Blood Stem Cell Transplantation at Memorial Sloan-Kettering

Nancy Kernan is Assistant Chief of Memorial Sloan-Kettering's Pediatric Bone Marrow Transplant Service, and Faculty Member Marcel van den Brink is Chief of the Adult Bone Marrow Transplant Service.

One of the Country's First Transplantation Centers Continues to Make Important Advances in the Field

Since 1973, when Center physicians performed the first successful transplant of marrow from an unrelated donor, Memorial Sloan-Kettering Cancer Center has been a leader in bone marrow transplantation. This achievement, and others, enabled Memorial Sloan-Kettering Cancer Center to launch the Center's bone marrow transplantation program as a combined service in pediatrics and medicine in 1976.

"In the early days of transplantation at Memorial Sloan-Kettering Cancer Center, our goal was to cure children with inherited immune disorders, such as severe combined immune deficiency. By 1978, we had expanded our program and were performing most of our transplantsin both pediatric and adult patients with leukemia. Our hope was to reach what then seemed to be difficult goals -- increasing the long-term survival of all transplantation patients, improving our success rates in adults to the levels we were obtaining in children, and extending curative transplants to patients who lacked a matched brother or sister," said Richard J. O'Reilly, founder of the marrow transplant program and Chairman of the Department of Pediatrics.

More than 30 years later, Memorial Sloan-Kettering Cancer Center has fulfilled these goals. More than 4,000 patients, from new borns to adults as old as 74, have been transplanted at the Center for a wide range of cancers, with approximately 50 percent of them going on to lead healthy lives -- even when treated for diseases once thought to be virtually incurable.

"During the first fifteen or twenty years of our program's existence, we achieved many milestones in the field of transplantation," added Nancy A. Kernan, Assistant Chief of the Pediatric Bone Marrow Transplant (BMT) Service. "Our priorities forthe next five years are to build on developments in both thelaboratory and the clinic so that every patient who comes to Memorial Sloan-Kettering Cancer Center for a blood stem cell transplantation procedure leaves a success story."

Blood stem cell transplantation may help cure cancers such as leukemia, Hodgkin's disease and other lymphomas, and multiple myeloma. Transplants have also been shown to be effective for treating patients with precancerous and noncancerous diseases affecting blood cell production, including myelodysplastic syndromes, aplastic anemia, and inherited immune disorders.

Blood stem cell transplantations allow physicians to replace a patient's diseased or damaged marrow with healthy blood-forming cells. First, patients receive high doses of chemotherapy and/or radiation to destroy the cancer cells; however, along with the cancer, normal cells in the marrow are also destroyed. So chemotherapy and radiation are followed by an infusion into the bloodstream of healthy donor blood stem cells. The transplanted cells migrate into the spaces inside the bones to create new marrow, which contains cells -- known as hematopoietic (blood) stem cells -- that have the ability to grow and make healthy new red blood cells,white blood cells, and platelets in a process known as engraftment.(Hematopoietic stem cells differ from embryonic stem cells, which are primitive cells derived from embryos.)

The body's ability to produce enough white blood cells to regenerate the immune system and prevent infections is vital for a successful transplantation. In the 1970s, Memorial Sloan-Kettering Cancer Center investigator Malcolm A.S. Moore and his Center colleagues isolated granulocyte colony stimulating factor (G-CSF), a naturally occurring protein that encourages bone marrow to produce more white blood cells. G-CSF is also used prior to stem cell collection to mobilize, or stimulate, stem cells to move from the marrow into the circulating blood, boosting the number available for transplantation.

Faculty Member Richard O'Reilly is the founder of Memorial Sloan-Kettering's marrow transplant program and Chairman of the Department of Pediatrics.

To reduce the toxicity and increase the anticancer activity of high-dose radiation, Memorial Sloan-Kettering Cancer Center scientists created a technique in 1978 called hyperfractionated total body irradiation, which allows patients to receive lower doses of radiation two or three times a day over several days prior to the transplantation, instead of receiving the entire high dose at one time.

Patients can receive a blood stem cell infusion in one of two ways: using their own stem cells or those from a donor. Autologous transplantation uses the patient's own marrow, which is removed from the patient's body and reinfused into the bloodstream. Allogeneic transplantation uses cells obtained from a donor -- either a family member or an unrelated individual -- whose tissue type closely matches that of the recipient.

"Matching donor and patient tissue type -- specifically molecular determinants called human leukocyte antigens (HLA) -- is critical for an effective allogeneic transplant, but only about 30 percent of people have a suitably matched sibling donor," said Marcel R.M. van den Brink, Chief of Memorial Sloan-Kettering Cancer Center's Adult BMT Service. The remaining 70 percent must look toregistries of unrelated volunteer donors, such as the National Marrow Donor Program.^® The program has almost six million registered donors, and now includes increasing numbers of minorities and people of mixed races who historically have had difficulty finding suitably matched unrelated donors.

When donor blood stem cells are transplanted into a patient to create new marrow and blood cells, there is a possibility of graft failure, in which donor cells may be rejected by the recipient. To prevent this complication, powerful immuno suppressive drugs, such as antithymocyte globulin, are given to the patient to ensure successful engraftment.

A major complication of allogeneic transplantation is graft-versus-host-disease (GvHD), in which some of the donor's immune cells, or T cells, attack cells in the recipient's body in areas such as the skin, liver, and gastrointestinal tract. "Thereare two types of GvHD -- acute GvHD, which occurs within the first months after transplantation, and chronic GvHD, which happens later and has some similarities with an autoimmune disease," explained Dr. van den Brink.

When GvHD was first characterized, Memorial Sloan-Kettering Cancer Center researchers recognized that it was caused by T cellsin the transplant. Reducing GvHD has been a major focus of the BMT Service. In 1981, the Memorial Sloan-Kettering Cancer Center transplantation program developed and introduced a new approach called T cell depletion. T cells, which develop in the thymus, are selectively removed from donor blood stem cells prior to their infusion, significantly reducing the chance that these donor T cells will attack the patient's body, thereby preventing GvHD, even when donor and recipient are only half HLA-matched. Following the transplant, new T cells develop from the donor's blood stem cells, providing a new immune system for the patient.

"The concept of T cell depletion is what has really driven Memorial Sloan-Kettering Cancer Center's allogeneic transplantation program for the past two decades," said Dr. Kernan, who played a keyrole in the technique's application. "Many of the most significant discoveries made here and elsewhere built upon the understanding of how T cell depletion affects specific patients. Ideally, this transplantation procedure enables the patient's new immune system to reconstitute itself effectively after transplantation without the need for the immuno suppressive drugs used to prevent GvHD in the absence of T cell depletion. Our protocols utilize what we call full T cell-depletion methods, where no drugs at all are required following transplantation." Currently, more than half of the allogeneic transplants performed at Memorial Sloan-Kettering Cancer Center use T cell depletion. This number may increase in other centers in light of the results of a large, multi-institutional randomized trial published in the August 3, 2005, online issue of The Lancet (of which Dr. Kernan was the senior author) demonstrating that T cell depletion is an effective method of preventing both acute and chronic GvHD while ensuring comparable long-term disease-free survival. However, clinicians must be trained in the management of complications seen more frequently in T cell-depleted infusion recipients. [PubMed Abstract]

Until the mid-1990s, blood stem cells could only be harvestedfrom bone marrow. However, recent discoveries -- many of themthe result of work by Memorial Sloan-Kettering Cancer Centerphysicians and researchers -- led to the discovery ofadditional stem cell sources.

"One of the key disadvantages of BMTs is the limited availability of blood stem cells, especially for adult transplantation patients," said Dr. Kernan. "Using peripheral blood (blood stem cells collected from the bloodstream), counter acts this problem because there are more cells available in blood than in marrow."

In a peripheral blood stem cell transplant, stem cells are collected from the circulating blood by a method called apheresis, in which blood is drawn from the patient's (or donor's) arm, and the stem cells are separated out. The remaining blood components are then transfused back into the patient's bloodstream. The white cell fraction containing the blood stem cells is then frozen until needed for transplantation.

Faculty Member Stephen Nimer is Head of the Division of Hematologic Oncology.

"Unlike bone marrow harvest, in which bone marrow is extracted from a patient's or donor's hip, apheresis does not require the individual to be in an operating room under general anesthesia," said Stephen D. Nimer, Head of Memorial Sloan-Kettering Cancer Center's Division of Hematologic Oncology. "And because the procedure yields more stem cells than bone marrow harvest, post-transplantation hospital stays tend to be shorter and less costly for patients undergoing peripheral blood stem cell transplantation." Peripheral blood has thus become the stem cell source of choice for autologous transplants, and is increasingly used for allogeneic transplants.

Another blood stem cell source is showing promise for both pediatric and adult patients: studies have shown that infusions using cord blood stem cells, collected from the umbilical cord and placenta of newborns, are successful between matched siblings in the treatment of both genetic and acquired blood disorders and can also be used for unrelated adult patients.

"A huge factor in the success of cord blood transplants for unrelated adults is that HLA matching does not have to be as stringent as for marrow or peripheral blood stem cell transplantations," said Juliet N. Barker, a clinical researcher who joined Memorial Sloan-Kettering Cancer Center earlier this year to lead the new Umbilical Cord Blood Transplantation Program. "And because blood stem cells obtained from cord blood are more immature, the likelihood of developing severe GvHD is also reduced."

Memorial Sloan-Kettering Cancer Center investigators are also helping to develop two additional transplant techniques. Reduced-intensity transplants (RIT) use lower doses of chemotherapy and radiation in the preparative regimen, suppressing a patient's immune system just enough so that it cannot attack and reject the donor's blood stem cells. RITs rely on the patient's new immune system -- growing from the donor's cells -- to destroy disease. Memorial Sloan-Kettering Cancer Center physicians use this approach for older patients, those with chronic leukemias and lymphomas and multiple myeloma, or patients who cannot tolerate standard transplantations due to poor overall health.

In a tandem stem cell transplantation -- sometimes referred to as a "double" transplantation -- an autologous transplant is followed six months later by a second transplantation, which is either autologous or an allogeneic reduced-intensity transplantation. "Although the benefits of this procedure are still not fully understood, early results have shown that tandem transplants may improve the survival rate of some cancer patients," said Dr. Nimer.

Juliet Barker heads Memorial Sloan-Kettering's new Umbilical Cord Blood Transplantation Program.

Memorial Sloan-Kettering Cancer Center laboratories are also making progress in blood stem cell transplantation research, with mouse models proving to be particularly helpful. "Using mouse models allows us to mimic the transplantation process in humans," Dr. van den Brink said. "This helps us understand some of the major complications, like GvHD, that occur after a transplant. We can use this knowledge to develop therapies to treat these problems and to prevent them in the future."

Dr. van den Brink's work focuses on elucidating the molecular mechanisms that govern the ways in which donor T cells cause GvHD and graft-versus-tumor (GvT) activity, and he is trying to develop new therapies to inhibit unwanted GvHD and boost the desired GvTeffect. Additional research involves the development of new growth factors to promote immune system reconstitution. Recent studies showed that the protein interleukin-7 (IL-7) helped regenerate the immune systems in mice more quickly following transplantation by boosting thymus function. "A phase I clinical trial is underway toassess IL-7's safety," said Dr. van den Brink. "We hope that IL-7can boost the regeneration of a patient's immune system and prevent infections and relapse following transplantation."

Mouse models have also led to the discovery of important proteins linked to the immune system's proper functioning. Dr. Nimer's hematology research group recently discovered that the MEF protein is essential for the development of natural killer cells, a vital part of a healthy immune system. Natural killer cells are also the subject of current work by Memorial Sloan-Kettering Cancer Center oncologist Katharine Hsu and clinical immunologist Bo Dupont who have shown that the killer immunoglobulin-like receptor is crucial for regulating natural killer cells' activity. "Our hope is that we can eventually use these results to develop more effective therapies, and ones that won't destroy healthy bone marrow," explained Dr. Nimer.

The story of Memorial Sloan-Kettering Cancer Center's transplantation program demonstrates the importance of collaboration among clinicians and basic research scientists. "To me, transplantation is the best example of Memorial Sloan-Kettering Cancer Center's commitment to furthering translational research," said Dr. O'Reilly. "Throughout our program's history, progress in basic research has shaped our clinical research initiatives. Our clinical trials have, in turn, either validated hypotheses or necessitated their re-examination and modification. Often, to our surprise and excitement, this process has resulted in discoveries and whole new areas of scientific inquiry."