New treatment for severe stem-cell transplant complications

SINGAPORE - For years, orthopaedic surgeons have used a type of stem cell in the bone marrow, called mesenchymal stem cells, to build new cartilage.

This is a form of stem cell that originates from the mesoderm, or middle layer of tissue, in a developing embryo. It can also be isolated from other types of tissue, including bone marrow and umbilical cord blood.

Now, a doctor here is using such stem cells to treat a severe form of graft-versus-host disease (GVHD), a major complication of stem-cell transplants between genetically separate people.

It occurs when the donor's lymphocytes (white blood cells), which are infused into the recipient's body, recognise the recipient's body as foreign and attempt to reject the recipient's body.

The condition can affect one or all of the three organs: skin, liver and gut.

GVHD can occur in 30 to 40 per cent of all bone marrow transplant patients. Severe GVHD, which is life-threatening, occurs in 5 to 10 per cent of patients - 10 to 15 patients a year here.

Dr Lim Zi Yi, a consultant at the department of haematology-oncology at the National University Cancer Institute, Singapore (NCIS), said mesenchymal stem cells stop the body's destruction from GVHD by reducing the production and function of overactive immune cells from the donor.

Several trials in the United States and Europe have shown that mesenchymal stem cells are effective in patients with GVHD.

In one study published in The Lancet in 2008, 30 out of 55 patients - more than half - had all their symptoms of GVHD resolved after they received mesenchymal stem cells.

Nine patients had some improvement of symptoms, while 13 had their GVHD progressing despite the treatment.

These results seem promising as currently, fewer than 15 per cent of patients with severe GVHD improve despite being put on multiple types of immunosuppressive drugs, said Dr Lim.

If patients do not respond to this treatment, they may be offered another form of treatment, termed extracorporeal photopheresis.

This requires the patient's blood to be temporarily drawn intravenously so the white blood cells are separated from the rest of the blood in a machine and treated with drugs. When these are infused back into the patient, the cells will stimulate an immune response in the body to fight the development or progression of GVHD.

A course of this can cost up to $250,000, with response rates that do not surpass that of treatment with mesenchymal stem cells, Dr Lim said.

She felt like giving up

He has offered mesenchymal stem cells to four NCIS patients who developed severe GVHD.

His first patient, housewife Tan Ah Gek, 53, had acute myeloid leukaemia, cancer of the blood and bone marrow.

On May 10 last year, she received cord blood from an unrelated donor and stayed in hospital for 1 1/2 months.

But four days after her discharge in July, she had to be admitted again for very bad stomach aches, recalled her husband, cabby Chew Eng Chye, 58.

Madam Tan was subsequently diagnosed with grade 4 GVHD, which is the most severe form.

Dr Lim put her on four types of drugs that worked to reduce her body's immune response.

But the medication did little to alleviate her suffering - she had diarrhoea up to 18 times a day, could not hold down even a mouthful of porridge and lost 10kg in less than a month.

Dr Lim could not give her more medicine, as each drug increased her risk of infections and "one bad infection would have killed her", he said.

She also had two episodes of intestinal bleeding, which required blood and platelet transfusions to save her life.

She faced an 80 to 90 per cent risk of death, which affected Mr Chew so much that he could hardly concentrate while driving.

He visited her twice a day, bringing her home-cooked porridge and decorating her high-dependency ward to cheer her up.

Madam Tan recalled in Mandarin: "I told him I felt like giving up, but he said I should not."

Last August, she received mesenchymal stem cells taken from her 21-year-old daughter's bone marrow. The couple also have a 26-year-old son.

For the new treatment, approximately 200ml of bone marrow blood is collected and then cultured in a special medium under controlled conditions in the laboratory for two to three weeks, Dr Lim said.

After Madam Tan received three rounds of infusion, her condition gradually improved.

The treatment costs between $10,000 and $15,000 for subsidised patients like her, and up to $30,000 for private patients.

By October, Madam Tan was able to walk out of the hospital using a walking aid.

Patients like her face a 30 to 40 per cent risk of a relapse of the leukaemia in the first year after a transplant, said Dr Lim.

With her leukaemia in remission, Madam Tan now returns to NCIS with her husband every two to three weeks for check-ups.


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