Taking a Chance on Stem Cell Transplantation

In February 2006, 33-year-old Mary Krohn of Hartford, Wis., visited her doctor for what she thought was a sinus infection. Despite making a return trip to the clinic and taking two different types of antibiotics, her symptoms worsened over the next four days, prompting her to return for blood work, which revealed she had leukemia.

“I had no clue what leukemia was,” Krohn says. “I think it took a full week for me to realize that it could kill me.”

Within 24 hours of making her diagnosis, Krohn’s doctor had performed a bone marrow biopsy, which confirmed she had acute myeloid leukemia, and in less than five months, she received a hematopoietic stem cell transplantation (HSCT) using donor cells from her sister, who was a good match.

HSCT refers to the process of infusing into a sick person hematopoietic stem cells (HSCs), specialized “mother” cells capable of developing into red and white blood cells, platelets and other bloodforming stem cells, essentially creating new healthy cells to replace abnormal ones.

Although HSCT can be used to treat a variety of non-malignant diseases, it is more frequently used to treat several cancers of the blood and bone marrow, such as acute myeloid leukemia, acute lymphocytic leukemia, chronic myeloid leukemia, non-Hodgkin lymphoma, Hodgkin lymphoma and multiple myeloma.

The origins of HSCT can be traced to the 1950s, when Edward Donnall Thomas, MD, and his colleagues achieved the first successful transplantation in two leukemia patients who received HSCs harvested from their identical twins’ bone marrow. Although their remissions were short-lived (approximately two to three months), the impact of this work was long-lasting and ultimately led to Thomas receiving the Nobel Prize in medicine in 1990. (Known as “the father of bone marrow transplantation,” Thomas died in October at age 92.)

Since then, researchers discovered that small numbers of HSCs travel to the bloodstream and can be drawn from the peripheral (circulating) blood or from blood retrieved from a newborn’s umbilical cord and placenta. This less invasive procedure simplified the collection process and transformed the field, dramatically increasing the number of donors worldwide.

Yet peripheral blood stem cell transplantation still requires stimulation of the donor’s bone marrow with stem cell factors given intravenously, then several days later, a three- to four-hour session where blood is circulated through a pheresis machine that selects stem cells which are then collected and frozen until ready for infusion.

Before HSCT is performed, patients receive high doses of chemotherapy and/or radiation to destroy rapidly dividing cells, which can include both cancerous and healthy bone marrow cells. Once the cells have been destroyed, the patient receives an infusion of previously collected healthy HSCs. These cells travel to the bone marrow, where, within about two to three weeks, they produce healthy, cancer-free blood cells that will ultimately repopulate the blood, helping to re-establish the immune system.

The source of HSCs can be either the patient (called an autologous transplantation) or a donor (called an allogeneic transplantation). Patients who provide their own HSCs have them removed from the bone marrow or the bloodstream prior to chemotherapy or radiation, and the cells are frozen for later use. In other cases, the HSCs come from a donor, which may be an identical twin, another close relative (often a sibling), an unrelated person or even ffrom an unrelated newborn.

The most important factor with donor stem cells is that the group of genes related to the immune system of the donor must match those genes of the immune system of the patient. If they don’t match closely enough, the patient’s immune system could reject the newcomers (the donor cells) or, worse, the donor cells could launch a full-scale attack on the patient’s body.

Identical twins are an exact match, and siblings are more likely to match the patient than the general population, but it is possible that unrelated people are close enough matches as well, which has given rise to bone marrow registries, such as the Be The Match Registry operated by the National Marrow Donor Program, that seek to identify matches for patients from among a large pool of unrelated donors. On the other hand, donor cells can also mount an immune attack on residual malignant cells, a term called “graft versus leukemia effect,” and may result in fewer relapses compared to an autologous transplant.

[Read about the National Marrow Donor Program]

Research published in August in Bone Marrow Transplantation shows that race and ethnicity have a direct impact on the success of transplantation. The registry has achieved a 90 percent rate for some degree of match for Caucasians, 70 percent for Hispanics and Asians, and 60 percent for those of African descent.

One match made through the registry in 2007 was for Krohn, who learned her cancer had progressed one year after receiving her initial transplantation. Despite needing another transplantation so soon, she remained determined, saying, “I was going to do whatever it took to beat this.” Fortunately, four months later, she received her second transplantation from a donor in Germany. Nearly five years after transplantation, her leukemia remains in remission and she was recently able to express her gratitude to him when he visited her in the U.S.

“I just stared at him, thinking that if he wasn’t alive, I wouldn’t be alive either,” Krohn says. The two became fast friends during his four-day visit and plan to meet again when she and her husband visit him in Germany next year.

Among the factors that determine which type of transplantation will most benefit a patient, one of the most important is the cancer type. Most autologous transplantations are performed on patients with multiple myeloma and lymphoma, whereas most allogeneic transplantations are performed on patients with myelodysplastic syndromes and leukemia or refractory lymphoma. However, Philip Bierman, MD, professor of internal medicine at the University of Nebraska Medical Center, says that some patients, particularly those with non-Hodgkin lymphoma, have disease that is amenable to either type of transplantation.

Transplantation survival rates vary dramatically depending on the patient’s age, disease type, stage of disease, type of transplantation and type of donor cells. Patients with Hodgkin lymphoma who are in remission prior to autologous transplantation have the best survival rates, achieving about 70 percent survival at six years. Conversely, adult patients with advanced acute lymphocytic leukemia treated with unrelated donor transplantations have approximately a 10 to 20 percent survival rate at six years after transplantation.

Transplantation survival rates vary dramatically, depending on the patient’s age, disease type, stage of disease, type of transplantation and type of donor cells.

Since autologous transplantation recipients receive their own cells back, they have no risk of rejection. However, because their own immune system does not have activity against the cancer, any residual cancer cells in the body or the stem cells collected could lead to relapse. Such was the case with Penny Lancaster of Neenah, Wis., who received a diagnosis of advanced follicular lymphoma in June 2000 at the age of 48. Because follicular lymphoma is a slow-growing type of cancer, she was able to enjoy four years of relatively good health, during which she ran 20 marathons, while undergoing intermittent chemotherapy, until she was told her cancer had transformed into a much more aggressive form of lymphoma that would require an autologous transplantation. Although the procedure was successful and she was able to run a marathon nine months after her transplantation, her cancer returned 18 months later.

With allogeneic transplantation, the main advantage is that donor HSCs are free of cancer (because they are taken from a healthy person) and may be able to identify and attack any cancer cells remaining in the patient. In fact, Bierman notes, unlike autologous transplantation, “this is a treatment that is potentially curative.” When Lancaster’s doctor recommended she receive an allogeneic transplantation after her cancer returned, she didn’t hesitate, saying, “It gave me hope for a longer future.”

However, with big reward comes big risk. Allogeneic transplantation carries a number of serious consequences, including risk of death due to complications from the procedure itself, so it may not always be ideal for initial treatment of most diseases. “There is consensus among oncologists and transplantation physicians that delaying allogeneic transplantation for some diseases, for example lymphomas, can give the patient a chance to benefit from conventional treatment and enjoy a good quality of life until that treatment no longer works,” says Mohamed Sorror, MD, a researcher at the Fred Hutchinson Cancer Research Center in Seattle. In other situations, such as some cases of acute myeloid or high-risk lymphocytic leukemia, it may be the best initial treatment, depending on the patient’s age, health and the availability of a good match.

View Illustration: To the Bone and Beyond

Transplantation-related deaths are primarily due to either graft-versus-host disease (GVHD) or infections. Sometimes they are due to organ damage from highdose chemotherapy. With GVHD, the donor HSCs (the graft) recognize the patient’s tissues (the host) as “foreign,” and attack those tissues. GVHD can produce a large number of complications affecting several different parts of the body, such as the gastrointestinal tract and skin, and some of these complications can be fatal.Lancaster experienced only minor complications due to GVHD—an itchy rash and painful mouth sores that made it difficult to eat.

The other major cause of transplantationrelated death—infection—is more likely to occur with allogeneic than autologous transplantations, due to immunosuppression and the risk of GVHD. In the year following her second transplantation, Krohn endured multiple infections, each time landing her in the hospital for several days to eliminate the infection from her body. As much as she wanted to go home from the hospital, each time she got the news that she was being released, anxiety would overtake her that something would go wrong at home. “I knew not only that my disease could kill me, but the complications of GVHD could, too,” Krohn says.

The introduction of the mini-transplantation may be the biggest improvement in the field of transplantation in recent history, according to Parameswaran Hari, MD, clinical director of the adult bone marrow transplant program at the Medical College of Wisconsin in Milwaukee. Although not quite qualifying as new—it’s been used in clinical trials since the 1990s—“Minitransplants open the door for new patients to be offered the potentially curative allogeneic transplantation with good chance of survival,” Sorror says.

The mini-transplantation works by using lower doses of chemotherapy and radiation prior to allogeneic transplantation, resulting in incomplete destruction of the bone marrow, yet appropriate suppression of the patient’s immune system to allow acceptance of the newcomers. While this approach increases the chance that cancer cells can survive the chemotherapy, it also preserves some natural immunity rather than leaving the patient completely defenseless. With mini-transplantation, the donor HSCs take over and can develop an immune response to the cancer. The mini-transplantation is typically tolerated better by patients because of the lower chemotherapy doses used, making it a viable alternative for older patients and those in poor health who would not be expected to handle the toxicity of conventional chemotherapy. Moreover, the patient’s blood counts don’t drop as low because some stem cells survive to make more blood cells.

However, as might be expected, the trade-off of these benefits is the higher risk of cancer relapse due to incomplete eradication of the cancer cells. “Most patients who come to us to receive a mini-transplantation have exhausted all other treatment options for their cancer,” Sorror says. Despite this being a last resort for most patients, the results have been encouraging. Sorror and his colleagues recently published the results of a number of clinical trials using this approach, reporting that 35 percent of clinical trial patients receiving a mini-transplantation were survivors five years later.

Patients surviving at least five years after transplantation can expect to have many more years, Hari says. While the risks of relapse may fade by this time, they are still at risk for a long list of late effects, some of which may be life-threatening, such as secondary cancers and organ damage, including to the liver, heart and lungs. Other late effects, such as cataracts, hormone changes and infertility, may not affect life span but can certainly impact quality of life.

Lancaster has been fortunate in that she has not experienced any long-term complications from her transplantations, aside from a nagging fatigue. Of course, this may be a relative term for her, considering she ran several half-marathons after her second transplantation and has been training for another full marathon, which she plans to run at age 61. Twelve years after her cancer diagnosis, she says, “I feel like I have aged just like any other person without cancer.”

[View Infographic: Need a Match?]

The major goals of transplantation research are to eliminate deaths from cancer recurrence, infections and GVHD. Currently, studies are examining several methods that use transplantation to better fight tumors. Other attempts are being made to engineer targeted cells that will prevent viral infections in transplantation patients. In Germany, a team of researchers is working on generating hematopoietic stem cells in a lab, which would eliminate both the need for finding a matching donor and the problem of GVHD. While none of these concepts are even close to benefiting today’s patients, they illustrate the potential reality for treating these cancers in the future.

A study published in October in The New England Journal of Medicine showed that patients who had received HSCs harvested from an unrelated donor’s bone marrow were significantly less likely to develop chronic GVHD than if they received stem cells from a donor’s peripheral blood, prompting transplantation experts to recommend a change to the practice of collecting HSCs primarily from blood. Whether the more invasive procedure would negatively impact donations remains to be seen.

With her transplantation now in her distant past, Krohn finally unpacked the bag that sat in her bedroom ready to be grabbed at a moment’s notice for an overnight hospital stay. Although it was initially uncomfortable for her to feel unprepared for potential complications, it signaled her readiness to hope for a future without leukemia.

“The outcome of my treatment has been fabulous,” Krohn says.