Classifying leukaemia: one size doesn’t fit all

Many of us have a moment in our lives where everything changes irrevocably, for better or worse. A moment imprinted on our memories for ever – the birth of a child, a first kiss, the fulfilment of an ambition, the loss of a loved one, a diagnosis of cancer…

For Mel Greaves, then one of our scientists at University College London, a visit to a children’s ward in 1973 was to set the path of his career – and change our fundamental understanding of childhood leukaemia.

“I had colleagues working at Bart’s Hospital and Great Ormond Street who took me round the wards at a time when my own children were two and four years old,” he told us.  “I saw children the same age stricken with leukaemia and found it appalling.

“When I asked: ‘What is leukaemia? What is the underlying problem here?’ it was clear that ignorance was pretty rampant. We had no idea about the nature of the disease except that an expanding population of cells was damaging the bone marrow and children were dying.

“I felt that this must be a tractable problem, so I started asking simple biological questions, such as ‘What sort of cell is involved?’.”

His new found interest was further enforced when he met a little girl who had been cured of leukaemia – at a huge cost to her quality of life. In his scientific ‘autobiography’, he writes:

“This brought home, vividly, the message that potentially curative therapy was an incredibly blunt instrument with harsh potential for collateral damage. And that much remained to be done.”

The right man, the right tools, at the right time

Serendipitously, Mel worked in immunology – the study of our immune system. White blood cells make up an important part of this protective barrier, keeping us safe from infection.   But it’s these cells that that go wrong in leukaemia.

As the diagram below shows, there are different types of white blood cells (leading to different forms of leukaemia). The two main forms are called T lymphocytes and B lymphocytes (often referred to as T-cells and B-cells), a terminology that Mel and his PhD supervisor Professor Ivan Roitt had introduced.

By the mid 1970s, Mel had been working for several years classifying and studying the development of these different cells and how they respond to infections.

To do this he generated a set of molecules called antibodies, that could specifically identify the T- or B-cells, and  could also distinguish between different stages of their development from stem cells, the cells from which all blood cells are produced.

Mel believed that understanding more about how leukaemia cells arose during normal white blood cell development would be key to treating the disease more effectively. His antibodies, together with a new lab technique he’d mastered – flow cytometry (enabling him to rapidly separate and count different types of white blood cell), meant that Mel was one of only two or three people in the world capable of doing this work.

He and colleagues from Great Ormond Street Hospital began to analyse samples of leukaemia cells from young patients with acute lymphoblastic leukaemia (ALL) –  the most common form of the disease in children.

He soon found that cells from different children reacted differently to the panel of antibodies, suggesting that the leukaemia cells weren’t the same in all of them.

In a landmark paper in the Lancet in 1977, they showed that they were able to group the disease into four separate sub-types – ‘T-cell’, ‘B-cell’, ‘common’ and ‘null’. These are now known today as  T-ALL, mature B-ALL, common-ALL and pro B-ALL.

From sub-type to treatment response

But their paper went further than just describing the different ALL types. Using their new classification, Mel and his colleagues turned this knowledge into something useful, by figuring out how the sub-type of leukaemia each child had was related to how well they did after treatment.

The aim of the first part of leukaemia treatment is to induce a state where there are no leukaemia cells visible in the blood or bone marrow, known as remission.

Mel measured both the length of time it took to get children into remission, and how long those remissions lasted. Although all the children had received exactly the same treatment, the outcomes were starkly different for children with different subtypes of the disease.

Almost all the children found to have common ALL or T-ALL had gone into remission within eight weeks of starting treatment.

In the ‘null ALL’ group, it generally took longer to achieve remission for the children who had cancer cells in the middle of their chest (known as a mediastinal mass) than those who didn’t.

And the children with B-cell leukaemia sadly didn’t go into remission at all.

There was more. Children with common ALL had much longer lasting remissions than children with T-ALL. And even within the children with common ALL, there were differences in length of remission, with children who had fewer leukaemia cells in their blood when they were diagnosed doing better.

Previously, doctors had predicted the outlook for individual children with leukaemia based on what they could see – the number of leukaemia cells in the blood or bone marrow, or the presence of a mediastinal mass. This new biological classification gave a valuable extra layer of prognostic information. And this was something doctors immediately started taking advantage of.

Mel’s lab at the Imperial Cancer Research Fund (the fore-runner of Cancer Research UK) became the UK ‘immuno-diagnostic’ service for childhood ALL. They tested samples from every child diagnosed with the disease in the UK to determine what type of leukaemia they had.

This work, showing that ALL was not one disease but a number of distinct subtypes of leukaemia with different characteristics and outcomes, paved the way for treatments to be tailored to each individual child.

Mel and his colleagues realised that if doctors could identify children who ALL type suggested they might relapse, then perhaps their treatment could be intensified to try and get rid of any remaining cancer cells.

And if a child was likely to have a good response to chemotherapy, could their treatment be made less aggressive, to spare them some of the side effects?

This opened up the possibility that treatments could be tailored to each individual child. And it laid the foundations for subsequent clinical trials that have changed the way children with leukaemia are treated to this day.

Meet Rufus

Thursday 2^nd May 2013 is the day that changed the lives of Fiona Egerick and her seven year-old son Rufus.

“It all happened very fast…he was a bit pale and washed out with an aching leg at his birthday party, which turned into chicken pox a couple of days later,” Fiona told us.

“A week later he was still not right, but then, literally overnight, he took a turn for the worse.”

By 8am they were at Chelsea and Westminster Hospital, and later that day Rufus was being rushed to Great Ormond Street Hospital in an ambulance. He had gone from pale and washed out to being unable to move with severe bone pain and a temperature that was off the scale, in a matter of hours.

Fiona then found herself faced with the words no parent ever wants to hear. “When they told me it was leukaemia, my first question was: ‘Is he going to die?’.”

Rufus was diagnosed with ALL. Now, like the vast majority of children diagnosed with leukaemia in the UK, he is having treatment as part of a clinical trial. The study, UKALL2011, is the latest in a series of trials which have been running since the 1970s, to test new and improved therapies.

This research has driven the impressive increases in survival that have been seen in childhood ALL, with almost nine out of 10 children now surviving. But these increases in survival are accompanied by challenging side effects for many children.

The main aim of the UKALL2011 trial is to test whether the best leukaemia treatments we have can be adapted according to the characteristics of each child’s disease and their chances of relapse, to reduce the side effects they experience while still treating the leukaemia effectively.

From past to present

Through trials like UKALL2011, Mel Greaves’s work from the 1970s is still influencing how children with leukaemia are treated today. Leukaemia cells are still classified depending on the type of white blood cell they have developed from, and the number of cells present in the blood at diagnosis is still used as an important indicator of outcome.

His work showing that children with T-ALL have a poorer outlook is reflected in the UKALL2011 trial design. These children are treated with a more intensive combination of treatments upfront, to try and force the disease into remission.

Alongside this, a whole battery of new tests has also been developed.

For example, measuring the number of leukaemia cells still detectable in the bone marrow after the first phase of treatment (so-called ‘minimal residual disease’) can help direct further treatment at the end of the first ‘induction’ phase of chemotherapy.

Children with low bone marrow levels of leukaemia cells have a lower risk of relapse, so as part of UKALL2011, doctors are testing whether it’s possible to safely adapt their treatment to reduce side effects.

The great news is that Rufus and his family have been told that there is a very good chance that he will recover completely from his leukaemia.

But we know that the picture isn’t the same for all children with cancer. That’s why we, like Mel, are continuing our research into understanding the different forms of childhood cancer, how they develop and how we can best treat them.

Understanding the origins of leukaemia

Mel, now Professor Greaves, has continued to investigate childhood leukaemia, focusing on the mysterious details of exactly how it develops, and how to halt its early stages.

He’s uncovered vital information through pioneering studies of sets of twins, where one child developed leukaemia and one didn’t. From this work, he developed a theory of how childhood ALL develops in two stages – the first of these is a pre-leukaemia change that happens before birth.

From a study of blood samples taken at birth from the umbilical cord, it was found that around one in 20 babies has this early change. However, only about one in every 100 of this group goes on to develop leukaemia, as a results of a second, later change that triggers the full development of the disease.

At the moment, the nature of this trigger is uncertain, but Professor Greaves has accumulated evidence that it could well be an inappropriate response to infection, caused by lack of exposure to foreign organisms early in life – the so-called ‘hygiene hypothesis’.

And now, in his 70s, Mel is still very active in research, as Founding Director of the Centre for Evolution and Cancer at The Institute of Cancer Research, in London.

He has continued his work on classifying cancers, and is a globally-respected pioneer of work into understanding the genetic diversity of cancers. Since his early, ground-breaking discoveries, he and other scientists around the world have discovered that, even in a single patient, there is significant genetic diversity between their cancer cells, with different groups (or ‘clones’) of cells showing different genetic changes.

This presents a huge challenge to developing effective, tailored treatments. But by understanding the genetic diversity and how and why it happens, we will open up massive opportunities for tackling all types of cancer in different, more effective ways in the future. And this will continue to help families of children with leukaemia, like Rufus, who are already benefitting from Professor Greaves’s work and the further research that it inspired.

As Rufus’s mum Fiona says: “In the late 1960s, only one in 10 children in Rufus’s position survived – and statistics like that frightened the life out of me. But, one year on from diagnosis, we have been told that, potentially, Rufus has a 95 per cent chance of complete recovery from his illness. This incredible improvement in the odds – in my lifetime – has only come as a result of research.”

We still have a long way to go before every single child survives cancer, but thanks to the work of Mel Greaves, and many other researchers like him, we’re getting there.

Anthea

Reference

• Chessells J.M., N.T. Rapson & M.F. Greaves (1977). ACUTE LYMPHOBLASTIC LEUKÆMIA IN CHILDREN: CLASSIFICATION AND PROGNOSIS, The Lancet, 310 (8052) 1307-1309. DOI: http://dx.doi.org/10.1016/s0140-6736(77)90361-0