Clinical and Health Affairs
Late Complications in Blood and Marrow Transplant Survivors
By Navneet S. Majhail, M.D., M.S.
Abstract
Hematopoietic stem-cell transplantation is a potentially curative therapy for many high-risk hematologic malignancies and other life-threatening disorders. Advances in transplantation over the last four decades have resulted in an increasing number of long-term survivors who may be at risk for developing late infections, noninfectious complications, and secondary cancers. Awareness on the part of primary care physicians of the risk factors and screening recommendations for late complications can lead to their early diagnosis and treatment.
Hematopoietic stem-cell transplantation (HSCT), commonly referred to as blood and marrow transplantation, is the only curative option for high-risk hematologic malignancies such as acute and chronic leukemia, multiple myeloma, and lymphoma as well as other life- threatening disorders such as severe aplastic anemia. Since the first successful HSCT at the University of Minnesota in 1968, significant advances have been made in transplantation technology and supportive care practices. An estimated 50,000 patients worldwide and 20,000 patients in the United States receive HSCT each year. The introduction of safer transplant techniques that allow this procedure to be done in older and sicker patients, availability of newer graft sources (eg, umbilical cord blood), and emerging indications are expected to contribute to an increase in the number of patients who receive HSCT in the future.
A large number of HSCT recipients survive long term. According to unpublished data from the Center for International Blood and Marrow Transplant Research, an estimated 80,000 to 100,000 HSCT survivors were living in the United States in 2007. Because of a variety of pre- and post-transplant-related exposures, these survivors are at increased risk for late complications of treatment, chronic health conditions, and secondary cancers.1-7 These late effects, which can first occur six months to one year or more following transplant, can cause significant morbidity and increase the risk for premature death in this population.8-10 Despite their risk for late complications, most HSCT survivors enjoy a quality of life similar to that of the general population, with the exception of those patients who develop a post-transplant complication called chronic graft-versus-host disease (GVHD), in which donor T cells mount an immunologic attack against host tissues.11 This article will review the spectrum of late complications that may be seen in this population and summarize recommendations for screening for and preventing them.
Risk Factors for Late Complications
Hematopoietic stem-cell transplantation can be performed using hematopoietic progenitor cells from the patient (autologous transplant) or a human leukocyte antigen (HLA)-matched related or unrelated donor (allogeneic transplant). The basic premise for HSCT is to provide total body irradiation and/or high-doses of chemotherapy to kill tumor cells, followed by the infusion of a hematopoietic progenitor cell graft to prevent prolonged myelosuppression. Allogeneic HSCT recipients receive the additional benefit of an alloreactive donor T-cell mediated graft-versus-tumor or graft-versus-leukemia effect. However, at the same time, these patients require immunosuppression to prevent GVHD. Graft-versus-host disease can be acute when it occurs within the first three months after transplantation or can manifest later as chronic GVHD.
A multitude of factors determine a patient’s overall risk for developing specific late complications. Risk factors for such complications include the patient’s age at the time of HSCT, gender, and lifestyle factors such as tobacco use. In addition, patients may have pre-existing comorbidities such as chronic renal failure that can be exacerbated by chemotherapy, radiation, and other medications they receive to treat their malignancy and during HSCT. Exposure to chemotherapy and radiation as part of initial treatment of an underlying hematologic disorder or as part of the conditioning regimen given prior to HSCT also can contribute to organ-specific complications. Allogeneic HSCT recipients who develop GVHD require long-term, and at times life-long, treatment with glucocorticoids, calcineurin inhibitors (eg, cyclosporine), or other immunosuppressive agents and can be prone to developing medication-related side effects and infections. Because so many factors can contribute to overall risk, a patient’s long-term follow-up plan should be based on his or her risk profile. In general, late complications can be categorized as late infections, noninfectious complications, and secondary malignancies.
Late Infections
Infections are an important cause of late mortality in HSCT survivors. Adequate reconstitution of the cellular and humoral immune systems takes place within six months to one year after autologous transplantation but can take up to two years or longer in allogeneic HSCT recipients. This immune dysfunction can be enhanced and prolonged by GVHD and its treatment. Immune reconstitution is also delayed with use of HLA-mismatched grafts, T-cell depletion of the graft, and use of unrelated donors.
Patients needing long-term immunosuppression for ongoing GVHD are particularly at risk and are susceptible to infections by encapsulated bacteria (Streptococcus pneumoniae, Neisseria meningitides, and Hemophilus influenzae), fungi (Aspergillus spp., Candida spp., and Pneumocystis jiroveci), and viruses (cytomegalovirus and varicella zoster virus).12 Patients typically receive antimicrobial prophylaxis until three to six months after cessation of all immunosuppression. They also need to be revaccinated. Vaccinations against the abovementioned infections and others should begin at six to 12 months after HSCT but may have to be delayed in patients on chronic immunosuppression for GVHD (Table 1). In addition, patients with GVHD who undergo dental procedures need antibiotic prophylaxis.
Noninfectious Complications
In general, major transplant-related risk factors for delayed noninfectious complications include the use of total body irradiation to condition a patient for HSCT, GVHD, and protracted use of corticosteroids or calcineurin inhibitors. Although any organ system can be involved, certain parts of the body have a greater prelidiction for late-onset problems following HSCT (Table 2).1-3,5,7,12-16 For example, more than one-third of patients develop cataracts within five years post-transplantation. Endocrine dysfunction is common in patients who have undergone HSCT, with the incidence of hypothyroidism approaching 50% and hypogonadism nearly 90%. The majority of HSCT survivors become infertile, although HSCT without total body irradiation can spare fertility in nearly one-third of men and women. Prepubertal children who undergo HSCT may retain fertility, although secondary sexual development may be delayed. Growth retardation is seen in up to 50% of pediatric HSCT recipients. In addition, HSCT survivors are prone to debilitating musculoskeletal complications including osteoporosis and avascular necrosis as well as cardio-metabolic problems such as the metabolic syndrome, diabetes mellitus, and cardiovascular disease. The risk for most organ-specific late complications continues to increase over time, and continued active surveillance for these problems is indicated in all HSCT survivors.
Secondary Cancers
Secondary cancers—new malignancies that can be attributed to treatment of a primary cancer—are a rare-but-devastating complication of HSCT. They account for 5% to 10% of deaths among HSCT recipients who survive two years or longer. These malignancies can be broadly categorized as post-transplant lymphoproliferative disorders (PTLD), hematologic malignancies, and solid cancers.6,17
Post-transplant lymphoproliferative disorders comprise a heterogeneous group of lymphoid proliferations, primarily involving B-lymphocytes that develop as a result of Epstein-Barr virus infection. They occur almost exclusively in allogeneic HSCT recipients, with an overall incidence rate of 1% to 2%; they typically manifest soon after transplantation with more than 80% of cases diagnosed within the first year.6,17,18 Since T cells play an important role in preventing proliferation of Epstein-Barr-infected lymphocytes, removal of T cells from the hematopoietic graft source is a strong risk factor for PTLD.19 A greater degree of immunosuppression, such as that resulting from GVHD and use of grafts from unrelated or HLA-mismatched donors, also increases the risk for PTLD.
Treatment of PTLD is often challenging, and available treatments are not very effective. Withdrawal of immunosuppression is usually attempted first but can be difficult in patients with active GVHD. Treatment options include antiviral therapy with acyclovir or ganciclovir, multiagent chemotherapy, anti-CD20 monoclonal antibody rituximab, or infusion of Epstein-Barr-specific cytotoxic lymphocytes. Since PTLD is associated with high mortality rates, active surveillance for Epstein-Barr reactivation in high-risk settings and initiation of pre-emptive therapy is currently under investigation.
Secondary myelodysplastic syndrome and acute myeloid leukemia can be seen in 5% to 15% of autologous HSCT recipients but are extremely rare among allogeneic HSCT recipients. Secondary myelodysplastic syndrome and acute myeloid leukemia usually occur following a latency period of two to five years.6,17,20 Bone-marrow evaluation can show characteristic cytogenetic abnormalities (eg, balanced translocations to 11q23, monosomy of 5q and 7q), and multiple chromosomal aberrations are frequent. Risk factors for secondary myelodysplastic syndrome and acute myeloid leukemia include older age at transplant, the type and intensity of pre-HSCT chemotherapy (especially alkylating agents), and use of total body irradiation. Outcomes are very poor, and long-term survival rates are less than 20%.
Secondary solid cancers have a latency period of three to five years following HSCT. Subsequently, their incidence continues to increase with time and is higher than what may be expected in age- and gender-matched general populations. Their cumulative incidence ranges from 1% to 2% at five years, 2% to 6% at 10 years, and 4% to 15% at 15 years post-transplantation.6,17,21 Younger age at transplantation, use of total body irradiation in a conditioning regimen, and chronic GVHD are important risk factors for solid cancers. Solid cancers at a variety of sites have been reported, including cancers of the head and neck, liver, brain and nervous system, thyroid, and bone and connective tissue. Since there is no plateau in the incidence of secondary solid cancers after HSCT, the overall risk for them has not been completely realized, and longer follow up is needed before the true magnitude of risk will become apparent. Lifelong cancer screening is recommended for all HSCT survivors according to the guidelines in Table 3.22
The Primary Care Physician’s Role
During the first few months following transplantation, HSCT recipients receive the vast majority of their medical care at the transplant center. Over time, their care is transitioned to their referring hematologist-oncologist. Eventually, most long-term survivors of HSCT who do not have ongoing transplant-related complications (eg, chronic GVHD) receive medical care through their primary care physician.23 As transplant centers get stretched to their capacity to accommodate the increasing number of patients who need HSCT, primary care physicians will play an even greater role in the long-term care of HSCT survivors and will need to be aware of the unique exposures, risk factors, and medical issues that these patients face.
When caring for a patient who has undergone HSCT, it is important to construct a risk profile, taking into account the patient’s age, gender, coexisting comorbidities, cancer, transplant-related exposures, and post-treatment complications. With the help of expert consensus guidelines and recommendations (Table 4),22,24,25 primary care physicians can do this and focus on preventing and screening for specific complications for which a particular patient may be at risk. MM
Navneet Majhail is an assistant professor in the Division of Hematology, Oncology, and Transplantation at the University of Minnesota and is assistant scientific director of the Center for International Blood and Marrow Transplant Research in Minneapolis.
References
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