Transcript Current Treatment in MDS the Scottish Perspective

Current Treatments in
MDS; the Scottish
Perspective
Dr Dominic Culligan
Aberdeen Royal Infirmary
Age-related Incidence of MDS
70
59
60
(per 100,000)
61
52
50
40
34
30
26
20
16
0
10
9
10
0
0
2
1
2
2
4
1
20- 25- 30- 35- 40- 45- 50- 55- 60- 65- 70- 75- 80- 85- 90- 95-
Age in 5-year blocks
Williamson PJ, et al. Br J Haematol. 1994 Aug;87(4):743-5.
Talk Outline
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
Therapeutic Options

Low Risk MDS

High Risk MDS
The Scottish Perspective

Scottish Medicine Consortium (SMC)
How it works
 What is good & what is bad!

Therapeutic Options

Low Risk MDS –
 Main problem is anaemia

High Risk MDS –
 Main problem is bone marrow failure &
leukaemia
Therapeutic Options

Low Risk MDS
 Supportive care/ blood transfusion /iron Chelation
 Erythropietic stimulating agent (ESA)
 Immunosuppression
 Lenalidomide

High Risk MDS
 Supportive care
 Azacitidine
 Chemotherapy
 Stem cell transplantation
Best supportive care
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Red cell transfusion on demand
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Antibiotics for treatment & prevention
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G-CSF during infection
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Iron chelation therapy
Treatment of Anaemia in MDS
Transfusion
Growth Factors
Symptomatic
anaemia in
low risk MDS
Immunosuppression with
Antithymocyte globulin
Lenalidomide in 5q-
Treatment of Anaemia in MDS
Transfusion
Growth Factors
Symptomatic
anaemia in
low risk MDS
Immunosuppression with
Antithymocyte globulin
Lenalidomide in 5q-
Iron chelation is beneficial on survival in thalassaemia
Survival by Birth Cohort: University College London
Hospitals
1975-97 (n=42) 100%
Survival probability
1.00
1965-74 (n=39)
1955-64 (n=21)
0.75
69%
0.50
0.25
Analysis September 2000
0
0
10
20
30
40
yrs
Age (years)
Thalassaemia Major treated with desferrioxamine only (N=103)
Davis and Porter. Adv Exp Med Biol. 2002;509:91.
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Which patients if any should get iron
chelation?
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IPSS score low or int-1
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Ferritin should be 1000-2000 ng/ml or clinical or
radiological evidence of iron loading at the start
of chelation
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This would often correlate with 20-30 units of
red cells transfused
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Candidates for allograft in whom there is a
significant delay until the procedure
Treatment of Anaemia in MDS
Transfusion
Growth Factors
Symptomatic
anaemia in
low risk MDS
Immunosuppression with
Antithymocyte globulin
Lenalidomide in 5q-
20 Years experience of erythropoietin
+/- G-CSF therapy in MDS

Overall response rate ~20-40%
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Best response group ~ 60-70%
 Refractory anaemia
 Low endogenous EPO level (<500mU/ml)
 Low transfusion requirement (<2u/month)
Prototype model for selecting patients for
treatment with EPO + GCSF
Score
>+1
RA, RARS, RAEB
-1 to +1
< -1
Good response 74%
Intermediate response 23%
Poor response 7%
Serum EPO <100 +2
100-500 +1
>500
Unit/mth < 2
= or >2
-3
+2
-2
Hellstrom et al, BJHaem 2003, 120, 1037-46
The ‘nitty-gritty’ of EPO therapy

Is there a quality of life benefit for EPO
responders?
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Is EPO therapy cost-effective?

Is there a survival advantage for EPO
responders?
Your doctors have still not answered
two major questions in low risk
MDS!
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Is erythropoietin therapy more beneficial than
transfusion?
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Is iron chelation therapy beneficial?:
Our drug companies are trying to
answer these questions!
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Johnson & Johnson – EPOANE3021
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Erythropoietin versus Placebo
Novartis – TELESTO
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Iron chelation (Exjade) versus Placebo
Treatment of Anaemia in MDS
Transfusion
Growth Factors
Symptomatic
anaemia in
low risk MDS
Immunosuppression with
Antithymocyte globulin
Lenalidomide in 5q-
5q- Syndrome
del(5)(q31q33)
5q- Syndrome: Diagnostic findings
Peripheral blood
 Anaemia
 Platelets normal or
increased
Bone marrow
 Megakaryocytes with
hypolobulated nuclei
 < 5% blasts, no Auer rods
 Isolated del(5)(q31)
More common in women
Median age at diagnosis 68yrs
Associated with a favourable prognosis; median survival
>5yrs, AML transformation 8-16%
Phase 2 Study of Lenalidomide MDS
Del 5q (MDS-003)
R
E
G Activation date: 7-15-03
Cohorts
I
10 mg × 21 days
S
10 mg po qd
T
E
R
Wk: 0
4
8
12
16
20
R
E
S
P
O
N
S
E
24
Treatment
until
progression/
relapse
Transfusion Independence Response
Del 5q (MDS-003)
See BD for data
N = 148
Transfusion
Independence
Median time to
response, wk (range)
99 (67%)
4.6 (1 - 49)
Durable Transfusion Independence (ITT)
Del 5q (MDS-003)
Median not yet reached median FU 104 wks
List A et al. N Engl J Med 2006;355:1456-1465
Case1
Exceptional in every
sense of the word!
Clinical presentation
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A 77 year old male retired farmer
2 year history:
Tired
 Lethargic
 Poor sleep pattern
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Known three vessel coronary artery disease
2 months more frequent angina
 Increasing breathlessness
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Laboratory findings
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FBC:
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Hb
WCC
Neuts
Plats
9.1 g/dl;
2.6 x 109/l
1.2 x 109/l
117 x 109/l
MCV 96fl
Myelodysplastic Syndrome (MDS)
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Refractory cytopenia with multilineage dysplasia (WHO)
Follow up visit
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Cytogenetics failed:
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Not keen on repeat bone marrow
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Hb 8.5 g/dl
Management
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Jehovah’s Witness!
Case 1 Question 2
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What would you recommend?
1)
2)
3)
4)
Tell him not to be so daft and have a blood
transfusion?
Tell his wife and daughter (not JWs) to persuade
him to have a blood transfusion?
Treat him with a trial of erythropoietic stimulants
(EPO, Darbopoietin)?
Try something else?
Case 1 Answer 2

What would you recommend?
1)
2)
3)
4)
Tell him not to be so daft and have a blood
transfusion?
Tell his wife and daughter (not JWs) to persuade
him to have a blood transfusion?
Treat him with a trial of erythropoietic stimulants
(EPO, Darbopoietin)? (high predicted response)
Try something else?
Initial therapy
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Erythropoietin 30,000u once per week
x 6wks
Erythropoietin 30,000u once per week
+ G-CSF 105ug three times per week
x 6 weeks
Erythropoetin 60,000u +G-CSF 2 weeks
No response-steady deterioration
March 2009
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Wheelchair- bound
Angina at rest despite maximum medical therapy
Hb 5.7g/dl
Repeat bone marrow:
Gross dysplasia, no increase in blasts
 Karyotype 46XY only
 IPSS intermediate-1

Case 1 Question 3
What would you opt for?
1). Palliative care with no further therapy?
2). Trial of azacitidine if approved?
3). Trial of lenalidomide if approved?
4). Trial of anti-thymocyte globulin (ATG)?
Case 1 Answer 3
What would you opt for?
1). Palliative care with no further therapy?
2). Trial of azacitidine if approved?
3). Trial of lenalidomide if approved?
4). Trial of anti-thymocyte globulin (ATG)?
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Exceptional Circumstances Group
Approved trial of lenalidomide based on
fulfilling local criteria for exceptionality:
 ‘Because
of his religious beliefs he is unable
to receive the standard therapy-blood
transfusion’
Case 1 continued
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22/04/09 started first cycle lenalidomide
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10mg od for 21 days out of 28 days
12/05/09 GP phoned:
Bedridden, home oxygen, not coming to hospital
again, no further treatment
 Most recent Hb 4.3g/dl
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Here is the really exceptional bit!
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22/09/09 FBC from GP!!!
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Hb 13.5 g/dl
WCC 6.6 x 109/l
Neuts 3.8 x 109/l
Platelets 166 x 109/l
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Contacted GP-It is him and repeat FBC same!
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Continued on lenalidomide for two years with normal blood
counts and no symptoms of anaemia
Case 1
What should you display in your MDS clinic?
Therapeutic Options

High Risk MDS – Main problems are bone marrow
failure & leukaemia

Supportive care
Azacitidine
Chemotherapy

Stem cell transplantation
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Azacitidine
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It has been suggested that azacitidine may
switch on important anti-cancer genes
AZA 001:
Study design schematic
Azacitidine 75 mg/m2 daily
for 7 days, every 28 days
Investigator selection
of conventional
care regimen
Randomisation
Conventional care regimen
•Best supportive care only
•Low-dose ARA-C (20 mg/m2 daily
for 14 days every 28-42 days)
•Standard chemotherapy (7 + 3)
AZA-001:
Vidaza is the only licensed drug that has
demonstrated a survival advantage in Int-2 and
High-risk MDS
1.
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Vidaza – increases the median survival to 24.5
months (compared to 15 months with CCR)
providing a 9.4 month benefit
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In a post hoc analysis Vidaza doubled 2-year survival
rate compared with CCR (p<0.001)
Fenaux P, et al. The Lancet Oncology 2009; 10: 200-01
AZA-001:
Setting a new standard in transfusion independence
100
Vidaza
90
% of transfusion
Independent patients
80
CCR
70
33.6% difference
p<0.0001
60
50
40
30
20
45.0
10
11.4
0
1.
2.
3.
Santini V. J Clin Oncol 2008
Fenaux P, et al. The Lancet Oncology 2009; 10: 200-01
Vidaza SmPC December 2008.
Azacitidine (Vidaza)
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Standard of care for high risk MDS patients
who are not candidates for transplantation
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Approved by NICE ( great help of UKMDS
Patient Forum)
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Not approved by SMC
The Scottish Perspective

The Scottish Medicines Consortium
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Statutory body which is part of:
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Quality Improvement Scotland (QIS)
To advice the NHS in Scotland as to the cost
effectiveness of new treatments
SMC vs. NICE

SMC decisions only apply in Scotland
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NICE single drug decisions only apply in
England, Wales and Northern Ireland

NICE multiple treatment assessments apply in
Scotland and replace any existing SMC guidance
The workings of the SMC
New Drug Committee
Drug
Company
Patient Access Scheme
Assessment Group
(PASAG)
Main SMC
Committee
Final Advice Document
Exjade
Azacitidine
What about stem cell
transplantation?
Current transplant activity in MDS
EBMT
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2008:
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1147 allografts for MDS ~ 10% of total
1998-2006
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1333 MDS patients > 50yrs allografted
Considerations for all potential
transplant candidates
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Disease characteristics
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Patient characteristics
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Age
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Co morbidities (other diseases or disabilities)
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Iron status at transplant
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40 yr old female works in our medical illustration department
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First time blood donor
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Failed the screening test
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Subsequent FBC
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Hb 12.1 g/dl
MCV 103 fl
WCC 1.9 X 109/l
Neut 1.2 x 109/l
Plat 258 x 109/l
Blood film: Significant dysplasia
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Bone Marrow
 Hypercellular-confirmed on trephine
 Trilineage dysplasia
 Blasts 1%

Karyotype: 46, XX, der(21)t(1;21)(q11;p11)[6]
46,XX[4]

Diagnosis:
MDS
 Refractory cytopenia with multilineage dysplasia
 Cytogenetic risk group- Standard ??
 IPSS score 0.5 Intermediate 1

What is your plan?
1)
Watch and wait-no plan to transplant
2)
Proceed to transplant now?
3)
Watch and wait-plan to transplant at
progression?
4)
Something else?
Answer 1
What is your plan?
1)
Watch and wait-no plan to transplant
2)
Proceed to transplant now?
3)
Watch and wait-plan to transplant at
progression?
4)
Something else?
Question 2
Would you…
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Proceed to transplant as first line therapy?
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Give one or two cycles of chemotherapy first?
Answer 2
Would you…

Proceed to transplant as first line therapy?

Give one or two cycles of remission induction
therapy prior to transplant?
Question 3
She is exactly 40 yrs old
Would you…
1)
Perform a traditional myeloablative
conditioned transplant?
2)
Perform a Reduced Intensity conditioned
transplant (RIC)?
Answer 3
She is exactly 40 yrs old
Would you…
1)
Perform a traditional myeloablative
conditioned transplant?
2)
Perform a reduced intensity conditioned
transplant (RIC)?
Outcome?!
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RIC allograft 11/05/07
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Alive and well
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Ongoing morphologic and cytogenetic remission

No GVHD and back at work full time

Would it be otherwise given I present it to you!
Thank you for listening!