From OncoLog, June 2007, Vol. 52, No. 6

Advances in Stem Cell Transplantation

by Don Norwood

When physicians at The University of Texas M. D. Anderson Cancer Center performed the first bone marrow transplant in Texas in 1975, they knew the procedure was risky. Experience in the early years proved them right. Although some patients were cured, many others died of complications related to the transplant. In addition, associated chemotherapy regimens often were highly toxic. Even so, because candidates for transplant were not responding to other regimens, many patients took the risk.

Today, however, the risk is much lower. Over recent years, continued work in the Department of Stem Cell Transplantation and Cellular Therapy and elsewhere has resulted in great strides in the transplantation of stem cells. More cancer patients are cured, the mortality rate of the procedure has fallen, there are fewer toxic effects, survival durations have increased, and the procedure is used in a wider array of patients and for more diseases.

Originally, physicians believed that transplantation of bone marrow or stem cells was merely a way to permit administering high doses of chemotherapy to eliminate malignant cells, said Sergio Giralt, M.D., professor in and deputy chairman of the Department of Stem Cell Transplantation and Cellular Therapy. However, physicians have since discovered that transplanted stem cells have a graft-versus-tumor effect, in which the transplanted cells actually kill cancer cells, especially in patients with hematological malignancies. This finding, along with new ways to reduce toxicity, opened the door for the expanded use of the procedure.

Stem cell transplantation can replace defective blood and immune cells and holds promise for the treatment of diseases such as sickle cell anemia and autoimmune disorders, as part of vaccinations against melanoma and other cancers, and in the regeneration of organs. However, the most promising result of the evolution of stem cell transplantation is the improvement in survival and reduced toxicity for the traditional population of recipients: patients with hematological malignancies.

“When I started here as a fellow in 1989, the main challenge that we had to overcome was that many patients could not get transplants because they were told, ‘You are too old, too sick,’” said Dr. Giralt. “Many other patients couldn’t get transplants because we didn’t have a source of stem cells for them. And of the ones who got transplants, many had very poor outcomes because their disease was advanced. We’ve actually been able to target and make major breakthroughs of all those barriers.”

Preparative regimens are now more effective, less toxic

One of these breakthroughs is the development of safer and much more effective preparative regimens that can be used in older and younger patients with better outcomes. Another is the discovery that other sources of stem cells besides bone marrow obtained from matched donors produce good results.

“Before, one out of three patients would die within the first three to six months,” said Dr. Giralt. “Now, that has gone down to one out of ten, and we’re hoping that it will continue to go down farther.”

Historically, patients who underwent stem cell transplants for hematological malignancies often died from the preparative chemotherapy and radiotherapy regimens rather than the disease itself. But with newer regimens, said Marcos de Lima, M.D., associate professor in the Department of Stem Cell Transplantation and Cellular Therapy, the occurrence of death due to the chemotherapy that precedes the infusion of stem cells from a donor has decreased dramatically. In fact, in some subgroups of patients with acute myelogenous leukemia, it is now down to numbers that are very similar to those seen with chemotherapy before autologous stem cell transplantation, which is traditionally the safest type of transplantation.

“The treatment-related death rate in the first 100 days is below 5%,” said Dr. de Lima, and below 10% in the first year, provided a well-matched donor and current best treatments are used. “Of course, people still relapse. We are not curing 100% of the people, but certainly we’re causing less toxicity.”

In the past, oral busulfan was the preparative regimen of choice for most transplants. Unfortunately, wide fluctuations in absorption from patient to patient led to inconsistent results. Too little absorption compromised engraftment, but complete absorption was often lethal. Therefore, Borje S. Andersson, M.D., Ph.D., professor in the Department of Stem Cell Transplantation and Cellular Therapy, developed an intravenous busulfan formulation that is now given in combination with fludarabine as a preparation for stem cell transplants. The new intravenous formulation allows much more precise and accurate dosing and permits close monitoring of drug levels in the body.

Minitransplants extend therapy to older patients

In addition, older patients are now better candidates for stem cell transplantation because of the improvement in preparative regimens. A prime example of this is the median age of patients with acute myelogenous leukemia who undergo this procedure at M. D. Anderson.

In the late 1990s, the median age of patients with acute myelogenous leukemia who underwent stem cell transplantation at M. D. Anderson was in the mid-30s, which is far below the median age of patients who have this disease. “See the catch here?” said Dr. de Lima. “We were selecting heavily toward younger patients who were fitter and in good shape, and the majority of the patients were excluded because they couldn’t survive the procedure. Now, our median age is in the low 50s. So in less than a decade, we went up almost 20 years in median age.”

This increase in the median age of stem cell transplant recipients was a result of Dr. Giralt and his colleagues being “professionally challenged” in 1994 by the Department of Leukemia to provide transplants to patients who need them the most. The response to this challenge was the development of a new procedure in which a patient with a donor who is a good match receives less-intensive chemotherapy before receiving at least one stem cell infusion.

“I think it’s fair to say that we were one of the first, if not the first, group that developed a program specifically dedicated to older and debilitated patients, in whom we would try to exploit a graft-versus-tumor effect using less-intense conditioning regimens,” said Dr. Giralt. “Initially it was called the minitransplant program. Now we talk about all of these as reduced-intensity programs or nonablative transplant programs.”

Dr. Giralt and his colleagues got the idea for minitransplants from a faculty member in the Department of Leukemia who had administered fludarabine to a patient as preparative therapy for an infusion of unirradiated white blood cells. The result was engraftment of the cells in the patient, a highly significant finding with crucial implications for patients with leukemias and lymphomas. Physicians learned from this result that transplanting white blood cells after administering fludarabine has an antileukemia effect and that high doses of fludarabine are not required to produce this effect.

Use of fludarabine as a preparative regimen for stem cell transplantation did not require the usual set of clinical trials first, said Dr. Giralt, because physicians in the Department of Leukemia were already using several fludarabine-based regimens for the treatment of acute and chronic leukemias. This experience facilitated use of the drug with transplants of stem cells from matched sibling donors at M. D. Anderson, where physicians were the first to show almost universal engraftment of donor cells, resulting in the potential for exploiting a graft-versus-tumor effect. However, several relapses occurred in these transplant recipients, which resulted in the evolution of the preparative use of fludarabine through intensification and the addition of melphalan or busulfan at doses lower than those used traditionally.

New sources of stem cells improve odds of finding donors

Another major stem cell transplantation breakthrough at M. D. Anderson has been in cell donation. In the past, physicians had to rely on autologous transplants and bone marrow donations from closely matched siblings: those with two identical sets of blocks of human leukocyte antigen genes on chromosome 6 inherited from their parents. Now, physicians are able to infuse cells from bone marrow donated by siblings who are only haploidentical—those with only one identical set of blocks of these genes—as well as from peripheral blood and umbilical cord blood obtained from unrelated donors.

Dr. Giralt highlighted the role of Richard E. Champlin, M.D., professor in and chairman of the Department of Stem Cell Transplantation and Cellular Therapy, in the advancement of transplanting stem cells obtained from unrelated donors. Upon his arrival at M. D. Anderson in 1990, Dr. Champlin, a pioneer of unrelated donor transplantation, helped build the institution’s unrelated donor program. In fact, M. D. Anderson was the first institution in Texas to perform a transplant using stem cells from an unrelated donor—also in 1990. That patient remains alive and is doing well. In addition, Dr. Champlin was one of the individuals who developed the National Marrow Donor Program in the United States.

Since its inception, the National Marrow Donor Program has grown to more than six million registered donors, and according to Dr. Giralt, the quality of the typing has increased to the point that now the results of transplantation of stem cells from an unrelated donor sometimes are equivalent to the results of transplantation of stem cells obtained from a matched sibling.

“One of the controversies in the field now is that a young, unrelated donor might actually be better than a brother or sister who is 60 or 70 years old, particularly in older patients,” said Dr. Giralt. “It’s an unresolved controversy but a very important one.”

As mentioned above, physicians can now perform stem cell transplants using cells obtained from umbilical cord blood. M. D. Anderson recently opened a Cord Blood Bank, providing an additional source of stem cells for those without matching related donors. This is particularly important because of the smaller families of today, which means fewer potential matching related donors.

“Our Cord Blood Bank is growing very fast, and it’s bound to be one of the biggest in the nation if we keep going like this,” said Dr. de Lima. “It’s barely a year old, and it’s already collected more than 1,000 units.”

Dr. Giralt said that the Cord Blood Bank has been beneficial for patients at M. D. Anderson because the infusion of stem cells from cord blood has had results equal to or better than the infusion of cells from bone marrow obtained from unrelated donors. This has been especially true in pediatric patients.

Confidence in therapy grows

The improvements in stem cell transplantation over the past decade have raised confidence in the procedure among both physicians and patients with diseases that can be treated with transplants. This increased confidence is reflected by what Dr. Giralt describes as a drastic change in the outlook for patients who undergo stem cell transplantation.

For more information on this topic or for questions about M. D. Anderson’s treatments, programs, or services, call askMDAnderson at (877) MDA-6789.

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