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Chronic Leukaemia and the future of stem cell therapy for its various forms

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What is Chronic Leukaemia?

Chronic Leukaemia is blood cancer that develops more slowly than the acute form.

Leukaemia is characterised by the overproduction of immature white blood cells, called leukocytes, in your bone marrow.

Because the system is being flooded by immature leukocytes, the normal white blood cells we need to fight disease cannot form properly, leaving you open to infection.

Chronic leukaemia’s slow development means that diagnosis is usually delayed as symptoms may be harder to spot.

Symptoms of chronic leukaemia can include:

  • anaemia
  • fatigue
  • frequent infections
  • bleeding and bruising more easily
  • fever
  • swollen glands in the neck, armpits, groin or stomach

Leukaemias are divided by subtype and severity. Broadly speaking Chronic Leukaemia is more common in older males, but the exception is Juvenile Chronic Myelomonocytic Leukaemia (JCML), which only occurs in young children.

The three main Chronic Leukaemia subtypes are:

Chronic Lymphocytic Leukaemia (CLL)

  • It starts from lymphocytes in bone marrow before spreading to the blood, then to lymph nodes, liver, spleen, brain and spinal cord
  • CLL can be classed as “Indolent” (meaning it grows very slowly) or “Aggressive”, requiring faster treatment and carrying a higher risk

Chronic Myeloid Leukaemia (CML)

  • Forms from the early version of the cells which make white blood cells (called myeloid cells), but it can also start from red blood cells or platelet-making cells (megakaryocytes)
  • It begins in the bone marrow before spreading to the blood – and can spread to other areas of the body
  • Although slow growing, it can become a faster growing acute leukaemia that is more difficult to treat
  • Generally occurs in older, male adults

Juvenile Chronic Myelomonocytic Leukaemia (JCML)

  • JCML begins with the production of abnormal white cells, or monocytes, in the bone marrow
  • It occurs in young children (primarily under 4 years old) and is very rare. Children with the genetic disorder neurofibromatosis 1 (NF1) are more at risk of developing JCML
  • The disease is also known as Juvenile Myelomonocytic Leukaemia (JMML)

How is Chronic Leukaemia treated today?

The CML and JCML forms of Chronic Leukaemia are both treatable by haemopoietic or peripheral blood stem cell transplants.

Following high-dose chemotherapy, the stem cells are infused intravenously into the patient to restore the bone marrow destroyed by chemotherapy.

Usually the transplant uses donor stem cells (allogeneic). You can have your own stem cells re-infused after chemotherapy (an autologous transplant), but this carries the risk of reintroducing cancerous cells.

For CML and JCML, an allogeneic stem cell transplant remains the only cure. However, severe complications such as Graft Versus Host Disease (GvHD) can occur. For this reason, stem cell transplants are usually only recommended for younger patients.

For older patients, treatment via drugs called tyrosine kinase inhibitors (TKIs) are normally used instead. These pharmaceuticals stop the enzymes responsible for activating many proteins — effectively preventing tumour growth. But they do not work for everyone.

For CLL, clinical trials are still being conducted in order to work out the effectiveness of stem cell transplants. Non-myeloablative allogeneic transplantation, or “mini-transplants” using peripheral stem cells without previously using chemo to wipe out the whole of a patient’s bone marrow, have been used successfully on older patients following early diagnosis.

Future science

The precise gene mutations that cause leukaemia are still a key area of research for scientists. Because Chronic Leukaemia is treatable with haemopoietic or peripheral blood stem cell transplants, improving the success of transplants is critical.

Stem cells may have very diverse functions but do not necessarily look obviously different to other cells.

A study published in Cell Stem Cell reveals the first time researchers have isolated single cells from populations of rare blood cells and used a technique to profile and test these stem cells’ capacity for transplantation.

The study, by Professor Bertie Göttgens and colleagues at the Cambridge University Department of Haematology, the Cambridge Institute for Medical Research and the Wellcome Trust/Medical Research Council Stem Cell Institute, brings with it the possibility of identifying the molecules that operate within a single stem cell and the potential outcomes for a transplant.

Although the exact implications for the treatment of cancers like lymphoma and leukaemia are unclear, the hope is that it will lead to the refinement of stem cell transplants, with targeted individual cells chosen.

T-cell Immunotherapy

Stem cells are used in a branch of immunotherapy that is yielding promising results in clinical trials throughout the world. T-cell engineering enables scientists to reprogramme stem cells into T-cells that can seek out and destroy tumours.

T-cells are a subtype of white blood cells and a key part of body’s ability to fight disease because they remember the immune response to different antigens.

The idea behind T-cell immunotherapy, is that a person’s own T-cells can be collected and reprogrammed to fight the leukaemia.

For this to happen, scientists take T-cells from the patient and engineer them to respond to the type of cancer the body needs to fight. This is called a Chimeric Antigen Receptor - which is why T-cell immunotherapy is referred to by the acronym CAR T.

The CAR T-cells can be mass-produced in the lab until there are enough to be re-infused into the patient. Technically these cells are not T-cells, but resemble T-cells.

Chronic Myeloid Leukaemia (CML)

Tyrosine kinase inhibitors, a pharmaceutical drug that inhibits the production of some proteins within our cells, can be used to treat Chronic Myeloid Leukaemia. However, they are not effective for all patients.

Studies are currently being conducted to determine whether they are effective for a greater proportion of patients if combined with other treatments, such as Farnesyl transferase inhibitors, a drug which turns off the function of a protein called Ras in our cells.

Chronic Lymphocytic Leukaemia (CLL)

Oblimersen is a key drug currently undergoing study. Administering this drug alongside chemotherapy has been shown to make it more likely that the Chronic Lymphocytic Leukaemia will stay in remission.

Immunotoxins, man-made proteins that can poison the leukaemia cells, such as BL22 and HA22 (CAT-8015) are also being tested.

A further drug undergoing study is lenalidomide, which is currently used to treat Multiple Myeloma.

Juvenile Chronic Myelomonocytic Leukaemia (JCML)

Current research is focused on reducing the rates of rejection or graft-versus-host-disease following a stem cell transplant. Cord blood transplantation is currently being investigated for this.

If this proves successful, it will greatly increase the size of the pool of potential donors for each patient.

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