Myelodysplasia: background and current treatment approaches in Australia

2. Michael Dickinson, Haematologist Peter MacCallum Cancer Centre Myelodysplasia: background and current treatment approaches in Australia

3. Overview • What is myelodysplasia? How does it affect you? • How doctors think about the disease and the words we use? • What on earth is epigenetics? • Treatments – When, what, how, practicalities…. Azaciditine & lenalidomide (MDS) • Trials

4. Understanding myelodysplasia isn’t easy!

5. Effects of MDS • Low white cell count (neutropenia) • Low red cell count (anaemia) • Low platelet count (thrombocytopenia) • In some patients there is a risk of leukaemia

7. What is myelodysplasia (MDS)? • “clonal disorder of the bone marrow” • MDS is a kind of cancer

8. Myeloproliferative disorders • Also a clonal disorder • Large spleen &/or liver • High white cell count, red cell count, or platelets

9. Clones.

11. Causes ?

12. DIAGNOSIS

14. Basic Diagnostic Evaluation • FBE, film • Bone marrow aspiration and biopsy • Cytogenetics • (flow cytometry) • Additional tests • Vitamin levels (B12, folate, iron and ferritin) • EPO (erythropoietin) • Other eg causes anaemia

15. Diagnosis • Low counts • The way the precursors look under the microscope • More than the normal amount of blasts.

16. What are “blasts”?

17. Classification of MDS - marrow Percentage of blasts AML ≥20%

18. Cytogenetics

19. What is ‘prognostication’?

20. Prognosis - IPSS

21. Prognosis – R-IPSS

22. TREATMENT - MDS

23. Managing marrow failure:Transfusion • Red cells • Platelets • ?white cells

24. For many people people, transfusion is no problem but sometimes there are complications • Inconvenient • Platelet transfusion refractoriness “platelet antibodies” • Red cell transfusion refractoriness “red cell antibodies” • Rate of transmitted disease is very low – ARCBS keeps blood safe.

25. Iron overload • Haemoglobin contains iron • Ferritin > 1000 (20units) • Evidence of iron overload

26. Iron overload

27. Exjade • Iron chelator • Orally available • Generally well tolerated • Some side effects

28. Extension Median Change in Serum Ferritin Levels from Baseline (By Initial Dose Group) Initial deferasirox dose, mg/kg/day 5–10 (n = 227) 20 (n = 182) 30 (n = 243) 1000 500 0 Median Change in Serum Ferritin Levels (µg/L) -500 −1000 Core −1500 2 0 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 38 40 42 Time Since Start of Treatment (months) Studies 106–109 With permission from Porter J, et al. ASH 2007. December 8-10, 2007. Poster 968.

29. Other treatments • Erythropoietin in renal failure • Immunosuppression in rare cases

30. New treatments for MDS • Big steps forward • Azacitidine (Vidaza) • Lenalidomide (for 5q-) (Revlimid) • New trials

31. Epigenetics • Things that change the way genes are expressed without changing the DNA code. • Histone modification • DNA methylation

32. Azacitidine (Vidaza) • Epigenetic drug • “low dose chemotherapy”

33. Azacitidine (VIDAZA) • Subcutaneous injection 7 days each month • Given as a maintenance therapy • PBS funded - >10% blasts, <30% blasts • Reduces the risk of progression to leukaemia • Reduces transfusion dependence Better than “best supportive care” and conventional chemotherapy

34. Key issues around azacitidine • Initial cytopenia cycle 1-2 (and sometimes ongoing) • Response at 4 cycles. • 7 consecutive days of therapy • Skin irritation • Azacitidine breaks conventional thinking. • PBS approval

35. Example of patient: 5-azacitidine

36. Lenalidomide (Revlimid) • Tablet - well tolerated. Best evidence 5q-disease • Available in Australia but not funded for myelodysplasia • Expensive • Reduces transfusion requirements but not a treatment for blasts • Side effects include low neutrophils and platelets • Doesn’t work in everyone • In high doses maybe anti-leukaemic

37. Other supportive things • Antibiotics – posaconazole (noxafil)

38. Allotransplantation • Mini-allo transplant • Uncertainty about timing

39. Why MDS studies are challenging • Toxicity of novel agents • Measuring responses • Leukemic transformation is part of the natural history • Drug development is also a business

40. Trials • MDS4 (Aza-rev)

41. Trials • MDS4 (Aza-rev) • Aza-eltrombopag Phase II

42. Trials • MDS4 (Aza-rev) • Aza-eltrombopag • Aza-panobinostat • Phase 1 studies • International studies • Eltrombopag • Estybon (rigosertib, ON 01910.NA) – cell cycle inhibitor via polo-like kinase inhibition • Tosedostat – aminopeptidase inhibitor • HDAC inhibitor combination studies

43. Conclusions • Myelodyspasia is heterogenous (everybody’s case is different) • Many advances in the last few years • Much progress in supportive care • Victoria is a great place to be!