Bone Marrow Transplantation (BMT) or Haemopoietic Stem Cell Transplantation (HSCT) is the only treatment currently available that can cure sickle cell disease. It is a difficult subject to understand and there is no consensus in the medical profession about how the treatment should be used for patients with sickle cell. What I will aim to do in this blog is to explain the concepts and define some of the terms that you might come across, and then discuss the difficulties of using this treatment in sickle cell disease and how these difficulties are being slowly overcome.
A BMT involves collecting bone marrow stem cells from a donor and giving them to a patient, whose own bone marrow is defective in some way. Either the patient has a malignant disease of the bone marrow, like leukaemia, or was born with, or developed sometime later, a serious bone marrow disorder, like sickle cell disease. Stem cells are the vital power houses of the bone marrow since they have the remarkable ability to develop into all the cells normally found in the blood – red cells, white cells and platelets.
Whilst stem cells are normally found living exclusively inside the bones of the body, in the bone marrow, in newborn babies, they are also present in the blood stream and can be collected from the placenta after the baby has been born. During adult life they can be induced to leave the bone marrow and circulate in the blood in large numbers by treatment with certain drugs, such as granulocyte colony stimulating factor (G-CSF).
Most bone marrow transplants have been undertaken with stem cells collected from a donor’s bone marrow rather than the blood. In order to collect the stem cells the donor has to have a general anaesthetic and, whilst they are asleep, large needles are introduced into the the pelvic bones, the bone marrow is sucked out and transferred to a sterile bag. Donation does not have any effect on the donor’s own bone marrow function or blood counts but they are usually quite sore, when they wake up from the anaesthetic, for a few days afterwards.
As with all organ transplants, kidneys, heart etc. the donor and the recipient have to be closely matched, otherwise the patient’s immune system will recognise the transplant as foreign and reject it. Rejection of a graft has always been the biggest problem in transplant medicine. The closest match you can have would be an identical twin, because in this situation the two individuals are genetically identical, there would be no risk of rejection at all. However, most of us do not have an identical twin and the next best thing is a Matched Sibling Donor (MSD), in other words a brother or sister who is closely matched at the main HLA genes. The HLA genes are the most important genes determining whether or not the immune system rejects a graft or transplant. The genetics of this means that only 1 in every 4 siblings will be a close enough match to act as a donor. Because of this restriction the chances are therefore that the majority of people with sickle cell disease will not have a closely matched sibling donor.
The alternative is a Matched Urelated Donor (MUD). The doctors looking after the patient will try and find a MUD by searching the various bone marrow registries, such as the Anthony Nolan Register. However, unrelated matched donors can sometimes be very hard to identify, particularly in minority ethnic populations. In African Caribbeans the main HLA genes occur at different frequencies compared to the majority white population, and there is more variation in the types of HLA genes present than in any other ethnic group. Both reasons to encourage as many African Caribbeans as possible to sign up as potential bone marrow donors with a register.
Where ever the bone marrow comes from it can either be used straight away or stored frozen until needed. Clearly, for patients with sickle cell disease the potential donor must not have sickle cell disease as well, but if the donor has sickle cell trait this is not a problem and the transplant can still go ahead.
Having identified a suitable donor and collected the bone marrow, actually giving the bone marrow is a straightforward procedure, but first of all the patient has to be prepared for the transplant. This is done by giving what is called “myeloablative conditioning”, usually high dose chemotherapy, with drugs such as busulphan and cyclophosphamide, and Total Body Irradiation (TBI). The conditioning destroys the patient’s own bone marrow, making space for the new bone marrow to grow, and also suppresses the patient’s immune system, reducing the chances that the bone marrow transplant will be rejected. Once the conditioning treatment has been given the donor bone marrow is transfused into a vein and the stem cells home in on the bone marrow spaces where they begin to grow and develop into new, healthy blood cells, which will be the same as those of the bone marrow donor, eventually replacing the diseased cells of the patient..
It usually takes from 7 to 25 days before the new bone marrow begins to work properly. During this period the patient is very vulnerable to serious infections and they are usually nursed in an isolation room and given a variety of drugs to reduce the risk of infection, including antibiotics if necessary. They also have to be given regular transfusions of red cells and platelets, because they are unable to produce any blood cells of their own. Once the new bone marrow is working the patient has to continue to take drugs to suppress their immune system (immunosuppressants) for a period of time, usually for six to twelve months, to reduce the risk that their body will reject the new bone marrow. Whilst they continue on these drugs, and until the immune system recovers, they remain at a continual risk of infection by many different viruses and bacteria. Apart from rejection and infection there are several other complications associated with bone marrow transplantion which can cause problems.
Graft Versus Host Disease (GvHD): the transplanted bone marrow contains many different cells, in addition to the haemopoietic stem cells, including cells from the donor’s immune system, known as lymphocytes. Sometimes these donor immune cells attack the tissues of the patient’s body, in other words the bone marrow transplant, or graft, attacks the host, or patient. This is GvHD and can usually be managed by treatment with steroids to suppress the immune reaction, although sometimes the condition can be severe and long lasting.
High dose chemotherapy and TBI, given as part of the conditioning regime, as well as having unpleasant short term effects, such as nausea and vomiting, hair loss and a sore mouth and tongue (mucositis), also has longer term effects, such as reduced fertility, in both men and women.
BMT is therefore a potentially dangerous treatment; there is a risk of dying as a result of the procedure as well as the risk of developing long term complications, nevertheless for many patients, with serious bone marrow disease, it has proved to be a life-saving and curative treatment. The first BMT in sickle cell disease was performed in 1984 at St Jude’s Children’s Hospital in Memphis, Tennessee and over the next 10 years small numbers were performed, mainly in the USA (5 patients) and France and Belgium (42 patients).
In 1994 these three countries summarised their experience. Out of a total of 47 patients, the mortality rate was 2% (1 patient) with an overall survival (OS) of 98%. Event free survival (EFS – in other words survival without the onset of any serious complications) was 83%; The main complications were rejection in 10% (5 patients) and GvHD in 4% (2 patients). In all 87% (41 patients) developed sustained engraftment of the new bone marrow and were cured of their sickle cell disease.
These were very encouraging results and, over the subsequent years, BMTs have continued to be performed, the majority using a MSD, but the total number remains disappointingly small. Seventeen years on, in 2011, the same three countries, which remain the main centres for sickle cell transplants, looked at their results again. By this time a total of 250 patients had been transplanted, with a median age <10 years. Overall survival was 93-100% and event free survival 79-92% with a graft rejection rate of 7-18%. Those children who successfully engrafted were all cured of their sickle cell disease with resolution of painful crises and no further sickle cell related complications. As expected they all had either none, or very little sickle haemoglobin in their blood.
The largest single centre experience is from Brussels, Belgium and the doctors there published their work in 2014, confirming these very good results. From 1988 to 2013 they transplanted 50 children with closely matched sibling donors (MSD’s). The OS was 94.1% (2 deaths; one at 7 years post transplant of unknown cause, the other of a brain haemorrhage 18 days post-transplant) and EFS 85.6%. Graft rejection was very unusual; 92% engrafted with only 4 patients rejecting their graft, all in the early years. Acute GvHD developed in 22% (11 patients) shortly after transplantation and 20% (10 patients) developed mild chronic GvHD at a later date, which resolved with treatment in all except one patient. Serious viral or bacterial infections were a problem in 36% (18 patients) all of which were successfully treated. Neurological complications were also quite common in the first weeks after the transplant; 22% (11 patients) had a seizure or “fit”, and 12% (6 patients) developed PRES (posterior reversible leucoencephalopathy syndrome).
These results are all very positive, however, the main problem is that very few patients with sickle cell disease are eligible for a BMT – 250 patients from 1984 to 2011, or less than 10 patients a year, is not very impressive. Why is this?
1. It became clear very early on that in teenagers or adults the risk of death or serious illness associated with the procedure was very significant, probably because their bodies and organs were already damaged by the sickle cell disease and, as a result, they reacted very badly to the conditioning treatment. Very few BMT’s have therefore been carried out in individuals >16 years of age.
2. Only a small proportion of children have a MSD; remember there is only a 1 in 4 chance that any brother or sister is closely matched enough to be a donor.
3. Because there are significant risks to the procedure of BMT, it was only young children seriously affected by their sickle cell disease who were offered a BMT. The transplant teams usually required children to have had a stroke or fit, to have had recurrent, serious attacks of the acute chest syndrome, to have frequent admissions to hospital for pain or to have evidence of early damage to the lungs or kidneys, before they would consider putting the child on the transplant list.
This is perhaps beat illustrated by a numerical example. One transplant centre in the USA identified a total of 4848 children with sickle cell disease in their area, but only 315 or 6.5% of these fulfilled the eligibility criteria listed above. Of those 315, only 44 or 14% had a closely matched sibling donor (MSD). So out of 4848 affected children a BMT could only be offered to 44, less than 1% of the total. The challenge at the moment therefore is how to increase the availability of BMT so that more patients, both adults and children, can benefit from this curative treatment.
Increasing the availability of BMT has been approached in several different ways:
1. By relaxing the criteria for acceptance. In other words putting forward children who are less severely affected by their sickle cell disease. Weighing up the risks of a BMT against the unpredictable dangers of the disease, whilst also bearing in mind the effectiveness of other, non-curative, treatments such as hydroxycarbamide and blood transfusion, is a very complex business. It can only be resolved on an individual basis by discussion between the doctor, the patient and their parents, focusing on what is best for the individual patient at that point in their lives.
2. By improving the safety of the procedure. This would make the risks of the transplant acceptable to more patients. There are two ways forward here, both of which involve changes to the conditioning treatment, which is the most dangerous part of the transplant process, particularly for older patients. Either by using better drugs for the conditioning regime, which are more specifically immunosuppressive, and allow faster recovery in the function of the grafted bone marrow, or by reducing the intensity of the conditioning regime. This is called Reduced Intensity Conditioning (RIC) or “non-myeloablative conditioning” and involves giving half the normal doses of chemotherapy and /or omitting the TBI.
In 2009 a group from Bethesda and the John Hopkins Centre in Baltimore in the USA published their results in 10 adult patients with sickle cell disease transplanted with RIC. They all received transplants from closely matched sibling donors, although the stem cells were collected from the donors bloodstream, after mobilisation with G-CSF, rather then directly from the bone marrow. There were no deaths and only 1 graft rejection; 90% (9 patients) achieved long term engraftment and cure. This was a remarkable achievement and proved that adult patients with sickle cell disease could be safely transplanted with RIC. But there was another very important outcome of this study.
When the researchers analysed the patients’ blood cells after the transplant there found a mixture of cells present, derived from both the patient’s own stem cells and the donor’s stem cells. This is called a donor-recipient chimera and is the result of the RIC, which does not completely eradicate the patient’s own bone marrow before the transplant.
You might think that as a result of this mixture of cells the transplant would be less successful and the patient would continue to have symptoms from their sickle cell disease, but this is not the case. Although a mixture of white cells were present, the red cells were almost exclusively from the donor’s stem cells, because any sickle red cells produced survived much less well and were rapidly destroyed. Even when there is a donor-recipient chimera post BMT therefore, all the symptoms of sickle cell disease still resolve and the actual amount of sickle haemoglobin in the patient’s blood is still very low.
This study proved that it is not necessary to completely eliminate the patient’s own bone marrow for a successful outcome, and that it is possible to use less toxic, safer conditioning regimes in adult patients.
3. Increasing the supply of potential bone marrow donors. This has been achieved in two ways; by using donors who are less closely matched to the patients and by using blood collected from the umbilical cord when a baby is born.
Less closely matched donors have always been problematic because there is a greater risk that the bone marrow graft will either be rejected or the patient will develop severe GvHD. However, almost everyone has a mother or father, half of whose HLA genes will closely match those of the patient, this is known as a haploidentical donor. If haploidentical donors could be safely used donor availability would be greatly increased.
The first haploidentical transplants in sickle cell disease were reported in 2008, and in 2012 the outcome in 17 adult patients (aged 15 to 46 years) was reported by John Hopkins Medical School in Baltimore. The doctors used reduced intensity conditioning RIC and increased the dose of immuno-suppressive drugs used after the transplant. There were no deaths and no GvHD, but a larger proportion of patients, 43% (6 patients), rejected the graft, nevertheless 67% (11 patients) achieved stable engraftment and were cured.
The second way to increase the availability of bone marrow, is by using blood collected from the umbilical cord, which is rich in haemopoietic stem cells, when a baby is born. Cord blood transplants can be from a sibling donor, but greater degrees of mismatching are permissible, and unrelated donors from “Cord Blood Banks” can also be used. The limited number of stem cells which can be collected from a newborn baby is sometimes a problem and graft rejection rates remain high. A summary of experience to date in Europe and the USA in 2011 reported on 16 children with sickle cell disease; OS was 94% (1 death), but in 44% (7 patients) the graft was rejected. It might be possible in the future to grow the baby’s stem cells in a test tube after collection to increase the number of stem cells available (ex vivo stem cell expansion).
How can we summarise the position of bone marrow transplantation in sickle cell disease at the present time. There is no doubt that bone marrow transplantation for children, if they have a closely matched brother or sister donor, is a valid treatment option, particularly if they have severe sickle cell disease with the early development of complications. All young children with sickle cell disease, together with their brothers and sisters, should therefore be HLA typed to see whether they have a suitable donor. The problem is the limited supply of donors, which at the moment, restricts the number of patients with sickle cell disease who can be offered curative treatment. The use of haploidentical donors or cord blood transplants may be a way to increase donor bone marrow availability in future.
For adult patients with sickle cell disease the situation is more complex, but there are encouraging results using reduced intensity conditioning regimes to increase the safety of the procedure. The possibility of partial transplants with donor-recipient chimerism is an exciting new development which may make transplants in older sickle cell patients a reality.