Using precision medicine to reduce long-term ALL treatment effects
Professor Deb White hopes to reduce the toxic impact of ALL therapy so surviving this acute leukaemia doesn’t burden patients for the rest of their lives, particularly those diagnosed young.
That’s a research aim of her ALL research group at the South Australian Health and Medical Research Institute in Adelaide where she is Deputy Precision Medicine Team Leader and group leader in ALL.
Prof. White is a Leukaemia Foundation Strategic Ecosystem Research Partnership grant recipient and her project title is Precision medicine in ALL. Funding for this research–$250,000 over three years (Oct 2019-Oct 2022)–is kindly supported through the Estate of Edward Eric Rhoades and Phil’s Dive for a Cure.
The primary focus of Prof. White’s group is genomics and her six PhD students “are all flat out” looking at the genomic profile of all ALL patients diagnosed around Australia and those who relapse.
“As part of this project, we’ve also moved into metagenomics*. This means we are studying the genomic profile of the microorganisms in faecal samples (microbiota) and how they interact and influence the immune response,” said Prof. White.
This investigation into the effect of the gut microbiota in various stages of the disease from diagnosis, through therapy and beyond, is an Australian first.
“We can’t give people any stronger drugs,” said Prof. White.
“The current standard therapies can be very toxic, so we want to explore what can we do to improve the efficacy of treatment, and is a systemic approach much better? I think it probably is, so what is it, what can we change?
“The gut is the interface to the immune system; we need to understand what’s happening in the gut.”
Prof. White said research by another group, in 2018, showed that 25 years after treatment, ALL survivors still had immune and gut changes, a much greater range of metabolic syndromes, and a five-fold higher rate of dying from a secondary malignancy.
“We started to wonder what was going on with the gut right from the beginning and decided to explore this in a systematic manner, from different angles,” she explained.
This involves collecting faecal samples across the disease course of ALL, both in mice models and in ALL patients, to understand how the gut microbiome changes and, at the same time, looking at changes in the immune system.
“We want to compare chemotherapy to immune-based therapies throughout the course of treatment, so patients on the immune-based therapy, blinatumomab (Blincyto®), are included to determine how that drug affects their immune system.
We also want to look at patients who receive high-dose therapy, to see what’s going on in the gut and does it recover.
“We’re looking at the burden on the body of the patient as a result of the treatment-related toxicity.”
To help identify significant changes in the gut microbiome and immune system of ALL patients, Prof. White will compare ALL patient faecal samples to an environmental control group (a housemate from the same dwelling, or sibling in the case of younger patients).
“This allows us to look at the gut microbiota composition as a result of the ‘environment’ and to differentiate this from the composition of the gut microbiota associated with ALL,” said Prof. White.
“I’ve never worked in the immune faecal space before. It’s really very exciting.”
“Risk stratification is really important” said Prof. White, which is why this research also will compare the microbiome and immune response in high-risk and normal-risk patients.
“What we want to know is… does the composition of a patient’s microbiome help to determine how they respond to treatment and, if we alter their microbiome, do they respond and recover better?
“Hopefully, in the not-too-distant future, we’ll be able to say, ‘you’re low-risk and you don’t need such high dose therapy’, which would be really great. These patients could get a low or shorter dose of therapy which would have fewer side effects and an overall lower burden of treatment-related toxicity.
“For high-risk patients, we might be able to change their microbiome by giving them some normal microbiota and they can have low dose therapy and they will be okay … this sort of thing.
“We have known for a long time that there are two broad classifications of ALL, B-cell ALL and T-cell ALL, and using cytogenetics to look at the chromosomes inside these ALL cells we were able to identify a few subgroups,” said Prof. White.
Next-generation sequencing technology has giving us a much deeper understanding of ALL and we are able to identify about 27 different subgroups of ALL, she said.
The first sequencing project in ALL was done by Dr Charles Mullighan at St Jude; the big children’s hospital in the U.S. Dr Mullighan studied and trained in Australia and is a long-term collaborator of Prof White.
“By using next-generation, or deep sequencing, to look at the transcriptome, we can now explore those patients with normal cytogenetics who we know do badly.”
Prof. White said about 20% of children with ALL, when diagnosed, “look like a garden variety of ALL”.
“There’s no way we can pick them apart (from the other 80%); there are no cytogenetic (chromosome) markers that distinguish these patients. When they get to Day 28 of treatment, and haven’t responded, the panic button gets hit.
“When we analyse the genomic profile of these children who don’t respond, we’re often finding that they have mutations that we can’t see using cytogenetic testing, and some of these mutations are targetable using new precision medicines,” said Prof. White.
“We’re aiming to look at everyone at diagnosis, so we can pick these people, and using genomics is really helping.
“So, it’s double-pronged. Do we change therapy or is it just a re-stratification issue where we identify high-risk and low-risk patients?
“We’re gathering the information for what that systemic approach looks like. It’s early days, but we have nice results so far, exciting enough to keep going.”
Prof. White said there was no denying there was a gross side to this research.
“Gross in that faecal material was never anything I wanted to work with, and it’s unattractive to patients.
“Anyone over 50 who’s had a faecal occult blood sample will still complain about it. So, it’s an interesting scenario to go down that path.
“But I think my patients realise there is a possibility we may be able to reduce toxicity and they love the fact that we can start to understand their disease better.
“Ultimately, it’s about how we use these adjuvant** therapies in clinical trials that will make life easier.
“If you’re doing an autologous faecal microbiota transplant (FMT)–giving patients their own faecal material back, which we haven’t done at this point–it’s limited risk.
“That’s part of the plan, which has been broadened to ALL patients enrolled in trials, as well as general ALL patients.”
Prof. White said, depending on the results of this research and clinical trials, and whether it’s a FMT or microbial material taken in tablet or capsule form, “in a perfect world this would become standard of care for all patients”.
“What we’re really keen to see is that these patients recover quicker and that they actually regain a normal life afterwards.
“Surviving ALL shouldn’t be a burden you carry for the rest of your life.”
Prof. White said, post treatment, ALL patients had an “incredibly high risk of metabolic syndrome–type 2 diabetes.
“We think this is probably an inflammatory-type response.”
ALL survivors also are prone to heart disease and have an increased risk of secondary cancers as they get older.
“To carry that from a young age is quite a trauma,” she said.
“These are figures we capture badly, and I think that happens around the world.”
This is because they become ALL survivors but when they get type 2 diabetes or heart disease and succumb to that, these are not registered as ALL-related deaths.
“Capturing data on the burden of disease moving forward is quite difficult,” she said.
“Some patients will say they have no problem, but if you delve back into their genomics and the way they were treated, they probably had low-risk disease.
“We know those with high-risk disease do survive but they go through a bigger burden of treatment. Total body irradiation and transplantation clearly will knock your system around, but we see problems in a large proportion of patients.”
Prof White’s career began as a pathology technician in haematology. Then, after studying part-time, she ended up in research, mainly molecular biology, initially in AML, then CML–the subject of her PhD–before building her own research group in ALL.
The transition from CML to ALL is not large, she says, “there are similarities between CML and ALL, at least in some subtypes at the genomic level”.
Early in her career, Prof. White was adamant about not working for childhood cancer, “because I found it way too depressive… I’m a sucker for little kids”.
“But it was a natural progression and I was keen to work in a space with an opportunity to work across the age spectrum, and ALL certainly does that.
“The bulk of our work is kids, but we do see an increasing number of adults, so this is a growing disease burden.”
* Metagenomics is the study of a collection of genomic material from a mixed community of microbial organisms (e.g. faecal samples).
** Adjuvant therapy is used after or in conjunction with primary treatments, to lessen the chance of the cancer coming back or to assist in the management of toxicity.