Is Bone Marrow Transplant a Risk for Cancers?

Introduction

Bone marrow transplants are increasingly being used in recent years to treat leukemia, malignant, and other non-malignant diseases. However, the procedure is known to produce few complications. Delayed consequences like impaired immune function or new cancer formed due to whole-body irradiation and high-dose chemotherapy when used as a conditioning treatment before transplant. Few studies conducted on long-term transplant survivors have shown the risk of lymphoproliferative neoplasm with an allogenic transplant and myelodysplastic syndrome and leukemia with an autologous transplant.

What Is a Bone Marrow Transplant?

Bone marrow transplant, known as stem cell transplant, is a procedure in which defective cells in bone marrow are replaced with healthy cells to produce adequate red blood cells. When stem cells from the own body are used, it is known as an autologous transplant, whereas when cells from the donor body are used, they are known as an allogeneic transplant.

What Are the Complications Associated With Bone Marrow Transplants?

Various complications arise after a bone marrow transplant. Some of the complications can be mild, severe, or even life-threatening. The possible complications of bone marrow transplant are:

• Graft-versus-host disease (immune-mediated inflammation in various organs).

• Stem cell failure.

• Organ damage.

• Infections.

• Cataracts (clouding in eye lens).

• Infertility.

• New cancers.

• Death.

Why Do New Cancers Form After Bone Marrow Transplants?

Although most patients survive the early period following bone marrow transplant and become originally disease-free, few patients do develop complications like secondary malignancies in the long term. A 15-year incidence of developing secondary malignancies was found to be 10 to 12 percent. The cause for developing secondary malignancies can be attributed to intensive cytotoxic conditioning therapies, history of chemotherapy and radiotherapy, immunosuppression in allogenic transplant, infection with EBV (Epstein-Barr virus), HBV (hepatitis B), or HCV (hepatitis C) virus, and genetic factors in diseases like Fanconi anemia (a rare genetic disorder of blood cells).

What Are the Clinical Symptoms of Secondary Malignancies?

The clinical symptoms when secondary malignancies develop following a bone marrow transplant are fatigue, reduced appetite, weight loss, and organ-specific symptoms. Dry cough or dyspnea occurs in lung cancer, headache, altered mental status in brain cancer, and bone pain. There is also a risk of infection and hemorrhage. New skin lesions, pallor due to anemia, breast mass, or icterus due to liver problems may occur in a few individuals.

What Secondary Malignancies Occur Following Bone Marrow Transplants?

Myelodysplasia and acute myeloid leukemia form after autologous bone marrow transplant for Hodgkin’s and Non-Hodgkin’s lymphoma. The incidence rate for malignancies is 4 to 18 percent and requires a median time of 12 to 24 months for development.

Risk Factors:

• Administering alkylating agents, topoisomerase II inhibitors, and radiation before transplant.

• It also develops when peripheral blood is used to obtain stem cells.

• Use of total body irradiation as a conditioning regimen.

Prognosis:

Individuals who develop these conditions have a poor prognosis and can survive only up to six months. Complete remission following bone marrow transplant occurs in less than half of patients. Non-relapse mortality is high in patients who underwent allogeneic bone marrow transplants. However, reducing the intensity of pre-transplant conditioning can reduce non-transplant mortality and result in better treatment outcomes.

• B-Cell Post-transplant Lymphoproliferative Disorder (BCLD): These are the most common malignancies that form in the first year after T-cell depleted bone marrow transplant. They occur due to compromised immune systems or EBV infection. They are a heterogeneous group of disorders.

Risk Factors:

• In vitro depletion of T-cells.

• Unrelated or HLA (human leukocyte antigen) mismatched donor.

• Moderate or extensive chronic graft versus host disease.

• Using ATG (anti-thrombocyte globulin) or anti-CD3.

• Total body irradiation, when performed as conditioning therapy.

• Primary immunodeficiency.

Mechanism:

A combination of depressed EBV-specific cellular immunity and the transforming reactivation capacities of EBV leads to malignancy. The EBV virus can infect huge populations as a latent infection in B-cell lymphocytes. Reactivation occurs when T-lymphocyte precursor frequencies are very low. The BCLD is diagnosed, and treatment is planned based on the load of the EBV virus in peripheral blood.

Treatment

Some success was achieved when alpha-interferon and intravenous immunoglobulin were used as treatment. However, treatment with anti-B monoclonal antibodies and EBV-specific cytotoxic T-cells is more effective. When treatment is initiated early, it can control the viral load.

Solid Tumors:

• Patients who underwent bone marrow transplants are at a higher risk for developing solid tumors.

• Solid tumors were reported in sites like the skin, oral cavity, head and neck, liver, uterine cervix, thyroid, breast, lung, and gastrointestinal cancers.

• The risk of tumors increases over time. The risk for malignancy is higher among children who underwent bone marrow transplants less than ten years of age.

• The cumulative incidence of 15 years for developing solid tumors was 11 percent. The tumor requires a median period of six years to develop.

• The risk factors for developing solid tumors were high-dose total body irradiation, younger age, and cancers of the tongue, salivary glands, thyroid, melanoma, brain, and central nervous system.

• A combination of cytotoxic therapy interaction, genetic predisposition, viral infection, graft versus host response, and the use of immunosuppressive therapy may stimulate tumor formation.

• The solid tumors following bone marrow transplant must be treated as de novo tumors to obtain better treatment results.

• Myelodysplasia, acute myeloid leukemia, and B-cell transplant lymphoproliferative disorder develop early following bone marrow transplant. However, solid tumors take a longer duration to develop.

How to Avoid Secondary Malignancies Development Following a Bone Marrow Transplant?

In patients undergoing allogeneic bone marrow transplants, life-long surveillance is recommended to check for secondary tumor development. It is necessary to avoid excessive exposure to risk factors like UV (ultraviolet) light and smoking. Frequent visits to the dentist will enable faster diagnosis of secondary malignancies of the oral cavity. Young women and children who receive radiation as a part of cancer treatment must undergo regular breast screening. The skin, breast, and thyroid glands must be regularly examined for tumor development. There have also been fewer reports of secondary malignancies development following reduced-intensity conditioning. Early diagnosis and adequate treatment of secondary tumors can improve treatment outcomes and survivability.

Conclusion:

Secondary malignancies are a rare complication of bone marrow transplant. The incidence of developing solid tumors is highest following transplants. However, other forms of malignancies do occur. There is a higher mortality risk for recurrent or relapsed cancer. It is necessary to diagnose the tumors at the earliest. The treatment provided for secondary tumors is based on standard malignancy protocols. It is important to consult medical professionals to better understand disease risk and decide the best treatment approach.