FAQs

What is Leukaemia?

Leukaemia is one of a group of cancers commonly referred to as cancers of the blood. More accurately leukaemia originates from one the various types of cells that produce normal red and white blood cells. These so called normal haematopoietic cells are located mainly in the bone marrow but can also be found in the thymus gland and elsewhere. It is the malignant transformation of just one individual bone marrow cell into a cancerous form that brings about the disease we call leukaemia. Because leukaemia originates from just one single bone marrow cell that then divides unrelentingly into billions of other identical malignant cells, the disease is said to be clonal. This is also the
case for the majority of other cancers in both adults and children.

There are several different types of leukaemia but these can be broadly divided into two major groups, lymphoblastic leukaemia and myeloid leukaemia. The type is determined entirely by which kind of haematopoietic cell becomes cancerous. Lymphoblastic and myeloid leukaemia are very different and each requires different type of treatment treatment.

Lymphoblastic and myeloid leukaemia can be further subcategorised into acute and chronic forms. The acute form occurs when the haematopoietic cell that becomes cancerous is at an immature state in its development at the point in time that it becomes leukaemic. Consequently all leukaemia cells in acute leukaemia look immature under the microscope and are called “blasts”. Chronic leukaemia on the other hand is when the malignant cell arises from a more mature precursor blood cell and looks more like a fully developed normal blood cell under the microscope. Malignant blood cells for both types of leukaemia still fill up the patients’ blood, bone marrow and other organs with useless cancerous cells but this process is far slower and indolent for chronic leukaemia than it is for acute leukaemia.

If left untreated, acute leukaemia will overwhelm and kill the patient very rapidly, usually in a matter of weeks, whereas chronic leukaemia is much slower burning and something patients may live with for many months or even years without treatment. This is because acute leukaemia cells grow and divide very rapidly, aggressively replacing most of the normal blood making cells in the bone marrow and elsewhere. This reduces or even completely abolishes the patient’s ability to make normal white and red blood cells and leads to rapid death. Chronic forms of leukaemia and quite rare in children but common in older people.

Acute lymphoblastic leukaemia (ALL) is the most common cancer in children and represents 75 – 80% of all childhood leukaemias with the other 25% being acute myeloid leukaemia (AML). In adults this figure is reversed with 80-85% being AML and only 15-20% ALL. Cure rates for adults and children are also very different even with the same or very similar treatment. After several decades of intense laboratory and clinical research ALL is now cured for between 85-90% of children using cocktails of drugs developed over many years. In contrast the cure rate of adult ALL is only between 40-50% depending on the age of the patient. Research has shown that these differences between adults and children are likely due to biological and genetic differences in the leukaemia cells that emerge from the single transformed haematopoietic cell.

Despite the enormous success that has been achieved over the past four decades in curing childhood leukaemia there is still much that can be done to reduce the toxicity and resultant dangers associated with current chemotherapy. The research strategy that Leukaemia Busters has always and continues to pursue has been to discover new improved, less toxic and thus far safer therapies to treat both newly diagnosed patients and patients who have relapsed or who are resistant to initial upfront treatment. This can only be achieved through further basic discovery and clinical research that is specifically tailored to devise new forms of gentler and safer treatments that are at least equally or preferably even more effective. Read more about this scientific challenge under the “What is the Treatment” and “immunotherapy” sections.

What is the cause of Leukaemia?

Leukaemia is the result of mutations or other changes in the DNA of master genes that control the normal behaviour of blood cells.

There is no simple answer to this question but what we can say is that leukaemia like all other cancers is caused by mutations and other of changes in genes that normally control the behaviour of normal cells. A whole multitude of different genes have been discovered in every type of leukaemia whose DNA has been altered in some way that then causes the gene to get inappropriately turned on or off.

Many of the affected genes are master switches that control the rate and extent to which cells divide, grow or die and should a gene that controls cell division get turned on permanently or a gene that inhibits cell growth or causes a cell to die get turned off due to a mutation then that cell begins dividing uncontrollably and a malignant transformation to leukaemia ensues. There are many genes that have been described with names such as the fusion of two different genes called ETV6-RUNX1 in B-Cell acute lymphoblastic leukaemia (ALL) or PHF6 in T-cell ALL.

This is a simple explanation to a story that is very complex, often with changes in multiple genes being detected that can vary from patient to patient even when it is the same form of leukaemia. Research has uncovered that when certain genes are affected this results in a poorer outcome for patients and on the flip side mutations in certain other genes lend a better prognosis to the patient. This is still an active area of research and discoveries made in the past now help guide clinicians on the type and intensity of treatment needed, leading to better outcomes for patients with known genetic abnormalities in their leukaemia cells.

The obvious question is what causes the mutations and other changes in the DNA of affected genes in the first place? In some instances this could be a spontaneous event where an “error” is made by the cells own molecular machinery that is responsible for repairing or duplicating the DNA each and every time the cell divides. Other environmental factors such as cancer causing chemicals (carcinogens) in food, water and air, ionising radiation from natural and unnatural sources and some types of virus can cause mutations and other changes to DNA and could also add to or amplify any spontaneous event. The scientific discipline that studies the relationship between environmental and other lifestyle factors associated with diseases is called epidemiology and is an active area for research in leukaemia and many other diseases in general. There is also some evidence from identical twin and other studies that the initial genetic change that eventually leads to leukaemia in a child occurs when the baby is in the womb possibly because the mother is exposed to radiation or carcinogenic chemicals in the environment. This initial DNA damage to a key gene that occurs in utero may not be sufficient to cause leukaemia on its own but then if the child then encounters a further DNA damaging event to other key genes after birth then this may provide the final triggering event.

Many parents, whose children have been diagnosed with leukaemia, report that their child had a severe viral-type infection just before diagnosis and this has led some researchers to speculate that there may be a link here. However, there is little evidence to support this and there needs to be caution in over-interpretation as it may well be that the leukaemia was present before the infection and that it was the leukaemia that caused decreased immunity that led to the infection.

Another school of thought, for which there is growing evidence, states that early childhood infections have a protective effect against the development of leukaemia in later childhood. This is thought to be due to the modifying effects that infections have on the development of the immature immune system in children that trains it in as yet little understood ways that in some way affords . Again, more research in this area will undoubtedly uncover the full details behind this effect and possibly lead the way towards being able to eventually prevent some if not all childhood leukaemia’s in the future.

The picture is clearly very complex and is most likely multifactoral involving two or more separate mutation events separated in time. Continuing research in this area will eventually uncover the true causes but for now

What is the treatment for Leukaemia?

Chemotherapy is the main type of treatment for leukaemia though in a small number of cases radiotherapy may also be necessary under certain circumstances. Chemotherapy involves the administration of cocktails of cytotoxic drugs intravenously (directly into the bloodstream), subcutaneously (just under the skin), intrathecally (into the spinal fluid) or by mouth as tablets. The different routes of administration for each type of drug is important and has been worked out over many decades of clinical research. What is also important is the combination of drugs used and the schedule on which they are given, again something worked out through clinicalm research over many decades.

Cytotoxic drugs work by interfering with vital processes within the leukaemia cell that allow that cell to live. There are many different types of cytotoxic drugs, some that attack the cells ability to divide by directly damaging DNA or by inactivating enzymes involved in DNA replication or repair, others that inhibit essential metabolic processes and others that act to persuade the leukaemia cell to commit suicide.

The majority, if not all forms of chemotherapy, are toxic to the leukaemia cells as well as normal cells in the patients body, in other words they are not selective. This results in side effects for the patient that can be life threatening if any major life sustaining organs or tissues are affected not managed correctly.

Following decades of laboratory and clinical research, new treatments have recently become available that draw on the body’s own immune system.

How does research work?

Everybody has heard of research and that without it we cannot make progress but exactly what is it and how does it work? Here the charity’s Scientific Director, Dr David Flavell answers this question and explains exactly why research is absolutely vital to improving existing treatments and in devising new ones for leukaemia and other cancers.

Put simply, research by definition is the process by which new facts are discovered about anything. This new information can then be put to good use for improving something that already exists by understanding it better or even to invent something that is entirely new. This is exactly the approach that Leukaemia Busters funded scientists have always adopted in pursuit of their potentially lifesaving research and it is the approach that has been proven time after time as the most effective way to conduct medical research that leads eventually to clinical improvements.

Research is not an activity conducted by researchers working in isolation, it is a process that involves the sharing of new information with other scientists worldwide, usually through the publication of scientific papers but also through specialized scientific and medical conferences and through personal contacts and collaborations between different laboratories with common interests. Research networks can grow as agglomerations of multiple bodies of research scientists often scattered around the globe who pursue a shared research interest together, with each contributing their own particular skills and know-how to the group. This is often termed the multidisciplinary approach and has an real accelerating effect on what is possible. Whilst such large bodies of collaborating networks of scientists can reach a critical mass for making discoveries this is not to underestimate the value of the individual or small teams of researchers who make valuable contributions to the body of knowledge that can then be drawn on by others.

In a nutshell there are basically three types of research in medicine each seamlessly integrating with each other to achieve the right outcomes at improving patient.

Basic Discovery Research

Basic or discovery research is laboratory based and is designed to uncover new facts about fundamental biological processes relevant to a particular disease. This type of research doesn’t always have an obvious immediate practical application. However, it is often the case that discoveries made this way are found to have an important practical value, many years into the future. Scientists who work in translational research (see below) are always on the lookout for basic discoveries made previously by others that they see can likely be turned into something of practical value either in the diagnosis, therapy or general care of patients.

But how does the discovery research process work? It begins with an observation that raises an unanswered question. A simple example would be something like this – some types of cancer cells grow in the laboratory more quickly than others and the research scientist asks the question “why?” The researcher may then do some online research searching the scientific literature and talking to other colleagues to find out which genes have been discovered that might account for such a difference in growth rates. The scientist will then create a hypothesis that speculates which gene or set of genes might be responsible and why. They then devise experiments that are designed to “test” their hypothesis and to prove if it is correct or not. If it is correct then this leads to further experiments to investigate things in more depth. If experiments prove their hypothesis wrong then it’s back to the drawing board, the hypothesis will be discarded and the researcher will have to look at other explanations and construct an alternative hypothesis that can be tested once again. The process continues and eventually the true facts emerge through an iterative process of hypothesis testing that is aptly named hypothesis led research. This is at the heart of all basic discovery research.

Translational Research

Translational research is really a direct extension of basic research that is focused on taking and developing results that look promising as being of practical application for patients. Scientists and institutes often work on basic and translational research in parallel. The secret of successful translational research is to be able to identify those discoveries that are most likely to be developed into something of practical value for patients. Once this has been identified it is the job of the translational research scientist to think of ways in which the discovery can be practically applied and to conduct experiments that demonstrate this. Such an example might be the further development of an antibody discovered through basic research that laboratory and animal experiments have shown to have positive therapeutic effects.

Clinical Research

Ultimately it is the intention of all research to be of direct benefit for cancer and leukaemia patients. This is achieved through meticulous clinical studies in the form of clinical trials that carefully test in real world patients whether a new treatment is both safe and effective against the cancer in question. The clinical trial process to approve a new drug can take many years and is expensive but it is currently the only assured way of knowing that a drug is safe and of any potential therapeutic value against the cancer in question. Formal clinical trials are complex undertakings and are carried out under a strict protocol that requires a multidisciplinary approach involving teams including specialised nurses, laboratory staff, pharmacists, statisticians, research managers and physicians to name but some.

Clinical trials can be broken down into four distinct phases.

Phase I

A phase I trial marks the very beginning of a long process that leads eventually to a new drug being approved for general use in patients with a specific disease. Phase I clinical trials in cancer usually involve a relatively small number of patients, maybe 20 -30 at most. The primary purpose is to evaluate the safety of the drug by administering increasing doses of the drug to cohorts of usually three patients and then escalating the dose for subsequent cohorts according to a strict mathematical formula. Patients are monitored very carefully for adverse effects or toxicities that are thought to be due to the drug until a dose level called the maximum tolerated dose (MTD) is reached where certain side effects of a given intensity are seen. The MTD is taken as being the starting dose for a follow-on Phase II clinical trial.

Phase II

Having established the safe dose to use in Phase I, a Phase II trial is designed to establish an estimate of the response rate using the drug at the MTD. Again, this usually involves a relatively small number of 20-30 patients. If this trial demonstrates that 20 percent or more of patients show a response to the drug without any serious side effects then the trial may progress to Phase III (see below)If any unexpected side effects arise in these Phase II patients or of there are no therapeutic results, then the Phase I trial may be repeated to re-evaluate the MTD, or the development of the drug may be discontinued.

Phase III

If all goes well in the Phase II trial and responses are seen without serious side effects, then large numbers of patients, that can number up to several hundred, are recruited into a Phase III trial and treated at the MTD dose. This is to get a more accurate evaluation of the response of the cancer to the new drug and is often called the pivotal trial. If the response rate is shown to be good without any serious side effects, then the drug can proceed to a Phase IV trial or trials.

Phase IV

The Phase IV trial usually involves large numbers of patients and is intended to compare the new drug against existing best current treatments or alternatively to incorporate the new drug into existing established drug cocktails (regimens) to determine whether adding the new drug to existing treatments improves the therapeutic effect for patients. These types of advanced trial are usually done on what is called a “double blind” basis to avoid any bias in the interpretation of results. Patients are split into two groups, one that receives the existing best current treatment plus a placebo (a dummy drug) and the other that receives the same existing best current treatment plus the new drug. Neither the patient nor treating physicians know who is receiving which treatment to avoid any bias in the observed outcomes. Groups of patients in Phase IV studies need to be large so an accurate statistical analysis can be undertaken to say definitively whether the drug is genuinely active.

At Leukaemia Busters we have always adhered to all these best practice principles that drive good meaningful research. It has been proven many times over that doing so leads to discoveries of real practical value for patients and is the best route to progress through so called evidence-based research in medicine.

What is immunotherapy?

The treatment of cancer has been revolutionised within the past two decades by the slow but sure, successful development of immunotherapies for a whole range of malignant tumours. Leukaemia and lymphoma in particular have benefited greatly from these developments.

Immunotherapy is one form of biotherapy that harnesses the power of the body’s own immune system or synthetic components derived from it, to selectively destroy cancer cells, without, in theory, damaging other normal cells in the patient’s body. The concept is not new and dates back over one hundred years to the time of William Coley, Paul Ehrlich and Frank Macfarlane Burnet to name just three of many other scientists and physicians who in the previous century pioneered this approach. It has taken until very recently to reach a point where immunotherapies have come into mainstream use simply because it was necessary to develop technologies that were just not available in those earlier days. It is those technologies that have now successfully enabled their development for safe and effective clinical use.

Immunotherapy is not one single treatment but rather a collection of different related treatments that utilise different aspects of the immune system to attack and kill cancer cells. This can be either through commandeering the patient’s own immune system directly or by artificially engineering antibodies or cells in the laboratory that can then be administered directly into the bloodstream from where they go on to attack and selectively kill cancer cells. It all sounds quite simple but in reality is highly complex requiring intensive research. The development process aimed at improving new immuontherapy treatments is still ongoing. Much more research is needed in order to refine and increase the effectiveness of these types of new so-called “biologic” therapies to the point where they effect cures in as many patients as possible without causing any serious side effects.

Image Credit to Dr Andrejs Liepins

These are the main different types of immunotherapy in use today

Antibodies.cdr

Immune Checkpoint Inhibition
ICI is the active stimulation of the patient’s own immune system using antibodies that act to take the brakes off the patient’s own immune system allowing the patient’s own killer T-cells to recognise cancer altered antigens (neoantigens or new antigens) on the cancer cell and then kill it. ICI is proving highly effective for a proportion of patients with solid tumours containing a large number of mutations such as malignant melanoma and lung cancer but in general it has been less successful for leukaemia and lymphoma patients. Understanding why this is the case may provide the key to also making this work for leukaemia patients and research into this area is actively ongoing.

Antibodies
Naked antibodies that are designed to attach to specific molecules termed antigens on the surface of the cancer or leukaemia cell either send a signal to the target cell to die or attract the patient’s own killer cells or killer proteins to the cancer cell surface where they are able to kill it. Highly successful examples of antibodies in regular clinical use now are Rituximab used against B-cell lymphoma and leukaemia and Daratumumab used in multiple myeloma but there are many others now available against a variety of different target antigens.

Antibody Drug Conjugates or ADCs
Antibody Drug Conjugates or ADCs is where a powerful cytotoxic drug is attached to an antibody that when injected into the bloodstream selectively seeks out the cancer cells and delivers the drug only to that unwanted cell. The selective delivery of drug by the antibody avoids exposing the majority of normal cells and tissues in the patient’s body to the drug thus reducing the toxicity whilst at the same time increasing potency.

Immunotoxins
Similar to ADCs but these antibody-based drugs use a large protein toxin instead of a small molecule cytotoxic drug. There are two immunotoxin-type drugs available for use in hairy cell leukaemia and cutaneous T-cell lymphoma that have proven highly successful. Immunotoxins is the research area that Leukaemia Busters scientists focussed their research on in earlier years.

CAR T-Cell Therapy
This approach is proving highly successful for patients with relapsed or resistant leukaemia and lymphoma.CAR T-cell therapy is really a living drug that not only kills large numbers of leukaemia cells upfront but also continues chipping away at any remaining leukaemia cells for months or even years after treatment. This type of immunotherapy is complex and involves taking the patient’s own T-cells, then genetically engineering them in the laboratory in such a way that when they are infused back into the patient they actively seek out and destroy the leukaemia cells they are designed to recognise. CAR-T cells are serial killers of cancer cells that go on working against any residual leukaemia cells for months or even years after infusion thus preventing a relapse of the disease.

Image Credit: Medical University of South Carolina

Vaccination
Vaccination gainst cancerous tumours that express neoantigens is another developing immunotherapy that holds great promise for some types of cancer including some leukaemias and lymphomas. Neoantigens are normal proteins in the cell that have been changed by one or more mutations in the cancer cell. This is also under active investigation and is also showing some positive signs of success in a number of cases.

Immune Modulators
Immune modulators are molecules that modify the activity of the patient’s own immune system in a way that stimulates the killing of tumour cells. Such examples are the messenger cytokines and TLR agonists that activate killer immune cells in the patient to actively destroy unwanted cancer cells.

Oncolytic Viruses
Certain viruses can be engineered to infect only tumour cells using immunological methods. Once inside the cancer cell the virus multiplies incessantly inside to the point that the tumour cell fills up internally with virus and eventually bursts open.

All these immunotherapies are very different from today’s conventional chemotherapy where the cytotoxic drugs used are very toxic, poisoning normal as well as leukaemia cells and therefore causing significant, sometimes life-threatening side effects. Indeed it is true to say that patients can and do sometimes die not due to the leukaemia but to the side effects of chemotherapy that suppresses normal blood cell production leaving patients vulnerable to infections, bleeding and profound anaemia. Immunotherapy in contrast launches a focussed attack on cancer cells avoiding much of the damage caused by chemotherapy and has begun to change cancer and leukaemia treatment dramatically.

Image Credit: Inaba & Pui https://doi.org/10.3390/jcm10091926

Potentially, further research could refine immunotherapy to the point of success where it replaces chemotherapy entirely but for now chemotherapy, often used alongside immunotherapy, is still a necessary weapon in the oncologists armory. Further research could well change that and eventually make chemotherapy obsolete to be replaced by safer and more effective treatments like immunotherapy and other targeted drug treatments. At Leukaemia Busters we are striving exactly towards this important vision of the future through the research we support with a firm belief that we can, working together, change things for the better for all patients.

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