Michael Dickinson Haematologist Peter Mac Callum Cancer Centre

Michael Dickinson, Haematologist Peter Mac. Callum 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 n FBE, film n Bone marrow aspiration and biopsy n ¨ Cytogenetics ¨ (flow cytometry) Additional tests ¨ Vitamin levels (B 12, 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 AML ≥ 20%

Cytogenetics

What is ‘prognostication’?

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 Percent blasts in the marrow (altered cutoffs) R-IPSS (more categories)

TREATMENT - MDS

Managing marrow failure: T ransfusion • Red cells • Platelets • ? white cells

For many 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 (20 units) • 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 5 q-) (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 5 qdisease • 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 • MDS 4 (Aza-rev)

Trials • MDS 4 (Aza-rev) • Aza-eltrombopag Eltrombopag plus azacitidine Azacitidine alone Phase II

Trials • • • MDS 4 (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!