Chronic lymphocytic leukaemia (CLL)

Chronic lymphocytic leukaemia (CLL)

Chronic lymphocytic leukaemia (CLL) is the most common leukaemia in adults in the UK with around 4,140 people being diagnosed every year.

CLL is a slow growing (chronic) blood cancer that affects white blood cells called lymphocytes, also known as B cells, which are found in bone marrow. Abnormal lymphoctyes build up in the bone marrow, and there isn’t room for enough normal blood cells to be made.

Researchers are still unsure about the exact cause of CLL, but it is thought that it is driven by a protein on the surface of B cells. 

Treatment for CLL depends on how fast the disease develops. Some people develop CLL quickly and feel unwell so will need treatment, others may never need treatment because they have no symptoms. Those who have symptoms are usually given chemotherapy with a monoclonal antibody, such as rituximab, which target a protein called CD20 on CLL cells. Others may receive a biological treatment like ibrutinib - a Bruton’s Tyrosine Kinase inhibitor that stops signals that cancer cells use to divide and grow. 

Our portfolio of research is aiming to find out how CLL starts and what drives the disease, so we can have a better understanding of how to stop this from happening. Although chemotherapy and monoclonal antibodies have provided great benefit to people with CLL, we need to find new drugs and new ways to treat those that stop responding, or relapse. And because CLL has such a varied course of disease, we want to develop tests that can predict the outcome of people, so doctors can tailor the course of treatment accordingly.

B cell receptor in CLL

CLL affects certain white blood cells called B lymphocytes, also known as B cells. 

B cells are part of our immune system and help fight disease. With the help of T-cells, B-cells make called antibodies, which attach themselves to the surface of infectious organisms, alerting the immune system to the presence of intruders. Molecules that can trigger an immune response, such as those found on the surface of bacteria and viruses, are called antigens.  

B cells have molecules like antibodies on their cell surface, which are called B-cell receptors (BCR). In some cases BCRs can also perceive molecules from our own body’s as antigens. 

The exact causes of CLL are unknown. One possibility is that CLL starts when the BCR becomes activated after being exposed to an antigen, causing B cells to divide out of control. Changes to the BCR may also occur through genetic changes, so that it becomes activated in the absence of antigens, but we still don’t know how these changes and BCR activity link together. 

Our researchers are looking at how genetic changes can affect BCR activity. Understanding this link is really important now, because new drugs that block the activity of the receptor are only effective if the BCR is active.

It’s also becoming apparent that CLL cells can find ways to overcome drugs that inhibit the BCR pathway. So our research is looking into why drug resistance happens, and exploring ways to reverse this. 


Predicting how people with CLL will respond to new BCR inhibitors

Lead researcher - Dr Francesco Forconi, University of Southampton
Leukaemia Chronic lymphocytic leukaemia (CLL)
The influence of altered genetics on B-cell receptor levels and function in CLL
Dr Forconi is defining the genetic alterations that change the activity of the BCR. This research could identify novel genetic markers associated with BCR activity, and possibly predict how people with CLL will respond to new BCR-inhibitors.

Tackling drug resistance in CLL

Lead researcher - Dr Andrew Steele, The University of Southampton
Leukaemia Chronic lymphocytic leukaemia (CLL)
B cell receptor signalling is modified by IL-4 in chronic lymphocytic leukaemia (CLL)
Signals produced by T cells, another type of blood cell, are able to enhance BCR signalling in the laboratory, and can cause resistance to drugs like ibrutinib.  Dr Steele and his team want to understand how this happens, so that they can develop new treatment strategies to tackle drug resistance in CLL.

Finding new treatments for people living with CLL

Chemotherapy and rituximab are providing excellent benefits for people with CLL. But not all people will do well on these drugs, and some eventually relapse. At the moment bone marrow transplantation is the only true cure for CLL, but some people may not be able to undergo this treatment because they are too frail. 

We are supporting clinical trials that are testing new biological treatments for people with CLL. Researchers are also looking for treatments that will slow down the disease in its early stages, so we can prevent progression and the need for strong drugs.

CyCLLe trial

Chief investigator - Professor Stephen Devereux, Kings College London
Chronic lymphocytic leukaemia (CLL)
An investigation of the effect of cyclosporine-A in chronic lymphocytic leukaemia: Development of a novel in-vivo strategy for dissecting the mechanism of drug action
Researchers are looking for treatments that will slow down the disease in its early stages and prevent progression and the need for such strong drugs. They want to see if cyclosporin A can affect the rate at which leukaemia cells grow, and if this could be an effective treatment for people with early CLL. 

IciCLLe extension

Chief investigator - Professor Peter Hillmen, St James's University Hospital
Chronic lymphocytic leukaemia (CLL)
A phase II assessment of the mechanism of action of PCI-32765 in B-cell receptor pathway inhibition in CLL
Bone marrow transplantation is the only cure for CLL at the moment, but some people may not be able to undergo this treatment because they are too frail. Chemotherapy can be effective, but can have serious side effects especially in older people. Researchers know that ibrutinib works for people with CLL, but they want to see if combining it with obinutuzumab gives added benefit.

Harnessing the immune system to attack leukaemia cells

Lead researcher - Professor Linda Wooldridge
Leukaemia Chronic lymphocytic leukaemia (CLL) Large granular lymphocytic leukaemia (LGLL)
Defining the antigen specificity of CD8+ T-cells in leukaemia
Professor Wooldridge is finding out why a particular type of T cell can divide without control. In some situations this can be harmful causing leukaemia, or it can sometimes be useful as the T cells can kill leukaemic cells. The team will use a new approach to find out what causes the trigger, which could help them harness the killing power of the T cells.

Switching off blood cancer cells

Lead researcher - Professor Graham Packham, University of Southampton
Leukaemia Chronic lymphocytic leukaemia (CLL)
Opposing kinase activation in B-cell malignancies – biology and therapeutic targeting of the SHIP1 phosphatase
Professor Packham’s team are exploring new ways to switch off the ‘keep growing’ messages in blood cancer cells. They are looking at proteins called phosphatases, which tell the cell to stop growing, and will see if there are drugs that help these proteins work. As not much is known about phosphatases’ role in cancer, this may open up new and exciting ways of treating blood cancers.

Reapplying the brakes in out of control CLL cells

Lead researcher - Dr Alison Michie, University of Glasgow
Chronic lymphocytic leukaemia (CLL)
Elucidating the mechanisms that regulate FOXO activity in chronic lymphocytic leukaemia – a novel target for therapeutic exploitation?
A group of proteins called FOXO can work like brakes in our cells, preventing them from growing too quickly. However, in chronic lymphocytic leukaemia (CLL), FOXO proteins can’t do their jobs properly. Dr Michie is exploring ways to reverse this, which may highlight a new way to treat CLL.

The STELLAR trial: Finding new treatments for Richter’s syndrome

Chief investigator - Dr Anna Schuh, University of Oxford
Chronic lymphocytic leukaemia (CLL)
STELLAR - A phase II randomised study of CHOP-R in combination with acalabrutinib compared to CHOP-R followed by acalabrutinib at disease progression for patients with newly diagnosed Richter’s syndrome
In this trial, researchers are adding a targeted drug called acalabrutinib to the standard treatment for Richter’s syndrome, an aggressive blood cancer that can develop from chronic lymphocytic leukaemia.

New tests to predict the outcome of CLL

We know that every person’s disease is different. Some people’s blood cancer may not develop much after diagnosis, and they might not need treatment straight away. But in others, the blood cancer can be aggressive and treatment is needed quickly.

Our research is studying the genetics and cell biology of CLL in different people to find out why there is such a variation in the clinical course of the disease. Knowing how a newly diagnosed person with CLL will progress could help guide doctors with their treatment decisions.

Developing a new test to predict the outcome of people with CLL

Lead researcher - Professor Duncan Baird, Cardiff University
Leukaemia Chronic lymphocytic leukaemia (CLL)
Telomeric prognostics
Our research led by Professor Baird has shown that the length of telomeres – the protective caps at the end of chromosomes – in CLL cells is a good predictor of whether the disease is likely to be aggressive or not. The team now will turn these findings into a quick and cheap diagnostic test, which would help doctors decide when and how best to treat a person newly diagnosed with CLL.

Tackling treatment resistance

Chemotherapy and monoclonal antibodies like rituximab are providing excellent benefits for people with CLL. But unfortunately, some people do not respond well to this type of treatment, or eventually relapse.

Resistance to treatment can happen when cancer cells acquire genetic changes to certain genes.

About 1 in 10 cases of CLL have genetic changes to the NOTCH1 gene, which can cause resistance to anti-CD20 monoclonal antibody-based treatments, such as rituximab. NOTCH1 is part of a signalling pathway that has lots of functions. It plays a key role in determining how different specialist types of cell develop, and it regulates cell growth, division and death.

CLL cells can also have changes in the ATM and TP53 genes, which in healthy cells produce proteins that check for DNA damage in the cell before it divides. In CLL cells that carry these gene changes, the proteins that check for DNA damage proteins are missing. People with CLL who have the missing proteins tend to respond poorly to chemotherapy, which works by damaging the DNA of rapidly dividing cells. They are also more prone to relapsing, and generally have a poorer outcome.

Our research wants to explore the mechanisms of drug resistance, and investigate possibilities for reversing it. We also want to find the right therapy choices for people who carry gene changes that cause drug resistance.

Tailoring therapies for people with treatment resistant CLL

Lead researcher - Professor Tatjana Stankovic, University of Birmingham
Leukaemia Chronic lymphocytic leukaemia (CLL)
New approaches for tackling refractory CLL
Professor Tatjana Stankovic and her team are analysing samples from people enrolled in clinical trials, so they can look at behaviour of blood cancers with defective ATM and TP53 cells. As part of this project, researchers will also test in the laboratory individual patients’ cells to determine which currently available treatment is most efficient in eliminating these cells.

Overcoming drug resistance in CLL

Lead researcher - Dr Stephen Beers, University of Southampton
Leukaemia Chronic lymphocytic leukaemia (CLL)
Understanding the regulation of antibody therapy by NOTCH1 mutations in CLL
Dr Beers and his team are using samples from people with CLL to discover the underlying mechanisms of rituximab resistance in CLL. They want to investigate possibilities for reversing resistance, which could lead to designing better treatment strategies for people with leukaemia and lymphoma in the future.

Why do CLL cells behave differently in different parts of the body?

Lead researcher - Professor Chris Pepper, University of Sussex
Chronic lymphocytic leukaemia (CLL)
In vitro modelling and therapeutic targeting of tumour cell migration in chronic lymphocytic leukaemia
Chronic lymphocytic leukaemia (CLL) cells can gather in the lymph nodes, where they grow more quickly and are much less treatable than CLL cells in the bloodstream. Professor Pepper and his team are exploring why this difference exists, and whether it’s possible to target CLL cells in the lymph nodes better than we currently do.

Using biobanking to drive the discoveries in CLL

Biobanking means collecting, processing and storing blood, fluid or tissue samples from people with a disease, or healthy people. 

We are collecting samples from people with CLL who are taking part in clinical trials. Using this rich resource, researchers hope to find new treatments for CLL, and design tests that will guide treatment decisions.

Biobanking: developing new treatments and tests for people with CLL

Lead researcher - Professor Andrew Pettitt, University of Liverpool
Leukaemia Chronic lymphocytic leukaemia (CLL)
Cell Bank: Core support for biobanking as part of NCRI trials in CLL and lymphoma
Professor Pettitt is collecting samples from people who have entered CLL trials in the UK. Using the biobanked samples, researchers will study CLL in great detail, shedding light on how the disease starts and progresses. The work will help to develop new targeted therapies for CLL that will be tailored to the needs of the individual patient. The bank complements the Southampton UK CLL biobank.

Biobanking: helping to improve the lives of people with CLL

Lead researcher - Dr Francesco Forconi, University of Southampton
Leukaemia Chronic lymphocytic leukaemia (CLL)
Cell Bank: Renewal of a non-trial CLL and mature B-cell malignancies tissue bank as a national resource
Dr Forconi is collecting samples from people with CLL in the UK who have not been entered in a clinical trial. The bank complements the Liverpool UK CLL biobank, which collects samples from people entered in a clinical trial. Samples from this bank have already been used to further our understanding of CLL, and to discover new therapies.

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