Overview
The type and severity of the side effects from high-dose chemotherapy and allogeneic stem cell transplant are influenced by the degree of HLA matching between donor and recipient; the condition and age of the patient; the specific high-dose chemotherapy treatment regimen; and the degree of suppression of the immune system. The safety of allogeneic transplant has improved a great deal because of advancements in supportive care to manage the many potential side effects. While high doses of chemotherapy and radiation therapy can potentially affect any of the body’s normal cells or organs, the more common side effects are well described and include the following:
Bone Marrow Suppression
High-dose chemotherapy directly destroys the bone marrow’s ability to produce white blood cells, red blood cells and platelets. Patients experience side effects from low numbers of white blood cells (neutropenia), red blood cells (anemia) and platelets (thrombocytopenia). Patients usually need blood and platelet transfusions to treat anemia and thrombocytopenia until the new graft beings producing blood cells. The duration of bone marrow suppression can be shortened by infusing an optimal number of stem cells and growth factors that hasten the recovery of blood cell production.
Infections
During the 2-3 weeks it takes the new bone marrow to grow and produce white blood cells, patients are susceptible to infection and require the administration of antibiotics to prevent bacterial and fungal infections. Bacterial infections are the most common during this initial period of neutropenia. Stem cells collected from peripheral blood tend to engraft faster than bone marrow and may reduce the risk of infection by shortening the period of neutropenia. The growth factor Neupogen® also increases the rate of white blood cell recovery and has been approved by the Food and Drug Administration for use during allogeneic stem cell transplant.
The immune system takes even longer to recover than white blood cell production, with a resultant susceptibility to some bacterial, fungal and viral infections for weeks to months. Patients are often required to take antibiotics to prevent infections from occurring for weeks to months after initial recovery from allogeneic stem cell transplant. Prophylactic antibiotic administration can prevent Pneumocystis carinii pneumonia and some bacterial and fungal infections. Prophylactic antibiotics can also decrease the incidence of herpes zoster infection, which commonly occurs after high-dose chemotherapy and allogeneic stem cell transplant.
Mucositis
Mucositis is an inflammation of the lining of the mouth or gastrointestinal (GI) tract. This condition is also commonly referred to as mouth sores. Mucositis is one of the most common side effects of the intensive therapy that precedes stem cell transplantation. The majority of patients treated with a stem cell transplant will develop mucositis. In fact, patients undergoing stem cell transplantation have complained that mucositis is the single most debilitating side effect from treatment.1
Chemotherapy and radiation therapy are effective at killing rapidly dividing cells, a hallmark characteristic of some cancers. Unfortunately, many normal cells in the body are also rapidly dividing and can sustain damage from chemotherapy as well. The entire GI tract, including the mouth and the throat, is made up of cells that divide rapidly. For this reason, the GI tract is particularly susceptible to damage by chemotherapy and radiation treatment, which results in mucositis.
Until recently, the only approaches to managing oral mucositis included good oral care; mouthwashes; cryotherapy (sucking on ice chips) to minimize the damage from chemotherapy drugs; Salagen®, a drug that stimulates salivary flow; and other investigational treatments.
A promising new approach to the prevention and treatment of mouth sores is the use of growth factors. Growth factors are natural substances produced by the body to stimulate cell growth. The body produces many different types of growth factors. Kepivance™ (palifermin) is a type of growth factor that is made through laboratory processes to mimic the natural compound made in the body. Kepivance™ has properties that stimulate the cells that line the mouth and GI tract (called epithelial cells) to grow and develop, which may help to reduce mucositis.
Kepivance™ is the first FDA-approved drug for the prevention and treatment of oral mucositis. In clinical trials, Kepivance™ has demonstrated the ability to protect the epithelial cells from the damaging effects of radiation, and chemotherapy in patients undergoing autologous stem cell transplants2,3,4,5 and is being further evaluated to determine whether it may benefit patients undergoing allogeneic stem cell transplantation.
Veno-Occlusive Disease of the Liver (VOD)
High-dose chemotherapy can result in damage to the liver, which can be serious and even fatal. This complication is increased in patients who have had a lot of previous chemotherapy and/or radiation therapy, a history of liver damage or hepatitis. Veno-occlusive disease of the liver typically occurs in the first 2 weeks after high-dose chemotherapy treatment. Patients typically experience symptoms of abdominal fullness or swelling, liver tenderness and weight gain from fluid retention. Development of strategies to prevent or treat veno-occlusive disease is an active area of clinical investigation.
Interstitial Pneumonia Syndrome (IPS)
High-dose chemotherapy can cause damage directly to the cells of the lungs. This may be more frequent in patients treated with certain types of chemotherapy and/or radiation therapy given prior to the transplant. This complication of transplant may occur anytime from a few days after high-dose chemotherapy to several months after treatment. This often occurs after a patient has returned home from a transplant center and is being seen by a local oncologist.
Patients typically experience a dry non-productive cough or shortness of breath. Both patients and their doctors often misinterpret these early symptoms. Patients experiencing shortness of breath or a new cough after allogeneic transplant should bring this to the immediate attention of their doctor since this can be a serious and even fatal complication.
Graft-versus-Host Disease (GVHD)
Graft-versus-host disease is a common complication of allogeneic stem cell transplant. Lymphocytes contained in donated marrow or blood stem cells cause a reaction called graft-versus-host disease. In this reaction, lymphocytes from the donor attack cells in the body of the recipient especially in the skin, gastrointestinal tract and liver. The common symptoms of acute graft-versus-host disease are skin rashes, jaundice, liver disease and diarrhea. Graft-versus-host disease also increases a patient’s susceptibility to infection. Graft-versus-host disease can develop within days or as long as 3 years after transplantation. Generally, graft-versus-host disease that develops within 3 months following transplantation is called acute graft-versus-host disease, whereas graft-versus-host disease that develops later is called chronic graft-versus-host disease.
Removal of T-lymphocytes from the stem cell collection and immunosuppressive drugs such as methotrexate, cyclosporine, prednisone and other new agents administered after bone marrow or blood stem cell infusion are used to prevent or ameliorate graft-versus-host disease. Graft-versus-host disease can also have an anti-cancer effect because donor lymphocytes can kill cancer cells as well as normal cells. When donor lymphocytes kill cancer cells, doctors refer to this as a graft-versus-cancer effect. There are ongoing studies attempting to control this “graft-versus-cancer” reaction for therapeutic purposes.
Graft Failure
Graft failure occurs when bone marrow function does not return. The graft may fail to grow or be rejected in the patient resulting in bone marrow failure with the absence of red blood cell, white blood cell and platelet production. This results in infection, anemia and bleeding. Insufficient immune system suppression is the main cause of graft rejection. Graft failure may also occur in patients with extensive marrow fibrosis before transplantation, a viral illness or from the use of some drugs (such as methotrexate). In leukemia patients, graft failure often is associated with a recurrence of cancer; the leukemic cells may inhibit the growth of the transplanted cells. In some cases, the reasons for graft failure are not known.
Long-Term Side Effects of Allogeneic Stem Cell Transplant
There are several long-term or late side effects that result from the chemotherapy and radiation therapy used with allogeneic stem cell transplant. The frequency and severity of these problems depends on the radiation or chemotherapy that was used to treat the patient. It is important to have the doctors providing your care explain the specific long-term side effects that can occur for the actual treatment they propose. Some examples of complications you should be aware of include the following:
Cataracts: Cataracts occur in the overwhelming majority of patients who receive total body irradiation in their treatment regimen. In patients who receive chemotherapy without total body irradiation, cataracts are much less frequent. The onset of cataracts typically begins 18-24 months following treatment. Patients who have received large doses of steroids will have an increased frequency and earlier onset of cataracts. Patients are advised to have slit lamp eye evaluations annually and early correction with artificial lenses.
Infertility: The overwhelming majority of women who receive total body irradiation will be sterile. However, some prepubertal and adolescent females do recover ovulation and menstruation. In patients who receive chemotherapy only preparative regimens, the incidence of sterility is more variable and more age related, i.e., the older the woman is at the time of treatment the more likely chemotherapy will produce anovulation. These are important considerations because of the need for hormone replacement. All females should have frequent gynecologic follow-up.
The overwhelming majority of men who receive total body irradiation will become sterile. Sterility is much more variable after chemotherapy only regimens. Men should have sperm counts done to determine whether or not sperm are present and should be examined over time, as recovery can occur.
New cancers: Treatment with chemotherapy and radiation therapy is known to increase the risk of developing a new cancer. These are called “secondary cancers” and may occur as a late complication of high-dose chemotherapy. Patients treated with high-dose chemotherapy and allogeneic stem cell transplantation appear to have an increased risk of developing a secondary cancer. In a report evaluating almost 20,000 patients treated with allogeneic stem cell transplantation, 80 patients developed a new cancer. This represents an approximate 2.5% greater risk compared to normal individuals
The longer patients survived after high-dose chemotherapy and allogeneic stem cell transplantation, the greater the risk of developing a secondary cancer. Patients treated with total body irradiation appear to be more likely to develop new cancer than those treated with lower radiation doses or high-dose chemotherapy. High-dose chemotherapy and allogeneic stem cell transplant is increasingly used to treat certain cancers because it improves cure rates. Patients should be aware of the risk of secondary cancer following high-dose chemotherapy treatment and discuss the benefits and risks of high-dose chemotherapy with their primary cancer physician.
References
1 Bellm LA, Epstein JB, Rose-Ped A, et al. Patient Reports of Complications of Bone Marrow Transplantation. Support Care Cancer. 2000;8:33-39.
2 Spielberger R, Emmanouilides C, Stiff P. Use of recombinant human keratinocyte growth factor (rHuKGF) can reduce severe oral mucositis in patients (pts) with hematologic malignancies undergoing autologous peripheral blood progenitor cell transplantation (auto-PBPCT) after radiation-based conditioning – results of a phase 3 trial. Proceedings of the 39th meeting of the American Society of Oncology 2003;22: Abstract #3642.
3 Emmanouilides C, Spielberger R, Stiff P, Rong A, et al. Palifermin Treatment of Mucositis in Transplant Patients Reduces Health Resource Use: Phase 3 Results. Proc Am Soc Hem. Blood. 2003;102(11):251a, Abstract #883.
4 Syrjala KL, Hays RD, Kallich JD, Farivar SS, et al. Impact of Oral Mucositis and Its Sequelae on Quality of Life. Proc Am Soc Hem. Blood. 2003;102(11):751a, Abstract #2771.
5 Stiff P, Bensinger W, Emmanouilides C, Gentil T, et al. Treatment of Mucositis with Palifermin Improves Patient Function and Results in a Clinically Meaningful Reduction in Mouth and Throat Soreness (MTS): Phase 3 Results. Proc Am Soc Hem. Blood 2003;102(11):194a, Abstract #676.
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