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New hope for children when leukemia treatment fails

St. Jude technique allows partial-match cell transplants for children with most resistant leukemia, boosting chance for cure while avoiding previous harsh forms of treatment

Clinicians at St. Jude Children's Research Hospital have successfully demonstrated an improved technique for blood stem cell transplantations in children that shows promise for those most likely to fail standard treatment for leukemia.

The St. Jude technique allows blood stem cells to come from parents or unmatched adult siblings; and it avoids the aggressive, toxic treatments that usually must accompany the transplant. This allows the majority of patients with leukemia or non-cancerous blood disorders to receive a transplant, according to Gregory Hale, M.D., St. Jude Bone Marrow Transplantation Division interim chief. A report on this work appears in the prepublication edition of the British Journal of Haematology.

A clinical trial of this technique demonstrated that it accelerated recovery of the immune system in recipients and shortened the duration of immune deficiency during the early post-transplant period, reducing the risk of infections. The immune system recovery included not only T and B lymphocytes, the major cells genetically programmed to attack specific targets, but also natural killer cells, a critical first-response army of cells that acts as a quick-strike force against a wide variety of targets.

"The overall success of this procedure suggests it holds promise for children who are likely to fail standard treatment for leukemia because they have treatment-resistant disease and no matched donor," Hale said.

The key to the St. Jude strategy--reduced intensity conditioning regimen (RICR)--is that it avoids the total-body irradiation routinely used to kill the recipient's own stem cells to make way for the transplantation. RICR also avoids the use of anti-thymocyte globulin (ATG), a drug commonly used to suppress the remaining immune system of recipients in order to reduce the chance they will reject the transplanted blood stem cells. ATG often delays rebuilding of the immune system in transplant recipients and can lead to a virus-related lymphoma. The standard treatment, called myeloablative conditioning regimen (MCR) uses total body irradiation, ATG and other drugs to eradicate the patient's own blood stem cells and suppress the remaining immune system to prevent rejection of the transplanted blood stem cells.

The underlying technique that permitted the team to eliminate total body irradiation and ATG was the use of haploidentical hematopoietic stem cell transplantation (HaploHSCT) for children, which was previously pioneered by St. Jude investigators. Before this technique, only matched transplants from a genetic twin or from a matched, unrelated donor could be used, since unmatched donations led to unacceptably high rates of severe graft-versus-host disease (GVHD).

However, the St. Jude technique treats partially matched donor blood stem cells to remove the aggressive immune system cells called T lymphocytes that normally cause GVHD. GVHD occurs when donor immune cells respond to the recipient as foreign and launch an attack on the body.

An additional advantage of this new treatment is that donor immune cells are likely to attack the leukemic cells remaining in the recipient, a reaction called a graft-versus-tumor response, according to the researchers.

During a 12-month follow-up after transplantation, the St. Jude team compared the results of its modified transplantation technique with results from a group of patients with refractory blood cancers who were treated with MCR. The investigators reported that following RICR in 22 children, 91 percent achieved full donor chimerism; that is, the recipients "adopted" the transplanted stem cells and built a blood system that was identical to that of the donor. In the MCR group that received the more aggressive therapy, 92 percent achieved full donor chimerism.

Also, although 12 patients in the RICR group and two in the MCR group experienced acute GVHD, and five in the RICR group developed chronic GVHD, none of the patients had died at the end of the first year as a result of GVHD. Acute GVHD arises within 100 days of transplant, while chronic GVHD arises after the third month.

The team also reported that these patients had a rapid recovery of immune system cells during the first four months after transplantation, compared to patients who had undergone the more toxic, standard treatment to prepare them for transplantation. This rapid recovery of the immune system reduced occurrence of viral infection, the researchers reported.

"Many viruses exist in the body in an inactive state, even after a person clears an initial infection," Hale explained. "A healthy immune system keeps those viruses in check, but after a transplant, the patient's immune system is rebuilding and not capable of mounting a strong defense. That leaves the patient vulnerable to developing hepatitis, gastroenteritis, encephalitis or other diseases that can be fatal."

Viral infections can also cause graft failure or prolong the need for transfusions to supplement red blood cells or platelets, he added. Viral infections can further weaken the immune system of transplant recipients, leaving them vulnerable to fungal infections. Moreover, the drugs used to treat those viral infections and reactivation of old infections can cause low blood counts and kidney damage.

Bonnie Kourvelas | EurekAlert!
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