1. Current Treatments in MDS; the Scottish Perspective
Dr Dominic Culligan
Aberdeen Royal Infirmary

4. Age-related Incidence of MDS
(per 100,000)
Age in 5-year blocks
Williamson PJ, et al. Br J Haematol Aug;87(4):743-5.

5. Talk Outline Therapeutic Options The Scottish Perspective Low Risk MDS
High Risk MDS
The Scottish Perspective
Scottish Medicine Consortium (SMC)
How it works
What is good & what is bad!

6. Therapeutic Options Low Risk MDS – Main problem is anaemia
High Risk MDS –
Main problem is bone marrow failure & leukaemia

7. 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

8. Best supportive care Red cell transfusion on demand
Antibiotics for treatment & prevention
G-CSF during infection
Iron chelation therapy

9. Treatment of Anaemia in MDS
Transfusion
Growth Factors
Symptomatic anaemia in low risk MDS
Immunosuppression with
Antithymocyte globulin
Lenalidomide in 5q-

10. Treatment of Anaemia in MDS
Transfusion
Growth Factors
Symptomatic anaemia in low risk MDS
Immunosuppression with
Antithymocyte globulin
Lenalidomide in 5q-

12. Iron chelation is beneficial on survival in thalassaemia
Survival by Birth Cohort: University College London Hospitals
100%
(n=42)
1.00
(n=39)
0.75
(n=21)
69%
Survival probability
0.50
Davis and Porter conducted a study of survival probability in 103 patients with beta-thalassemia who were born between 1955 and ,2
These patients were treated with transfusion plus deferoxamine at University College London Hospital.
Survival curves show improvement with advances in care.
Patients born between 1955 and 1964 had a 69% survival rate at age 40 years.
Patients born between 1965 and 1974 had a 78% survival rate at age 35 years.
Patients born after 1974 had a 100% survival rate at the time of analysis.
The overall survival rate among all birth cohorts was 78% at age 40 years.
These survival curves compare favorably with those from the UK Thalassaemia Register.
0.25
Analysis September 2000
yrs 10 20 30 40
Age (years)
Davis and Porter. Adv Exp Med Biol. 2002;509:91.
Thalassaemia Major treated with desferrioxamine only (N=103)
1. Davis BA, Porter JB. Unpublished data
2. Davis BA, Porter JB. Results of long term iron chelation treatment with deferoxamine. Adv Exp Med Biol. 2002;509:

14. Which patients if any should get iron chelation?
IPSS score low or int-1
Ferritin should be ng/ml or clinical or radiological evidence of iron loading at the start of chelation
This would often correlate with units of red cells transfused
Candidates for allograft in whom there is a significant delay until the procedure

15. Treatment of Anaemia in MDS
Transfusion
Growth Factors
Symptomatic anaemia in low risk MDS
Immunosuppression with
Antithymocyte globulin
Lenalidomide in 5q-

16. 20 Years experience of erythropoietin +/- G-CSF therapy in MDS
Overall response rate ~20-40%
Best response group ~ 60-70%
Refractory anaemia
Low endogenous EPO level (<500mU/ml)
Low transfusion requirement (<2u/month)

17. Prototype model for selecting patients for treatment with EPO + GCSF
Score
>+1
Good response 74%
RA, RARS, RAEB
-1 to +1
Intermediate response 23%
< -1
Poor response 7%
Serum EPO <100 +2
>500 -3
Unit/mth < 2 +2
= or >2 -2
Hellstrom et al, BJHaem 2003, 120,

18. The ‘nitty-gritty’ of EPO therapy
Is there a quality of life benefit for EPO responders?
Is EPO therapy cost-effective?
Is there a survival advantage for EPO responders?

19. Your doctors have still not answered two major questions in low risk MDS!
Is erythropoietin therapy more beneficial than transfusion?
Is iron chelation therapy beneficial?:

20. Our drug companies are trying to answer these questions!
Johnson & Johnson – EPOANE3021
Erythropoietin versus Placebo
Novartis – TELESTO
Iron chelation (Exjade) versus Placebo

21. Treatment of Anaemia in MDS
Transfusion
Growth Factors
Symptomatic anaemia in low risk MDS
Immunosuppression with
Antithymocyte globulin
Lenalidomide in 5q-

22. 5q- Syndrome
del(5)(q31q33) 22

23. 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% 23

24. Phase 2 Study of Lenalidomide MDS Del 5q (MDS-003)R E G I S T R E S P O N
Activation date: Cohorts
10 mg × 21 days 10 mg po qd
Treatment until progression/relapse
Wk:

25. Transfusion Independence Response Del 5q (MDS-003)
4.6 ( )
99 (67%)
Median time to response, wk (range)
Transfusion Independence
N = 148
See BD for data

26. 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:

27. Case1 Exceptional in every sense of the word!

28. Clinical presentation
A 77 year old male retired farmer
2 year history:
Tired
Lethargic
Poor sleep pattern
Known three vessel coronary artery disease
2 months more frequent angina
Increasing breathlessness

29. Laboratory findings FBC: Hb 9.1 g/dl; MCV 96fl WCC 2.6 x 109/l
Neuts 1.2 x 109/l
Plats 117 x 109/l
Myelodysplastic Syndrome (MDS)
Refractory cytopenia with multilineage dysplasia (WHO)

30. Follow up visit Cytogenetics failed: Not keen on repeat bone marrow
Hb 8.5 g/dl

31. Management
Jehovah’s Witness!

32. Case 1 Question 2 What would you recommend?
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?

33. Case 1 Answer 2 What would you recommend?
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?

34. Initial therapy Erythropoietin 30,000u once per week x 6wks
+ G-CSF 105ug three times per week
x 6 weeks
Erythropoetin 60,000u +G-CSF 2 weeks
No response-steady deterioration

35. March 2009 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

36. 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)?

37. 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)?

38. 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’

39. 22/04/09 started first cycle lenalidomide
Case 1 continued
22/04/09 started first cycle lenalidomide
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

40. Here is the really exceptional bit!
22/09/09 FBC from GP!!!
Hb 13.5 g/dl
WCC 6.6 x 109/l
Neuts 3.8 x 109/l
Platelets 166 x 109/l
Contacted GP-It is him and repeat FBC same!
Continued on lenalidomide for two years with normal blood counts and no symptoms of anaemia

41. Case 1 What should you display in your MDS clinic?

42. Therapeutic Options
High Risk MDS – Main problems are bone marrow failure & leukaemia
Supportive care
Azacitidine
Chemotherapy
Stem cell transplantation

43. Azacitidine
It has been suggested that azacitidine may switch on important anti-cancer genes

44. 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 days)
Standard chemotherapy (7 + 3)

45. AZA-001: Vidaza is the only licensed drug that has demonstrated a survival advantage in Int-2 and High-risk MDS
Vidaza – increases the median survival to 24.5 months (compared to 15 months with CCR) providing a 9.4 month benefit
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:

46. AZA-001: Setting a new standard in transfusion independence
100 80 60 40 20
% of transfusion Independent patients 90 70 50 30 10
45.0
11.4
33.6% difference
p<0.0001
Vidaza
CCR
Santini V. J Clin Oncol 2008
Fenaux P, et al. The Lancet Oncology 2009; 10:
Vidaza SmPC December 2008.

47. Azacitidine (Vidaza)
Standard of care for high risk MDS patients who are not candidates for transplantation
Approved by NICE ( great help of UKMDS Patient Forum)
Not approved by SMC

48. The Scottish Perspective
The Scottish Medicines Consortium
Statutory body which is part of:
Quality Improvement Scotland (QIS)
To advice the NHS in Scotland as to the cost effectiveness of new treatments

49. SMC vs. NICE SMC decisions only apply in Scotland
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

50. The workings of the SMC New Drug Committee Patient Access Scheme
Assessment Group
(PASAG)
Drug
Company
Main SMC
Committee
Final Advice Document
Exjade
Azacitidine

51. What about stem cell transplantation?

52. Current transplant activity in MDS
EBMT
2008:
1147 allografts for MDS ~ 10% of total
1333 MDS patients > 50yrs allografted

53. Considerations for all potential transplant candidates
Disease characteristics
Patient characteristics
Age
Co morbidities (other diseases or disabilities)
Iron status at transplant

54. 40 yr old female works in our medical illustration department
First time blood donor
Failed the screening test
Subsequent FBC
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

55. Bone Marrow
Hypercellular-confirmed on trephine
Trilineage dysplasia
Blasts 1%
Karyotype: 46, XX, der(21)t(1;21)(q11;p11)[6]
46,XX[4]

56. Diagnosis: MDS Refractory cytopenia with multilineage dysplasia
Cytogenetic risk group- Standard ??
IPSS score 0.5 Intermediate 1

57. What is your plan? Watch and wait-no plan to transplant
Proceed to transplant now?
Watch and wait-plan to transplant at progression?
Something else?

58. Answer 1 What is your plan?
Watch and wait-no plan to transplant
Proceed to transplant now?
Watch and wait-plan to transplant at progression?
Something else?

59. Question 2 Would you… Proceed to transplant as first line therapy?
Give one or two cycles of chemotherapy first?

60. Answer 2 Would you… Proceed to transplant as first line therapy?
Give one or two cycles of remission induction therapy prior to transplant?

61. Question 3 She is exactly 40 yrs old Would you…
Perform a traditional myeloablative conditioned transplant?
Perform a Reduced Intensity conditioned transplant (RIC)?

62. Answer 3 She is exactly 40 yrs old Would you…
Perform a traditional myeloablative conditioned transplant?
Perform a reduced intensity conditioned transplant (RIC)?

63. Outcome?! RIC allograft 11/05/07 Alive and well
Ongoing morphologic and cytogenetic remission
No GVHD and back at work full time
Would it be otherwise given I present it to you!

64. Thank you for listening!