1. Current Treatment Options in MDS Dick Wells MD, DPhil, FRCPC Director, Crashley Myelodysplastic Syndrome Research Laboratory Odette Cancer Centre

2. Tale of Two Patients Mr. Blue Low Hb, WBC, platelets >90% chance of developing leukaemia within 2 years Life expectancy about 18 months Ms. Green Anaemia only ~10% chance of developing leukaemia ever Life expectancy more than 10 years They both have MDS, but do they both have the same disease?

3. 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

4. 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

5. 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

6. 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

7. 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

8. 2u PRBC/wk Dacogen x 18 cycles

9. 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?

10. 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

11. 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

12. 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

13. 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

14. Response to immune suppression

15. Immune suppression in MDS Upside Durable responses Can improve all blood counts Downside Expensive Very toxic (especially ATG) Not everyone responds

16. 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

17. Most frequent chromosomal deletion in MDS patients –10-20% (+/- other abnormalities) –5-6% as sole abnormality Better-than-average prognosis –Low risk of leukaemia Deletion 5q [del(5q)] A problem with the long arm…

18. MDS-003 trial Revlimid in 5q- MDS 67% of patients achieved transfusion independence 90% of patients who achieved a transfusion benefit did so by completion of 3 months of therapy Durable responses (>2 y) 67% Transfusion Independence (99/148 patients) List et al., N Eng J Med, 355, 1456, 2006

19. Start Lenalidomide Last Transfusion Haemoglobin Platelets

20. G-CSF 300 mcg BIW Start Lenalidomide Haemoglobin Neutrophils

21. “Doc, I’m a new man!” Start Lenalidomide Last Transfusion Haemoglobin

22. Revlimid in MDS Upside Amazingly active in 5q- MDS 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

23. Summary: Algorithms for MDS 1.If 5q-, revlimid 2.If epo<500, try growth factors 3.Immune suppressive therapy (ATG and/or cyclosporine) 1.If feasible, BMT 2.Supportive/palliative care 3.…or clinical trial 4.… or hypomethylating drugs