More than 80% of children newly diagnosed with acute lymphoblastic leukaemia (ALL) are successfully treated today – an achievement deemed by Dr Michael Osborn as “one of the true success stories of modern medicine”.

“Back in the 1950s, no child with ALL survived,” said the senior consultant haematologist/oncologist at the Women’s and Children’s Hospital in Adelaide.

Yet there are several key needs that still need to be met for people with ALL, including better treatments for the 10-20% of children with ALL who relapse, developing treatments with less side effects, better treatments for older adults, and new therapies for T-ALL.

These are some of the areas Dr Osborn is working on in his quest “to see all children with leukaemia cured of their disease, and then go on to have excellent quality of life with no long-term side-effects”.

Background on Dr Michael Osborn

Dr Osborn, who is also lead clinician of the state-wide Youth Cancer Service at the Royal Adelaide Hospital and clinical senior lecturer at the University of Adelaide Medical School, chose a career in medicine because he “felt compelled to help people and improve their lives”.

“It sounds like a cliche, but it was absolutely the motivation for me,” he said.

While studying medicine at the University of Adelaide, where he first developed an interest in immunology and genetics, it became apparent to him that the best way to help was to intervene during childhood, “because a healthy childhood often sets people up for a healthy adulthood”. 

This led Dr Osborn into paediatrics, and he trained at the Women’s and Children’s Hospital in Adelaide.

“What kept me in paediatrics was the combination of fascinating science, the interactions with children and their families, and the immense satisfaction of seeing young people returning to normal life after being terribly unwell.”

These same factors then drew Dr Osborn to further specialise in haematology and oncology.

“The treatment of childhood cancer had improved dramatically over the last decades of the twentieth century without a good understanding of the biology. 

“Then, when I was training, the Human Genome Project successfully mapped the 20,000 genes in human DNA. At that time, it was becoming evident to us that the dramatic technological advances that helped us understand normal human genetics might also be able to shed light on the changes inside cancer cells. 

“We hoped that insights into the molecular biology of cancer would help identify potential vulnerabilities in cancer cells which we could then attack with specifically-designed targeted therapies.” he said. 

“It became obvious that we were on the cusp of several new developments within haematology oncology, and we were all feeling very optimistic that this would then translate into better treatments.

“Looking back over the last two decades that I’ve worked in haematology and oncology, there have been a number of examples of that hope becoming reality. We’re continuing to see new understandings in molecular biology being translated into better treatments for patients, and hopefully more cures for childhood cancers.”

It was when Dr Osborn went to the Bristol Royal Hospital for Children in the UK to train in stem cell transplantation that he first developed an interest in adolescent and young adult (AYA) oncology.

“The bone marrow transplant unit in Bristol was a combined paediatric and adult unit at the time, and that really highlighted to me the unique challenges faced by teenagers and young adults who sit between paediatric and adult medicine.”

When Dr Osborn returned to Australia, he undertook adult haematology training at the Royal Adelaide Hospital and continued to develop an interest in haematological malignancies in adolescents and young adults.

“My experience looking after young adults with leukaemia at the Royal Adelaide Hospital drove home to me some of the challenges this age group faced. This coincided with a burgeoning interest internationally in trying to improve the outcomes for teenagers and young adults with cancer.

“One of the first cancers where major developments occurred for adolescents and young adults was acute lymphoblastic leukaemia.”

“For some time, we knew that adults with acute lymphoblastic leukaemia had a much lower chance of being cured than children, but we did not understand why. 

“In the early 2000s, North American and French research found that adolescents who were treated on a paediatric chemotherapy protocol had dramatically better outcomes than adolescents of the same age who were treated on a protocol designed for older adults. 

“At first, many haematologists were very sceptical about this, but almost every subsequent study showed similar findings. Over time, treatment on a paediatric protocol has become the standard of care for adolescents and young adults. 

“I was one of the investigators on the first Australasian Leukaemia and Lymphoma Group (ALLG) study of ALL in AYAs, and this clinical trial influenced Australian haematologists to adopt this approach in young adults much faster than many other countries,” said Dr Osborn. 

“Since then, the ALLG has continued to run exciting clinical trials to improve outcomes for AYAs with ALL. Our most recently completed study, ALL9, will be presented at the highly regarded American Society of Hematology meeting later this year by A/Prof. Matthew Greenwood from Royal North Shore Hospital (Sydney).

“At the same time as these studies, a number of new insights into the biological differences between ALL in children, teenagers, young adults and older adults were identified by some incredible scientists. I have been lucky enough to work with Prof. Deb White and her excellent team at the SAHMRI [South Australian Health and Medical Research Institute], who have become internationally recognised for their work in this field.

“It has been enormously satisfying to see such dramatic improvements in our understanding of the biology and treatment of AYA with ALL, and I am really optimistic that we will find ways to cure more and more young people with ALL.” 

About acute lymphoblastic leukaemia (ALL) – symptoms and diagnosis

Acute lymphoblastic leukaemia is the most common cancer in children, making up just over 25% of new cancer diagnoses in childhood. Even though most children with ALL are now cured, relapsed ALL remains one of the most common causes of cancer death in children.

“ALL is a type of cancer of the bone marrow and blood and, pleasingly, most children diagnosed with ALL will be cured with frontline treatment,” said Dr Osborn.

“In 2022, we usually tell families of newly diagnosed children that their child has an over 80% chance of being successfully treated with frontline therapy. For some biological subgroups of ALL, over 90% are cured, which is an amazing testament to the work of my predecessors.

“Most children with ALL will present with a short history of symptoms that often are not particularly specific.

“Typically, they present with a fever and may have had a few weeks, at the most, of easy bruising, paleness, and sometimes some pain in their legs,” said Dr Osborn.

“It’s usually quite a shock for parents when their child is diagnosed with leukaemia.”

“Typically, they’ll be diagnosed by having a blood test requested by a doctor who is trying to work out why the child has these symptoms. Often the results will show they’ve got low numbers of red cells, platelets, and normal white cells, and often we will see leukaemic cells in their blood when we look down the microscope,” he explained.

“They’ll usually be referred to a haematologist on the same day, and within days will have a bone marrow biopsy and other tests to try and confirm that diagnosis [ALL]. In most cases, treatment will start within a week of being diagnosed. 

“The treatment for ALL is complex, long, and while the outcomes are good, it’s often a very difficult journey for families. They usually need to bring their child into hospital at least once every week for planned treatment in the early months. And often there’ll be some unexpected hospital admissions with infections or needing to have a blood transfusion.

“This intensive phase of treatment will last about seven months. This is followed by a prolonged maintenance phase of chemotherapy. 

“During the initial intensive phase, most children can’t get to school for any significant length of time, and the intensity of treatment means it’s very difficult for both parents to work. 

“Clearly that has an impact on the parents, the brothers and sisters, the whole family, as well as the child’s schooling and education. 

“Thankfully, during the maintenance phase of treatment, life starts to become a bit more normal. A child’s hair grows back, they go back to school, and the frequency of blood tests drops down to once a fortnight. 

“All in all, most children with ALL will be treated for at least two years. So, it’s a long and challenging time for families,” said Dr Osborn.

Relapse in acute lymphoblastic leukaemia 

Most children treated for ALL will stay in remission long-term, “but unfortunately a small proportion, 10-20% of them, will relapse”, said Dr Osborn. 

“If you relapse with ALL, the chance of survival is not as good.” 

“Until recently, less than 50% of children with relapsed ALL would go on to be long-term survivors, but in the last five to 10 years, new therapies have come on the scene that have substantially improved that figure. 

“In particular, drugs like blinatumomab (Blincyto®) and inotuzumab (Besponsa®) have really changed the outcomes for relapsed ALL. Incredibly, CAR T-cells have been able to cure some children who’ve had multiple relapses.”

“However, even with these new drugs, there are some children who still relapse or some children for whom these new drugs can’t be used.

“Blinatumomab, inotuzumab, and CAR T-cells are all for patients who have B-ALL. Unfortunately, there haven’t been any new targeted therapies developed for patients with T-ALL,” said Dr Osborn. 

“Targeted agents like blinatumomab, inotuzumab, and CAR T-cells rely on the leukaemic cells having a specific target protein on the cell surface for the drug to latch on to. If a patient relapses with leukaemia cells that don’t have that target, then those treatments would not be effective. 

“Blinatumomab and CAR T-cells target the CD19 protein on the surface of the leukaemia cells, and inotuzumab targets the CD22 protein. 

“So there is still a need for better treatments for patients with relapsed T-ALL, patients with multiple relapsed B-ALL, or relapsed patients who don’t express the target for these new agents on their leukaemia cells.”

“That’s where our RAVEN study comes in,” said Dr Osborn who is the Australian principal investigator of this innovative new international trial for children and AYA which is being run out of St Jude Children’s Research Hospital in Memphis (U.S.). 

“We hope this approach will be effective in T-ALL and for patients who wouldn’t otherwise be suitable for those other drugs. And for patients who are suitable for those other drugs, we hope that the addition of the RAVEN treatment will result in even better survival outcomes.”

“We’ll be opening the study in early 2023. We couldn’t have had this opportunity without the generous funding of the Leukaemia Foundation and Snowdome Foundation in Australia, and the Minderoo Foundation in New Zealand,” said Dr Osborn.

Another unmet need in ALL is that the treatment used in relapse is very intensive and is often associated with substantial side effects.

“Children can frequently develop life-threatening complications from our current treatment,” said Dr Osborn.

“So, as well as needing to develop more effective treatments, it’s essential that we are trying to develop treatments with less side effects.

“One of the greatest unmet needs in acute lymphoblastic leukaemia is coming up with better treatments for older adults, particularly elderly adults with ALL.”

“That age group often has a very aggressive form of ALL, and they usually can’t tolerate the types of treatments used in children. 

“Interestingly, a number of the treatments that have been effective in children have been implemented for adolescents and young adults. This change in our approach to treating young adults with ALL has dramatically improved the number who get cured,” said Dr Osborn.

“But as people have tried to use those combinations of drugs in people in their 50s, 60s, and beyond, they’ve found that the side effects limit how much of that treatment regimen they can receive.

“There is evolving evidence that the new targeted agents like blinatumomab, added to less intensive chemotherapy or other anti-cancer agents, may be very effective in older adults.

“It will be really interesting to see if venetoclax (Venclexta®) is useful in our paediatric ALL study (RAVEN) and whether it also can be applied to older adults with ALL in the future,” said Dr Osborn.

The risk of relapse in acute lymphoblastic leukaemia

The risk of relapse with ALL varies substantially across different age groups. 

“For children, the highest risk of relapse is if their ALL was diagnosed before age one or after age 10,” said Dr Osborn. 

“In the infants, this is because they often have a particular cytogenetic change in their leukaemic cells called KMT2A rearrangement, which is associated with a highly aggressive form of ALL.

“At the moment Dr Rishi Kotecha from Perth Children’s Hospital is leading some international clinical trials that are trying to improve outcomes in infants with ALL. These studies will be very important in the future treatment of this high-risk group.  

“Toddlers and pre-schoolers more commonly have cytogenetic rearrangements in their leukaemia cells that are associated with better outcomes.

“To explain this concept further, when we look at the chromosomes in leukaemia cells, we see certain patterns of change over and over. This includes extra chromosomes, chromosomes that have broken and fused together with other chromosomes, or missing parts of chromosomes,” said Dr Osborn.  

“We know that some of these patterns of change are associated with a lower risk of relapse and others are associated with a higher risk of relapse. Typically, children in that preschool age group have cytogenetic changes that are associated with a lower risk of relapse. This is the main reason why this age group has excellent survival outcomes.

“In other words, their disease is not as biologically aggressive as what we often encounter in infants or in older people.

“Once people reach their teenage years, we start to see some adverse cytogenetic and molecular changes becoming more common. These are associated with worse outcomes. For instance, there’s an entity called Philadelphia-like-ALL, which increases in frequency in the teenage years. There is also Philadelphia-positive-ALL, which increases during teenage and adult years.

“Much of the difference in survival outcomes in ALL relates to the biology of the disease.” 

“The other issue is that as people get older, they’re often less tolerant of chemotherapy. Even in the teenage years, we see more side effects (such as clots, steroid-induced diabetes, and osteonecrosis of bone) than we see in the younger age group. 

“Then once you get into adulthood, a number of these side effects become even more common.

“The difference in outcomes between different age groups is due to differences in the biology of the disease, and also how people of different ages tolerate treatment differently,” he said.

Advances in molecular biology help in tailoring therapy

“Advances in molecular biology have really helped us to tailor therapy to the individual in ALL,” said Dr Osborn.

“For many years, the early paediatric haematologists did not understand why some children relapsed after conventional ALL treatment, and why others did not. The reason is that there are many molecular subtypes of ALL which are all slightly different to each other. 

“One of our challenges is to try to identify children who are at the highest risk of relapse and give them more intensive treatment, but to not give such intensive treatment to the patients who are destined to do well.

“It’s really important that we try to work out who’s got the higher risk of relapse and who doesn’t, and to tailor their treatment accordingly.”

“Advances in molecular biology have allowed us to identify more children who might be high-risk and more children who might be lower risk, and to then adjust their treatment based on their risk of relapse.

“These advances have also enabled us to identify potential targets for treatment, in other words, to identify the Achilles heel of the leukaemia, and to try and target that specifically with new treatments.

“Older chemotherapy agents typically act on any rapidly dividing cells irrespective of whether they are cancer cells or normal cells. That is one reason why people get so many side effects affecting other normal parts of the body,” explained Dr Osborn.

“The aim of targeted therapies is to target one specific vulnerable aspect of the cancer cell. The more we understand the biology of leukaemia, the more we will be able to identify lesions that we can target.”

Everyone with the subtype, Philadelphia-positive ALL, has an abnormal protein called BCR-ABL.

“Over two decades ago, it was discovered that BCR-ABL could be targeted with a drug called imatinib (Glivec®), and it’s been demonstrated that using imatinib with chemotherapy in ALL results in much, much better outcomes,” said Dr Osborn.

“Prior to imatinib, children with Philadelphia-positive ALL had a poorer outcome even with a stem cell transplant. By adding imatinib to chemotherapy, we’re now able to get away without transplanting a proportion of these children. So we now have much better treatment outcomes because of this targeted therapy.

“In older adults with Philadelphia-positive ALL, a chemotherapy-free approach has been trialled using blinatumomab and a drug that’s similar to imatinib, called ponatinib. This has demonstrated very promising outcomes despite not including any chemotherapy.

“Our hope is that the more we understand the molecular biology, the more we’ll be able to come up with cleverer, more targeted therapies that might not have the same side effects that you see with conventional chemotherapy,” said Dr Osborn.

Tests that identify different types of ALL and minimal residual disease

Several tests are done at the time of an ALL diagnosis.

“Usually, the first indication that someone has ALL is when we look at their blood or bone marrow smear down the microscope and see leukaemia cells, called lymphoblasts. The next investigations are flow cytometry which tells us whether the person has B- or T-ALL, and cytogenetics to look at the chromosomes of the leukaemia cells,” said Dr Osborn.

“And increasingly, we’re looking at the molecular changes in the leukaemia cells as well. 

“Most children in Australia with ALL are treated as part of international clinical trials and most of these incorporate a panel of genetic tests looking for various molecular abnormalities. 

“We have a particular interest in this at the South Australian Health and Medical Research Institute,” said Dr Osborn.

“These tests can detect many abnormalities that would not be detected with conventional cytogenetics testing.

“Interestingly, at relapse, we sometimes see new molecular changes that weren’t present on the person’s original leukaemia cells. These insights are helping us to better understand how and why relapse occurs. This will hopefully help us develop better treatment for relapse in the future,” he said.

“Improved molecular insights have also helped us in measuring the response to treatment. The results of this “minimal residual disease” test are one of the most important prognostic factors in ALL.” 

“The amount of minimal residual disease at the end of the first block of chemotherapy gives us a readout of how sensitive the leukaemia is to chemotherapy. Some of the newer, more sensitive tests that measure minimal residual disease utilise some of these molecular markers.

“Depending on the minimal residual disease results, we can either intensify treatment for patients who have high levels of minimal residual disease or stay on the same treatment path for those who are responding well.

“We are still learning about some of the molecular changes and the molecular landscape of ALL, but with each passing year, we are working out more and more how to incorporate this information into initial diagnostic testing and into risk stratification and it’s becoming part of standard approaches to management.

Improving outcomes through clinical trials

Dr Osborn said that all the children’s haematology/oncology units around Australia are members of either the Children’s Oncology Group (COG) or the International BFM Study Group (I-BFM). 

“And all of them, whenever possible will offer clinical trials to children when they are initially diagnosed as part of their frontline treatment.

Current clinical trials for newly diagnosed children are investigating the role of blinatumomab for standard-risk ALL, and inotuzumab for high-risk ALL.

“And, in the relapse setting, we have participated in clinical trials from various groups including the COG, the I-BFM and, most recently, the St. Jude Study Group.  

“Paediatric haematologists co-operating together in clinical trials has been one of the most important reasons why we’ve been able to improve outcomes for children with ALL.”

“And the hope is that our current clinical trials will further improve frontline treatment, so that there’ll be less patients that we need to enrol on our relapsed ALL studies.

“Even though ALL is the most common cancer in children, most sites would not see enough children to run their own in-house clinical trials. So paediatric haematologists and oncologists from around the world have joined together in collaborative clinical trial groups to try to improve treatments. Typically, they take the current best possible treatment, make small modifications to that, such as adding a new drug or changing the scheduling of one part of treatment. Then over successive clinical trials, we have seen stepwise improvements in outcomes for children with cancer,” explained Dr Osborn.

Looking at history, in the 1940s, American paediatric pathologist, Sidney Farber first started trying to treat some children with leukaemia. While he successfully achieved a remission in some of them, ultimately, they all relapsed. It was then discovered that if the child was given continued treatment with additional drugs after achieving a remission, they lived for longer and a very small proportion did not relapse. Gradually over time, improvements in treatment from clinical trials resulted in more and more children becoming long-term survivors. Now, in 2022, over 80% of children who are diagnosed with ALL will become long-term survivors.

“This highlights how when paediatric cancer doctors from different countries work together in co-operative group clinical trials, we make enormous strides in improving outcomes for children with cancer,” said Dr Osborn. 

“One of the hopes is that in the future, we might be able to omit some of the more toxic elements of treatment and have those replaced by targeted therapies, which would hopefully have less side effects. We are not ready for this yet, but I am optimistic that we are not too far away.”

Anxiety around risk of relapse and late effects

When treating young ALL patients, Dr Osborn said, “our hope is that most of our young ALL patients will go on to live a long and healthy life and achieve the potential that they were going to before they got sick”.

“Once they’ve been through cancer treatment, patients and their families frequently worry about that risk of relapse,” he said.

“When patients come to the clinic for a check-up, particularly in the early years, it can be a very anxious time waiting for those blood results.

“Hopefully, over time, those feelings of worry about relapse reduce, and we try and reassure patients that usually the longer they get after finishing treatment, the lower the risk of relapse. 

“Once the patient is beyond five years after finishing treatment, the chance of relapse is very low.”

“With well over 80% of children with ALL becoming long-term survivors, it’s important to ensure that we are considering their future health. Children who are treated for cancer are at risk of late effects of treatment, and we need to try and minimise these or identify them early.

“One such late effect which is very relevant for adolescents and young adults is fertility,” said Dr Osborn.

“Most young people who are treated for ALL, can still have children of their own when they’re older, although there is a risk of impaired fertility – especially in patients who have a stem cell transplant. 

“Before young patients start treatment for cancer, their doctor should discuss the potential impact on fertility and consider whether anything can be done to help preserve their fertility. For teenage boys and young men, we would usually encourage them to store sperm prior to starting treatment. For some cancers, young women will be given the opportunity to have eggs collected and frozen before starting treatment, but in leukaemia there are frequently factors which make this more challenging to achieve. This is another area where there is important research yet to be done.

“While young females who are treated for cancer may still be fertile after treatment, there is a risk of premature menopause. We often refer young women to reproductive medicine doctors after their treatment to discuss this further, assess their fertility, and to help them make decisions around having children.

“Other late effects we watch out for after ALL treatment are overweight and obesity. Also, a minority of patients can develop cardiac issues. Consequently, ALL survivors should have a heart check at least once every five years for the rest of their life. 

“We want to make sure we’re not causing significant cardiac toxicity with some of our chemotherapy drugs, and we try to limit the risk of late effects in the future,” said Dr Osborn.

“As there is an increased risk of becoming overweight or obese after ALL treatment, I always ask my ALL survivors whether they are currently playing any sports and staying active. Encouraging physical activity and healthy eating in ALL survivors is one way to minimise the risk of weight gain and all of the medical complications that go along with that.” 

Another challenging late effect is that one in five teenagers who are treated for ALL develop avascular necrosis of the bone. This can cause chronic pain, limit activity, and some of these young adults may ultimately need to have a joint replacement.  

“This is another area of real difficulty in the treatment of ALL which we desperately need to come up with better approaches for,” said Dr Osborn. 

There is about a 1-3% chance of developing a second unrelated cancer because of the intensity of the treatment for ALL.

“As a haematologist, I always feel really bad when I tell families about this risk of treatment-related malignancies. Clearly my aim as a haematologist is to try and get rid of cancers, so knowing that some of our treatments can cause a second cancer is very difficult. 

“Thankfully, this is extremely rare. I’ve only seen this complication a handful of times in my career but when it does happen, it’s clearly devastating for the patient and their family.

“The most common treatment-related cancer is acute myeloid leukaemia. This is not a relapse of the original cancer, but a completely new one. Often, treatment-related leukaemias are biologically quite aggressive, and they can be quite difficult to treat.

“Previously, we thought treatment-related cancers were solely caused by the treatment we gave, but increasingly we are finding that these are more likely to occur in patients who have a genetic predisposition towards getting cancer,” said Dr Osborn.

“Whenever somebody gets a treatment-related cancer, we look very carefully at their family’s history and do some genetic tests to see whether they carry a gene for a family cancer predisposition syndrome like Li-Fraumeni syndrome. 

“Not everyone who gets a secondary cancer has one of these cancer predisposition syndromes, but they do seem to happen more often in that situation,” said Dr Osborn.

“Up to 8% of childhood cancers probably have some kind of genetic predisposition behind them.

“We’re still learning a lot more about that, and most childhood cancers cancer are not because of the genes that the child has inherited from their mum and dad, but there is a minority where that is a factor.

“It’s important to identify these cases, not just because the child has an increased risk of another different cancer in the future, but other family members also might have an increased risk as well. If we identify a cancer predisposition syndrome, we can then refer the patient to a cancer geneticist who can advise on appropriate surveillance. That way, we would hope to identify cancers early in such individuals.”

An ALL diagnosis affects all aspects of life now and in the future

For every child or young person with blood cancer and their family, the impact is huge.

“Right from when we first meet a child with leukaemia, we need to think more broadly than just about the disease. We need to think about who the patient is holistically, about their parents and siblings, and all of the different aspects of their life now and for the future,” said Dr Osborn.

“ALL treatment is intense. This often means children miss significant parts of school. For younger children, we try and link in with their school and have the hospital school provide some work for them so that when they finish their treatment and go back to school, they’re not behind in their learning. 

“Even then, some children do struggle with going back to school and several charities provide tutoring to help these children get back on track with their learning.

“Furthermore, school isn’t just about reading, writing, and arithmetic. It’s also about social development, and children who have their schooling interrupted by cancer don’t necessarily have the same opportunities to grow socially with their peers,” he said. 

“This is particularly important for adolescents and young adults, but at any age group we would encourage children to continue to interact with their friends and maintain those relationships because they’re important for their development and mental health. 

“When cancer strikes, it’s not just the child that’s affected. It’s also important for us to think about the broader family. Clearly, the parents and the siblings are very worried.

“Cancer in children affects families in many ways. If children are coming into hospital frequently, it’s often difficult for both parents to work which can create financial difficulties and strain their relationship. So, it’s important we introduce families to social work early on, and direct them to appropriate support groups, like the Leukaemia Foundation, or other supporters of childhood cancer, to help them get the psychosocial support they need,” said Dr Osborn.

Many cancer treatments can result in deconditioning and a decrease in fitness. Dr Osborn said more was being learnt about the importance of children staying active.

“Previously, people had the mentality that if you’re sick, you should rest in bed, whereas we know now that’s one of the worst things you can do for your physical fitness,” he said.

“It’s important to keep those muscles strong, and increasingly we are incorporating aspects of exercise and physical fitness into patients’ treatment. That’s an area of particular interest in our Youth Cancer Service and we’ve recently published one of our randomised control trials in exercise in cancer.

ALL treatments – new therapies, stem cell transplantation and CAR T-cell therapy

Blinatumomab and inotuzumab “have absolutely transformed the way we treat relapsed B-ALL, and CAR-T cells are allowing us to successfully treat patients who, in the past, would have had no other options,” said Dr Osborn.

For Australians with B-ALL, blinatumomab and inotuzumab are now available for patients with relapsed disease, and CAR T-cells are also available for patients with B-ALL meeting specific criteria. Blinatumomab and inotuzumab are also being explored in clinical trials of newly diagnosed children, adolescents and young adults, and also older adults with B-ALL.

“There are further agents on the horizon that are quite exciting and there’s no doubt CAR-T cell technology is going to get better.” 

“One of the big challenges at the moment is to try and develop CAR-T cells or other newer therapies that’ll be useful in T-ALL. This is a really important area of need as T-ALL is lagging behind B-ALL in new therapies.” 

The other interesting class of drugs, which Dr Osborn hopes will be useful in ALL – the BH3 mimetics, like venetoclax and a related drug, navitoclax – is being explored in the RAVEN study for paediatric ALL and is being considered for other studies internationally.

Other potential targets that can be attacked in ALL have been identified and some early phase studies are looking at these.

“I’m optimistic that over the next five to 10 years we’ll be seeing even more agents that can be utilised in this space,” said Dr Osborn.

“Stem cell transplantation is a highly effective treatment in ALL, but it comes with significant side effects.” 

Transplantation is frequently used in relapsed childhood ALL when a patient has an early relapse or high minimal residual disease after having a lot of chemotherapy. While stem cell transplants can cure high risk ALL, they can be associated with potentially life-threatening complications, Dr Osborn said. 

“That’s why we usually reserve stem cell transplants for patients who would benefit the most from it. In children, that means patients who relapse early, don’t respond as well as we would like to relapse therapy or, in some cases, who have a very high-risk leukaemia at the outset,” he said.

CAR T-cell therapy is becoming more and more important, and when first developed there was some hope it might replace bone marrow transplantation in ALL. 

“Bone marrow transplant is still the standard of care for most relapsed ALL patients,” said Dr Osborn.

“But for patients who’ve already had a bone marrow transplant, and relapsed again, CAR-T cell therapy offers another chance of cure. 

“Over the coming decade I suspect our CAR-T cell therapies will become better and better.”

“In the future, it is possible that CAR-T cell therapy will be utilised earlier for some very high-risk ALL subtypes, rather than being reserved for multiple relapsed patients.

“We still need to conduct more clinical trials to work out exactly which patients should get CAR-T cells and when, but for those patients who have relapsed after a transplant or who have refractory disease despite all of our current therapies, CAR-T cells offer hope,” said Dr Osborn.