Allogeneic hematopoietic cell transplantation (HCT) provides curative therapy for a variety of diseases. Over the past several decades, significant advances have been made in the field of HCT, and now HCT has become an integral part of treatment modality for a variety of hematologic malignancies and nonmalignant diseases. Historically, the limitation of HCT has been transplant-related mortality (TRM). In order to offer the curative HCT treatment option to most patients, safer regimens with acceptable graft-versus-host-disease (GVHD)-associated morbidity and TRM are preferred. The development of less toxic pretransplant conditioning regimens, more effective prophylaxis of GVHD, improved infection control, and other advances in transplant technology have resulted in a rapidly growing number of transplant recipients surviving long-term free of the disease for which they were transplanted.1
Since its introduction in the early 1970s the number of patients who undergo HCT for a variety of malignant and nonmalignant disorders has increased steadily and, today, nearly 60,000 allogeneic HCT are performed worldwide annually,1
a number that has been increasing yearly. With broadening indications, more options for HCT, and improvement in survival, by 2020 there may be up to half a million long-term survivors after allogeneic HCT worldwide.6
In this era, a stem cell source can be found for virtually all patients who have an indication to receive HCT. Since 2007, more allo-HCT procedures have been performed using alternative donor stem cell sources, such as volunteer unrelated donors (URD) or cord blood, than related donors.5
Haploidentical-related donor or cord blood transplantations (CBT) have emerged as alternatives to fill the gap for those patients who do not have matched related donors or URD, and the outcome of these types of transplantations are expected to be better than chemotherapy alone or even better than autologous-SCT for selected indications. All these result in a steady increase in numbers of long-term survivors after HCT, creating an enlarging pool of children, youth, and mature adults at risk for long-term complications of HCT.
Many patients who recover from immediate posttransplant problems eventually regain health and return to normal activities of life. For those who survive 2 or more years post-HCT, the prospect for long-term survival is excellent (85% at 10 years after HCT). Yet, among long-term survivors, mortality rates are 4- to 9-fold higher than observed in an age-adjusted general population for at least 30 years after HCT, yielding an estimated 30% lower life expectancy compared with someone who has not been transplanted.8
The most common causes of excess death other than recurrent malignancy are chronic GVHD (cGVHD), infections, second malignancies, respiratory diseases, and cardiovascular diseases (CVDs).3
cGVHD is a multisystem chronic alloimmune and autoimmune disorder that occurs later after HCT. It is characterized by immune dysregulation, decreased organ function, significant morbidity, and impaired survival. Approximately 10% to 30% of patients require continued immunosuppressive treatment because of cGVHD beyond 5 years after HCT.8
Therefore, it is not surprising that cGVHD, corticosteroid, and other immunosuppressive therapies are major contributors to late complications after HCT.
With survivorship, a shift in survivorship care occurs from large transplant centers to community health care providers. As a result, many hematologists/oncologists and primary care physicians are assuming the post-HCT care of late effects. Preventive measures as well as early detection and treatment are important aspects to reducing morbidity and mortality. This chapter focuses on the essentials of diagnosis, screening, treatment, and long-term surveillance of survivors after HCT.
CARDIOVASCULAR EVENTS AND METABOLIC SYNDROME
CV causes are not only the leading contributor to mortality in the general population but also impact the health of long-term transplant survivors.12
CV morbidity and mortality is typically latent in the early survivorship period because of the younger age and superior performance of transplant candidates. Nevertheless, there is growing data suggesting that traditional CV risk factors are elevated in long-term survivors, and that risk factor elevation is persistent and eventually results in premature CV events. CVD manifests as coronary artery disease/events, cerebrovascular disease/events, or peripheral vascular disease/events. Susceptible patients need to be identified early, and screened for modifiable risk factors with early intervention where possible.
Tichelli et al. were the first to show that CV events occurred prematurely in transplant survivors (median age 49 years), albeit at a long interval after transplantation, with the cumulative incidence of late CVD being 22% at 25 years (Fig. 106.1
Interestingly, allogeneic HCT recipients were significantly more likely to have arterial events than autologous transplant recipients. The Late Effects Working Group of the European Group for Blood and Marrow Transplantation (EBMT) found a cumulative CV event incidence of 6% at 15 years.9
In a matched cohort study of 1,491
long-term survivors, transplant recipients experienced increased CV mortality (adjusted incidence rate difference, 3.6 per 1,000 person-years; 95% CI, 1.7 to 5.5) with increased cumulative incidence of ischemic heart disease, cardiomyopathy or heart failure, stroke, vascular diseases, and rhythm disorders.14
FIGURE 106.1. The cumulative incidence of cardiovascular events at 15 years, adjusted for age. (From Tichelli A, Bucher C, Rovo A, et al. Premature cardiovascular disease after allogeneic hematopoietic stem cell transplantation. Blood 2007;110:3463-3471.)
Coronary artery disease and/or CV accidents are much more common than isolated peripheral artery disease. In a case control study of 63 patients with late CV disease, 44 subjects had coronary artery disease, and 19 had cerebrovascular diseases. Thirty-four of these 63 patients with CVD died, 31% of them from a CV event.15
Furthermore, CVD may contribute to chronic ill health seen in long-term survivors. The magnitude of chronic illness in a study of 1,022 HCT survivors was 59% at 10 years after HCT and increased in comparison to their sibling controls.16
Cardiovascular Risk Factors
Traditional CV risk factors include male gender, family history, dyslipidemia, diabetes mellitus, obesity, hypertension, chronic kidney disease (CKD), and smoking. In addition, transplant survivors have unique risk factors such as exposure to ionizing radiation, immunosuppressant use (including steroids), and endocrinopathies.
CV risk factors generally increase with age and it is difficult to attribute the emergence of new CV risk factors to the transplant process itself without a good control population. A clear increase in the incidence of diabetes and hypertension was seen in a study of 1,022 HCT survivors, with the incidence of CVD being 3-fold that of their sibling controls.16
In a cross-sectional study, HCT survivors had a 2.2-fold increase in the prevalence of metabolic syndrome, a clustering of CV risk factors characterized by abdominal obesity, dyslipidemia, hypertension, and elevated fasting glucose, compared to age- and gender-matched controls.17
In a long-term study (17.5 years median) of 44 pairs of recipients and their respective donors after HCT, recipients were more likely to have hypertension (P
= 0.015), dyslipidemia (P
= 0.002), lower glomerular filtration rates (GFRs) (P
< 0.0001) and reduced thyroid function (P
The occurrence of dyslipidemia is a function of age and immunosuppressive treatment. Dyslipidemia appears to play a central role in the elevated CVD risk after HCT.19
De novo dyslipidemias may even impact a pediatric population.20
The factors leading to persistent elevation of CV risk in HCT survivors long after cessation of immunosuppression remain unclear. Residual effects from radiation, endocrine dysfunction (including steroid exposure, hypogonadism, hypothyroidism, and growth hormone deficiency), and endothelial damage have been implicated.
Chest irradiation is a validated cause of CV mortality. Extrapolating from the CV impact of chest irradiation in nontransplant populations with malignancy, it is reasonable to suspect that the use of total body irradiation (TBI) in transplant conditioning contributes to increased CVD risk, but this remains to be proven in a well-controlled study. Pretransplant chest radiation exposure was associated with a 9.5-fold higher risk of CVD.15
Hypothyroidism is a frequent late effect in transplant survivors and is related to conditioning with TBI and prolonged cGVHD.21
Hypothyroidism may affect ˜30% to 40% of survivors, is often subclinical in presentation, and is strongly linked to dyslipidemias. Gonadal dysfunction will occur in the majority of transplant survivors and is linked to conditioning intensity and recipient age. Endocrinopathy and metabolic syndrome are strongly associated with gonadal dysfunction.22
In males, metabolic syndrome and low androgen levels are strongly correlated,23
and in females, estrogens are necessary for maintenance of CV health.24
In a series of 109 long-term allogeneic HCT survivors, CV risk factors were significantly elevated in males but not in females who were all recipients of hormonal supplementation.26
Relative growth hormone deficiency may be a factor in adult and pediatric transplant survivors. Growth hormone deficiency in adults leads to insulin resistance and is characterized by dyslipidemias and hypertension.27
Pediatric survivors of cancer treatment and HCT are particularly sensitive to the metabolic consequences of impaired growth hormone secretion.22
Leptin is an adipokine responsible for regulating food intake and energy metabolism. Hyperleptinemia has been implicated as the pathobiologic link between transplant and metabolic syndrome.29
Vascular endothelium may be the target of damage by radiation exposure and by alloreactivity (e.g., GVHD). Radiation has a dose-dependent impact on vasculature and endothelium in animal models. In a rodent model, TBI with 10 Gy injured coronary microvasculature, and altered endothelial physiology and myocardial mechanics.31
Host endothelial cells are a target of alloreactive donor cytotoxic T lymphocytes, and chronic skin GVHD is characterized by the progressive loss of microvessels.32
cGVHD is also characterized by elevations in von Willebrand factor,18
which may be released by endothelial injury. Chronic hypomagnesemia is common early after transplantation33
and is known to induce insulin resistance, diabetes, and metabolic syndrome. However, its precise impact on CV risk, if any, requires confirmation.
Management of Cardiovascular Risk
Since the burden of CV risk in transplant survivors has been poorly defined till now and CV events occur late, management of CV risk has often been a low priority. In a recent cross-sectional study of 86 adult survivors at a median of 3 years from HCT, 25% of cases with hypertension, 17% with abnormal glucose metabolism, and 60% with dyslipidemia were untreated.17
Current guidelines suggest a central role for transplantation centers in counseling primary health providers on screening and prevention.34
The management focus should be on modifiable CV risk factors: lifestyle (diet, smoking, and activity), obesity, diabetes, dyslipidemias, hypertension, hypothyroidism, hypogonadism, and other endocrinopathy. Dyslipidemias may be the most important driver of CV risk and are susceptible to therapy.26
The management of CV risk in transplant survivors is an evolving effort, but expert guidelines are now available.6
, 19 Table 106.1
summarizes the approach to the hyperlipidemia in long-term survivors after HCT.
The risk of second malignancies as an important late effect after HCT was first recognized in the early 1990s. As the age and life expectancy of survivors continue to rise, second malignancies are expected to become an increasingly common complication.3
Secondary malignancies following HCT are commonly categorized into one of three histologic types: leukemia, lymphoma, and solid tumors.35
However, these disorders have distinctive chronology. Secondary leukemia generally occurs at a median of 6.7 months after auto-SCT, lymphoma at a median of 2.5 months, while the median time to development of solid tumors lies between 5 and 6 years.3
Risk of Second Malignancies and Risk Factors
Based on large retrospective analyses, the cumulative incidence of solid tumors following HCT ranges between 1.2% and 1.6% at 5 years, 2.2% and 6.1% at 10 years, and from 3.8% to 14.9% at 15 years post-HCT.36
The incidence rate does not plateau; rather, there is a steady increase over time.39
Second cancers are
a very important contributor to late nonrelapse mortality (NRM) in patients who survive more than 2 to 5 years posttransplantation, accounting for 5% to 10% of such deaths.8
And, in a recent study of 28,874 HCT survivors, the incidence of new solid tumors was double that of an age- and gender-matched general population.39
The risk increased over time, reaching 3-fold among patients followed for 15 years or more after transplantation.
TABLE 106.1 APPROACH TO LIPID MANAGEMENT IN HCT PATIENTS
Obtain fasting lipid profile prior to transplantation
Evaluate CVD Risk
If patient has CVD or CVD risk equivalent, then manage as high-risk with appropriate therapy to reach LDL goal
a. Option to consider allogeneic HCT patients age 40 or older as high-risk
Otherwise, calculate 10-y risk with online risk assessment tool (www.nhlbi.nih.gov) and manage LDL per ATP-III Guidelines
Monitor lipid profiles after HCT
Check lipid profile within 4 wk after HCT then at least every 3 mo for patients on IST
For patients at treatment goal on stable therapy every 6-12 mo as indicated, or after significant change in IST regimen in patients with dyslipidemia
If patients develop significant dyslipidemia after HCT compared to baseline, consider secondary causes of dyslipidemia (IST, diabetes, hypothyroidism)
Even patients without dyslipidemia should have lipids monitored every 1-2 y after allogeneic HCT, given increased CV risk
If patient has high CVD risk (>20% 10-y risk), treat dyslipidemia with appropriate agent(s) to meet LDL goal, but monitor clinically if on IST or renal dysfunction
In patients with low (<10%)or moderate CVD risk (10-20%), consider drug treatment based upon severity of dyslipidemia, estimated prognosis post-HCT, and risks of lipid drug therapy (if on long-term IST for GVHD)
Patients with low CVD risk that develop moderate secondary dyslipidemia on IST can be managed conservatively, if IST will be tapered off
Patients with low to moderate CVD risk that develop severe hypertriglyceridemia (>500 mg/dl) should be treated to prevent pancreatitis
Consider referral to a lipid specialist for the following:
Severe dyslipidemia (total cholesterol > 300 or LDL > 180, triglycerides > 500-1,000)
Patients with dyslipidemia refractory to treatment and not meeting goals
Patients with intolerance or contraindications to lipid lowering therapy
Patients requiring combination lipid therapy, particularly in setting of IST
Patients needing individualized CV risk assessment due to strong family history of premature CVD or other factors
ATP-III, adult treatment panel-III; CV, cardiovascular; CVD, cardiovascular disease; GVHD, graft-versus-host-disease; HCT, hematopoietic cell transplant; IST, immunosuppression therapy; LDL, low density lipoprotein.
The process of malignant transformation of secondary solid tumors after HCT is not well understood but multiple factors have been implicated.42
These include exposure to TBI, primary disease, male sex, and pretransplantation therapy. The risk of developing a nonsquamous cell cancer (SCC) is associated with younger age at transplantation and the use of radiation in the conditioning regimen. Radiation is also a known significant risk factor for the development of several other solid tumors, particularly cancers of the breast, thyroid, brain, central nervous system, bone and connective tissue, and melanoma; and screening is available for some of these tumors.10
For the majority of these sites, risks are greater among those who survived 5 or more years after initial radiotherapy, in keeping with the latent period typical for radiation-related solid cancers.8
cGVHD and immunosuppressive therapy (IST) are associated with SCC of the skin and mucosa.43
A particularly high-risk was observed in the 1 to 4 year interval after HCT, which remained elevated among long-term survivors. Duration of IST, and particularly prolonged exposure to azathioprine, has been associated with development of SCC.46
Several oncogenic types of human papillomavirus (HPV) have been implicated in the etiology of SCC of the female genital tract and head and neck, and may play a role in HCT-associated SCC.46
Certainly, some inherited genetic polymorphisms have been reported to increase the risk of malignancies in patients who received alkylating agents either as pretransplant chemotherapy or as part of the conditioning regimen.48
Types of Secondary Solid Cancers
In a 2009 registry data study, 189 new cancers were found in 28,874 HCT recipients who underwent long-term follow-up.39
The average age at HCT was 27 years, and 67% received TBI as part of their conditioning regimen. The findings demonstrated that the risk of developing a nonSCC was dependent on the age at exposure to conditioning radiation. The relative risk of nonSCC for patients irradiated at ages <30 years was 9-fold that of nonirradiated patients, while the comparable risk for older patients was 1.1. cGVHD and male gender were the main determinants for the risk of SCC. The oral cavity, salivary glands, liver (prior hepatitis C exposure), skin, brain, breast, thyroid, and bone/connective tissue were the sites with a significant increase in secondary malignancy. These data indicate that HCT survivors, particularly those irradiated at young ages, face increased risks of solid cancers, supporting strategies to promote lifelong surveillance among these patients.
The risks of secondary solid cancers in HCT survivors who have not received irradiation are not well understood and deserve further study, because radiation-free conditioning regimens are being more frequently utilized. When chemotherapy alone is used for conditioning, the rates of solid tumors are still increased, as evidenced by a report examining solid tumor incidence in survivors who underwent high-dose busulfan-cyclophosphamide conditioning. In this study of 4,318 patients who received HCT for AML and CML, the cumulative incidence of solid tumors at 5 and 10 years after HCT was 0.6% and 1.2% for AML, and 0.9% and 2.4% for CML patients. The recipients had invasive solid cancers at a rate that was 1.4 times higher than expected in the general population.49
Sites with a significant increase in secondary malignancy included the oral cavity, esophagus, lung, soft tissue, and brain. cGVHD was found to be an independent risk factor for all solid cancers. Recipients of HCT using busulfancyclophosphamide conditioning are thus similar to TBI in the risk for developing solid cancers.
Successful management of second malignancies requires recognition of the special attributes of transplant survivors and close collaboration between the transplant center and the primary physician. Impaired hematopoietic reserve may be evident years after HCT and may manifest as prolonged myelosuppression after standard doses of cytotoxic agents or XRT. cGVHD management will often be a great challenge to treatment. Secondary SCC is biologically more aggressive, with frequent invasion beyond free surgical resection margins and metastasis to draining lymph nodes. Support should be provided for psychologic vulnerability in survivors facing a new diagnosis of malignancy.
INFECTION AND IMMUNE RECONSTITUTION
Infection remains an immense challenge in long-term survivors, especially in patients requiring prolonged IST for cGVHD. Infection in survivors, even in the absence of cGVHD, is over 20 times greater than reported in the general population. About 20% of patients remain on IST beyond 3 years post-HCT, with a higher incidence in older patients receiving HCT.8
There is an elevated risk of bacterial, fungal, and viral infections occurring even years after HCT, although this plateaus after 2 years.73
Infections remain a significant contributor to morbidity, rehospitalization and NRM in 5-year survivors.50
Immune reconstitution of the B and T cell repertoire from the donor can be insufficient, and long-term survivors still have an increased risk of infectious diseases.8
cGVHD and the use of systemic IST for cGVHD are the main risk factor of long-term poor immune reconstitution after HCT.80
Immune status should be monitored periodically,34
especially in those with recurrent severe infections.
Bacterial infections such as pneumococcal infection can be lethal, especially in patients with cGVHD. Fortunately there are effective preventive options such as antibiotic prophylaxis and vaccinations.34
Prolonged antibiotic prophylaxis is generally recommended for preventing infection by encapsulated organisms among patients with active cGVHD on systemic IST. Oral penicillin is generally preferred, but consideration of susceptibility patterns may warrant other options such as second-generation cephalosporins, macrolides, or fluoroquinolones. However, because of the risks of resistance, vaccinations should always be initiated if available. Several guidelines have been published34
; our current vaccination schedule is summarized in Table 106.3
The optimal timing of vaccination is also important34
; the guidelines recommend not postponing vaccinations with nonlive vaccines in patients with ongoing active cGVHD.82
Checking antibody titers is useful in monitoring the success of vaccination in such patients. Live vaccines are generally avoided in subjects
with ongoing IST. Another investigational approach to hasten the recovery of immunity is to boost donors prior to graft collection to enhance immune recovery in the eventual recipients.
TABLE 106.3 ROUTINE VACCINATIONS RECOMMENDED FOR HCT RECIPIENTS
Recommendation after HCT
Time Post-HCT to Initiate Vaccine (mo)
Number of Doses
Improved by Donor Vaccination
Pneumococcal conjugate (PCV)
Yes, may be considered when recipient is at high-risk for GVHD
Tetanus, diphtheria, Acellular Pertussisc
Tetanus: likely Diphtheria: likely Pertussis: Unknown
Haemophilus influenza conjugate
Recombinant hepatitis B
Measles, mumps and rubellag
GVHD, graft-versus-host disease; HCT, hematopoietic cell transplant.
a A uniform specific interval between doses cannot be recommended, because various intervals have been used in studies. As a general guideline, a minimum of 1 month between doses may be reasonable.
b If immunization is started early, consider evaluating for antibody levels and if they are low, revaccinate. Following the primary series of 3 PCV doses, a dose of the 23-valent polysaccharide pneumococcal vaccine (PPSV23) to broaden the immune response might be given. For patients with chronic GVHD (cGVHD) who are likely to respond poorly to PPSV23, a fourth dose of the PCV should be considered instead of PPSV23.
c DTaP is preferred; however, if only Tdap is available (e.g., because DTaP is not licensed for adults), administer Tdap. Acellular pertussis vaccine is preferred, but the whole-cell pertussis vaccine should be used if it is the only pertussis vaccine available.
d See text for consideration of an additional dose(s) of Tdap for older children and adults.
e Significant improvement of recipient response to hepatitis B vaccine posttransplant can be expected only if the donor receives more than 1 hepatitis vaccine dose prior to donation.
f For children <9 years of age, 2 doses are recommended yearly between transplant and 9 years of age.
g Measles, mumps, and rubella vaccines are usually given together as a combination vaccine. In females with pregnancy potential, vaccination with rubella vaccine either as a single or a combination vaccine is indicated.
h In children, 2 doses are favored.
Late fungal infection is associated with cGVHD and systemic IST with Aspergillus spp. being the most common pathogen.76
There is very limited evidence to demonstrate clinical benefit of antifungals in the setting of cGVHD; however, antifungal prophylaxis especially against Aspergillus is usually recommended for patients with severe cGVHD.85
Iron overload, a frequent finding after HCT, has shown a possible association with fungal infections and this represents a potential therapeutic target.86
Iron overload is an established risk factor for infections in patients with myelodysplastic syndromes.90
Iron chelation or phlebotomy could not only reverse transfusional overload, but might mitigate the risk of fungal infection.
Viral infections, including CMV, varicella zoster virus (VZV), and influenza are responsible for late hospitalization, morbidity, and mortality in HCT survivors and are frequently associated with cGVHD.73
While most CMV reactivations occur early, recent developments in transplant techniques such as preemptive CMV treatment strategies, cord blood, mismatched-related or URD HCT, and reduced-intensity conditioning have led to the emergence of late CMV reactivation and infection. CMV seropositive recipients of CMV seronegative grafts are at particular risk for prolonged reactivation.
Acyclovir prophylaxis to prevent VZV reactivation is nontoxic, effective, and routinely recommended for at least the first year after HCT.91
Longer duration acyclovir prophylaxis beyond 1 year should be considered in patients with cGVHD or systemic IST. Vaccination against VZV requires administration of an attenuated virus, and early reports are promising.93
However, live vaccines should be administered no earlier than 24 months after HCT; there may be differences in the safety profiles of different vaccine brands and, as yet, no VZV vaccine has been approved for HCT recipients.
There is considerable high-level evidence that annual influenza vaccination is beneficial to HCT recipients.34
After HCT, the first dose is often insufficient in producing satisfactory antibody titers, but a booster dose can improve the immune response.95
However, even with two doses of vaccine the most vulnerable HCT recipients, i.e., those who have a shorter transplant-tovaccination interval and active GVHD, might fail to be protected.95
Consequently, attention must also be paid to other proven measures, such as exploiting herd immunity by vaccinating household members and avoiding symptomatic contacts.
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