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. Low white cell count (neutropenia) Low red cell count (anaemia)
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

13. DON’T FORGET MYELOPROLIFERATIVE

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
When assessing anyone with suspected MDS, it is important not only to make a correct diagnosis but to determine firstly what subgroup or classification of MDS it is and secondly to determine some key risk factors, or prognostic factors, which help to predict what the natural course of the disease will be.
Performing a full blood count and looking at the blood cells under a microscope are essential tests to diagnose and monitor the disease. A number of other blood tests are often performed to rule out other causes of the abnormalities and possibly direct some specific treatments. In most people however, it is necessary to perform a bone marrow biopsy, usually at the back of the pelvic bone under local anaesthetic, to further assess the blood cells. It is important to look at the chromosomes of the bone marrow cells which are abnormal in about half the cases and can provide additional information about the prognosis.

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
<5%
Normal
Refractory anaemia (RA)
Refractory anaemia with multilineage dysplasia (RCMD)
5-9%
Refractory anaemia with excess blasts 1 (RAEB-1)
CMML-1
10-19%
Refractory anaemia with excess blasts 2 (RAEB-2)
CMML-2
Percentage of blasts
AML ≥20%

18. Cytogenetics

19. What is ‘prognostication’?

20. Percent blasts in the marrow
Prognosis - IPSS
IPSS score
Number of cytopenias
Cytogenetics
Percent blasts in the marrow

21. Prognosis – R-IPSS Cytogenetics (more categories)
R-IPSS (more categories)
Number of cytopenias with severity scoring
Cytogenetics
(more categories)
Percent blasts in the marrow (altered cut-offs)

22. TREATMENT - MDS

23. Managing marrow failure:T ransfusion
Red cells
Platelets
?white cells
Discuss thresholds

24. Platelet transfusion refractoriness “platelet antibodies”
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. Haemoglobin contains iron
Iron overload
Haemoglobin contains iron
Ferritin > 1000 (20units)
Evidence of iron overload
Polycythaemia rubra vera

26. Iron overload
Polycythaemia rubra vera

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

28. 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
Median Change in Serum Ferritin Levels (µg/L)
-500
−1000
Core
Extension
−1500 2 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 December 8-10, Poster 968.

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

30. Lenalidomide (for 5q-) (Revlimid) New trials
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. “low dose chemotherapy”
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
This means that transfusion requirement may s increase

35. Example of patient: 5-azacitidine
This is an example of the blood counts and transfusions of an MDS patient (with high risk disease – RAEB-2) successfully treated with 5-azacitidine. The white bars represent the 7 days of treatment with 5-azacitidine. You can see that before treatment, his haemoglobin (red cells) was under 100 and he required red cell transfusions (red arrows). His neutrophils (white cells) were very low (under 0.5x109/L) and his platelets were about 50x109/L. After his first treatment with 5-azacitidine, the blood counts all lowered initially, something we commonly see, and he required not only more frequent red cell transfusions but also platelet transfusions to prevent bleeding. By the end of the second cycle however, his blood counts made a very good recovery and he required no further blood or platelet transfusions. His haemoglobin, white cells and platelets were all normal and a bone marrow biopsy showed the chromosome abnormalities he had initially had all gone away. After further doses of 5-azacitidine you can see some drops in his platelets and neutrophils- though still better than when he started, this was probably due to a side effect of the 5-azacitidine and has improved with some modification of the dosing and scheduling. He encountered some of the typical side effects of the treatment – low blood counts (sometimes difficult to separate from the effects of the MDS!), some abdominal upset requiring anti-nausea medications and some minor reactions on the skin where the injection is given.

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. Uncertainty about timing
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. Eltrombopag plus azacitidine
Trials
MDS4 (Aza-rev)
Aza-eltrombopag
Azacitidine alone
Eltrombopag plus azacitidine
Eltrombopag
Phase II

42. Trials MDS4 (Aza-rev) Aza-eltrombopag Aza-panobinostat Phase 1 studies
International studies
Eltrombopag
Estybon (rigosertib, ON 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!