Blood cancers

AML in 2019 and beyond: challenges amid new promise

The treatment landscape for acute myeloid leukaemia (AML) – and hopefully patient outcomes – are expected to change significantly over the next couple of years.

Haematologist Associate Professor Andrew Wei, from Monash University and head of leukaemia research at The Alfred Hospital, told the limbic the fact that the main chemotherapy drugs in use were discovered in 1950 and 1953 meant change was well overdue.

“Those drugs have delivered some good benefits for younger people but there are still a substantial number of patients who relapse – that’s the first challenge – and then in the older population, just the lack of effectiveness all-round has been an eternal challenge.”

“After a long drought of no new drugs entering the clinic for this condition, in 2017/18 there were eight new drugs approved by the FDA. At this stage only one of them, midostaurin which targets a protein called FLT3, is currently available in Australia.”

Associate Professor Wei, a speaker at an AML Update held by the Australasian Leukaemia & Lymphoma Group at the Walter and Eliza Hall Institute of Medical Research (WEHI) in Melbourne, said there was enthusiasm to determine how the new drugs could best be used in clinical practice and what impact they will have on the biology of AML and patient outcomes.

“Targeting FLT3 is a bit like targeting branches of a tree. Is targeting that branch enough to stop the whole tree from growing or will another branch just grow out and overtake everything?”

He said there was reason to be optimistic given the randomised controlled trial leading to FDA approval had shown the drug did indeed improve survival.

Midostaurin is available to all patients who are young enough and fit enough to receive intensive chemotherapy as their first line therapy, he said.

“We’re likely to see several of the other drugs come to Australia over the next couple of years so the implication of that is the treatment landscape will change quite dramatically over the next two or three years in this country.”

“There will be a greater level of personalisation of therapy because several of these medications are targeting specific mutations. Patients will need to have the mutation identified and then they will get a specific drug.”

“We are moving more into a precision medicine era whereas for the last 50 years we were basically just using the same chemotherapy drugs for everyone.”

“The next challenge is how do we make further improvements in outcome?”

Earlier treatment options

Given some drugs are being used quite late in the disease course when a patient relapses, it might be possible to deliver the medications at a much earlier stage – potentially before patients became unwell – in order to change the course of the disease.

“And that leads on to new molecular technologies which can track the leukaemia at very low levels many months before the patient progresses.”

He said next generation sequencing was not yet widely enough available in the clinic for patients to benefit from the technology.

“At the moment we have assays which can detect a small number of mutations but the potential is the technology exists to detect all of the mutations simultaneously at multiple time points. I think that is where the future lies, developing that technology to a level [where] we can survey the whole landscape rather than just certain parts of it.”

“The hope is that having better technologies to detect evolving disease at a much earlier stage and bringing in new drugs to try and change the course of the disease earlier rather than later will have benefits for people across all ages.”

Associate Professor Wei said the most difficult patient group was the older patients who make up the majority of patients with leukaemia and whose disease was much more complex.

“They have acquired mutations over a much longer period so they have more mutations, they have worse mutations and they have more drug-resistant mutations. That has really been one of the biggest challenges and where we have made the least amount of progress over the last 50 years.”

However the BCL-2 inhibitor venetoclax allowed the low-dose chemotherapy normally used in older patients to work better.

“We showed we could produce remissions in over 50% of elderly patients even up to the age of 90, and at 10 months, half the patients were still alive. And there was a second study using another low dose chemotherapy in combination with venetoclax and it showed similar results.”

The Phase Ib/II study has just been published in the Journal of Clinical Oncology.

“Those two trials actually led to the approval of venetoclax for AML in older patients in the US in November 2018.”

“Despite these very substantial improvements obviously we still want to understand why some patients fail or relapse on that therapy and so we have done molecular studies on samples from patients at the time of relapse.”

“We have identified new targets which have driven the development of new trials combining drugs to target those drug resistant mechanisms and those trials are going to be launched later this year.”

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