How bone marrow transplant cures adult sickle cell disease

Sickle cell disease, named for the “deflated” sickle-shaped appearance of red blood cells in those with the disease, hinders the cells’ ability to carry oxygen throughout the body. In severe cases, it causes stroke, severe pain and damage to multiple organs, including the lungs, kidneys and liver.

Sickle cell disorder is by far the commonest inherited disorder in the world and three quarters of cases occur in Africa.

Researchers at the United States government’s National Institutes of Health (NIH) reported recently in the New England Journal of Medicine that bone marrow transplants, already used to treat some children with sickle cell disease, also may cure some adults with this deadly genetic defect that causes red blood cells to contort.

According to the report, nine of 10 adult patients given an experimental bone marrow transplant treatment were cured of sickle cell disease.

Also, results of a preliminary study by scientists at NIH and Johns Hopkins, United States show that ‘mini’ stem cell transplantation may safely reverse severe sickle cell disease in adults.

The phase I/II study to establish safety of the procedure, published December 10 in the New England Journal of Medicine, describes 10 patients with severe sickle cell disease who received intravenous transplants of blood-forming stem cells. The transplanted stem cells came from the peripheral blood of healthy related donors matched to the patients’ tissue types.

Bone marrow gives rise to blood cells. Destroying a patient’s bone marrow and replacing it with healthy marrow from a donor, often a sibling, is considered too risky for adults.

In conventional bone marrow transplants, doctors try to destroy all of a patient’s own bone marrow. Using the new technique, adults are given a lower dose of radiation, only partially destroying the patient’s bone marrow.

This approach leaves enough space inside the patient’s bones for the donated marrow to find a home and produce enough healthy red blood cells to compensate for the defective ones.

In sickle cell disease, an inherited disorder, blood cells become stiff and sickle-shaped, causing them to block blood vessels and starve tissues of oxygen.

It had been thought that by the time people with sickle cell disease become adults, they have suffered too much kidney, lung and liver damage to allow for a safe transplant.

According to a World Health Organisation (WHO), “frequencies of the carrier state determine the prevalence of sickle-cell anaemia at birth. For example, in Nigeria, by far the most populous country in the sub region, 24 per cent of the population are carriers of the mutant gene and the prevalence of sickle-cell anaemia is about 20 per 1000 births. This means that in Nigeria alone, about 150 000 children are born annually with sickle-cell anaemia.”

WHO noted that the sickle-cell gene has become common in Africa because the sickle-cell trait confers some resistance to falciparum malaria during a critical period of early childhood, favouring survival of the host and subsequent transmission of the abnormal haemoglobin gene. Although a single abnormal gene may protect against malaria, inheritance of two abnormal genes leads to sickle-cell anaemia and confers no such protection, and malaria is a major cause of ill-health and death in children with

sickle-cell anaemia. There is increasing evidence that malaria not only influences outcome but also changes the manifestations of sickle-cell anaemia in Africa.

According to the WHO, when health impact is measured by under-five mortality, sickle-cell anaemia contributes the equivalent of five per cent of under- five deaths on the African continent, more than nine per cent of such deaths in west Africa, and up to 16 per cent of under-five deaths in individual west African countries.

Meanwhile, Dr. Miguel Abboud of American University of Beirut Medical Centre in Lebanon said in an editorial accompanying the New England Journal of Medicine study:

“If the early results from the bone marrow transplant procedure hold, the treatment could be ideal for patients with severe sickle cell disease.”

Dr. John Tisdale of the NIH’s National Heart, Lung and Blood Institute, who led the study, said: “All of these organs are essential for getting through a bone marrow transplant.”

Tisdale and his team used about one quarter of the conventional dose of radiation, which was enough to wipe out part of the marrow. They also eliminated chemotherapy normally given to suppress the immune system.

As a result, each patient’s bone marrow was a mix of cells from the patient and the donor.

But that was enough to cure nine out of the 10 patients who underwent a transplant and keep them well for an average of two and half years. The ages of the patients in the study ranged from 16 to 45 at the time of their transplants.

The healthy disc-shaped red blood cells produced by the donated marrow overwhelmed the diseased sickle-shaped cells generated by the patient’s remaining marrow.

Tisdale said: “Because sickle red blood cells only live about six or seven days and normal red blood cells live 120 days, if you can get a little bit of the donor cells in there, the donor cells take over.”

Abboud cautioned that the technique’s applicability is still limited by the small number of available siblings of patients with matching bone marrow types. Only 24 of the 112 eligible patients in this study had a compatible donor.

Dr. Jonathan Powell, associate professor at the Johns Hopkins Kimmel Cancer Centre, United States says the intravenous transplant approach for sickle cell disease, caused by a single mutation in the haemoglobin gene, does not replace the defective gene, but transplants blood stem cells that carry the normal gene.

All patients in the study, ranging in age from 16 to 45, were treated at the NIH with what researchers call a non-myeloablative or “mini” transplant, along with an immune-suppressing drug called rapamycin.

Conventional transplant methods use high doses of chemotherapy to wipe out the immune system before the transplanted cells are injected, a process that has many side effects, including serious bacterial and fungal infections, which may kill some patients. In mini-transplants, lower doses of medication and radiation are used to make room for the donor’s cells, the new source for healthy red blood cells in the patient.

According to Powell, side effects, including low white blood cell counts, were few and very mild compared with conventional bone marrow transplantation. But in nine of the 10, donor cells now coexist with the patients’ own cells. One patient was not able to maintain the transplanted cells long term.

Minitransplants for sickle cell disease were tested in patients almost a decade ago, but were unsuccessful because the patients’ immune systems rejected the transplanted cells, according to Powell, but by employing the drug rapamcyin, he says this new approach promotes the coexistence of the host and donor cells.

Powell’s earlier research in mice showed that rapamycin inhibits an enzymatic pathway that suppresses the immune system and makes the host and donor cells tolerant to each other.

The NIH/Johns Hopkins team is conducting further studies on immune cells gathered from patients in their study and looking at a combination of rapamycin with a well-known cancer drug called cyclophosphamide.

Other teams at Johns Hopkins are studying the use of half-matched donors for transplants in sickle cell patients, helping to widen the pool of potential donors for stem cell transplantation.