New hope with haplo-identical bone marrow transplant

Posing for a photo at the first anniversary celebration of Yusuff’s transplant are (from left) Aduratun, Yusuff, Mohd Hambali and younger daughter Dheakhawla Nuwaibah Mohd Hambali. Photo: The Star/Samuel Ong

Having worked at University Malaya Medical Centre’s (UMMC) Paediatrics Department for 20 years, senior consultant paediatric oncologist Prof Dr Hany Mohd Ariffin has had to tell her fair share of parents that there is nothing more that can be done for their terminally ill child.

As head of the Paediatric Haematology-Oncology and Bone Marrow Transplantation Unit, this is usually because there is no suitable donor available for a life-saving bone marrow transplant for the child.

Bone marrow transplants, also called stem cell transplants, are used in conditions where the patient’s bone marrow is damaged or destroyed by disease or intensive cancer treatment, and is unable to carry out its job of producing healthy red blood cells, white blood cells and platelets.

Because white blood cells or leukocytes are part of the immune system that protects our body against foreign invaders, it is critical in such a procedure to match the so-called immunological fingerprints of the patient and the donor.

As Prof Hany explains, these “fingerprints” are known as human leukocyte antigens (HLAs).

HLAs help the immune system distinguish between the body’s own cells and foreign cells, usually bacteria and viruses that infect us, so that our white blood cells can find and destroy them.

It is crucial that a bone marrow donor and the patient have the same HLAs in order to minimise the chances of the donated bone marrow’s white blood cells considering its new host body as foreign and attacking it.

Perfect match needed

Standard bone marrow transplantations require that all 10 HLAs in both patient and donor are a match.

As HLAs are inherited half from each parent, this means that only a patient’s siblings are a possible perfect match.

Explains Prof Hany: “If you look at statistics, out of four, one sibling will be completely matched, one sibling will be completely not matched, and two siblings would be half-matched.

“So, the chances of finding a match is 25%, but that is statistical randomisation.

“In the real world, you can have 10 siblings and all of them might not be matched with you.”

If a patient does not have a sibling that matches perfectly with them, or does not have a sibling at all, their only other option is to check for an unrelated match in international stem cell registries or blood banks.

However, Prof Hany notes that this usually requires a sum of RM100,000 for a unit of bone marrow and at least three to four months of waiting – two luxuries not all patients have.

She adds: “But it is not easy to get a good match for Asians as these registries are usually Caucasian.

“And it’s even worse if you are an Indian patient, as you can’t even go to a Taiwanese blood bank.”

In the case of Muhammad Yusuff Iskandar Mohd Hambali, time was a critical factor.

The firstborn of two teachers had been referred to UMMC at 10 months of age for recurrent pneumonia.

His mother, secondary school physical education teacher, Aduratun Nasyihin Mokhtar shares: “He started falling sick at the age of seven months – he had a persistent cough.

“Initially, the doctor thought it was pertussis, but it didn’t get better after three months as pertussis should, so he was admitted to the hospital.

“However, none of the antibiotics they tried worked, so he was referred to UMMC to check his lungs.”

This filepic shows a thalassaemia patient with his infusion pump machine for iron-chelating therapy. Thalassaemia is one of the conditions curable by a bone marrow transplant.

It was in UMMC that Yusuff, as he is called, was discovered to have X-linked severe combined immunodeficiency (SCID).

This rare genetic condition, also known as bubble boy disease, results in the malfunction or lack of two specialised white blood cells called T and B cell lymphocytes.

This means that Yusuff effectively had a non-existent immune system.

This was the reason he could not fight off the pneumonia. In fact, his lungs had deteriorated so badly that he was on oxygen therapy from the age of eight months.

In addition, the Mycobacterium bovis in his BCG vaccination had spread to his back, he had chronic diarrhoea and he was very much underweight.

Yusuff needed a bone marrow transplant, and he needed it fast.

Having reached out to her international colleagues at that time, Prof Hany says: “One thing constant in all their advice was that if we delayed the procedure, he would never get better from his disseminated BCG, his pneumonia would just worsen, and once you reach a critical point, there would be no turning back.

“He would have been dead by six months.”

Only five necessary

The problem was that Yusuff was then an only child.

Although his mother was pregnant with his younger sister at that time, she would not have been born in time to help him, assuming that she was a match for him in the first place.

With no time to waste, Prof Hany and her team decided to try a procedure called haplo-identical bone marrow transplantation.

Bone marrow transplant
On whether she and her team were ready to carry out the new procedure, Prof Hany says that you will never be ready until a life is dangling precariously in front of you. Photo: The Star/Samuel Ong

In this procedure, only five out of 10 HLAs need to be matched in order for the donor to be able to give bone marrow to the patient.

“The beauty of this procedure is that you always have two parents (to donate),” says Prof Hany.

So, Yusuff’s father, sports science and physical education teacher Mohd Hambali Din @ Ismail, could now donate his bone marrow cells to his son.

First though, Yusuff needed to be “fattened up” via nutritional fluids infused into his veins, his pneumonia brought under control and his M. bovis infection treated with anti-tuberculosis therapy.

This was so that he would be in a decent enough condition to withstand the procedure.

Following the protocol established by Johns Hopkins University in the United States, but modified to suit Yusuff’s condition, Prof Hany and her team first killed off Yusuff’s remaining bone marrow cells through chemothera-py, before infusing 30ml of his father’s donated bone marrow into him.

Prof Hany explains that it takes two to three weeks for the new bone marrow cells to grow, during which time the patient is completely vulnerable to any infection.

“This is why they remain in a completely sealed room where the air is hepa-filtered, they receive no visitors, and their food and linen are completely sterile,” she says.

He was also treated with high-dose cyclophosphamide, a chemotherapy drug that targets T cell lymphocytes.

This was in order to destroy the half-matched mature T cells that came with his father’s donated bone marrow.

“T cells are your soldier cells. His father’s T cells would recognise Yusuff as foreign and destroy everything in their wake.

“And that is what has precluded mismatched transplants all this while,” explains Prof Hany.

After the mature T cells are destroyed, she says: “What you then get are T cells from stem cell origin, which learn to tolerate the environment of being in Yusuff’s body, and therefore, they will be less aggressive and more friendly to these cells that they consider foreign.”

Despite that, Yusuff still experienced graft-versus-host disease (GvHD) where his new white blood cells attacked the cells of his skin, gut and lungs.

“In between, he also had two episodes of sepsis and he had to go to the ICU once.

“He also had to go on the ventilator at one point,” says Prof Hany.

She explains that GvHD, which is due to aggressive donor white blood cells, and infections, which are due to the still incomplete immune system, can co-exist, creating a dilemma for the medical team.

“On the one hand, to ameliorate GvHD, you have to give steroids (in addition to standard immunosuppresants) to dampen down the immune system.

“You dampen down the immune system, then you allow bacteria and fungi to grow.

“And that is why it is very challenging,” she says.

She admits: “For the first 20 days, it was all very smooth and you think, ‘Wah, I’m a hero’, but then the challenges came.

“There were certain moments when I thought, ‘That’s it, we’re going to lose him’.”

It took 149 days after the transplant before Yusuff was deemed well enough to be sent home.

And it was one year before Prof Hany and her team felt confident enough to declare him cured.

“We estimate anything between six months to a year for the new bone marrow cells to grow and propagate.

“So usually, after a year, if the GvHD doesn’t appear anymore, it is very unlikely to suddenly appear,” she explains.

For the future

This first anniversary of Yusuff’s transplant, celebrated at UMMC on April 6, was not just sweet because of Yusuff’s survival, it was also the opening of a new path for Prof Hany and her team.

“On a personal note, there were many times when you have this period of self-doubt.

“So, you think that we are just a bunch of stupid, gung-ho people, who are unrealistic; this is not America, this cannot be done – that sort of feeling.

“There were some moments when you think, have I done a disservice to this child? Would if it have been better to just let go, for the parents to just let go? Is God just testing me?” shares Prof Hany.

However, a few months after Yusuff’s transplant, she received the case of a baby boy with myelodysplastic syndrome.

“Myelodysplastic children will progress to develop acute myeloid leukaemia within a year, and it is only curable with transplant, or not it is certain death by two years,” she explains.

“And this patient had two siblings, both of whom were only half-matched.

“But we were able to offer a transplant to this child, because we knew that from the experience of Yusuff, if he has very bad GvHD of the gut, skin, lung, we would be able to handle it – been there, done that.

“We were already scarred for life,” she says with a laugh. And in fact, due to their prior experience, Prof Hany and her team were able to more precisely determine the amount of donated bone marrow cells needed for transplant.

As a result, she says: “The second patient sailed through and was discharged after only five weeks, as opposed to five months for Yusuff.”

Explaining the potential impact of having this treatment option available, Prof Hany shares that bone marrow transplantation is a cure for conditions like leukaemia, blood disorders like thalassaemia, congenital defective immune systems and certain rare congenital metabolic conditions.

“The major reason why transplants are not being done is because of the lack of an available donor,” she says.

But haplo-identical bone marrow transplantation now opens the way for many more potential donors to help the patient.

“The learning curve is steep,” Prof Hany admits, but adds that after Yusuff, they were able to apply what they learnt to their second patient with great effect.

“I’m not saying it is easy, but I think it is worth developing further, because it can solve one of the greatest health problems in our country, which is inherited blood disorders.”

Giving the example of thalassaemia, she estimates that it costs some RM3.5mil to treat a patient with regular blood transfusions and iron-chelating therapy for 30 years.

A haplo-identical bone marrow transplant costs approximately RM45,000 and will cure the patient.

The risk of dying from this procedure – usually because of infections and GvHD during the period when the patient has no working immune system – is estimated to be about 10%.

This is at the upper limit for standard bone marrow transplants, where the risk ranges from 5% to 10%.

She adds that studies have shown that the risk of severe GvHD is similar for haplo-identical transplants and sibling-matched transplants, which are both lower than transplants from an unrelated donor.

Although Yusuff is the first successful haplo-identical bone marrow transplant patient in the country, to the best of Prof Hany’s knowledge, she believes that the procedure can be easily done in other major hospitals around the country.

The facilities are already there and specialists trained in bone marrow transplants need only learn the procedure once before they should be able to conduct it, she says.

“So it’s not just having a big celebration to tell the world that we saved one boy with SCID, it’s having the ability to tell parents that there is always hope, as we can now do haplo-identical transplants in our centre,” says Prof Hany.

It is about no longer having to tell parents that nothing more can be done for their terminally ill child.

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