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Michael Dickinson, Haematologist
Peter MacCallum Cancer Centre
Myelodysplasia:
background and current
treatment approaches in
Australia
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
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
<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
Cytogenetics
Prognosis - IPSS
Cytogenetics
Percent
blasts in the
marrow
Number of
cytopenias
IPSS
score
Prognosis – R-IPSS
Cytogenetics
(more
categories)
Number of
cytopenias
with severity
scoring
R-IPSS
(more
categories)
Percent
blasts in the
marrow
(altered cutoffs)
TREATMENT - MDS
Managing marrow failure:T
ransfusion
• 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)
Median Change in Serum Ferritin Levels (µg/L)
Initial deferasirox dose, mg/kg/day
5–10 (n = 227)
20 (n = 182)
30 (n = 243)
1000
500
0
-500
−1000
Extension
Core
−1500
0
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 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 5qdisease
• 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
Eltrombopag
Eltrombopag
plus
azacitidine
Azacitidine
alone
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!