Combination of two drugs shows promise in treating B-cell acute lymphoblastic leukemia

A combination of two drugs could improve outcomes and reduce the need for toxic chemotherapy for B-cell acute lymphoblastic leukemia (B-ALL), the commonest cancer in childhood and one that can be particularly difficult to treat in older patients, according to Cambridge scientists.

Although the research has so far only been conducted in cell lines and mice, the team is seeking funding to begin clinical trials in patients shortly.

More than 500 people a year in the UK are diagnosed with B-ALL, many of whom are children, where it makes up 40% of all childhood cancers. Although the disease is curable in the majority of younger patients, the treatment requires over two years of chemotherapy, leaving the patient susceptible to infections and experiencing toxic side effects including bruising and bleeding, hair loss, nausea and vomiting, as well as potential long-term damage notably to nerves, joints and the heart. Outcomes tend to be much poorer for older children and adults.

Every week, I see adult patients who are undergoing treatment for this incredibly aggressive form of leukemia, and although the chemotherapy can cure many of them, the side effects are often really challenging. We need to find treatments that are kinder and more effective."

Dr. Simon Richardson from the Cambridge Stem Cell Institute and Department of Hematology, University of Cambridge

In recent years, new treatments have begun to emerge, including bone marrow transplants and immunotherapies such as CAR-T cell therapy, but these also come with significant side effects and are expensive.

Now, in research published today in Nature Communications, a team led by Dr Richardson and colleague Professor Brian Huntly has developed a new treatment with the potential to be less toxic than current treatment and to be effective in all age groups.

B-ALL is characterised by malignancies of early-stage B-cells. These are cells produced in our bone marrow that play an important role in our immune systems, producing antibodies to protect us from infection. However, in B-ALL, the body produces an overabundance of these cells that build up in our bone marrow and stop healthy blood cells from developing. They can also spread to other parts of the body.

"There's a constant stream of these cells coming out through the bone marrow into the immune system," said Dr Richardson. "The ones that cause cancer are very primitive and not yet useful. They build up in the bone marrow and then often move around the body, such as invading into the brain where they can hide from chemotherapy. It's a really nasty kind of cancer."

Treatments for B-ALL focus on killing these malignant B-cells. The approach being trialled by the team at the Cambridge Stem Cell Institute involves the use of two oral drugs in tandem, venetoclax and inobrodib.

Venetoclax is already used to treat a related condition, acute myeloid leukemia (AML). It works by targeting the protein BCL2 within the B-cells, causing them to die through a process of 'programmed cell death' known as apoptosis. However, venetoclax is not consistently effective in B-ALL.

The team was studying another gene called CREBBP, certain mutations of which contribute to disease progression and are also associated with resistance to chemotherapy in B-ALL. They found that when CREBBP is switched off, it leads to a rewiring of the fat metabolism of B-cells. When BCL2 activity is subsequently inhibited – for example by using venetoclax – it leads to cell death, but by a completely different process known as ferroptotic programmed cell death. This is where the cells are no longer able to protect themselves against damage to the fats in their membranes, causing the cells to become overwhelmed and break down.

The researchers used a new drug called inobrodib, developed by CellCentric, a University of Cambridge spinout company, to switch off CREBBP in human and mouse models of B-ALL. Combining it with venetoclax potently killed early-stage B-cells, even those cells that carried a genetic mutation making them resistant to venetoclax treatment alone.

Professor Brian Huntly, also from the Cambridge Stem Cell Institute and Head of the Department of Haematology, said: "These are very promising findings, and even though our work was only in mice, we're optimistic that we will see similar effects in patients. Venetoclax and inobrodib have already been used together in an early-stage clinical trial for AML, so we know they are safe to use. We now want to trial our approach in adults and teenagers with B-ALL."

B-cells are a vital part of the immune system, and although this drug combination will destroy the cells while the patient is on treatment, the body should begin producing them again once treatment is stopped. This makes this approach potentially much safer than CAR-T cell therapy, for example, which can permanently eradicate the body's ability to produce B-cells.

Dr. Richardson, who is also a Fellow at St. Catharine's College, Cambridge, added: "The good news is that the cost of venetoclax is expected to fall in coming years with the introduction of generic alternatives, making its use much more cost effective."

Professor Huntly and Dr Richardson are Honorary Consultant Hematologists at Addenbrooke's Hospital, Cambridge. Professor Huntly is Chair of the Haematology Service at Cambridge University Hospitals NHS Foundation Trust.

The research was largely funded by Cancer Research UK and Leukemia UK.

The University of Cambridge and Addenbrooke's Charitable Trust (ACT) are fundraising for a new hospital that will transform how we diagnose and treat cancer. Cambridge Cancer Research Hospital, a partnership with Cambridge University Hospitals NHS Foundation Trust, will treat patients across the East of England, but the research that takes place there promises to change the lives of cancer patients across the UK and beyond. .

"There were a lot of sleepless nights – it was really hard": Gill Murphy

Gill Murphy was on extended maternity leave, aged 42, and her daughter had just turned two when her friend convinced her to speak to her GP about feeling excessively tired.

"I'm very pale anyway, thanks to my Irish Heritage, but the GP thought I look particularly pale," she says, "so she ordered a blood test. She thought it might be low iron or anaemia."

It turned out to be far more serious – Gill would be diagnosed with B-cell acute lymphoblastic leukemia (B-ALL). She went into hospital in August 2013 for what she assumed would be an overnight stay. It turned out to be five-and-a-half weeks of chemotherapy.

Prior to her treatment, Gill had been a biomedical researcher studying tumour-suppressing proteins before becoming a programme manager at the Medical Research Council. She knew all about clinical trials – including the fact that patients on trials seem to fare better even when receiving only the placebo – and so requested she join one. She was enrolled onto a trial at the Royal Marsden Hospital, one of the UK's leading cancer hospitals, where she received treatment.

Gill was given chemotherapy alongside rituximab, a trial immunotherapy drug. Chemo drugs can attack every part of your body, not just the cancer. The side effects were terrible, she says, from vomiting and diarrhoea (giving way to horrific constipation) to migraines, hair loss and fatigue. Because she was immunosuppressed, she was unable at times to see her daughter, who developed infections after just starting nursery.

After her first round of chemo, Gill would come home for a week before returning to hospital for more treatment in an ongoing cycle, giving countless blood samples, bone marrow biopsies and lumbar puncture tests and receiving regular chemotherapy into her spine. (The one bright spot, she says, was the steroid dexamethasone, which "can make you feel an awful lot better than you should. So, while my husband was trying to cope with everything at home, with our two-year-old and short working days, I was busy planning a kitchen extension from my hospital bed and overwhelming him with my plans!")

Because of the genetics underlying her leukemia, her medical team recommended a stem cell transplant. With her background in medical research, she knew this was a risky procedure and that she could die as result of the transplant or her blood cancer relapsing – and that even if successful, it was going to make her very ill.

"I'd been quite stoic when I was first diagnosed. I treated it as a project, like, 'Right, you've got to get rid of this cancer'. The longer it went on, the more scared I got. There were a lot of sleepless nights, when I just got out of bed and went and had a cup of hot milk with the nurses. It was really hard."

The treatments Gill received in preparation for the donor stem cell transplant were particularly harsh, she says, probably the worst she felt through the entire process. And then after the treatment, she had to take immunosuppressants to prevent the stem cells turning her immune system against her. There were frequent trips back to the hospital because she was unable to keep food down. She was constantly freezing, wearing layers of coats and cardigans and blankets and a bobble hat at night.

"I remember lying in bed looking through the blinds when I was at home and marking the days by looking at how late the streetlights were coming on, because I was thinking, 'Every day I'm going to get a bit better'."

It worked: the transplant was a success and Gill's leukemia is now in remission.

"I was very lucky. I had a really, really good donor match. I still don't know who my donor is, but I'm so grateful to them for signing up to do something so altruistic. There's no doubt that they saved my life."

Even so, Gill's life has not returned to normal. It has become what many cancer survivors describe as a "new normal". She is still affected by fatigue – not tiredness, but rather a sense of "hitting a wall" if she pushes herself too hard (though she says she can "sleep for every country in the world, not just for England"). Other later side effects have included early menopause, steroid-induced diabetes, cataracts, osteomyelitis in both lower legs and a susceptibility to infections. She believes her cognition and memory have also taken a hit.

Yet despite this, Gill has found a new life as an ambassador for Blood Cancer UK, talking to other patients, researchers and politicians about ALL, sitting on interview panels for the charity, advising on its five-year strategy, and many more tasks.

"We [cancer survivors] all say we want to give something back, but it's true. I've gained more from being involved with Blood Cancer UK as an ambassador than anything I've ever done before."

She has also taken on walking challenges to raise money for Blood Cancer UK, Anthony Nolan and the Royal Marsden: three charities that have helped her immensely over the years.

Gill says that despite how terrible her treatment was, she knows that others have experienced much worse. But she is also keen to stress that in the 12 years since her treatment, things have improved and there are better treatments now available.

"The doctors I meet all want to see kinder, more targeted treatments," she says. "Anything that we can do to improve treatments so more people can survive their blood cancer and fewer people have to go through incredibly harsh therapies is a win-win.".