Professor Andrew Cant
For many illnesses and conditions there is more than one treatment option, and not all treatments are suitable for everyone. Haemopoietic Stem Cell Transplantation (HSCT) is an option for some patients with CGD and in the future, gene therapy may be another. However, while we are hoping for a good outcome to the gene therapy trials it is important to remember the progress that has taken place in HSCT and it has become very successful. For each patient the potential risks and benefits of each possible treatment need to be carefully weighed up. Professor Andrew Cant has provided the following update about HSCT:-
Sixty years ago nuclear weapons were unleashed. In the aftermath of this cataclysmic event, many people died because radiation killed their bone marrow. Studies were then performed to find out how to protect individuals from deadly radiation, and scientists found that transplanting bone marrow stem cells - more correctly described as pluripotent Haemopoietic Stem Cells (HSCs), from a healthy donor could lead to the return of all the cells of the haematological and immunological systems, and so prevent death from bone marrow failure in radiation victims. HSCs are found in several places in the body. Bone marrow, the soft, spongy tissue found in the centre of bones, is the first place where HSCs were identified. The three main types of blood cells: red blood cells, platelets and white blood cells (which include lymphocytes and neutrophils) all develop from HSCs, passing through several stages of maturation in the bone marrow before being released into the bloodstream. More recently it has become possible to collect HSCs from blood and umbilical cord. A Haemopoietic Stem Cell Transplant (HSCT) involves collecting healthy cells from a donor and introducing them into the patient. To allow these new cells to grow and develop, the patient has to undergo 'conditioning', when several powerful medicines, called chemotherapy and usually used in cancer treatment, are given for about a week. This process kills the patient's old bone marrow, so making space for the new stem cells and also suppressing the immune system in order to encourage acceptance of new cells. However, these drugs also can damage the liver and lungs, and for a period of some weeks leave the patient vulnerable to infection.
Phagocytes arise from stem cells found in bone marrow; so replacing these by doing a HSCT can cure CGD. Transplant works best if the donor is a brother or sister who shares the same tissue types as the patient. As only 1 in 4 brothers and sisters share the same tissue types, this used to mean that not everyone will have brother / sister donor. In the past this meant that the number of transplants that could be performed for any condition was limited. However, there are now large numbers of volunteer donors available and ways of doing the tissue type matching are more sophisticated. It is therefore now often possible to find an unrelated volunteer who shares the same tissue type and is willing to donate stem cells. As a result, transplants using unrelated donors are now much more successful than before.
In the early days
A small number of transplants for CGD were performed 30 years ago, but only some were successful. Attempts were then abandoned as it was considered to be too risky for a condition that was not immediately life threatening. This was for several reasons. Firstly, the cytotoxic (anti-cancer) drugs needed to 'make space' in the bone marrow could damage the lungs and liver as well as leaving the patient vulnerable to life threatening infections. Secondly, the donor cells could attack the patient, causing inflammation of the skin, gut and sometimes the liver, a process called 'Graft versus Host Disease' (GvHD). Thirdly, there was concern about the long-term effects of the drugs used.
Studies in cancer patients revealed many side effects from the cytotoxic drugs, but more recent work suggests that it is radiotherapy and repeated courses of these drugs that are most harmful. When, as in HSCT for CGD, drugs alone are used, and once only prior to transplant, there seem to be fewer side effects. The main one is reduced fertility, although this does not always occur.
The picture now
Over recent years the results of bone marrow transplants have improved considerably. Looking at the European HSCT registry, which includes people who have had a transplant for all types of immunodeficiency conditions and using all types of donor, success has risen from 43% to 71% in the 20 years up to 1999. It looks as if there has probably been a further 10% improvement since 2000. With a well-matched donor the chances of success are now about 90%. This is not due to a dramatic 'breakthrough', which perhaps explains why this had not attracted the media attention that might have been expected for such a major advance. Instead it results from a series of innovations and developments made by many transplant teams who share results and experience. The most important developments have been:-
- Better availability of well-matched donors, which has lessened the risk of GvHD and increased the chances of successful graft take.
- Modifications to the drug regimens that ensure that the donor cells have the best chance of 'taking' but also lessen damage to the patient and decrease the risk of GvHD.
- Better ways of diagnosing and treating infection, especially viral infection, at an early stage.
Studies of HSCT for CGD have been carried out in both Europe and the United States, albeit using slightly different approaches.
In the United States study, only stable well patients were included. Less toxic drugs were used to 'make space' in the bone marrow and the mature lymphocyte white cells were removed before giving the bone marrow with the aim of reducing the risk of GvHD. This study had a success rate of 60%.
The larger European report described 25 patients who were treated in a more radical way. Unlike the US study ill patients were included. These were patients with severe inflammatory disease of the lungs and bowel as well as those with poorly controlled fungal infection. Two patients received transplants from matched unrelated donors rather than from sibling donors. Despite all this, the results were very encouraging indeed. All 11 patients who were well at the time of transplant survived and were cured of their CGD (only 1 developed GvHD and that resolved with treatment). All 7 of the patients who had severe inflammation of the lungs or bowels survived and were cured. Three of them developed GvHD, (which in 1 case was severe) but all of them recovered after treatment. Most remarkably the inflammation completely resolved in all the patients: one man whose lungs were so severely inflamed that he needed oxygen all the time and was wheelchair bound no longer needed oxygen or a wheelchair after HSCT. For the patients with active fungal disease at the time of transplant, the results were much less good and only half were cured.
Overall the cure rate was 82%. Very recent results suggest that results for high risk patients can be considerably improved by further modification of the combination of drugs given during pre-HSCT conditioning treatment. Four high risk adult patients with active inflammation / infection have successfully come through HSCT without GvHD or infectious complications and are now cured of CGD with 100% of their neutrophils having entirely normal function.
The Newcastle team transplanted 4 of the patients in the first European report and the excellent results encouraged us to continue. To date 17 patients have been transplanted, many of whom were ill at the time with gut or lung inflammation. Two had severe fungal infection. Sadly, in keeping with the wider European experience, the 2 with severe fungal infection at the time of transplant both died. However, the other 15 are alive, well and cured. Two developed mild GvH D that only lasted for a few days and 2 more had severe GvH D which resolved and now needs no treatment.
The patients have been carefully followed up for between 2 months and 8 ∏ years and the improvement in their health and wellbeing remains remarkable. One boy with such severe bowel disease that he had put on no weight and had grown only an inch in 4 years then gained over 2 ft in height and over 3 stone in weight in the 18 months after transplant.
What does HSCT mean? A family perspective.
In writing this article about the effects of transplant in CGD, we asked one of our families for their thoughts and experiences. Here are their words, which perhaps better express what it means than the scientific data:-
"When our two boys were diagnosed with CGD at the age of 10 and 7 it felt like the end of the world. We had never heard of this disorder, even after everything was explained. The full implications and seriousness of CGD does not sink in during those few months ahead, all the hospital visits and then you become complacent over the years because they are keeping well with the medication they are receiving and just get on with life until all of a sudden our oldest boy became ill with Aspergillus Nidulans.
He was given the chance of HSCT with a 50 / 50 chance, which he bravely took as his only hope of life.
It was a hard 5-6 months in hospital before his transplant on medication to try and beat the Aspergillus for all of us, especially our other son who helped to look after his brother. When Thomas died the day before his transplant it felt like someone had taken a piece of my heart out and has kept it. John was devastated but has never said much to us about how he felt and still feels. We had felt that Thomas was indestructible, he had come through so many operations and pain, he very rarely complained.
Then of course John had to make the same decision as his brother did while he was still relatively well and did not have a serious infection. We could only advise and support John on this decision after hearing all the facts and options as the final decision was his, he decided to go ahead with a HSCT.
We had mixed feelings about this, if the same happened to John we could not bear it, but he had to have that chance of life, also we had every faith in the doctors and nurses, especially their consultants.
John's HSCT went better than we could have hoped for. Our life with the children has been a bit like a roller coaster since they were diagnosed with CGD.
It still hurts a lot after three and a half years and always will, your feelings don't go away, you just learn to cope with them better.
Our experience with this disorder made us realise that the need to transplant as soon as possible is very important, both the boys' donors were unrelated."
John has made a full recovery following his HSCT. He is completely fit and healthy and able to lead an independent life the same as any other teenager.
Work to improve the results of HSCT in CGD is ongoing across Europe. Professor Reinhard Seger and Dr Terry Flood have modified the conditioning regimen for patients with severe active inflammation to reduce the risk of GvHD. Early results are encouraging. The data for other immunodeficiency conditions suggest that this regimen could also result in better survival and cure for patients with fungal infection at the time of transplant.
Now more patients have been treated and followed up for longer we can conclude:-
- When there is no active fungal infection, transplant using an HLA matched brother or sister donor is highly successful with a 90% chance of cure and little risk of GvHD.
- Transplants with matched unrelated donors look to be as successful as transplants using a matched brother or sister donor.
- Patients with active inflammation at the time of transplant are usually cured and well, perhaps with more risk of GvHD; modifications to the conditioning regimen may significantly lessen this risk.
- HSCT seems to resolve longstanding inflammation in lungs and bowel, leading to tremendous improvements in growth and quality of life.
- Transplant works better if stronger drugs are given as conditioning and mature lymphocyte white blood cells are not removed from the donor cells. These drugs may have long-term effects, particularly on fertility. Further research is needed to see whether slightly less intensive drug regimens could be just as successful.
- The results from transplant need to be compared with not having a transplant and continuing to take daily preventative medication, highlighting the importance of the UK and European CGD registry projects.
- Gene therapy may be another alternative treatment, but if it can only be attempted after conditioning with cytotoxic drugs, the procedure may not greatly differ from HSCT.
Professor Andrew J Cant
(Consultant in Paediatric Immunology & Infectious Diseases)
( 6 October 2006)
(Growth chart before and after HSCT in CGD)
GLOSSARY
Bone marrow
The tissue found in the centre of bones (it looks very much like blood but has a slightly thicker consistency). It is responsible for producing the three main types of blood cells: red blood cells, white blood cells and platelets.
Haemopoietic Stem Cell Transplant (HSCT)
Involves collecting healthy bone marrow stem cells from a donor and introducing them into the patient.
Cytotoxic drugs
A special group of drugs usually used in the treatment of cancer to kill abnormal cells.
Chemotherapy
Drug treatment that involves using cytotoxic drugs.
Conditioning
Where chemotherapy drugs are used to 'make space' in the bone marrow for the new stem cells.
Graft versus Host Disease (GvHD )
A complication of HSCT where the donor cells attack the patient, causing skin, gut and sometimes liver problems. Usually responds to treatment.
Stem cell
'Parent cell' from which all the cells of the immune system develop. These cells mature in the bone marrow and are then slowly released into the bloodstream.
IMPORTANT NOTE :
The information contained on this website is intended only as a guideline, not as a substitute for medical advice. Always consult your doctor if you or your child has any CGD symptoms or concerns.
© 2001-2007 The Chronic Granulomatous Disorder (CGD) Research Trust
Registered Charity No. 1003425 email:cgd@cgdrt.co.uk
The CGD Research Trust is a member of the Association of Medical Research Charities (AMRC), the Genetic Interest Group (GiG) and an associate member of the International Patient Organisation of Primary Immunodeficiencies (IPOPI)
Site Map | Terms and Conditions | Privacy
