An article published Online First and in a future edition of The Lancet reports that minimal-intensity conditioning (MIC) regimen using antibodies instead of high dose chemotherapy may reduce the short and long term toxicity related with stem cell transplants in children. This could allow successful transplantation even in the sickest children. The article is the work of Dr Persis J Amrolia, Department of Bone Marrow Transplantation, Great Ormond Street Children’s Hospital, London, UK, and collaborators.
Children with primary immunodeficiencies (PID) suffer from genetic defects of their immune systems that cause them to be susceptible to infection and other complications. Many of these children will die in childhood without a stem cell transplant. Such transplants can cure these diseases. They replace the defective immune system with one derived from healthy normal donor bone marrow. Each year in the UK approximately fifty children with PID are transplanted.
Conventional conditioning for a stem-cell transplant is essential to create space for the donor stem cells, and prevent the patient from rejecting them. It involves chemotherapy, radiotherapy, or both. This chemoradiotherapy may result in severe damage to the liver, gut or lungs, as well as hair loss and sickness. It also often causes problems with growth, puberty and infertility in later life. The BMT unit at Great Ormond St Hospital, led by Dr. Paul Veys, has pioneered over the last ten years the use of gentler chemotherapy drugs with reduced intensity conditioning. This permits bone marrow transplant in children with PID with fewer side effects. This approach has improved survival. Still in specific groups of patients, such as babies under one year old, those going into transplant with severe damage to their lungs or liver, and those with DNA repair disorders, chemotherapy conditioning is badly tolerated and results in high rates of mortality.
This study breaks new ground because the authors used monoclonal antibodies which are immune molecules made by white blood cells instead of high-dose chemotherapy to wipe out the patients’ diseased bone marrow, create space for the healthy bone marrow from the donor, and avoid rejection. This innovative technique uses antibodies directed against molecules called CD45 and CD52. Because these molecules are specific to bone marrow and blood cells, the monoclonal antibodies aim only at the immune cells that cause rejection. They do not attack other body tissues. As a result, this method avoids much of the toxicity linked with chemotherapy. This study examined the results of antibody-based conditioning in sixteen children with PID who were too sick to undergo a traditional stem cell transplant. The average age of these patients was 11 months. Of the sixteen, eleven had previously been ventilated on a life-support machine. Eleven of them were transplanted from unrelated donors and five from matched siblings.
Findings indicated that antibody-based MIC was well tolerated even though most patients were extremely sick at the time of transplant. There were only two cases of serious toxicity. The sickness and hair loss linked with high dose chemotherapy were not experienced. In addition, there was much less damage to the liver, lungs, and gut. Patients recovered twice as quickly as those given standard treatment. The rates of graft-versus-host disease (GVHD: in which the transplanted cells see the patient as foreign and attack the host’s skin, gut or liver) were comparable to conventional transplant. Fifteen out of sixteen patients (94 percent) engrafted, which means the donor stem cells survived long-term. Although in two cases this was not sufficient for cure. After an average of forty months after transplant, thirteen of sixteen patients (81 percent) were alive and cured from their underlying disease. Almost all of these patients now have excellent quality of life. It is predicted that they will have very little late effects.
This innovative method incorporates a change from the concept that intensive chemotherapy or radiotherapy is necessary for donor stem-cell engraftment. The researchers conclude that antibody-based conditioning is well tolerated and can complete curative engraftment even in patients with severe organ toxicity or DNA repair defects. This procedure may decrease toxicity and late effects. It enables stem cell transplants in almost any primary immunodeficiency patient with a matched donor.
Dr Persis Amrolia, a consultant in bone marrow transplant at GOSH who led the research, described the results as “remarkable”. She mentions: “Because this approach was experimental, we only used it on the sickest children, who we felt could not tolerate standard transplant chemotherapy. Given how sick these children were before transplant, the results are remarkable. What’s really encouraging is in most of the children who had severe damage to their lungs, liver or gut prior to transplant, this has now resolved or improved, so we hope they will grow up to lead normal healthy lives. There’s still a lot to do – at the moment this approach is probably not strong enough to enable transplant in patients with other genetic diseases and leukaemia and the challenge now is to develop similar targeted approaches for these diseases.”
In an associated note, Dr Robert F Wynn, Blood and Marrow Transplant Unit, Royal Manchester Children’s Hospital, Manchester, UK, and Dr Jaap Jan Boelens, Blood and Marrow Transplant Programme, Universitair Medisch Centrum Utrecht, Utrecht, Netherlands, mention: “We hope that today’s study will be the basis for further optimisation of minimal-intensity conditioning, not only to improve engraftment but also to reduce short-term complications such as GVHD and viral complications, which although acceptable were still substantial in this study. This innovative conditioning will definitely improve, as have others in the past…so that therapy can be individualised.
They continue by saying: “[Stem cell transplantation] is effective in certain disorders such as sickle-cell anaemia, thalassaemia, and mild phenotypes of some inborn errors of metabolism that are not immediately fatal but restrict the patient’s quality of life and reduce life expectancy. HSCT is not used in these diseases because of perceived and real risks of short-term mortality and long-term morbidity. With continued refinement, this undoubtedly effective therapy can be offered to such patients.”
“Haemopoietic stem-cell transplantation with antibody-based minimal-intensity conditioning: a phase 1/2 study”
Karin C Straathof, Kanchan Rao, Matthias Eyrich, Geoff Hale, Prudence Bird, Eleanor Berrie, Lucinda Brown, Stuart Adams, Paul G Schlegel, Nicholas Goulden, H Bobby Gaspar, Andrew R Gennery, Paul Landais, E G Davies, Malcolm K Brenner, Paul A Veys, Persis Jal Amrolia
Written by Stephanie Brunner (B.A.)