The Australian Familial Haematological Cancer Study (AFHCS) leads the world in the field and has a research cohort of more than 200 families with a history of blood cancer.
The AFHCS was initiated in 2004 by Adelaide geneticist, Professor Hamish Scott. Prior to this, it was recognised that blood cancers did run in some families, but very few of the gene mutations that cause this to occur were known.
Prof. Scott and Dr Anna Brown, who was working collaboratively with him in another lab, started studying a few families.
“Of course, as soon as people realise you’re studying genetics, they come to you with their stories,” said Dr Brown, Head, Molecular Oncology in the Department of Genetics and Molecular Pathology at SA Pathology (Adelaide).
Enrolling patients in the study
A framework was developed for haematologists with patients where MDS, AML or other blood cancers ran in their family, to enrol them in the research study, which started looking into the gene changes underlying these family’s histories.
“We have one of the longest running familial blood cancer studies in the world. It’s a systematic study to find answers for these families,” said Dr Brown.
“Over 200 families are enrolled and because there are multiple family members with all kinds of different blood cancers, or carrying a mutation, we’ve got thousands of individuals across the families we are studying.
“We have very good relationships with haematologists all over Australia.”
Most referrals to the AFHCS come from haematologists treating a family member with a blood disorder/blood cancer whose medical history showed a strong family history of the condition. Information about the study was then given to the patient, via their haematologist, to see if the patient was interested in participating in the research.
“If they are, a research nurse then contacts a family member for more information and to give more information about the study. If they want to go ahead, the research study consenting process is started.
“The study coordinator normally starts with one family member and gets a family history, then sequentially contacts other family members who are interested in participating as well,” said Dr Brown.
“We build up a very detailed family history, go through their medical background, and if there is blood cancer in their family, collect samples from them for genomic testing.
“All this is done in a research setting and the information is de-identified, so we don’t see names of individuals we are studying.
“Some people are really happy to participate in the research, want to know everything and are really engaged. Others want to help for the betterment of everyone, but don’t necessarily want to know that personal information about themselves,” said Dr Brown.
“We do gene sequencing on family members who have provided material, researching their genomes, to see if we can find a genetic change that’s present in the family members who have reported either a blood disorder or a blood cancer.”
Dr Brown said the AFHCS often gave presentations to organisations, including the Leukaemia Foundation, at their patient education days, “and sometimes individuals contact us directly.”
Familial linkages occur in “pretty much all the different types of blood cancers and disorders to some degree or another”, she said.
“We have MDS and AML, but we also have a lot of lymphoma families, myeloma families, and chronic lymphocytic leukemia. Basically, in every type of blood cancer we can find a family where it seems to be occurring more often than you would expect.
“That suggests that there’s something genetic underlying that.”
In 2016, the World Health Organisation published clinical testing guidelines for familial predisposition to myeloid malignancies.
“As well as our research study, for families with a history of myeloid blood cancers such as MDS and AML, we are part of an international clinical network of experts and our laboratory offers accredited genomic testing that can be ordered through clinical genetics centres and clinical haematologists,” explained Dr Brown.
Why does it seem blood cancer may be occurring more often?
“Diagnosing blood cancers has become a lot better with modern medicine,” said Dr Brown.
“In the past, people might have been affected by leukaemia and passed away without it being diagnosed or identified as the reason they passed away.”
And blood cancer is more visible now.
“If someone younger gets this kind of disease, it stands out more, and makes it easier for us to identify when there is a family history.
“There is some concern that the age of diagnosis of some of the blood cancers is getting younger in more recent generations, and that is something we’re actively researching.
“The field hasn’t done the right studies yet to show whether that’s actually true, but in some cases it seems like it might be.
“That’s something we definitely want to look into – whether other factors are also interacting with the genetic changes in these families, maybe environmental factors, but we don’t know of any at the moment.”
Why familial research is important
“There are benefits in participating in this research,” said Dr Brown.
Information from this research is most important when a family member is looking at having a stem cell transplant or bone marrow transplant as a curative therapy, “because most frequently you’ll look for a family member to be the donor”.
“It is really important to offer genomic testing to these people, to make sure they’re not carrying any mutations that we can identify that might be causing that family history, and to make sure any potential bone marrow donors aren’t carriers of those mutations without realising.
“You don’t want to transplant bone marrow that’s got an inherited mutation. We know that gives you a risk of complications with how well the bone marrow transplant works.
“We’re focusing on identifying carriers of known gene mutations early, and enrolling them in the study, so we can work with their haematologist, to monitor them more closely.
What we would like to do in our research is figure out ways to stop leukaemia from developing in people who’ve inherited a mutation.
“A new aspect of the study is looking at why they go from a state of having an inherited mutation, to developing blood cancer. Something else has to happen in between, to trigger that. What is it?
“Can we find out how that happens and find a way to treat at that point? So patients don’t go on to get leukaemia. We’ve got a lot of research projects in that area.
“And having this knowledge, the haematologist knows to keep a really close eye on someone who’s at a greater risk, which allows them to manage their health better,” she said.
Testing a blood cancer prevention strategy
Dr Brown said clinical frameworks were being put in place “to find clever ways to test a leukaemia prevention strategy” because it is being given to a patient who has a gene mutation but is otherwise well, and it may take a longer time to know the answer, and “that’s ethically difficult”.
We’re still working through the ways in which we could get to the point where we could have a human clinical trial. I don’t think it will be too far away.
Stopping blood cancer from developing “is absolutely the aim of a lot of the research we are doing right now”, she said.
“The field recently moved from just trying to identify what some of the mutations are, to figuring out a pathway to generate models in the lab and find therapies that might intervene at a much earlier point than waiting for a person to get full-blown leukaemia.
“The main thing for treating someone, to prevent leukaemia, is finding a compound with a good safety tolerability profile, unlike intensive chemotherapy which is used to treat acute myeloid leukaemia.
“You wouldn’t give that to somebody who’s otherwise healthy, because there’re just too many side-effects,” said Dr Brown.
“We’re looking at other agents that might change the blood compartment in ways that relieve some of the stress that the inherited mutation puts on it.
“If we can relieve that stress on blood cells and stem cells, it might reduce the chance that they become leukaemia,” she said.
Anyone interested in the AFHCS can contact Dr Anna Brown on [email protected] or Professor Hamish Scott on [email protected]
