World-first trials to test new blood cancer treatment for elderly

Acute Myeloid Leukaemia (AML) is a rapidly fatal blood cancer which, despite improvements gained through intensive chemotherapy, has a five-year survival rate in adults of around 25%. Elderly patients however have a median survival rate of less than six months.

Associate Professor Andrew Wei has been awarded a four-year $1.07M NHMRC project grant to conduct research improving outcomes for elderly people with AML.

A haematologist at the Alfred Hospital and researcher in the Australian Centre for Blood Diseases at the Central Clinical School, A/Prof Wei has a strong track record in the field.

In 2016, he presented results of a clinical trial combining the BCL-2 inhibitor venetoclax with low-dose cytarabine (a chemotherapy medication), which was shown to increase the clinical response rate of older patients with AML from less than 18% to more than 60%, with 12-month survival rates of almost 50%. The study contributed to the FDA approval of venetoclax for older unfit patients with AML in the US on 21 November this year. This represents the first major drug breakthrough for older patients with AML for several decades.

A/Prof Wei has worked to further improve survival rates by exploring the molecular basis of primary drug resistance and relapse to low-dose chemotherapy/venetoclax.

Analysing patient samples, his laboratory has identified two major mechanisms of treatment failure, involving mutations affecting the FLT3 and TP53 genes. FLT3 is important for the development of the haematopoietic and immune systems; TP53 provides instructions for making a protein that acts as a tumor suppressor. The researchers demonstrated the potential to overcome these molecular barriers associated with treatment failure by combining venetoclax with FLT3 inhibitors in FLT3 mutant cases and histone deacetylase inhibitors, such as panobinostat and pracinostat in TP53 mutant AML.

“Based on these findings, we will commence a world-first investigator-initiated randomised trial to combine venetoclax/LDC with the recently approved FLT3 inhibitor midostaurin in intermediate cytogenetic risk AML and pracinostat in adverse risk AML,” Assoc. Prof. Wei said. “This will be conducted nationally in approximately 25 hospitals in collaboration with the Australasian Leukaemia and Lymphoma Group.”

The NHMRC funding will allow A/Prof Wei to validate his preliminary findings and study the molecular mechanisms of response and resistance in the national trial.

“These studies will continue our goal of identifying more effective ways to treat leukaemia and delivering clinical improvements to patients with AML,” he said.

The research team includes collaborators from the US, New Zealand, the Walter and Eliza Hall Institute of Medical Research and Associate Professor John Reynolds from Monash University.

A/Prof Wei, who joined the Alfred Hospital in 2008 to develop its AML research program, has been chief investigator on 33 AML trials to date. He is a Medical Research Future Fund Clinical Research Fellow and chairs the Australasian Leukaemia and Lymphoma Group AML disease committee and the Cancer Council Victoria Clinical Network.

See more about the research at:
www.monash.edu/medicine/ccs/blood-disease/research/leukaemia-tr-group