Myelodysplasia: background and current treatment approaches in Australia

Michael Dickinson, HaematologistPeter MacCallum Cancer Centre

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

Understanding myelodysplasia isn’t easy!

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

What is myelodysplasia (MDS)?

• “clonal disorder of the bone marrow”• MDS is a kind of cancer

Myeloproliferative disorders

• Also a clonal disorder• Large spleen &/or liver• High white cell count, red cell

count, or platelets

Clones.

Causes

?

DIAGNOSIS

http://www.ashimagebank.org/cgi/content/full/2001/1205/100197/F3

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

Diagnosis

• Low counts• The way the precursors look under the

microscope• More than the normal amount of blasts.

What are “blasts”?

Classification of MDS - marrow

Percentage of blasts

Cytogenetics

Prognosis - IPSS

Prognosis – R-IPSS

TREATMENT - MDS

Managing marrow failure:Transfusion

• Red cells• Platelets• ?white cells

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.

Iron overload

• Haemoglobin contains iron

• Ferritin > 1000 (20units)• Evidence of iron overload

Iron overload

Exjade

• Iron chelator• Orally available • Generally well tolerated• Some side effects

Median Change in Serum Ferritin Levels from Baseline (By Initial Dose Group)

−1500

−1000

-500

0

500

1000

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)

Med

ian C

han

ge in S

eru

m F

err

itin

Levels

(µg/L

)

0

Core Extension

5–10 (n = 227) 20 (n = 182) 30 (n = 243)Initial deferasirox dose, mg/kg/day

Studies 106–109With permission from Porter J, et al. ASH 2007. December 8-10, 2007. Poster 968.

Other treatments

• Erythropoietin in renal failure• Immunosuppression in rare

cases

New treatments for MDS

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

Epigenetics

• Things that change the way genes are expressed without changing the DNA code.

• Histone modification

• DNA methylation

Azacitidine (Vidaza)

• Epigenetic drug• “low dose chemotherapy”

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

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

Example of patient: 5-azacitidine

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

Other supportive things

• Antibiotics – posaconazole (noxafil)

Allotransplantation

• Mini-allo transplant• Uncertainty about timing

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

Trials

• MDS4 (Aza-rev)

Trials

• MDS4 (Aza-rev)• Aza-eltrombopag

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

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!