Helen O’Callaghan talks to two leading doctors who are driven to find targeted therapies with minimum long-term toxicities to treat childhood cancer.
HOW quickly it all happened, how rapid it was —that’s what stayed with Professor Owen Smith all these years. His nine-year-old cousin, Derek Reid, taken in 1966 to a Dublin paediatric hospital, nursed in a back room, died three weeks later of acute lymphoblastic leukaemia.
In Ireland, as in most of Europe in 1966, children diagnosed with leukaemia lived six to 12 weeks. Clinical care was purely palliative — intravenous drugs and morphine to make them comfortable. “I was brought to see Derek when he died. He was laid out in the bed. Seeing him against the white sheets and he was as white as them, and you could see all the bruising. It left a scar.”
Professor Smith is consultant paediatric haematologist at Our Lady’s Children’s Hospital, Crumlin, and he has just been appointed national clinical lead for Childhood, Adolescent and Young Adult Cancers by the National Cancer Control Programme. “As soon as I went into Medicine, I knew I wanted to work in leukaemia,” he said.
Around 210 children are diagnosed annually with cancer in Ireland. Approximately one-third have acute leukaemia — other common cancer types are brain tumours and neuroblastoma.
“Today, we’re curing over 90% of children with acute lymphoblastic leukaemia — the most common childhood cancer. But we’re doing it at a price, [which] is usually long-term toxicities for these children,” says Professor
Smith, explaining that these toxicities affect 60-70% of patients and can include bone disease, heart disease, problems with metabolism, obesity, diabetes and fertility loss.
On Grafton Street 10 years ago, a woman with a buggy stopped him, a woman he didn’t recognise — long-haired, fit-looking and in her early 20s. “She said: ‘Professor Smith, do you remember me?’ She’d been one of my patients in Harcourt Street Hospital in 1996 where she was treated for leukaemia. She showed me her baby.
While he might not readily remember the children he helped cure, he never forgets those who don’t make it or who die of refractory (stubborn) or relapsed disease. In a sense they haunt him. “So I’m interested in looking at ways to find treatments for that other 10% so we can cure 100% of these children — and [do so] without toxicity and side-effects.”
For 70 years, real efforts in curing childhood cancers have focused on acute leukaemia as the most accessible form of cancer. “If you stick a needle into a vein, you can get a cancer biopsy, as opposed to going into a solid tumour which takes more time and is more invasive,” explains Professor Smith.
He compares cancer treatment over the past 40-50 years to carpet-bombing — cocktails of different chemo drugs that hit healthy systems as well as cancer cells. They attack the hair follicle. They break down the gut lining — an immunological barrier that prevents bacteria from crossing into the bloodstream. “This causes infection, which in turn causes significant amount of death among cancer patients.”
This scattergun approach to treatment also attacks normal bone marrow function: the patient gets neutropenia — low white blood cell level. “So there’s a double whammy — if you can’t fight infection, you can get sepsis and septic shock,” says Professor Smith, explaining that once the “bombs are released”, doctors must wait until the patient recovers normal gut mucosal barrier and normal bone marrow function before any more treatment. “Essentially before you give them more chemo — and then you’re back into the same vicious cycle.”
But the 1990s and the noughties brought new hope — more targeted cancer treatments, what Professor Smith calls “sniper fire”. “These target genetic abnormalities driving the cancer within the cancer cell. The classic example is Imatinib, a drug that targets a specific genetic abnormality — BCR-ABL fusion — within two types of leukaemia: chronic myeloid leukaemia and a small percentage of acute lymphoblastic leukaemias.”
This was a paradigm shift, says Professor Smith. Now, patients with chronic myeloid leukaemia take Imatinib orally and it pushes them into remission. And in a small percentage of acute lymphoblastic leukaemias, using Imatinib in combination with chemo improves outcomes by up to 40%. “We now have more of these targeted therapies in the clinic for different types of cancer, which is fantastic.”
Immunotherapies, arriving in the last five to 10 years, are — says Professor Smith — the newest kid on the block, a yet more sophisticated weapon in our cancer-fighting arsenal. These are antibodies that target a cancer Achilles heel — a protein unique on the cancer cell.
“The antibody binds with the protein, then kills the cancer cell, avoiding toxicity on other cells. At the same time the antibody — called BiTE or bi-specific T-cell engager – engages the patient’s own T-cells (type of immune system cell), calling on them to engage in the killing of the cancer cell,” explains Professor Smith, adding that enlisting the patient’s own T-cells is “an even better way” to kill the cancer.
Immunotherapies are currently only used in patients who are high risk, refractory to treatment and who have relapsed.
Like Professor Smith, Professor Jonathan Bond is one of Ireland’s top cancer researchers and was appointed last year to the Brendan McGonnell UCD Professor of Paediatric Molecular Haemato-Oncology Chair. His focus is capitalising on the knowledge explosion in the last 10-15 years in the biology of leukaemia, in particular, the genetic mutations in leukaemia cells.
“We know a huge amount about the genetic landscape of leukaemia and leukaemia in children, so we can think of ways to target it specifically instead of the old ways, which were like using a sledgehammer to crack a nut. Immunotherapy is extremely promising in leukaemia that has been treated but where there’s relapse.”
Professor Smith agrees: “With patients who relapse or who are difficult to get into remission, we can’t keep giving them block after block of chemo — whereas, with immunotherapy, it’s possible for them to enter remission.”
The latest breakthrough treatment — emerging only in the last year or two — is chimeric antigen receptor T-cell therapy or CAR T-cell therapy.
“We take T-cells from the patient and perform a form of gene therapy on them to make them active against the patient’s own cancer and they’re then put back into the patient,” explains Professor Smith, adding this can put patients into remission who’d previously have been deemed incurable.
CAR T-cell therapy has been approved by European and North American regulatory bodies and is in place across 10 European countries. Professor Smith confirms this treatment will start later this year — for childhood leukaemia, adult leukaemia and lymphoma — in the Children’s Hospital Crumlin, and in St James’s Hospital. “CAR T-cell therapy will get wider in its application — it’s being pushed out now for other cancers like ovarian. And there’s some US research [emerging] that it can be used for neuroblastoma in children.”
Oncology treatment at Our Lady’s Hospital, Crumlin, is on par with the world’s best paediatric hospitals, according to Professor Smith. The 2015 report, Childhood Cancer Mortality in the UK and Internationally, 2005-2010 showed the hospital has best results in the EU for childhood lymphoblastic leukaemia (commonest cancer in children). “That’s a huge plus for everybody working within the programme — we share care with 16 other centres around Ireland so it’s a combined effort, a multidisciplinary approach across Ireland for childhood cancers.”
Professor Bond leads the Childhood and Adolescent Leukaemia Research Group based in Systems Biology Ireland at UCD. Worldwide, there are only about five of these institutes dedicated to systems biology and this is the only one in Ireland. “We combine computational techniques with traditional lab experiments. There’s a mix of expertise — in computers, medicine, biology. It’s a collaborative effort where we all work together to do science. It’s quite powerful.”
Professor Bond says the beauty of computational techniques is you can do lots of experiments very quickly on the computer without going into the lab like you’d previously have done. “You can make computer models of biological systems, of molecular pathways. It’s like road-testing a car on the computer — if the car’s in a crash, what happens? Analogous to road-testing a car, you can do similar things with leukaemia cells,” he says, adding that it’s about finding different targets for attack within the leukaemia cell.
“If something goes wrong within the leukaemia cell — if there’s a mutation in a gene — we can work out that this may make the cell vulnerable to a particular type of treatment.”
It means, he says, you can target your lab experiments much more easily, saving time and money. “You can find things you wouldn’t expect. For example, other scientists – working on computer models – have found particular combinations of drugs are effective against certain cancers where the individual drug on its own mightn’t have been. They worked this out only because of computational modelling and they were then able to test it in the lab.”
Professor Smith believes, going forward, it’ll be possible to predict which patients will get long-term toxicities.
“By interrogating the patient’s genetics, can we find the genetic determinants that predispose the patient to long-term toxicities? The answer is ‘yes, we can’ — by using the whole area of next-generation sequencing.”
The term, he says, is precision oncology, meaning every patient’s treatment will be designed for that patient. And he believes this should be possible for leukaemia patients in the next three years or so.
Professor Smith says the story of cancer treatments over the past 50 years can be compared to approaches taken with an overflowing sink. “You can mop up the water on the floor — like what we’ve been doing with cancer in the last 50 years, the carpet-bombing. You can take out what’s down the plug-hole, which is like the targeted treatment. But what you need to do is turn off the tap, unravel what’s going on, which is analogous to the genomics we’re doing in the UCD group.”
But do the new breakthrough treatments exact payback too? Are there side-effects? In immunotherapy, the antibody kills the leukaemia B cells. “Frequently, your normal B cells that fight viral infection are slow to recover, so you can be more prone to viral infections but it’s a small price to pay when you consider leukaemia would kill you,” says Professor Smith.
“But it can be treated and is rarely fatal.”
With CAR T-cell therapy, toxicity’s a real issue, says Professor Smith. “It can cause neurological disturbance, respiratory and cardiac failure, necessitating the patient going to ICU — most of these toxicities can be reversed using an antibody.”
But the biggest price, he says, is quite literally that — financial cost. Immunotherapy antibody treatment per patients costs around €20,000. CAR T-cell rises to a staggering €300,000 per patient. “But with cost-benefit analysis, it’s cheaper compared to carpet-bombing. These patients don’t occupy beds for a lot of time. They’re not in ICU so much — or having antibiotics.” And, after all, he asks: What price can you put on a life?
Anna Barrett, 13, was first diagnosed with leukaemia at age of five. Successful treatment brought her into remission for over four years. Then last summer came the bombshell.
Breathless on the playing pitch, Anna wondered if she was asthmatic.
“She’d been for her six-monthly check-up two months earlier and everything was fine. We said we’d bring it up with her doctor at the next appointment,” says mum Therese.
In June on a school tour to an outdoor pursuit centre, Anna couldn’t keep up with classmates.
“Halfway through the day she was tired, dizzy, and nauseous. The teacher asked if we’d collect her. On the way home in the car she was falling asleep.”
Next evening, Anna’s blood results indicated she needed to go straight to the Mercy Hospital’s leukaemia unit. It was quickly confirmed the leukaemia was back and she was transferred to Crumlin Children’s Hospital, where Minimal Residual Disease (MRD) testing was done – this would guide treatment. She also had a cytogenetic test to identify the leukaemia’s genetic profile. Pending results, Anna was treated much as in 2011 – with chemo drugs that caused vomiting, hair loss, tiredness, and neutropenia.
Over the summer, she developed complications — sepsis, pneumonia, thrombosis — rendering treatment challenging. Her MRD results showed she needed a bone marrow transplant. Anna’s sisters, Natasha (10) and Elizabeth (7) were tested and Natasha was found to be a match.
“Natasha never for one second hesitated. In later life, she’ll realise what a special thing she has done,” says dad-of-three Eddie.
In preparation for bone marrow transplant, Anna went on Blinatumomab, a bispecific T-cell engager antibody — immunotherapy — for 28 days last December. “For bone marrow transplant to be successful, a patient has to be intensely treated to ensure the least amount of residual leukaemia cells in the patient,” says Eddie.
“Blinatumomab is very targeted. Anna was one of the first children in Cork to receive it — only seven in Ireland have had it. She had a far higher tolerance of it — nothing like the side-effects she had with the older treatment.”
For best possible chance of success, patients need to achieve high Karnofsky score pre-transplant. “The older chemo drugs cause fatigue, nausea, weight loss, making it harder to reach a high Karnofsky score. The fact Anna was able to tolerate Blinatumomab meant less side-effects and a higher score,” explains Eddie.
Anna had the transplant in January. She was discharged from the unit 28 days later, which the family understands was an early discharge. Currently on antiviral and antifungal medication, as well as immunosuppressants, Anna’s feeling much better.
“I’m getting stronger,” she says.
“The hardest part [of it all] was wondering would I ever be able to do what other girls my age do. I’ve been told I’ll never go scuba-diving or trek across deserts — but I was never going to do those anyway. I’m very positive I’ll be able to have a normal life.”
Eddie says when families get news of serious disease, it’s very challenging. “Anna told us she felt it was all over. But of course it wasn’t — and it isn’t. You take each hour at a time and there’s hope and light at the end of the tunnel. You have confidence in your medical team. There’s a fantastic team in Cork with Dr Clodagh Ryan and in Dublin with Professor Smith. It wouldn’t be possible without them — and without our family and friends’ support which was huge.”
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