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!

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

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

DON’T FORGET MYELOPROLIFERATIVE

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.

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 <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%

Cytogenetics

What is ‘prognostication’?

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

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)

TREATMENT - MDS

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

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.

Haemoglobin contains iron Iron overload Haemoglobin contains iron Ferritin > 1000 (20units) Evidence of iron overload Polycythaemia rubra vera

Iron overload Polycythaemia rubra vera

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

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 2007. December 8-10, 2007. Poster 968.

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

Lenalidomide (for 5q-) (Revlimid) New trials 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

“low dose chemotherapy” 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 This means that transfusion requirement may s increase

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.

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)

Uncertainty about timing 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)

Eltrombopag plus azacitidine Trials MDS4 (Aza-rev) Aza-eltrombopag Azacitidine alone Eltrombopag plus azacitidine Eltrombopag Phase II

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!