Criterion for new stem-cell transplant 50 per cent match

SINGAPORE - Every day, about six people in Singapore are diagnosed with blood disorders or blood cancer.

For some of these patients, a haematopoietic stem-cell transplant, which replaces defective bone marrow or immune system with a healthy donor's, may be their only option for cure. Haematopoietic stem cells give rise to all of the blood cells that are first formed in the bone marrow.

Unfortunately, not everyone can find a suitable donor easily.

But now, advances in medical science in treating rejection that occurs after a transplant mean that donors who are not very closely matched can be used anyway, with success.

Finding a match depends on the donor's and recipient's human leukocyte antigen (HLA) types.

These are an inherited set of genetic markers on the surface of many human cells. The higher the number of matching HLAs, the greater the likelihood that the donor's stem cells will be accepted by the patient's body.

Donor cells can come from the bone marrow or blood stem cells of adults, and umbilical cord blood which has been collected from newborn babies and stored in cord blood banks.

In general, patients have a one in four chance of finding a full match - all eight HLA types matching - with one of their siblings.

Dr Lim Zi Yi, a consultant at the department of haematology-oncology at the National University Cancer Institute, Singapore (NCIS), said more than half of patients who need a transplant will lack a fully matched sibling, while a third will be unable to find a suitable volunteer donor in local and international registries.

The chances of finding a fully matched unrelated donor are greatly influenced by a patient's ethnicity.

This chance is about 70 per cent for a Caucasian, 40 to 50 per cent for a Chinese, and 20 to 30 per cent for Malays and Indians, Dr Lim said. This is because donor registries tend to have more Caucasian volunteers than those of other races. But a new type of stem-cell transplant, termed a haploidentical transplant, requires only a 50 per cent match of a patient's HLA, instead of the conventional full match.

Dr Tan Poh Lin, a senior consultant at the division of paediatric haematology-oncology at the National University Hospital (NUH), said as a person gets half his genes from his father and the other half from his mother, this means parents, children and some siblings are instantly available as donors in haploidentical transplants.

Dr Lim noted that this new technique has been available for more than a decade, but has been used more widely only in recent years after doctors learnt to handle the rejection that usually occurs from a less- than-ideal match.

With such an option now, he estimated that patients who lack a matched sibling and matched unrelated donor have a 70 to 80 per cent chance of finding a half-matched donor.

Haploidentical transplantation is now offered to patients at three public institutions and one private one here. The public institutions are NCIS, NUH and Singapore General Hospital (SGH). NCIS and SGH treat only adult patients, while NUH treats only children. The private centre that offers this treatment is Asian Centre for Blood and Bone Marrow Transplantation at Gleneagles Hospital. However, it has not treated any patient with this method yet.

In NUH, nine children aged between two and 16 have had the procedure since November 2007. Two suffered a relapse and died a few months after the transplant.

In late 2011, NCIS and SGH launched their haploidentical transplantation programmes.

Three of the six acute leukaemia patients who have had the transplant at NCIS are still in remission, while the rest died from complications months later.

Associate Professor Aloysious Ho, a senior consultant at the department of haematology at SGH, said three of its four patients are still in remission. He declined to reveal what happened to the last patient, citing patient confidentiality.

He said a clinical trial by both hospitals, targeting 20 adults, is under way to look at how a person's immune system rebuilds itself after such a transplant.

The new method is also cheaper than getting a transplant from an unrelated donor.

Dr Lim said a haploidentical transplant, along with four to six weeks of hospital stay, costs between $70,000 and $110,000 for an adult private patient, similar to that for a transplant from a sibling donor. The patient pays an additional $10,000 to $15,000 for procuring the stem cells from a donor.

For paediatric private patients at NUH, it costs between $100,000 and $200,000, including 45 days of hospital stay, said an NUH spokesman. This does not include the $10,000 for procuring stem cells from the donor.

Dr Lim added that a full-matched bone marrow or blood stem-cell transplant from an unrelated donor, plus four to six weeks of hospital stay, can cost between $90,000 and $150,000 for an adult private patient. The procurement fee is between $20,000 and $60,000.

The NUH spokesman said the same sort of transplant for children in private wards, along with 45 days of hospital stay, costs between $180,000 and $250,000. The procurement fee is between $18,000 and $55,000.

Dr Lim said a transplant done using two units of cord blood, typically the requirement for an adult patient, and eight weeks of hospital stay in a private ward, costs between $100,000 and $180,000. The procurement fee is between $40,000 and $90,000.

Transplant for children using cord blood, along with 45 days of hospital stay in a private ward, costs between $180,000 and $250,000, said the NUH spokesman. The procurement fee is between $30,000 and $75,000.

Reducing risk of graft problems

Early attempts at haploidentical transplants frequently ended in death, mainly because of graft-versus-host disease (GVHD) and graft rejection in transplantation.

In GVHD, the lymphocytes (white blood cells) in a donor's stem cells recognise certain antigens in the recipient as foreign and attack the recipient's tissue. The condition typically affects the skin, liver and gastrointestinal tract and can be acute or chronic.

In graft rejection, there is destruction of the transplanted stem cells by the donor's body because of the body's defence mechanism.

Doctors said that some degree of GVHD can be beneficial as it correlates with a graft-versus-leukaemia effect, in which the donor's lymphocytes attack the patient's leukaemia cells directly and help in eradicating the leukaemia.

But severe GVHD can be fatal. Dr Yvonne Loh, a haematologist at Asian Centre for Blood and Bone Marrow Transplantation, said those who receive fully matched donor cells run a 10 to 15per cent risk of developing severe GVHD, and 60 to 70 per cent risk if they receive half-matched donor cells.

Following a haploidentical transplant, doctors administer chemotherapy drugs to patients to significantly reduce their T-cells. This is a type of blood cell that protects the body from infection and is responsible for GVHD.

T-cells may also be "cleaned" away by passing a donor's stem cells through a cell selection machine after they are harvested and before they are infused into the patient.

The GVHD rates after a haploidentical transplant is now similar to fully matched transplants after using either of these two methods, Dr Loh said.

But having fewer T-cells increases a patient's risk of relapse and infection.

Dr Daryl Tan, a consultant haematologist at the Raffles Cancer Centre and the director of research at Raffles Hospital, said the role of haploidentical transplant thus "must be considered in the context of current improvements in the treatment of blood cancer".

He said: "Transplant is not the penultimate treatment modality for all types of blood cancer. It involves a major overhaul of the body's immune system to fight cancer and, hence, complications can be enormous."

Though a stem-cell transplant is important in the treatment of aggressive leukaemia, other types of blood cancer such as chronic myeloid leukaemia (cancer of the white blood cells) and multiple myeloma (cancer that affects cells in the bone marrow) now have effective drugs that come with fewer side effects.

Doctors who perform haploidentical transplant said they offer it only to patients with high-risk acute myeloid leukaemia and acute lymphoblastic leukaemia - two types of cancer of white blood cells - myodysplastic syndrome (disease of the bone marrow stem cells), very severe aplastic anaemia (when the bone marrow fails to produce enough new blood cells) and some types of lymphoma.

These patients have conditions which are incurable without a transplant as they no longer respond to chemotherapy, said doctors.

Comparable results

For years, an HLA-identical sibling donor has been the gold standard for a source of stem cells.

Next comes an unrelated adult donor or cord blood. Last is a haploidentical family donor.

What is clear is that these are all welcome advances in the fight against cancer.

A study has shown that children with very high-risk leukaemia do well with stem-cell transplants, regardless of donor source.

Blood, a medical journal by the American Society Of Hematology, reported in May 2011 that the five-year survival rates were 70 per cent for sibling donors, 61 per cent for unrelated ones and 88 per cent for haploidentical ones.

Another study published in Blood in April 2011 involved patients with leukaemia or lymphoma who lacked a suitable related donor.

A total of 100 patients from 27 transplant centres in the United States had either an unrelated cord blood transplant or a related haploidentical bone marrow transplant.

After the cord blood transplantation, 54 per cent of patients were alive after a year and 46per cent were in remission and progression-free. After a year of follow-up, 25 per cent of patients had chronic GVHD.

After the haploidentical bone marrow transplant, 62 per cent of patients were alive after a year and 48 per cent were in remission. After a year of follow-up, 13 per cent of patients had chronic GVHD.

The study was not designed to compare the two methods, so more research is under way.

The results, however, suggest that patient outcomes from these two methods of transplant are comparable with those reported after matched unrelated donor transplants, the authors said.

For these reasons, haematopoietic stem cell transplant is offered to more patients these days, said Dr Loh, who is also the medical adviser of the Bone Marrow Donor Programme.

Almost half, or 230, of the 500 transplants that the programme has helped facilitate since 1993 were done in the last five years.

Previously, when outcomes of unrelated donor transplants were inferior to sibling transplants, only very young and fit patients, or those whose disease was very advanced or faced poor prognosis, would have this option.

With improvements in HLA-typing techniques and, hence, better matching between donors and recipients, the results for unrelated donor transplants have "improved a great deal in the last seven years worldwide", Dr Loh said.

Now, even those in their early 70s would also be candidates for stem-cell transplant.

With a growing and ageing population, the demand for stem-cell transplants will continue to grow, Dr Loh added.

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