Transplant innovation

The Daily Mail reported today that children who need a bone marrow transplant could be spared the “worst side-effects of chemotherapy thanks to a 'remarkable' breakthrough”. The newspaper said researchers have developed an experimental technique to prevent the body rejecting cells from a donor. The technique involves using antibodies rather than chemotherapy to destroy the marrow, leaving the rest of the body unaffected.

This new treatment has demonstrated that it can be used in children with primary immunodeficiency disorders who may otherwise be unsuitable for transplant due to the severity of their illness preventing the use of chemotherapy.

This is only a very small phase 1-2 study involving 16 children. A far greater number will need to be treated to confirm the proportions of people who have successful transplants, the complications associated with it, and those who achieve a long-term cure.

Despite the apparent effectiveness of this new treatment in this specific group, no assumptions can be made about its use for other blood disorders such as leukaemia.

Where did the story come from?

The research was carried out by Dr Karin C Straathof and colleagues from Great Ormond Street Hospital, London, and other institutions in the UK, Germany and the US. The study received no financial support and was published in the peer-reviewed medical journal, The Lancet .

What kind of scientific study was this?

In this case series, the researchers reported on the effectiveness of a new treatment for children with primary immunodeficiency disorders. These are a group of genetic disorders that result in the child being vulnerable to infection and often having chronic illness.

A bone marrow transplant is the only cure for this condition, where haemopoietic stem cells (cells that can develop into any type of blood cell) from a healthy donor are transplanted into the child.

Before the transplant can take place, a “conditioning regimen” is needed to suppress the child’s own diseased stem cell development (myelosuppression) and to suppress the immune system so that the body does not reject the new transplanted cells (immunosupression). Conditioning typically involves chemotherapy, radiotherapy or other drugs.

Children with primary immunodeficiency disorders are often very unwell due to prior infections and other complications of their disease and so have a higher risk of death if undergoing such conventional conditioning regimens. In addition to destroying the diseased cells, chemotherapy also has the side effects of hair loss, sickness, organ damage and risk of infertility.

The new treatment involves using a new method of transplanting stem cells following antibody-based minimal-intensity conditioning (MIC) rather than chemotherapy to prepare the body for donor transplant. The researchers suspected that reducing the intensity of the conditioning could reduce the side effects and deaths related to the transplants.

In the new technique, antibodies (molecules produced by the body to defend itself against infection or other tissues identified to be harmful) are used as an alternative way of suppressing the bone marrow and immune system . The researchers used two rat anti-CD45 monoclonal antibodies for myelosuppression (CD45 is expressed on all white blood cells and haemopoetic stem cells, but is not present on other non-blood cells of the body), and alemtuzumab (anti-CD52) for immunosuppression.

The technique was trialled in 16 high-risk patients who were undergoing stem-cell transplantation for primary immunodeficiencies. All children were unsuitable for conventional conditioning because they were considered to be at increased risk of treatment-related mortality (because they were younger than one year, had pre-existing organ toxicity, or had associated problems of DNA repair or maintenance of the ends of the chromosomes). In five children, the donor stem cells came from matched siblings, nine were matched unrelated donors and two were from mismatched donors.

The outcomes the researchers were studying were the rate of non-engraftment (where the donor stem cells do not successfully establish themselves in the bone marrow), rejection (where the hosts body rejects the donor cells), frequency of graft-versus-host disease (GvHD, where the donor cells attack the body of the host), and the rate of illness and death caused by conditioning.

What were the results of the study?

The researchers report that the antibody-based conditioning was well tolerated. There were no cases of ‘grade 4’ toxicity (life threatening or disabling) and only two cases of ‘grade 3’ (one with a slight rise in a pre-existing oxygen requirement and one with raised liver enzymes associated with a reactivation of a fungal infection).

There were six cases of clinically significant acute graft-versus-host disease (GvHD), and five cases of chronic GvHD; rates that are considered to be ‘acceptable’. The stem cell transplant was successful in 15 out of 16 cases (although in three cases this was only a cell line that produced T-lymphocytes), and one patient needed retransplantation. An average of 40 months after the transplant, 13 of the 16 patients (81%) were alive and cured from their underlying disease.

What interpretations did the researchers draw from these results?

The researchers conclude that monoclonal antibody-based conditioning seems well tolerated and can achieve curative engraftment in patients with severe disease who would otherwise be considered unsuitable for transplant.

They say that the new approach challenges the belief that intensive chemotherapy, radiotherapy, or both, are needed for donor stem-cell engraftment. The antibody-based regimen may reduce toxicity and side effects and allow stem cell transplant in almost any person with a primary immunodeficiency who has a matched donor.

What does the NHS Knowledge Service make of this study?

This research has demonstrated that antibody-based minimal-intensity conditioning may be possible prior to stem cell (bone marrow) transplant in children with a primary immunodeficiency disorder who may otherwise be unsuitable for a transplant because they would not be able to tolerate the intensity of conventional chemotherapy-based conditioning.

This research seems to offer great potential as a treatment that could allow a child, who would not normally be able, to undergo bone marrow transplant; often the only curative option for primary immunodeficiencies. However, this is only a very small phase 1-2 study involving 16 children. A far greater number will need to be treated to confirm the proportions of people who have successful transplants, the complications associated with it, and those who achieve a long-term cure.

The children in this trial were chosen to receive the new technique as they could not have the conventional chemotherapy-based conditioning due to being at increased risk of treatment-related mortality. As such, for people with such severe illness, it would not be possible to carry out the usual test for a new treatment and directly compare this technique to the conventional conditioning in a randomised controlled trial. Therefore, only indirect comparisons can be made to other chemotherapy conditioning regiments.

Despite the apparent effectiveness of this new treatment in this specific group, no assumptions can be made about its use prior to bone marrow transplant for other haematological indications such as leukaemia.