Managing the Long-Term and Late Effects of Transplantation

As stem cell transplantation (SCT) becomes more common, it has also become safer. This is great news for the more than 40,000 people who receive a SCT worldwide each year. People receiving SCT are living longer after transplantation, often with improved quality of life immediately after treatment. But as the numbers of people surviving SCT increase, long-term and late effects may also become more common.

Researchers have pinpointed some of the most common late-term effects after SCT, including:

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Chronic graft-versus-host disease (cGVHD)

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Chronic infections, such as fungal infections

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Cardiovascular events and lung disorders

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Metabolic and endocrine disorders (metabolic has to do with the metabolism, and endocrine refers to tissue, such as the pituitary, thyroid, and adrenal glands, that makes and releases hormones that travel in the bloodstream and control the actions of other cells or organs)

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Risk of secondary cancers

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Cataracts

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Bone

thinning and fracture risk

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Infertility

“One of the reasons it is becoming clearer to us that we have to concentrate on the later effects of transplantation is that we thankfully have more survivors from the transplant process itself,” says Robert Soiffer, MD, clinical director of the Center for Hematologic Oncology at Dana-Farber Cancer Institute in Boston.

Better supportive therapies, including advances in antifungal medication, boost the strength of the immune system, helping patients rebound more quickly. And over the past decade, more people receive less-intensive chemotherapy or radiation prior to transplant. This practice reduces the chances of acute toxicity, infections, and other serious illness or death.

“One of the results of all this progress is that, as we get more survivors, we are seeing complications that can occur much later, often 10 to 20 years afterwards,” explains Soiffer.

“The bad news is that over the long-term, SCT survivors are at risk for some complex late effects,” says Leona Holmberg, MD, PhD, of the clinical research division at Fred Hutchinson Cancer Center in Seattle. These patients have a disrupted immunological reconstitution, susceptibility to infection, secondary cancer risk (skin and other cancers), chronic organ dysfunction, metabolic [and endocrine] issues, and quality of life issues.

For these reasons, researchers are studying the relationship between SCT and possible long-term effects—and possible ways to prevent them or reduce risk.

About one third to one half of allogeneic transplant recipients develops acute GVHD, which can occur within the first three months after the transplant

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and manifest as skin rashes, mouth sores, diarrhea, and muscle aches.

Patients receiving an allogeneic transplant—when patients receive stem cells from a donor—are at risk for graft-versus-host disease (GVHD), where the donor cells recognize the recipient’s cells and tissues as foreign and attack them

Sometimes, however, the condition becomes chronic and can lead to serious long-term problems including damage to the liver and lungs, or even death. Chronic GVHD is defined as either beginning more than 90 to 100 days after the transplant or when the acute condition extends beyond 90 days after transplantation.

Many of the treatments for cGVHD center on modulating the immune system. T-cells, a type of white blood cell of the immune system, can cause harm to the patient’s body after an allogeneic transplant. Doctors can treat cGVHD with T-cell depletion—where patients receive antibodies targeted to the donated T-cells to simply reduce their number and activity.

Researchers are also looking at targeting another type of white blood cell, B-lymphocytes, to see if removing these cells may have a potential role in cGVHD. Clinical studies with Rituxan (rituximab), an agent approved to treat B-cell lymphomas, are ongoing for both therapy and prevention of cGVHD.

Additional immune therapies used to treat cGVHD include interleukin-2 and sirolimus, a drug used to prevent organ transplant rejection. Sirolimus has sparing effects on regulatory T-cells, which may make it useful in treating cGVHD. Also, extracorporeal photopheresis (ECP), a procedure used to treat cutaneous T-cell lymphoma, may be beneficial for treating cGVHD. With ECP, a person’s blood is treated with light-inducible drugs outside of the body. It is then passed under ultraviolet A radiation and reinfused into the body. This technique allows for larger numbers of donor regulatory T-cells. Studies suggest use of ECP earlier in the treatment course may be most beneficial.

Cardiac, lung, and metabolic issues are increasingly recognized as a long-term consequence of SCT.

“Following stem cell transplantation, we see accelerated atherosclerosis leading to increased risk for heart attacks,” says Soiffer. Survivors are also more likely to develop chronic cardiotoxicity in the form of pericarditis and congestive heart failure if they have received cardiotoxic drugs or radiation as part of their treatment with transplantation. Additionally, patients who have received chest radiation in the form of mantle or mediastinal radiation are at increased risk for long-term heart problems.

The use of immunosuppressive medications also increases the risk for cardiovascular issues, as well as metabolic disorders. “Those drugs can somehow influence development of the metabolic syndrome,” says Soiffer. Patients with metabolic syndrome have higher blood sugar and cholesterol and overall abnormal lipid profiles.

In addition, about 10 percent of patients with cGVHD develop lung inflammation from three months to two years post-transplant.

Development of secondary solid tumors 10 to 30 years after transplant, particularly allogeneic, is a serious potential complication. Tissue damage resulting from previous radiation or inflammation as well as immunosuppression may be largely the cause. Those at the highest risk include patients who received total body irradiation or have cGVHD.

“We have always seen an increased number of skin cancers,” says Soiffer. “But there is also an increased risk of epithelial cancers (mouth cancers, gastrointestinal tract cancers), and breast and lung cancers.”

Cataract development is more common in SCT patients who received total body irradiation or steroids to treat GVHD. Another long-term effect of steroid treatments is bone loss (osteoporosis) and increased fracture risk, which can be addressed by using approved drugs such as bisphosphonates. Similarly, the chemotherapy and/or radiation given during SCT procedures unfortunately can leave patients infertile.

“As transplants have improved drastically in the last several years, we have more patients living longer, staying in remission from their underlying care, and the patient care focus changes to long-term survivor management issues,” says Holmberg.

And those issues don’t always involve cancer. “As patients are living longer from their disease, we have to make sure they are living well apart from non-oncologic issues,” says Soiffer.

Over time, SCT patients tend to return to their general practitioner or internist for medical care.

“As we become more cognizant of these long-term complications, programs need to be put in place to track these patients,” says Soiffer. “We increasingly have the ability to do this—in part because of better database tools—so we should get a better sense of long-term follow-up.”

Certainly surviving the immediate cancer crisis after successful SCT is cause for great happiness and hope. “But we have to remain vigilant for other issues, particularly starting within a year of transplant that we are screening them for a whole variety of issues such as blood pressure, cholesterol, diabetes, colorectal, breast, prostate, and cervical cancers,” says Soiffer.

The American Society for Bone and Marrow Transplantation recommends all SCT survivors seek care from physicians capable of providing general care and that associated with hematologic oncology.

“As health providers, we need to take the lead on this and remain vigilant and help our patients remain vigilant for an extended time beyond their transplant to ensure the best quality of life for the long-term,” Soiffer says.

Learn more about the various treatment approaches in “What’s New With Stem Cell Transplants?”