options for high risk MDS
Hypomethylating drugs
• Vidaza (Pharmion)
• Dacogen (MGI Pharma)
What they do: “Rehabilitate” bone
marrow cells in MDS by changing their
pattern of gene expression
Hypomethylating drugs:
Clinical trials
• Vidaza and Dacogen beat supportive care
– Major responses in 20-25%
– Responders remained or became transfusion
independent and symptoms improved
– Duration of response <1year
• Delayed time to AML progression or death
• Trend toward improved survival
180
Hb
plt
300
160
250
200
100
150
80
60
100
40
20
Dacogen x 18 cycles
2u PRBC/wk
0
50
0
Platelet count
120
J
A
S
O
N
D
J
F
M
A
M
J
J
A
S
O
N
D
J
F
M
A
M
J
J
A
S
Haemoglobin (g/L)
140
Hypomethylating drugs for MDS
•
•
•
•
Upside
Improve counts
Delay leukaemia
May improve
survival
Improve quality of
life
•
•
•
•
•
Downside
NOT AVAILABLE!
Expensive
Not everyone responds
Temporary responses
Best duration of
treatment unknown
– Forever?
Treatment Options for Low Risk MDS
-alleviate anaemia, reduce transfusion harm
• Transfusion
– 90% of patients
– Iron chelation
• To remove excess iron due to transfusion
• “Growth factors”
– To boost red blood cell production
• Immune suppression
– To protect developing blood cells
Epo and Red Blood Cells
• Red blood cells carry
oxygen
• If not enough oxygen
gets to the kidney, epo is
released
• Epo tells the bone
marrow to make more
red blood cells
Giving extra epo can help boost haemoglobin in MDS
Growth factors for MDS
Upside
• Easy
• Not toxic
• Can get transfusion
independence
•
•
•
•
•
Downside
Expensive
Needles!
Not everyone responds
Temporary responses
No effect on platelets or
WBC
Immune Suppression
• The theory:
– In MDS, as in aplastic anaemia, the
immune system attacks the bone marrow.
Drugs that block the immune system may
help.
• The evidence:
– About 50% of MDS patients respond to this
sort of treatment
06
06
9/
9/
0
10 6
/9
/0
11 6
/9
/0
12 6
/9
/0
6
1/
9/
07
2/
9/
0
3/ 7
9/
07
4/
9/
07
5/
9/
07
6/
9/
07
7/
9/
07
8/
9/
7/
9/
Hb (g/L)
160
ATGAM
Cyclosporine
140
120
100
80
60
Hb
plt
40
20
0
100
90
80
70
60
50
40
30
20
10
0
Platelet count
Response to immune suppression
Immune suppression in MDS
Upside
• Durable responses
• Can improve all
blood counts
Downside
• Expensive
• Very toxic
(especially ATG)
• Not everyone
responds
Is that all there is?
Other options for low risk MDS
Revlimid
• “Cousin” of thalidomide
• Many biological activities
• Early studies: amazingly active in patients
with MDS and chromosome 5 abnormalities
Deletion 5q [del(5q)]
A problem with the long arm…
• Most frequent chromosomal
deletion in MDS patients
– 10-20% (+/- other
abnormalities)
– 5-6% as sole abnormality
• Better-than-average
prognosis
– Low risk of leukaemia
MDS-003 trial
Revlimid in 5q- MDS
• 67% of patients achieved
transfusion independence
67%
Transfusion
Independence
(99/148 patients)
• 90% of patients who
achieved a transfusion
benefit did so by
completion of 3 months of
therapy
• Durable responses (>2 y)
List et al., N Eng J Med, 355, 1456, 2006
331 Jan
28 -Ja -07
-F n-0
8- eb 7
15 Ma - 07
r
19 -Ma -0 7
r
23 -Ma - 07
-M r- 0
5- ar 7
13 Ap - 07
-A r-0
pr 7
1
27 8 -0 7
-A -Ap
3- p r
24 Ma r-0 7
-M y-0
6- ay- 7
15 Jun 07
22 -Ju n-07
-J -0
u
4- n-07
19 Jul 7
25 -Ju l 07
15 -Ju - 07
-A l- 0
ug 7
-0
7
Hb (g/L)
100
40
Start Lenalidomide
120
400
80
Last Transfusion
300
60
Platelets
20
0
200
100
0
Platelet count
140
600
500
Haemoglobin
2M
a
7- y-0
M 7
a
9- y-0
M
14 a y 7
-M -0 7
22 ay
-M - 07
30 ay
-M - 07
14 ay-J 07
18 u n-J 07
un
3- -07
Ju
9- l- 07
J
16 ul- 0
-J 7
23 u l- 0
-J 7
25 u l- 0
- 7
13 Ju l
-A - 07
20 ug
-A -0 7
ug
-0
7
Hb (g/L)
140
40
20
Start Lenalidomide
120
Haemoglobin
100
2.5
80
2
60
1.5
Neutrophils
G-CSF 300 mcg BIW
0
1
0.5
0
Absolute neutrophils
Hb
ANC
3.5
3
“Doc, I’m a new man!”
160
140
Last Transfusion
100
80
60
Haemoglobin
Start Lenalidomide
40
20
8/4/2007
7/4/2007
6/4/2007
5/4/2007
4/4/2007
3/4/2007
2/4/2007
1/4/2007
0
12/4/2006
Hb (g/L)
120
Revlimid in MDS
•
•
•
•
Upside
Amazingly active in 5qMDS
Oral, once daily
Pretty easy to take
Currently available on
SAP; Health Canada
approval around the
end of 2007
Downside
• Lowers WBC and
platelet counts (initially)
• Expensive!
• Restricted to low risk
5q- MDS
Summary:
Algorithms for MDS
1. If 5q-, revlimid
2. If epo<500, try growth
factors
3. Immune suppressive
therapy (ATG and/or
cyclosporine)
1.
2.
3.
4.
If feasible, BMT
Supportive/palliative care
…or clinical trial
… or hypomethylating
drugs