Robert S. Dinsmoor

Once reserved as a last resort when chemotherapy was no longer effective, hematopoietic stem cell transplantation (HCT) for blood cancers has improved remarkably over the past 30 years, and the field continues to evolve.

Even among advanced cancer patients whose disease did not respond to other treatments, some are cured by HCT. “There are patients who are surviving more than 20 or 30 years after HCT who would have died within a few weeks or months had they not received transplants,” says H. Joachim Deeg, MD, of the Fred Hutchinson Cancer Research Center in Seattle.

Transplants are used to treat patients with a variety of blood cancers, including leukemia, lymphoma, and myeloma. There are two main types of HCT: allogeneic and autologous. An allogeneic transplant uses stem cells from a healthy donor whose tissue type ideally matches that of the patient. High-dose chemotherapy is given prior to the transplant to kill off cancer cells, but it also damages the patient’s healthy stem cells. To replace those stem cells, donor cells are infused into the patient. Autologous transplantation, on the other hand, uses the patient’s own stem cells, which are collected before high-dose treatment, frozen, and then thawed and returned to the patient after high-dose therapy with chemotherapy, radiation, or both.

It has long been recognized that radiation or chemotherapy at doses that are tolerated by patients will not kill all cancer cells. To eliminate residual cancer cells, “We’re relying heavily on the immunotherapy provided by allogeneic donor cells,” says Deeg.

In transplants that use reduced-intensity conditioning regimens (sometimes referred to as “mini-transplants”), patients are given lower, less toxic doses of chemotherapy or radiation, which makes the regimen more tolerable for older patients or for those with other medical problems who may not be able to withstand high-dose treatments.

Another innovation, according to Deeg, involves the use of high-dose therapy with autologous stem cell rescue (with the intent of reducing the amount of cancer cells in a patient’s body, followed by a reduced-intensity allogeneic transplant. This strategy combines the anti-cancer effects of high dose therapy with the immunotherapeutic effect of allogeneic donor cells.

There are also more recent developments of interest. The Food and Drug Administration approved Mozobil (plerixafor) late last year. This drug, which “mobilizes” stem cells from the marrow into the bloodsteam, given alone or in combination with granulocyte-colony stimulating factor (G-CSF), allows the collection of sufficient numbers of stem cells even in patients in whom more established methods were not successful. As a result more patients with diseases such as non-Hodgkin lymphoma or multiple myeloma are able to undergo an autologous transplant. Side effects of the drug include nausea, fatigue, and diarrhea.

A major obstacle to allogeneic stem cell transplantation has been graft-versus-host disease (GVHD), a clinical disease that is triggered by donor cells, which recognize the recipient’s cells and tissues as foreign and attack them. Patients are treated with steroids and immunosuppressive drugs, including mycophenolate mofetil, tacrolimus, sirolimus, and others.

An immunosuppressive antibody preparation called antithymocyte globulin is now being tested in certain stem cell transplant patients. Although currently approved to prevent kidney transplant rejection, it may also reduce chronic GVHD when it is given as part of the conditioning regimen in preparation of HCT.

As of late, the chemotherapy drug Cytoxan (cyclophosphamide) is also being used after transplantation in an effort to prevent GVHD. “We infuse the donor cells, allow them to become activated for a couple of days, and then give cyclophosphamide. This strategy appears to be able to eliminate activated cells T cells that react against the patient and leave non-activated T cells intact. Those cells are expected to speed up the recovery of the immune system and to help fight cancer cells,” Deeg says.

Campath (alemtuzumab), approved for the treatment of B-cell chronic lymphocytic leukemia, is also used to prevent or treat GVHD. Current studies are investigating whether Campath, combined with other immunosuppressive drugs, can further prevent or manage GVHD in transplant patients.

In addition to the developments described above, the landscape for treating blood cancers has undergone many changes in recent years. This includes changes in when transplantation should be used.

“Myeloma has become sort of a poster child for what has been happening in the non-transplant field. Overall survival has probably doubled over the last couple of decades,” Deeg says, partly due to treatment options, such as Thalomid (thalidomide) or Revlimid (lenalidomide), which help fight anemia, decrease the blood supply to tumors, and induce changes in the immune system.

A class of drugs called proteasome inhibitors, which interfere with the breakdown of proteins thus killing cancer cells, has also made an impact on multiple myeloma. Velcade (bortezomib), approved in 2003, has improved survival for myeloma patients. “As a result, transplants are now typically used later in the disease course,” he says.

Even more striking, in chronic myeloid leukemia (CML), the arrival of Gleevec (imatinib) and next-generation drugs such as Sprycel (dasatinib) have improved patient outcomes, with a majority of individuals able to sustain long-term remissions on chronic therapy.

“Now that tyrosine kinase inhibitors [such as Gleevec] have become available, the frequency of transplants for that disease have decreased considerably,” says Edward Copelan, MD, director of the Acute Leukemia Program at the Cleveland Clinic in Ohio. As a result, relatively few patients with CML are now treated with stem cell transplantation.

With the combination of improved drugs and the recent and ongoing advancements in stem cell transplantation, patients—and their physicians&mdash;are welcoming the many options in treating blood cancers.

For more information on stem cell transplantation, read “

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Advances in stem cell transplantation leads to a changing landscape in treating blood cancers, such as lymphoma, leukemia, and multiple myeloma. 

What's New with Stem Cell Transplants?

Stem cell transplantation has emerged as an important treatment for some types of cancer, specifically leukemia, lymphoma, and multiple myeloma. Although the technique faces many obstacles, cancer experts say the technology is steadily improving, allowing for more widespread use and better patient outcomes.

High doses of chemotherapy and radiation for treating cancer damage or destroy cells within the bone marrow called hematopoietic stem cells, which give rise to the three types of blood cells—red blood cells that carry oxygen throughout the body, white blood cells that fight infection, and blood-clotting platelets. Stem cell transplantation restores these cells.

In allogeneic transplantation, the cells come from a donor whose tissue type closely matches that of the patient. Autologous transplantation uses the patient’s own stem cells, which are extracted before cancer treatment and infused back into the patient after treatment.

Bone marrow is taken from the pelvic bone while the person is under anesthesia. However, the preferred method used today is stem cells, which can be collected from the bloodstream for all autologous and most allogeneic stem cell transplants.

Both the high-dose cancer treatment and stem cell transplant can have serious side effects. Cancer treatment can increase a person’s risk of infection, bleeding, and long-term complications such as infertility and damage to various organs.

People receiving allogeneic stem cell transplants may develop a serious condition called graft-versus-host disease (GVHD), in which white blood cells from the donor identify cells in the recipient’s body as foreign and attack them. Interestingly, this effect can also work against malignant cells, so mild GVHD is actually associated with less risk of recurrence.

Access to the procedure is also a barrier for some patients, including those who are too old to qualify and those in certain minority groups who cannot have transplants because no matching donors are available.

Recent innovations have improved the availability and outcome of stem cell transplantation, including better tissue matching between donor and patient to decrease the risk of GVHD. Researchers have found proteins called HLA antigens on the surface of cells, and the more HLA antigens on the donor’s cells that match those of the recipient’s stem cells, the less likely it is that the recipient will develop GVHD. 

With better stem cell mobilizers, we can obtain stem cells in a higher proportion of people--and we can do it faster.

“When we started doing transplants, we needed matched siblings,” says Frederick Appelbaum, MD, director of the Division of Clinical Research at Fred Hutchinson Cancer Research Center in Seattle. “Now, we can carry out transplants using matched, unrelated donors and obtain results very close to those of matched siblings.”

A reduced-intensity transplant, or “mini-transplant,” in which patients are given lower, less toxic doses of chemotherapy and/or radiation, allows doctors to perform allogeneic stem cell transplants in more patients. The doses do not completely eliminate the patient’s bone marrow, but once the donor’s cells engraft, they are thought to destroy the cancer cells not destroyed by the chemotherapy and/or radiation.

“In people who, because of age or other diseases, are at increased risk for toxicity, the use of less toxic regimens has allowed us to administer transplants more safely,” says Edward Copelan, MD, director of the Program of Acute Leukemia at the Cleveland Clinic in Ohio, adding that doctors can now deliver the drug busulfan intravenously instead of orally, and can monitor blood levels of the drug and adjust dosage accordingly. “Both of these changes have decreased the toxicity of doing transplants,” Copelan says.

Blood from umbilical cords and placentas collected after childbirth are rich in stem cells and have greatly increased the supply of donor cells. Stem cells from cord blood require less stringent HLA matching, as mismatched cord blood cells are less likely to cause GVHD but retain their ability to kill cancer cells.

“The availability of cord blood makes an allogeneic transplant a possibility for the majority of patients who need it,” says Appelbaum.

Other improvements in stem cell transplantation include:

> Potent immunosuppressive drugs, such as cyclosporine and tacrolimus, have lowered the risk of GVHD.

> Stem cell mobilizers move stem cells from the bone marrow into the circulating blood where they can be collected for allogeneic or autologous transplantation. “Due to underlying disease, age, and past treatment, there are some patients in whom it is extremely difficult or impossible to obtain enough stem cells to do an autologous transplant. With better stem cell mobilizers, we can obtain stem cells in a higher proportion of people—and we can do it faster,” says Copelan.

> Agents have improved for fighting infections such as cytomegalovirus, a complication for people with a suppressed immune system. Doctors are now better able to monitor for the virus and treat it with an effective agent called ganciclovir. “What has improved cure rates over the past two decades has been better understanding and control of infections,” Appelbaum says. Treatments for fungal infections have also improved.

> Donor databases have broadened and include the National Marrow Donor Program (

Research into potential improvements in stem cell transplantation continues. "More than fifty thousand patients worldwide will have a stem cell transplant this year, and we have to continue to make it safer and better," Appellbaum says.

Stem cell transplantation is safer and more accessible than ever before. 

Robert S. Dinsmoor

What's New with Stem Cell Transplants?

Cell Restoration

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