A Researcher’s Insight – Azacitidine/Eltrombopag study

In a final analysis of the Peter Mac sponsored Azacitidine/Eltrombopag study, haematologist and research fellow, Dr Michael Dickinson, targets myelodysplastic syndromes and gives us a lay summary of the purpose of the trial. 

Myelodysplastic syndromes are a group of conditions that lead to ineffective production of normal blood cells by the bone marrow. Patients present with low blood counts. Some require red blood cell transfusions or platelet transfusions and others have issues fighting infection due to low white cell count. These problems cause a significant impact on the quality of life. More seriously, a significant proportion of patients with myelodysplastic syndrome will go on to develop acute myeloid leukaemia. That complication is almost universally fatal. Acute myeloid leukaemia arising from myelodysplasia and myelodysplasia itself cannot be cured in the majority of patients and allogeneic transplantation offers curative treatment only to patients young enough and well enough to tolerate the side effects of that intensive therapy.

In 2011 azacitidine was approved for therapy of patients with myelodysplastic syndromes shown to be particularly at risk of conversion to AML. Azacitidine is a maintenance treatment and can improve blood counts in approximately 50% of patients and reduces the risk of transformation to acute myeloid leukemia, prolonging overall survival. Azacitidine is active for patients with lower risk myelodysplasia but is not approved in the Australian regulatory environment.

It has recently been recognised that thrombocytopenia (low platelet count) portends a higher risk of transformation to acute myeloid leukaemia. Patients with very low platelet counts have a higher risk of bleeding complications. This group of patients likely requires intervention with azacitidine; however, there is very limited evidence that early intervention changes long-term outcomes at this stage. This is clearly a higher-risk population that needs disease-modifying therapy.

As a complication of treatment azacitidine causes a transient worsening in the platelet count before its anti-disease effect occurs and the platelet count ultimately increases. Patients who suffer from low platelet counts during therapy with azacitidine are at risk of increased bleeding complications.

Eltrombopag is an agent that increases the platelet count by increasing the production of platelets by the bone marrow. This trial looked at the combination of the platelet-increasing agent together with azacitidine to assess whether the combination was tolerable and safe.

Between 2010 and 2013, 25 patients were recruited and the final results were presented at the Australian haematology conference in October 2014 and at the American Society conference in December 2014. Interim results had demonstrated that eltrombopag increased platelet count in a subset of patients and that the combination of eltrombopag and azacitidine was deliverable. The side effect profile was established and the preliminary evidence had provided the drug makers of eltrombopag with sufficient preliminary evidence to move towards a randomised trial to assess whether eltrombopag is both efficacious and safe in this patient population.

The randomised study has recently opened in Australia at 5 sites, and will open at a further 165 sites in 28 countries.  Michael Dickinson is the global Principal Investigator .  The AzaE study placed Michael in a leadership role for this new randomised study and gave access to azacitidine and eltrombopag to 25 patients in Melbourne who otherwise may not have had access to disease-modifying therapy for their high-risk myelodysplasia.

The samples taken from the azaE study are allowing new research into the mechanisms of action of eltrombopag, the effect of this drug on stem cells in the bone marrow and research establishing peripheral blood biomarkers for diagnosis and prognosis in myelodysplastic syndromes. These pilot studies may then be extended to the samples collected from the MDS3 and MDS4 Australian myelodysplasia studies, which have larger patient cohorts. A new scientific collaboration with the Albert Einstein Hospital in New York has been established and Dr Mark Dawson’s new epigenetics fellow will be undertaking research using samples arising from this study (see article re George & Yolanda Klempfner Fellowship).


Dr Michael Dickinson is a haematologist at Peter MacCallum Cancer Centre and worked as the epigenetics Snowdome fellow from 2010 to 2013. He has recently been appointed as the Julie Borschmann fellow in multiple myeloma at the University of Melbourne and Peter Mac, where he will be continuing his research into blood cancers and epigenetics. Michael has been supported through the Victorian Cancer Agency and the Snowdome Foundation, the University of Melbourne and Peter MacCallum Cancer Centre.