Late effects

Late effects Gérard Socié, Smita Bahtia and André Tichelli

Non-malignant late effects Late effects of chronic graft-versus-host disease Chronic GvHD and its associated immune deficiency state are the prime causes of transplant-related mortality late after marrow grafting, and contribute directly or indirectly to most late complications. Since c-GvHD is reviewed elsewhere in this book, only the main points relating to late complications will be highlighted here. Despite the advent of new treatment modalities, the incidence of c-GvHD is being sustained by changes in clinical SCT practice5,6 as follows: • the expanded use of matched unrelated as well as mismatched related donors • the increasing use of SCT in older patients • the increasing use of donor lymphocyte infusions to treat relapsed disease or to achieve full donor chimerism after non-myeloablative transplantation • the increasing use of peripheral blood stem cells instead of bone marrow. Immune reconstitution has a pivotal role in the long-term outcome of allogeneic SCT. Chronic GvHD is the major factor influencing immune

Late ocular effects Ocular complications of the posterior segment These can be divided into microvascular retinopathy, optic disk edema, hemorrhagic complications and infectious retinitis. Ischemic retinopathy, with cotton-wool spots and optic disk edema, has been described in 10% of patients following SCT. Microvascular retinopathy occurs mainly after TBI-conditioned allogeneic SCT, in patients receiving ciclosporin as GvHD prophylaxis. Visual acuity is decreased in most patients, but recovers when ciclosporin is withdrawn. In most cases, retinal lesions resolve with withdrawal or reduction of immunosuppressive therapy.8

5

MANAGEMENT OF POST-TRANSPLANT COMPLICATIONS

Large numbers of patients now survive long term following stem cell transplantation (SCT), and the late clinical effects of SCT are thus of major concern in the 21st century. Secondary malignant diseases are of particular clinical concern as more patients survive the early phase after transplantation and remain free of their original disease.1,2 Nonmalignant late effects are heterogeneous and although often non-life threatening, they significantly impair the quality of life of long-term survivors.3 The main aims of this chapter are to present an overview of these malignant and non-malignant late complications and to provide some recommendations regarding their prevention and early treatment. Extensive reviews with references have already been published.1,2 Thus, only main references are included in this chapter. Recommendations for screening are those derived from a joint publication by international experts,4 summarized in Tables 46.1 and 46.2. The major risk factors for late complications post SCT are chronic graft-versus-host disease (c-GvHD) and/or its treatment and the use of irradiation in pretransplant conditioning. The inter-relationships between c-GvHD, total-body irradiation (TBI), and non-malignant late effects are summarized in Figure 46.1.

reconstitution of B-cells and CD4- and CD8- T-cells.5,6 Donor source (marrow versus peripheral blood), unrelated versus sibling transplant, and the degree of human leukocyte antigen (HLA) compatibility between donor and recipient also affect the pace of immune reconstitution. Low B-cell count, reversed CD4/CD8 ratio and a decreased IgA level are all risk factors associated with late infections. Factors contributing to post-SCT immune deficiency are summarized in Figure 46.2. Late bacterial and viral infections have been extensively reviewed, and guidelines for preventing and treating these opportunistic infections after SCT have been proposed in a document published under the auspices of the Centers for Disease Control (CDC), the Infectious Disease Society of America and the American Society of Blood and Marrow Transplantation.7 Susceptibility to encapsulated bacteria (S. pneumoniae, H. influenzae, and N. meningitidis) has been well documented, especially in patients with current or previous cGvHD. Late (>2 years) fungal or cytomegalovirus (CMV) infections are rare, and almost invariably occur in patients with ongoing immune suppression from GvHD. Varicella zoster, in contrast, is extremely frequent even in patients without GvHD, but usually occurs within a few months of SCT, after aciclovir prophylaxis has been discontinued. Finally, of the parasitic infections, late Pneumocystis carinii (PCP) and Toxoplasma gondii infections are more common in patients receiving active treatment for c-GvHD. Since PCP prophylaxis with trimethoprim-sulfamethoxazole is highly active, this regimen should be given to all patients receiving treatment for c-GvHD and/or those with CD4+ cells below 0.2 × 109/l. PCP prophylaxis should probably be continued for several weeks after the cessation of immunosuppressive therapy, in view of the long-lasting T-cell defects characteristic of patients who have developed c-GvHD. Also, as described later, cGvHD is the main risk factor for squamous cell cancer occurring after SCT.

PART

Introduction

CHAPTER 46

MANAGEMENT OF POST-TRANSPLANT COMPLICATIONS Donor source HLA disparity Tcell depletion Graft-versus-host disease (GvHD) Venous access devices

GvHD Radiotherapy Cumulative transfusion exposure

Corticosteroids GvHD Intensive conditioning regimen Radiation exposure Infectious agents GvHD

Radiotherapy to head, neck,mantle TBI Prolonged corticosteroid usage TBI Intensive chemotherapy Young age Intensive prior chemoradiotherapy CNS radiotherapy Hypothyroidism Gonadal insufficiency

Infections

Sicca syndrome Caries

GvHD Viral hepatitis Iron overload

Myopathy Myositis fasciitis

Interstitial pneumonitis Bronchiolitis obliterans Chronic obstructive disease

Hypothyroidism Hypoadrenalism Gonadal failure Growth

Immune system

Oral

Liver

Muscle and fascia

Respiratory

Endocrine

Risk factors

Late complications

Tissues/organs

5

Thyroid function testing yearly post transplant in all patients, or if relevant symptoms develop Slow terminal tapering of corticosteroids for those with prolonged exposure Consider stress doses of corticosteroids during acute illness for patients who had received chronic corticosteroids Annual clinical and endocrinologic gonadal assessment for postpubertal women Clinical and endocrinologic gonadal assessment for prepubertal women within 1 year of transplant, with further follow-up as determined by pediatric endocrinologist in the peripubertal period Gonadal function in men including FSH, LH, testosterone should be assessed as warranted by symptoms (lack of libido, erectile dysfunction) Monitor growth velocity in children annually, assessment of thyroid, and growth hormone function if growth velocity is abnormal

Clinical assessment for all patients at 6 months, 1 year and annually thereafter Avoidance of smoking tobacco should be recommended for all patients PFT and focused radiologic assessment for allogeneic recipients at 1 year for signs or symptoms of compromise, or earlier as clinically indicated. Annual testing for those with deficits or appropriate clinical circumstances. Some experts suggest screening PFT evaluation every 3–6 months in the first 2 years, particularly in patients with c-GvHD PFTs should be performed for autologous recipients with known pretransplant deficits, or exposure to radiation or other lung toxic agents Radiographic evaluation as determined by diagnostic PFT testing or based on symptoms

Frequent (monthly) clinical screening for corticosteroid myopathy. Physical therapy consultation for patients with prolonged corticosteroid exposure, fasciitis or sclerodermatous GvHD may minimize loss of function

Liver function testing (LFT) every 3–6 months in 1st year, then individualized but at least yearly Monitor HbsAg and viral load by PCR for patients with known hepatitis B or C, with liver and infectious disease specialist consultation Liver biopsy to assess cirrhosis should be considered for those with chronic HCV infection after 8–10 years Serum ferritin at 1 year after transplant, with consideration of confirmatory liver biopsy for abnormal results based upon magnitude of elevation and clinical context. Subsequent monitoring is suggested for patients with elevated LFTs, continued RBC transfusions or presence of hepatitis C infection

Dental assessment at 6–12 months, individualized follow-up schedule thereafter according to dental professional. Subsequent dental/oral follow-up care should occur at least annually. Particular attention to intraoral malignancy evaluation in c-GvHD patients and recipients of radiotherapy

Antibiotic prophylaxis targeting encapsulated organisms for duration of immunosuppressive therapy for c-GvHD. Some experts recommend antifungal prophylaxis for those receiving chronic corticosteroids Administration of prophylactic antibiotics for oral procedures should follow American Heart Association guidelines for endocarditis prophylaxis PCP prophylaxis for initial 6 months for all HCT recipients, or duration of immunosuppressive therapy to treat or prevent c-GvHD Some experts recommend continued CMV antigen or PCR testing for allogeneic recipients with chronic immunosuppression or chronic GvHD. Some experts recommend prophylaxis for HSV in patients receiving chronic immunosuppression for c-GvHD Immunizations per CDC or EBMT guidelines initiated at 1 year after HCT. Delayed initiation beyond 1 year may be considered in situations where recipients are unlikely to respond

Monitoring tests and preventive measures

PART

Table 46.1 EBMT/CIBMTR/ASBMT summary recommendations for screening and prevention in long-term HCT survivors

468

Corticosteroids TBI Inactivity Gonadal insufficiency Male gender Chemotherapy Radiotherapy Immunodeficiency Chronic GvHD EBV infection Cranial radiotherapy Intrathecal chemotherapy Fludarabine GvHD Chemotherapeutic exposure TBI, platinum exposure Adenovirus, CMV Cyclophosphamide Gonadal failure

Prior psychiatric Gonadal failure

Osteopenia Avascular necrosis

Solid tumors Hematologic malignancies Post transplant lymphoproliferative disorders

Leukoencephalopathy Late infections Calcineurin neurotoxicity Peripheral neuropathy

Nephropathy Bladder dysfunction

Coronary disease Cerebrovascular disease

Depression Anxiety Fatigue Sexuality

Skeletal

Second cancers

Nervous system

Kidney and bladder

Vascular

Quality of life

General health

TBI, corticosteroids GvHD, TBI Ciclosporin Radiotherapy

Cataracts Keratoconjunctivitis sicca Microvascular retinopathy

Recommended screening as per general population (see text)

Clinical assessment and psychosocial throughout recovery period, adjustment at 6 months, 1 year and annually thereafter, with mental health professional counseling recommended for those with recognized deficits. Encouragement of robust support networks Query adults about sexual function at 6 months and yearly

Routine clinical assessment of cardiovascular risk factors as per health maintenance Clinical assessment for vascular complications at regularly scheduled follow-up visits Testing for hypercoagulability for patients with significant thrombosis history

Blood pressure assessment at every clinic visit, with aggressive hypertension management Screening assessment of blood pressure, urine protein, BUN, creatinine at 6 months, 1 year, and annually if abnormalities on earlier studies Ultrasonography and/or renal biopsy as warranted to diagnose etiology of renal insufficiency

Clinical evaluation for symptoms and signs of neurologic dysfunction at 1 year Diagnostic testing (radiographs, nerve conduction, etc.) for those with symptoms or signs

Risk awareness counseling annually Screening clinical assessment annually Routine self-examination of breasts and skin, as per healthcare maintenance section Pap smear and mammogram annually as per healthcare maintenance section. Some experts recommend screening mammography earlier than age 40 for women with radiation exposure Avoidance of tobacco or excessive, unprotected UV exposure

Dual-photon densitometry at 1 year for adult women, or any patient with prolonged corticosteroid or calcineurin inhibitor exposure. Subsequent densitometry testing determined by defects or to assess response to therapy Exercise, calcium and vitamin D supplementation and bisphosphonates are treatment options for osteopenia, and may help prevent loss of bone density. Clinicians should assess role of gonadal and thyroid function in patients with decreased bone density Some experts recommend use of bisphosphonates as prophylaxis for patients at high risk due to chronic corticosteroid usage. Screening for avascular necrosis is not recommended

Routine clinical evaluation at 6 months, 1 year and yearly thereafter, with instruction regarding sicca and cataract risk Schirmer’s testing for those with c-GvHD Some experts recommend routine ocular exam (visual acuity, fundus exam) at 1 year for all patients, subsequent frequency of screening individualized according to symptoms or predisposing factors Prompt ophthalmologic examination in all patients with visual symptoms

Chapter 46 Late effects

Ocular

469

470

PART MANAGEMENT OF POST-TRANSPLANT COMPLICATIONS

5

Table 46.2 EBMT/CIBMTR/ASBMT abbreviated summary recommendations for screening and prevention in long-term HCT survivors organized by time after transplantation Recommended screening/prevention

6 months

1 year

Annually

Immunity Encapsulated organism prophylaxis

3

3

3

PCP prophylaxis

1

3

3

CMV testing

3

3 1

1

1

1

1

1

1

+

1

+

Immunizations Oral complications Dental assessment

Chronic GvHD and corticosteroids

TBI

Damage to tissues with low repair potential

Immune deficiency

Chemotherapy

Late infections

Fertility, hypogonadism Growth and development Thyroid dysfunctions Dental

Liver Liver function testing Serum ferritin testing

Cataract Sicca syndrome Osteoporosis Necrosis of bone Lung complications Chronic kidney

Figure 46.1 Inter-relationship between total body irradiation and chronic graft-versus-host disease in the genesis of late complications after allogeneic stem cell transplantation.

Respiratory Clinical pulmonary assessment

1

1

1

Smoking tobacco avoidance

1

1

1

2

+

+

+

Pulmonary function testing Chest radiography

+

Endocrine Thyroid function testing

1

+

Growth velocity children

1

1

1

1

1

1

Gonadal function assessment (prepubertal men and women)

1

Gonadal function assessment (postpubertal women)

Chronic GvHD

Steroids

Decreased generation of naive T-cells

Impaired T-cell mediated immunity

Low lymphocyte count

Low CD4 count

Impaired B-cell help/CD4 Low B-cell count Impaired B-cell function

Poor opsonization Impaired dendritic cell function IgA and IgG subclass deficiency

Ocular 1

1

Schirmer’s test

3

3

Ocular fundus exam

1

+

1

+

Ocular clinical symptom evaluation

Impaired thymic function

1

Figure 46.2 Factors contributing to late immune deficiency and late infection following allogeneic stem cell transplantation.

Skeletal Bone density testing (women and patients with prolonged corticosteroid, calcineurin use) Second cancers Second cancer vigilance counseling

1

1

Breast/skin/testes self-exam

1

1

Clinical screening second cancers

1

1

Pap smear/mammogram (over age 40 years)

1

1

1

+

Nervous system Neurologic clinical evaluation Kidney Blood pressure screening

1

1

1

Urine protein screening

1

1

+

BUN/creatinine testing

1

1

1

1

1

Vascular Cardiovascular risk factor assessment Psychosocial Psychosocial/QOL clinical assessment

1

1

1

Sexual function assessment

1

1

1

1 = Recommended for all transplant patients. 2 = Recommended for allogeneic patients only. 3 = Recommended for any patient with ongoing c-GvHD or immunosuppression. + = Reassessment recommended for abnormal testing in a previous time period or new signs/symptoms.

Ocular complications of the anterior segment The two most common late complications affecting the anterior segment are cataract formation and keratoconjunctivitis sicca syndrome. Cataract formation, particularly posterior subcapsular cataracts, has long been recognized in recipients of SCT as one of the most frequent late complications of TBI.9–11 After single-dose TBI, almost all patients develop cataracts within 3–4 years, and most, if not all, need surgical intervention. Although the probability of developing cataracts after fractionated TBI lies at around 30% at 3 years, the incidence may reach over 80% 6–10 years post SCT (Table 46.3). On multivariate analysis, use of TBI in a single dose, rather than fractionated, and the use of steroid treatment for longer than 3 months were associated with a significant risk of cataract development. The effect of dose rate of irradiation on subsequent cataract development is also established. In the largest series evaluating a cohort of 1064 patients, factors independently associated with an increased risk of cataracts were older age (>23 years), higher dose rate (>0.04 Gy/min), allogeneic SCT and steroid administration. Finally, in prospective studies comparing cataract incidence and risk factors, it has been shown that patients who receive cyclophosphamide and TBI (Cy/TBI) have a higher incidence of cataract formation than do those treated with busulfan and cyclophosphamide (Bu/Cy).12 The only treatment for cataracts is to surgically remove the lens from the eye to restore transparency of the visual

Table 46.3 Cataract after stem cell transplantation Type of study

Number of patients

Probability of cataract formation fTBI

No TBI 19% at 6 years

Single center (Seattle)

277

80% at 6 years

18% at 6 years

Single center (Basel)

197

100% at 3.5 years Surgery 96%

29% at 3.3 years 83% at 6 years

Single center (Seattle)

492

85% at 11 years

Risk at 11 years 50% (>12 Gy) 34% (12 Gy)

Single center (Paris)

494

34% at 5 years

11% at 5 years

Risk at 10 years 60% Surgery 32%

Risk at 10 years 43% Surgery 3%

–

Risk factors: – older age – higher dose rate – allogeneic SCT – no heparin

–

Risk at 7 years AML 12.4% CML 47%

Risk at 7 years AML 12.3% CML 16%

Comparison TBI versus Bu/Cy – increased risk for CML patients with TBI

EBMT registry

4 randomized studies

1063

488

Sparing effect of fTBI TBI Single dose Corticosteroids >3 months

19% at 11 years

Need of surgical repair – 59% sTBI – 33% fTBI – 23% no TBI Highest yearly hazard of cataract formation earlier with sTBI than fTBI High dose rate, main risk factor

TBI, total-body irradiation; sTBI, single-dose TBI; fTBI, fractionated TBI; BuCy, conditioning with busulfan/cyclophosphamide; Gy, gray.

axis. Today, cataract surgery is a low-risk procedure and improves visual acuity in 95% of eyes which have no other pathology. Results of surgical repair in transplanted patients are not yet available. Keratoconjunctivitis sicca syndrome is usually part of a more general syndrome with xerostomia, vaginitis and dryness of the skin. All these manifestations are closely related to c-GvHD which may lead in its most extensive forms to a Sjögren-like syndrome. Ocular manifestations include reduced tear flow, keratoconjunctivitis sicca, sterile conjunctivitis, corneal epithelial defects, and corneal ulceration. The incidence of late-onset keratoconjunctivitis sicca syndrome may reach 20% 15 years after SCT , but reaches nearly 40% in patient with c-GvHD, compared to less than 10% in those without GvHD.13 Risk factors for late-onset keratoconjunctivitis include c-GvHD, female sex, age >20 years, single-dose TBI, and the use of methotrexate for GvHD prophylaxis. Treatment is based on the management of cGvHD with repeated use of topical lubricants. Topical corticosteroids may improve symptoms but can cause sight-threatening complications if used inappropriately when herpes simplex virus or bacterial keratitis are present. Topical ciclosporin A or retinoic acid may also be used.

Pulmonary late effects Significant late toxicity involving both the airways and lung parenchyma affects 15–40% of patients after SCT. Most studies have been performed on adult patients and results are still conflicting due to varying selection and evaluation criteria, limited sample size, and short follow-up. Moreover, clinical syndromes are not well defined or definable because of overlapping mechanisms and/or because they represent a continuum rather than a distinct disorder. Sensitivity to cytotoxic agents and irradiation, infections, and immune-mediated lung injury associated with GvHD are the most prominent factors which contribute to late respiratory complications. Impaired growth of both lungs and chest can be additional factors in children.

Restrictive lung disease Restrictive lung disease is frequently observed 3–6 months after SCT in patients conditioned with TBI and/or receiving allogeneic SCT, but in most cases it is not symptomatic. Restrictive disease is often stable and may recover, partially or completely, within 2 years. However,

some patients do develop severe late restrictive defects and may eventually die from respiratory failure (reviewed in reference 3).

Chronic obstructive lung disease Chronic obstructive pulmonary disease with reduced FEV1/FVC and FEV1 can be detected in up to 20% of long-term survivors after SCT.14 Its pathogenesis is not yet well understood. It has been mainly associated with c-GvHD, but other potential risk factors including TBI, hypogammaglobulinemia, GvHD prophylaxis with methotrexate, and infections have been described.15 While direct immune-mediated damage by donor T-lymphocytes and cytokines is classically the main mechanism, airflow obstruction can also be due to indirect consequences of c-GvHD, for example aspiration secondary to esophageal GvHD, sicca syndrome, abnormal mucociliary transport, and recurrent infections. Mortality is high among these patients, particularly in those with an earlier onset and rapid decline of FEV1. Symptoms consist of non-productive cough, wheezing and dyspnea; chest radiography is normal in most cases. High-resolution computed tomography (CT) scanning may reveal non-specific abnormalities. Symptomatic relief can be obtained in some patients with bronchodilators; however, in most cases obstructive abnormalities are not improved by this treatment. Patients with low IgG and IgA levels should receive immunoglobulin to prevent infections, which may further damage the airways. Immunosuppressive therapy may be of benefit but typically, improvements occur in less than 50% of cases, probably because damage has already become irreversible or because other pathogenetic factors persist. Asymptomatic patients with abnormal pulmonary function tests (PFT) should be closely monitored for the development of respiratory symptoms; early recognition of airflow obstruction allows the initiation of treatment at a potentially reversible stage (reviewed in reference 3). Obliterative bronchiolitis (OB), the best characterized obstructive syndrome, has been reported in 2–14% of allogeneic SCT recipients and carries a mortality rate of 50%.3,15,16 OB is strongly associated with c-GvHD and low levels of immunoglobulin. GvHD is probably responsible for the initial epithelial injury to small airways, with further damage caused by repeated infections. Initial symptoms often resemble those of recurrent upper respiratory tract infections, and then persistent cough, wheezing, inspiratory rales and dyspnea appear. PFT

471

Chapter 46 Late effects

sTBI

Remarks

472

PART MANAGEMENT OF POST-TRANSPLANT COMPLICATIONS

5

gradually deteriorate, with severe and non-reversible obstructive abnormalities. Chest radiographs and CT scanning may reveal hyperinflation with or without infiltrates and vascular attenuation. However, radiologic findings do not correlate with lung function changes, probably because of the patchy nature of the disease. Bronchoscopy with transbronchial biopsy can help to rule out infection and may reveal obliteration of bronchioles with granulation tissue, mononuclear cell infiltration or fibrosis. It is not clear to what extent combined immunosuppressive treatment can be effective in the treatment of this disease, which typically does not respond to treatment with steroids. Azathioprine and mycophenolate may lead to improvement in symptoms in some cases. Prophylaxis and prompt treatment of infections are the most important elements of clinical management and may help to alter the clinical course of a disease whose pace can vary from slow progression to rapidly fatal respiratory failure. Single or double lung transplantation has been suggested for patients with advanced disease, although the transplanted lung may also be a target for immune-mediated damage.

Late liver complications Late liver complications may be difficult to assess in cancer survivors, because patients are often asymptomatic. Several causes of liver dysfunction may co-exist, and the pattern of viral serology may be atypical. Hepatitis B (HBV) or C (HCV) infections play a central role in late survivors.17 The hepatitis may be asymptomatic, progress to fulminant hepatitis or evolve to chronic active hepatitis and cirrhosis. Before the systematic screening of blood products commenced in 1990, the rate of post-transfusion hepatitis exceeded 20%, although even for cancer patients treated since 1990 the prevalence of HBV+ and HCV+ transplanted recipients is 3.1% and 6%, respectively. Longterm studies of cancer survivors usually show a chronic pattern of liver disease with a mild course. In some patients, discontinuation of chemotherapy favors spontaneous arrest of virus replication. However, in patients with a follow-up of more than 10 years, a significant number are at risk of such adverse outcomes as impaired quality of life, liver cirrhosis, and liver carcinoma.18,19 Transplanted patients infected with HBV usually exhibit mild liver disease on long-term follow-up, and progression to cirrhosis has not been reported to date. Chronic hepatitis C is often asymptomatic, with fluctuating transaminase levels for many years after SCT. However, in HCV+ long-term survivors, cirrhosis is a common late complication. Even asymptomatic patients with persistently normal alanine aminotransferase levels may eventually progress to cirrhosis; the cumulative incidence of cirrhosis after allogeneic HSCT is 11% and 24% at 15 and 20 years post transplant, respectively. The risk of cirrhosis in transplant recipients is significantly higher, and median time to diagnosis is significantly shorter compared to a control population.20 An increased risk of cirrhosis appears in long-term survivors after more than 10 years of follow-up. The role of possible risk factors for fibrosis, such as iron overload, viral genotype or histologic pattern, has not yet been elucidated. Iron overload in cancer patients is essentially related to multiple transfusions and is therefore most commonly found in long-term survivors of acute leukemia or after SCT.21 In addition to transfusion, prolonged dyserythropoiesis and increased iron absorption contribute to accumulation of iron.22 These patients may present with hepatic dysfunction due to iron overload. Therapeutic phlebotomy can reduce iron overload, and normalize ferritin and liver function tests. After SCT, up to 88% of long-term survivors have iron overload with high ferritin levels and a high liver iron content. A clear correlation exists between iron overload and persistent hepatic dysfunction. However, the clinical consequences of iron overload and therapeutic

iron depletion in transplant recipients have not been extensively evaluated. In heavily transfused patients, such as those with thalassemia, iron accumulation may contribute to the development of liver fibrosis, cirrhosis and liver carcinoma.23 A similar evolution can be expected decades after SCT in healthy long-term survivors with iron overload. Thus, in long-term survivors liver function should be monitored yearly. Patients with known HBV or HCV infection should be monitored for HBs and viral load by polymerase chain reaction (PCR). Liver biopsy and determination of alpha-fetoprotein level should be considered in patients with chronic hepatitis C infection, to determine the extent of cirrhosis and detect hepatocellular carcinoma. Long-term results of treatment with ribavirin and/or interferon to prevent cirrhosis are not available.24 In long-term survivors at risk of iron overload, serum ferritin and transferrin saturation should be monitored. Patients should be counseled to avoid excessive iron intake, and alcohol. Those with a documented liver iron content of greater than 7 mg/g dry weight should be treated with phlebotomy and/or chelation therapy. The use of erythropoietin may facilitate phlebotomy in patients with a low hemoglobin level.

Late complications of bones and joints Avascular necrosis of bone (AVN) The published incidence of AVN varies from 4% to over 10% in the largest series.25–28 The mean time from transplant to AVN is 18 months (range 4–132 months), and pain is usually the first sign. Early diagnosis can rarely be made using standard radiography alone and magnetic resonance imaging is the investigation of choice. The hip is the affected site in over 80% of cases, with bilateral involvement occurring in more than 60% of patients. Other locations described include the knee (10% of patients with AVN), wrist and ankle. Symptomatic relief of pain and orthopedic measures to decrease pressure on the affected joints are of value, but most adult patients with advanced damage require surgery. The probability of total hip replacement following a diagnosis of AVN is approximately 80% at 5 years.28 While short-term results of joint surgery are excellent in the majority (>85%) of cases, it is clear that long-term follow-up of the prostheses is needed in young patients who have a long life expectancy. Studies evaluating risk factors for AVN have clearly identified steroids (both total dose and duration) as the strongest risk factor.25,29,30, Thus, unnecessary long-term low-dose steroids for non-active chronic GvHD should be avoided. The second major risk factor for AVN is TBI, the highest risks being associated with single doses of 10 Gy or higher, or >12 Gy in fractionated doses.

Osteoporosis Hematopoietic SCT (HSCT) can induce bone loss and osteoporosis via the toxic effects of TBI, chemotherapy, and hypogonadism (see reviews in references 31, 32). Osteopenia and osteoporosis are both characterized by a reduced bone mass and increased susceptibility to bone fracture.33 These conditions are further distinguished by the degree of reduction in bone mass and can be quantified on dual-photon densitometry. The cumulative dose and number of days of glucocorticoid therapy and the number of days of ciclosporin or tacrolimus therapy showed significant associations with loss of bone density.12,33,34 Non-traumatic fractures occurred in 10% of patients. Using WHO criteria, nearly 50% of patients have a low bone density, a third have osteopenia and roughly 10% have osteoporosis 12–18 months post transplant. Preventive measures for osteoporosis must include sex hormone replacement in patients with gonadal failure. The efficacy of new treatments for osteoporosis in long-term survivors of SCT requires evaluation.

Dental late effects

Endocrine function after SCT Thyroid dysfunction After allogeneic SCT, 7–15% of patients develop subclinical hypothyroidism.35,36 The incidence of hypothyroidism requiring l-thyroxine replacement therapy is highly variable and depends on the type of pretransplant conditioning therapy given. Single-dose TBI has a higher incidence than do fractionated TBI and conditioning without irradiation. Onset of thyroid organ dysfunction varies. It usually starts approximately 5 years after irradiation, although its appearance has been observed as late as 20 years after cancer treatment. Thus, patients treated with TBI should be evaluated for thyroid function throughout their remaining life. Treatment with l-thyroxine is indicated in all cases of frank hypothyroidism (elevated thyroid-stimulating hormone (TSH) with low free T4 blood levels). Thyroid hormone levels should be measured after commencement of replacement therapy, and dosage should be tailored thereafter to the individual patient and adjusted accordingly. Older patients should have an electrocardiogram prior to commencing treatment to exclude associated ischemic heart disease and/or arrhythmias.

Growth Linear growth is an intricate process that may be influenced by several factors including genetic (i.e. mid-parental height), nutritional, hormonal and psychologic. Children who undergo SCT form a heterogeneous group due to the different treatment protocols employed. In addition, post-transplant factors such as GvHD and its treatment, especially the use of long-term steroids, may induce growth failure in childhood. Final height achievement has been reported in some studies.37–40 Impaired growth has been described in patients who underwent SCT during childhood. Growth deficiency is more pronounced in children transplanted at a younger age (less than 10 years) and in those who have received irradiation. In contrast, children who are conditioned with non-TBI regimens, such as cyclophosphamide or busulfancyclophosphamide, usually grow normally.40 Patients who have been exposed to cranial radiotherapy (CRT) prior to conditioning with TBI show a greater retardation in growth. The role of growth hormone (GH) deficiency as a cause of growth failure and its substitution in

Puberty and gonadal failure Gonadal failure (both testicular and ovarian) is a common long-term consequence of the chemotherapy given prior to SCT, and of the pretransplant conditioning. The major cause of gonadal damage leading to hypergonadotropic hypogonadism is irradiation. Similar damage can also be caused by busulfan.

Male gonadal function Radiation to the testes is known to result in germinal loss, with decreases in testicular volume and sperm production and increases in follicle-stimulating hormone (FSH). Radiation therapy may also be toxic to Leydig cells, although at doses higher than those which are toxic to germ (Sertoli) cells. Alkylating agents decrease spermatogenesis in a dose-dependent manner.41,42 Gonadal damage following cumulative doses of cyclophosphamide lower than 200 mg/kg, as used in SCT, has been shown to be reversible in up to 70% of patients after therapy-free intervals of several years. In contrast to their prominent effects on germ cell epithelium, chemotherapy effects are less striking on slowly dividing Leydig cells and may be age related. Following exposure to alkylating agents in prepubertal boys, normal pubertal progression and normal adult levels of testosterone are the rule. Screening for problems related to male gonadal function in survivors includes an annual age-appropriate history with specific attention to problems with libido, impotence or fertility and examination for gynecomastia, Tanner staging of body hair, and assessment of penile and testicular size. Hormonal evaluation, including at least a single measurement of serum luteinizing hormone (LH), FSH and testosterone levels, is recommended as a baseline. At age 14 years patients should be counseled for pretransplant sperm cryopreservation whenever possible, and may benefit from semen analysis post transplant; honest and sensitive discussions of fertility should be part of their follow-up visit. When abnormalities in testicular function are detected, close co-operation with an endocrinologist is essential in planning hormone replacement therapy or in monitoring patients for spontaneous recovery. When no abnormalities are noted on history and physical examination but sexual maturity has not been completely attained, these studies should be repeated every 1–2 years. Conversely, in light of the potential for recovery of spermatogenesis and interpatient variations in gonadal toxicity, reminders about contraception should be given.

Female gonadal function In contrast to the process in male survivors, germ cell failure and loss of ovarian endocrine function occur concomitantly in females. Radiation effects are both age and dose dependent. In women older than 40 years at the time of treatment, irreversible ovarian failure is an almost universal result of 4–7 Gy of conventionally fractionated radiation delivered to both ovaries. In contrast, prepubertal ovaries are relatively radioresistant. Increasing age at the time of TBI has been found to predict ovarian failure. Premature menopause is very frequent in the setting of HSCT. Ovarian failure has been associated with chemotherapy, especially the alkylating agents, and the gonadotoxicity is dose and age dependent.37,43 Following myeloablative doses of alkylating agents such as busulfan and cyclophosphamide, permanent ovarian failure can be expected at all ages. Diagnostic evaluation of ovarian dysfunction relies on history (primary or secondary amenorrhea, menstrual irregularity, and pregnancies or difficulties becoming pregnant), and Tanner staging of breast and genital development. Serum gonadotropin (FSH, LH) and estradiol levels should be obtained in children as a baseline

473

Chapter 46 Late effects

Both TBI-based regimens and those without irradiation can result in severe damage to the enamel organ and developing teeth. These defects may be prolonged or permanent. After TBI in children, underdevelopment of the mandible and anomalies in the mandibular joint may also occur. In children, long-term clinical and radiologic followup reveals hypoplasia and microdontia of the crowns of erupted permanent teeth and thinning and tapering of the roots of erupted permanent molars or incisors. Caries are found more frequently in transplanted patients compared to age-matched healthy children. The defects in dental elements post SCT may occur at any age of tooth development, and only the severity seems to depend on age at SCT. Recommendations to minimize this adverse effect aim to preserve the enamel layer and prevent, by active oral hygiene, dental plaque, periodontal and oral mucosal infections and xerostomia, all of which contribute to the development of caries. Specialist dental consultation before SCT and yearly post transplant should be requested to register any specific dental problems, to provide treatment, and to give instruction on oral and dental care. In the long term, three key elements to reduce dental complications are brushing teeth, application of fluoride and the use of antiseptic mouth washes. Brushing teeth should be done twice daily, with a soft brush and fluorinated toothpaste.

children after SCT is still controversial; the reduced growth observed in irradiated patients may be explained by the direct effect of irradiation on the gonads, the thyroid gland, and/or the bone epiphyses.

474

PART MANAGEMENT OF POST-TRANSPLANT COMPLICATIONS

5

at age 13 years and systematically in adults. In the absence of clinical evidence of puberty (menarche, development of secondary sexual characteristics), in order to assess the need for hormone therapy to induce puberty, these tests are obviously mandatory. In addition, because young women who have received gonadotoxic therapy and have progressed through puberty may experience early onset of menopause, they should also undergo assessment of gonadotropin and estradiol levels if there are clinical symptoms of estrogen deficiency (irregular menses, amenorrhea, hot flashes and vaginal dryness). Survivors with concerns regarding fertility are urged to seek a consultation with a reproductive endocrinologist.

Fertility following stem cell transplantation Despite the potential gonadotoxicity of pretransplant conditioning, gonadal recovery and pregnancies following SCT are well described. The precise incidence of fertility following SCT is hard to establish. The Bone Marrow Transplant Survivor Study used a mailed survey to describe the magnitude of compromise in reproductive function and investigate pregnancy outcomes in 619 women and partners of men treated with autologous (n = 241) or allogeneic (n = 378) hematopoietic cell transplantation (HCT) between 21 and 45 years of age, and surviving 2 or more years. Median age at HCT was 33.3 years and median time since HCT 7.7 years. Thirty-four patients reported 54 pregnancies after HCT (26 males, 40 pregnancies; eight females, 14 pregnancies), of which 46 resulted in live births. Factors associated with reporting no conception included older age at HCT (≥30 years: odds ratio (OR) = 4.8), female sex (OR = 3.0), and TBI (OR = 3.3). Prevalence of conception and pregnancy outcomes in HCT survivors were compared to those of 301 nearest-age siblings. Although the risk for not reporting a conception was significantly increased among HCT survivors (OR = 36), survivors were not significantly more likely than siblings to report miscarriage or stillbirth (OR = 0.7).44 Data from the EBMT Late Effects Working Party (LEWP) relating to incidence of pregnancy in patients transplanted prior to 1994 who survived for a minimum of 2 years indicated that the overall incidence of pregnancy is low (<2%) except for patients transplanted for severe aplastic anemia (SAA), and this is in accordance with the available literature.45 Such data are limited in their ability to accurately predict the likely return of fertility post SCT, however, because many patients do not wish to become parents following the diagnosis of a potentially life-threatening illness, may have already completed their family before transplantation or may have partners beyond the normal biologic age of conception.

Fertility following SCT for non-malignant disease Return of gonadal function following cyclophosphamide conditioning for SAA was noted in 56 of 103 adult female survivors in Seattle (as indicated by return of menstruation and normal gonadotropin and estradiol levels); 28 (27%) women subsequently conceived.46 Of 109 adult male survivors in the same study, 61% had return of sperm production and 28 (26%) subsequently fathered children. Previous data from this and from other centers indicate that gonadal recovery is usual in women less than age 25 at the time of transplant but sharply decreases thereafter.

Fertility following SCT for malignant disease The majority of patients who have received TBI experience gonadal failure. Recovery of gonadal function occurs in 10–14% of the women and the incidence of pregnancy is less than 3%.45,46 In men, recovery of

gonadal function has been reported in less than 20% of patients and use of increasing doses of TBI may be associated with considerably lower recovery. Parenting a child following TBI is a rare event in men. Busulfan and cyclophosphamide (Bu/Cy) are also associated with a high incidence of gonadal failure in women, and there have been no pregnancies reported using Bu/Cy for patients with leukemia.45,46 In men, this conditioning appears to be associated with return of gonadal function in approximately 17% of cases, which is similar to the recovery after TBI conditioning.

Pretransplant counseling and treatment options Ideally, the pretransplant counseling process should include data on the incidence of gonadal failure and should assess the relevance of this to the patient. If the patient is of reproductive age and wishes to parent a child following SCT, it may be possible to alter the choice of conditioning protocol without compromising other factors such as survival. Clearly this is not always an option and discussion of management approaches for gonadal failure is thus essential. This should include explanation of assisted conception techniques and, in women, management of premature menopause. In women with no residual ovarian function following SCT, implantation of embryos cryopreserved prior to SCT is currently the only option for parenting their own genetic child. This, however, requires that prior to SCT the underlying disease can tolerate a minimum 4–6 weeks delay in treatment for controlled stimulation of the ovary and egg collection. It also requires that the patient has a committed partner to provide sperm. In situations where treatment cannot be delayed or there is no committed partner, consideration can be given to freezing ovarian tissue prior to SCT. Centers in some countries provide this service for young women, but patients must be aware that currently this is a research rather than clinical tool and that to date there have been no successful pregnancies in human subjects using this methodology. Although the incidence of assisted conception increases annually there are few published reports of pregnancy outcome following assisted conception in SCT recipients Sperm cryopreserved prior to SCT may be used post SCT for artificial insemination, in vitro fertilization (IVF) and embryo transfer, or for in vitro injection into the cytoplasm of the oocyte (ICSI). Semen collection should ideally occur at diagnosis before chemotherapy has been given. Concurrent administration of chemotherapy is not an absolute contraindication to storage, but the patient must be informed of potential risks. Post-transplant management should routinely include symptomatic and biochemical monitoring of gonadal function. While the patient should be prepared for infertility, the possible need for contraception soon after SCT must also be emphasized, particularly in women who resume menstruation or in patients who do not wish to become parents. Patients have conceived within 6 months of SCT and an unexpected pregnancy may result in requests for termination. Distressing vasomotor symptoms may commence acutely post SCT but this may be prevented by initiating hormone replacement therapy (HRT). Alternatively, HRT can be initiated at the onset of symptoms or when gonadotropin levels indicate ovarian failure. HRT does not suppress ovulation and will not, therefore, prevent recovery of gonadal function or pregnancy. It is therefore important to withdraw HRT intermittently and to assess gonadotropin levels. If there are signs of gonadal recovery, patients may benefit from contraceptive advice. Alternatively, since recovery in women is likely to be followed by a premature menopause, this period may be perceived by the patients as a window of opportunity to conceive naturally. Only regular followup will identify this point in time.

Quality of life and neuropsychologic function

Secondary malignancies Secondary malignancies are a known complication of conventional chemotherapy and radiation treatment for patients with a variety of primary cancers and are now being increasingly recognized as a complication among HCT recipients. The magnitude of risk of secondary malignancies after HCT has ranged from fourfold to 11-fold that of the general population. The estimated actuarial incidence is reported to be 3.5% at 10 years, increasing to 12.8% at 15 years among recipients of allogeneic HCT.1,2,47–50 Risk factors for the development of secondary malignancies include exposure to chemotherapy and radiation prior to transplant, use of TBI and high-dose chemotherapy for myeloablation, infection with viruses such as Epstein–Barr virus (EBV) and HBV and HCV, immunodeficiency after transplant, aggravated by the use of immunosuppressive drugs for prophylaxis and treatment of graft-versus-host disease, including monoclonal and polyclonal antibodies, HLA non-identity,

Myelodysplasia and acute myeloid leukemia after autologous SCT Autologous HCT has become the treatment of choice for patients with Hodgkin’s disease (HD) and non-Hodgkin’s lymphoma (NHL) who have a suboptimal response to initial therapy, those with refractory or relapsed disease or for those at high risk of relapse after conventional therapy. Autologous HCT is also being increasingly used in specific clinical situations among patients with multiple myeloma, breast cancer and advanced-stage germ cell tumors. With improvement in survival following autologous SCT, therapyrelated myelodysplasias (t-MDS) and therapy-related acute myeloid leukemias (t-AML) are emerging as serious long-term complications. The cumulative probability of t-MDS/t-AML reported in the literature has ranged from 1.1% at 20 months to 24.3% at 43 months after autologous transplant.51–56 The median time to development of t-MDS/ t-AML is 12–24 months after transplant (range, 4 months to 6 years). t-MDS/t-AML have also been observed after conventional chemotherapy, and to a lesser extent radiotherapy, for HD and NHL. The incidence of t-MDS/t-AML following conventional chemotherapy or radiation therapy ranges from 0.8% at 20 years to 6.3% at 30 years. The median time to development of t-MDS/t-AML has been reported to be 3–5 years, with the risk decreasing markedly after the first decade. It therefore appears that the magnitude of risk of t-MDS/tAML is higher after HCT when compared to conventional chemotherapy and radiation therapy. In addition, the time to development of t-MDS/t-AML is shorter after HCT, as compared to that after conventional chemoradiotherapy. Factors associated with an increased risk of t-MDS/t-AML include host factors such as older age at transplant, pretransplantation therapy with alkylating agents, topoisomerase II inhibitors and radiation therapy, method of stem cell mobilization (use of peripheral blood stem cells, priming with etoposide for stem cell mobilization) and transplant conditioning with TBI. Some other factors reported recently include a lower number of CD34+ cells infused at transplant, and a history of multiple transplants. Therefore, t-MDS/t-AML appears to be related to pretransplant chemotherapy and radiotherapy, transplantrelated factors such as the stem cell priming and transplant conditioning regimens, or the cumulative effect of all these exposures. The significant impact of primary chemotherapy and radiotherapy on the risk of t-MDS and t-AML after transplantation points toward an origin of events prior to transplant. Moreover, the nature of the pretransplant cytotoxic exposure (alkylating agent versus topoisomerase II inhibitor) has a significant impact on the type of t-MDS/t-AML which evolves post transplant, reinforcing this observation. A role for pretransplant exposures is supported by the observation that specific

475

Chapter 46 Late effects

The psychosocial effect of cancer has been well studied during the past few years. Psychosocial and quality-of-life late effects include aspects relating to adaptation of the patient to the personal consequences of cancer diagnosis and adjustment to the social consequences of the disease. People who have cancer experience the effect of the disease in many different ways and at different times. In turn, these issues exert an effect on perceived quality of life of the patient. At any age, disruption of function, even when temporary, becomes disturbing if it involves valued life activities. Few studies on quality of life with a specific questionnaire on long- term cancer survivors have been published. These questionnaires differ from the cancer-specific quality of life assessments designed for use during therapy, which include treatment-specific concerns such as nausea and vomiting that are not relevant in a healthy long-term survivor population. On the other hand, questionnaires developed for a healthy population may omit symptoms and concerns that continue to be important to long-term cancer survivors. Many survivors continue to experience negative effects of cancer and treatment on their daily lives, resulting in a decreased quality of life well beyond completion of therapy. However, it is important to assess positive as well as negative psychosocial effects of cancer and its treatment. Positive psychologic effects of cancer and its treatment include feelings of being grateful and fortunate to be alive, an enhanced appreciation of life, and increased self-esteem. Documented negative psychosocial effects include concerns about the future, heightened sense of vulnerability, a sense of loss for what might have been (e.g. loss of fertility) and increased health worries or hypervigilance. Large HSCT survivor studies conclude that less than half of survivors report normal functional status in most domains. Fatigue and sleep disturbances are common for both autologous and allogeneic patients. Many specific physical symptoms and limitations persist, particularly for allogeneic recipients. Continued improvement over time, with readaptation and return to some form of normalcy, has been observed. Within the first 3 years after HSCT, quality of life is significantly worse compared to the general population, while long-term survivors of more than 3 years declare improvement particularly in social functioning, mental health and vitality. At a minimum, screening for depression is recommended. Clinical assessment for psychologic symptoms should be maintained annually, with mental health professional counseling for those with recognized deficits. Attention should also be given to the partner of the patient, who often reports loneliness, and the patient’s children, who may suffer from separation from one of the parents.

and T-cell depletion, type of transplant (autologous versus allogeneic), type of hematopoietic stem cell (HSC), and the primary malignancy. However, global assessment of risk factors for all secondary malignancies in aggregate is somewhat artificial because of the heterogeneous nature of secondary malignancies, their differing clinicopathologic features, distinct pathogeneses, and hence very distinct risk factors associated with their development (reviewed in references1,2). It has become conventional practice to classify secondary malignancies after HCT into three distinct groups: • myelodysplasia and acute myeloid leukemia • lymphoma, including lymphoproliferative disorders • solid tumors. Leukemia and lymphomas develop relatively early in the post-transplant period. On the other hand, solid cancers have a longer latency period, and are being increasingly described because of improved survival after HCT and longer follow-up.

476

PART MANAGEMENT OF POST-TRANSPLANT COMPLICATIONS

5

cytogenetic abnormalities are observed in the pretransplant marrow or peripheral blood stem cell product among patients who develop tMDS/t-AML after transplant. Several studies support a role for genetic abnormalities induced by prior cytotoxic chemotherapy in the etiology of t-MDS/AML. However, prospective studies of larger groups of patients are warranted to determine the significance of these observations. The use of TBI in the conditioning regimen has been reported to be associated with an increased risk of t-MDS/t-AML after autologous HCT, although other studies fail to confirm this association. An association of TBI with increased risk for t-MDS/t-AML raises the possibility that the disease may arise from residual stem cells that persist in the patient despite myeloablative treatment, rather than from reinfused stem cells, although it is also possible that TBI-induced alteration in the hematopoietic microenvironment may contribute to the development of t-MDS/t-AML. Therefore, it is unclear whether tMDS/t-AML arises from the infused marrow (or peripheral blood) stem cells, from residual cells in the patient or as a result of a damaged microenvironment.51–56 A higher risk of t-MDS/t-AML has been demonstrated among recipients of CD34-enriched cells isolated from peripheral blood after chemotherapy priming and growth factors, as compared to autologous transplant using CD34+ cells from the bone marrow without pretreatment. Potential explanations offered for this observation include harvesting of hematopoietic precursor cells damaged by chemotherapy at a time before they have completed DNA repair, or an overrepresentation of damaged cells in the mobilized product. Supporting this hypothesis is the study by Krishnan et al, demonstrating an increased risk of t-AML with 11q23 abnormalities among patients with HD and NHL mobilized with high doses of etoposide for collection of stem cells prior to autologous HCT.54 Friedberg et al reported an increased risk of t-MDS among patients who received a significantly smaller number of cells reinfused per kilogram of body weight.57 In the setting of low stem cell numbers, reconstitution of bone marrow clearly represents a great proliferative stress, which may increase susceptibility to irreversible DNA damage associated with t-MDS. These findings are corroborated by in vitro data suggesting that an increased proliferative stress is placed upon committed progenitors at the expense of the primitive progenitors. It therefore seems that, in addition to the important role of pretransplant exposure to cytotoxic agents, the transplant process itself may potentiate the risk of t-MDS/t-AML through several mechanisms, including stem cell mobilization, collection and storage, chemotherapy and radiation used for myeloablation, and the stress on hematopoietic precursors of engraftment and hematopoietic regeneration.58–60 The prognosis of t-MDS after autologous SCT is uniformly poor, with a median survival of 6 months. Because of the poor response to conventional chemotherapy, allogeneic transplantation has been attempted, with an actuarial survival ranging from 0% to 24% reported at 3 years. Witherspoon et al reviewed data from patients transplanted for t-MDS/t-AML with the aim of identifying patient characteristics that are associated with a better long-term disease-free survival after an allogeneic transplant.61 The probability of survival after transplantation for all patients was 13%. By stage of disease this was 33% for refractory anemia, 20% for refractory anemia with excess blasts, and 8% for refractory anemia with excess blasts in transformation or acute leukemia. The overall probability of non-relapse mortality was 78%, divided equally among infection or organ failure-related cause of death. Patients with t-AML tended to have lower disease-free survival (8.3%) and a higher relapse rate (43%) than did patients whose leukemia was not therapy related. There was no statistically significant difference in outcome in the results of these previously untreated patients compared to 20 patients (12 therapy related, eight myelodys-

plasia-related) transplanted with chemotherapy-sensitive disease after induction chemotherapy. In a subsequent report, results of related or unrelated hematopoietic stem-cell transplants in 111 patients with treatment-related leukemia or myelodysplasia performed consecutively at the Fred Hutchinson Cancer Research Center between December 1971 and June 1998 were reviewed.62 The 5-year disease-free survival was 8% for TBI, 19% for Bu/Cy, and 30% for Bu/Cy-t (targeted dose Bu/Cy) conditioning regimens. The 5-year cumulative incidence of relapse was 40% for secondary AML, 40% for refractory anemia with excess of blasts in transformation (RAEB-T), 26% for refractory anemia with excess of blasts (RAEB), and 0% for refractory anemia (RA) or refractory anemia with ringed sideroblasts (RARS). The 5-year cumulative incidence of non-relapse mortality after TBI was 58%; after Bu/Cy, 52%; and after Bu/Cy-t, 42%. Yakoub-Agha et al analyzed the predictors of survival, relapse and treatment-related mortality among 70 patients with t-MDS/AML undergoing allogeneic HCT. Older age (greater than 37 years), male sex, positive recipient CMV serology, absence of complete remission (CR) at HCT and intensive conditioning schedules were independently associated with poor outcome.63 These studies indicate that in spite of the significant treatment-related mortality, disease-free survival was better when transplantation was undertaken earlier in the evolution of the disease because it resulted in a lower relapse rate. Treatment of t-MDS/t-AML should include consideration of the likelihood of success of inducing remission with chemotherapy and, depending on availability of an appropriate donor, the likelihood of a successful outcome with an allogeneic transplant. The few patients with favorable cytogenetics may have a better chance of attaining remission with chemotherapy. However, patients with unfavorable cytogenetics without a high peripheral blast count may be considered for immediate transplant. It is important to follow patients at risk of developing t-MDS closely to identify any myelodysplasia early. Prompt transplantation should be considered after diagnosing secondary AML or high-risk myelodysplasia, particularly in patients with low peripheral blood blast cell counts. Innovative transplant strategies are needed to reduce the high risks of relapse and non-relapse mortality seen in this patient population. Since the poor outcomes of allogeneic transplant for t-MDS/t-AML are related in part to the high risk of treatment-related mortality, it is appropriate to consider reducedintensity conditioning approaches, since preliminary reports suggest that these are feasible and may result in improved outcomes in patients who have had a previous autologous HCT, compared to a conventional allogeneic transplant.

Lymphomas Lymphoproliferative disorders are the most common secondary malignancy in the first year after allogeneic HCT. Most of these cases are related to compromised immune function and EBV infection. The large majority of the post-transplant lymphoproliferative disorders (PTLD) have a B-cell origin, although some T-cell PTLD have been described.64,65 These malignancies are thus excluded from this chapter on late effects and have been extensively reviewed elsewhere. Several cases of late-occurring lymphoma have been reported. It is believed that these represent an entity that is distinct from the earlyoccurring B-cell PTLD.66–70 In a large study of 18,000 HCT recipients, the only risk factor associated with the development of the late-occurring lymphoma was extensive chronic graft-versus-host disease.66 Hodgkin’s disease developing among SCT recipients has also been described. SCT recipients followed as part of a large cohort were at a sixfold increased risk of developing HD when compared with the general population.71 Most of the reported cases were of the mixed cellularity subtype, and most of the cases contained the EBV genome.

Solid tumors Solid tumors have been described after syngeneic, allogeneic and autologous HSCT. The magnitude of the increased risk of solid tumors has ranged from 2.1-fold to 2.7-fold when compared to an age-and sex-matched general population.72,73 The risk increases with lengthening follow-up and among those who have survived 10 or more years after transplantation, this was reported to be 8.3 times as high as expected in the general population. Types of solid tumors reported in excess among HCT recipients when compared to the general population are those typically associated with exposure to radiation therapy. They include melanoma, cancers of the oral cavity and salivary glands, brain, liver, uterine cervix, thyroid, breast, bone and connective tissue. Although most studies have focused on allogeneic transplant recipients, there is emerging evidence for an increased incidence of new solid malignancies among patients conditioned with TBI and receiving autologous transplants. There is therefore a need to follow this cohort of patients long term in order to ascertain the risk of new solid malignancies with precision. Sites significantly at increased risk of second cancers include: oral cavity, salivary glands, liver, skin, brain, thyroid, breast, bone and connective tissues.48,49,73–77 Thus, the risk of solid tumors increases sharply over time, and has been reported to be higher among children who have undergone SCT at less than 10 years of age.78 TBI is associated with an increased risk of solid tumors. The risk of solid tumors rises with the dose of radiation, with three to four times the risk at the highest dose levels, as compared to those who have not received radiation therapy.

Pathogenesis of solid tumors after HCT Little is known about the pathogenesis of solid tumors. An interaction between cytotoxic therapy, genetic predisposition, viral infection, and graft-versus-host disease with the consequent antigenic stimulation and use of immunosuppressive therapy, all seem to play a role in the development of new solid tumors.12,79 Radiogenic cancers generally have a long latent period, and the risk of such cancers is frequently high among patients undergoing irradiation at a young age. Both thyroid cancer and brain tumors have been reported after exposure to radiation to the craniospinal axis and the neck used as part of the conventional therapy for childhood acute lymphoblastic leukemia, HD and other primary brain tumors. Similarly, osteogenic sarcoma and other connective tissue tumors have been reported as secondary malignancies developing among patients receiving radiation therapy as part of conventional therapy for other primary malignancies such as retinoblastoma, and other bone tumors. Studies indicate the presence of a strong dose–response relationship for radiation exposure, in addition to an increased risk with increasing exposure to alkylating agents. The increased risk of thyroid, breast, brain and bone and soft tissue cancers seen after HCT appears to be related to cumulative doses of radiation exposure, both as a result of the pretransplant treatment regimen and the conditioning regimen used for transplant.74,75,78 Immunologic alterations may predispose patients to squamous cell carcinoma of the buccal cavity, particularly in view of the association with c-GvHD. Patients transplanted for aplastic anemia have been reported to be at increased risk of solid tumors, predominantly tumors of the buccal cavity and skin. The risk of these tumors was significantly increased after the administration of azathioprine for c-GvHD.80

In immune-suppressed patients, oncogenic viruses such as human papillomaviruses may contribute to the development of squamous cell cancers of the skin and buccal mucosa after transplantation. The observation of the excess risk of squamous cell cancers of the buccal cavity and skin in males is unexplained, but may be indicative of an interaction between ionizing radiation, immunodeficiency, and other risk factors more prevalent among men than women. The increased risk of new solid tumors after HCT is thus likely to be related to the TBI used for pretransplant myeloablation, altered immune function in association with viral infections (HBV, HCV or human papillomavirus), and prior treatment for the primary disease. Patients with a family history of early-onset cancers have been shown to be at an increased risk of developing a secondary cancer. Genetic predisposition also has a substantial impact on risk of secondary cancers. Studies exploring genetic predisposition and gene– environment interactions have focused thus far on patients exposed to non-transplant conventional therapy for cancer. Future studies are needed in the transplant population to clarify the roles of an interaction between genetic predisposition and myeloablative chemotherapy, TBI and the attendant post-transplant immune suppression in the development of secondary solid tumors. Treatment strategies for patients developing solid tumors after transplantation are not well defined.81,82 Concerns regarding limited bone marrow reserve and excessive organ toxicity because of prior therapy preclude the use of intensive approaches. However, some small case series indicate favorable outcomes after an intensive approach, and others note aggressive tumor growth and early relapse after standard therapy. A comprehensive study of a large number of patients with second solid tumors will help determine the nature of these tumors and their outcomes as compared to de novo tumors. Extending the follow-up of SCT recipients to 20 years after transplantation will help clarify the risks for radiation-associated cancers such as breast, lung, and colon cancers. These epithelial cancers typically develop a median of 15–20 years after exposure to radiation therapy and are now beginning to emerge among cancer survivor populations treated with conventional therapy. These data indicate that SCT survivors face an increasing risk of solid cancers with time from transplantation, thus supporting the need for life-long surveillance. Preventive measures which need to be considered include programs to educate clinicians and survivors about the risk of secondary malignancies, and measures should be taken to decrease the morbidity associated with secondary malignancies, such as adopting healthy lifestyle choices. Other measures include intervention programs for smoking cessation, periodic and aggressive screening for breast, lung, skin, colorectal, prostate, thyroid and cervical cancers, chemoprevention for specific cancers, and avoidance of unnecessary exposure to sunlight, especially among patients who have received radiation. By understanding the risk factors for secondary malignancies and taking measures to avoid them, it may be possible to decrease the incidence of the most devastating consequences of surviving cancer while maintaining the high cure rates in this population.

References 1. 2. 3. 4.

5. 6.

Deeg HJ, Socie G. Malignancies after hematopoietic stem cell transplantation: many questions, some answers. Blood 1998;91:1833–1844 Ades L, Guardiola P, Socie G. Second malignancies after allogeneic hematopoietic stem cell transplantation: new insight and current problems. Blood Rev 2002;16:135–146 Socie G, Salooja N, Cohen A et al. Nonmalignant late effects after allogeneic stem cell transplantation. Blood 2003;101:3373–3385 Rizzo JD, Wingard JR, Tichelli A et al. Recommended screening and preventive practices for long-term survivors after hematopoietic cell transplantation: joint recommendations of the European Group for Blood and Marrow Transplantation, the Center for International Blood and Marrow Transplant Research, and the American Society of Blood and Marrow Transplantation. Bone Marrow Transplant 2006;37:249–261 Vogelsang GB. How I treat chronic graft-versus-host disease. Blood 2001;97:1196–1201 Lee SJ, Vogelsang G, Flowers ME. Chronic graft-versus-host disease. Biol Blood Marrow Transplant 2003;9:215–233

477

Chapter 46 Late effects

These cases differed from the EBV-associated PTLD by the absence of risk factors commonly associated with EBV-associated PTLD, by a later onset (>2.5 years), and relatively good prognosis. The increased incidence of HD among SCT recipients can possibly be explained by exposure to EBV and overstimulation of cell-mediated immunity.

7.

478 8.

PART MANAGEMENT OF POST-TRANSPLANT COMPLICATIONS

5

9. 10.

11.

12.

13.

14.

15.

16.

17.

18. 19. 20. 21. 22.

23.

24. 25.

26.

27.

28. 29. 30. 31. 32. 33. 34.

35. 36. 37.

38. 39. 40.

CDC, IDSA, ASBMT. Guidelines for preventing opportunistic infections among hematopoietc stem cell transplant recipients, 2000. www.cdc.gov/mmwr/preview/mmwrhtlm, pp. 659–741 Bernauer W, Gratwohl A, Keller A, Daicker B. Microvasculopathy in the ocular fundus after bone marrow transplantation. Ann Intern Med. 1991;115:925–930 Tichelli A, Gratwohl A, Egger T et al. Cataract formation after bone marrow transplantation. Ann Intern Med 1993;119:1175–1180 Deeg HJ, Flournoy N, Sullivan KM et al. Cataracts after total body irradiation and marrow transplantation: a sparing effect of dose fractionation. Int J Radiat Oncol Biol Phys 1984;10:957–964 Belkacemi Y, Labopin M, Vernant JP et al. Cataracts after total body irradiation and bone marrow transplantation in patients with acute leukemia in complete remission: a study of the European Group for Blood and Marrow Transplantation. Int J Radiat Oncol Biol Phys 1998;41:659–668 Socie G, Clift RA, Blaise D et al. Busulfan plus cyclophosphamide compared with totalbody irradiation plus cyclophosphamide before marrow transplantation for myeloid leukemia: long-term follow-up of 4 randomized studies. Blood 2001;98:3569–3574 Tichelli A, Duell T, Weiss M et al. Late-onset keratoconjunctivitis sicca syndrome after bone marrow transplantation: incidence and risk factors. European Group for Blood and Marrow Transplantation (EBMT) Working Party on Late Effects. Bone Marrow Transplant 1996;17:1105–1111 Clark JG, Crawford SW, Madtes DK, Sullivan KM. Obstructive lung disease after allogeneic marrow transplantation. Clinical presentation and course. Ann Intern Med 1989;111:368–376 Freudenberger TD, Madtes DK, Curtis JR et al. Association between acute and chronic graft-versus-host disease and bronchiolitis obliterans organizing pneumonia in recipients of hematopoietic stem cell transplants. Blood 2003;102:3822–3828 Santo Tomas LH, Loberiza FR Jr, Klein JP et al. Risk factors for bronchiolitis obliterans in allogeneic hematopoietic stem-cell transplantation for leukemia. Chest 2005;128: 153–161 Locasciulli A, Testa M, Valsecchi MG et al. The role of hepatitis C and B virus infections as risk factors for severe liver complications following allogeneic BMT: a prospective study by the Infectious Disease Working Party of the European Blood and Marrow Transplantation Group. Transplantation 1999;68:1486–1491 Strasser SI, Myerson D, Spurgeon CL et al. Hepatitis C virus infection and bone marrow transplantation: a cohort study with 10-year follow-up. Hepatology 1999;29:1893–1899 Strasser SI, Sullivan KM, Myerson D et al. Cirrhosis of the liver in long-term marrow transplant survivors. Blood 1999;93:3259–3266 Peffault de Latour R, Levy V, Asselah T et al. Long-term outcome of hepatitis C infection after bone marrow transplantation. Blood 2004;103:1618–1624 Strasser SI, Kowdley KV, Sale GE, McDonald GB. Iron overload in bone marrow transplant recipients. Bone Marrow Transplant 1998;22:167–173 Mariotti E, Angelucci E, Agostini A et al. Evaluation of cardiac status in iron-loaded thalassaemia patients following bone marrow transplantation: improvement in cardiac function during reduction in body iron burden. Br J Haematol 1998;103:916–921 Muretto P, del Fiasco S, Angelucci E et al. Bone marrow transplantation in thalassemia: modifications of hepatic iron overload and associated lesions after long-term engrafting. Liver 1994;14:14–24 de Latour RP, Asselah T, Levy V et al. Treatment of chronic hepatitis C virus in allogeneic bone marrow transplant recipients. Bone Marrow Transplant 2005;36:709–713 Socie G, Selimi F, Sedel L et al. Avascular necrosis of bone after allogeneic bone marrow transplantation: clinical findings, incidence and risk factors. Br J Haematol 1994; 86:624–628 Atkinson K, Cohen M, Biggs J. Avascular necrosis of the femoral head secondary to corticosteroid therapy for graft-versus-host disease after marrow transplantation: effective therapy with hip arthroplasty. Bone Marrow Transplant 1987;2:421–426 Enright H, Haake R, Weisdorf D. Avascular necrosis of bone: a common serious complication of allogeneic bone marrow transplantation. Am J Med 1990;89:733– 738 Bizot P, Nizard R, Socie G et al. Femoral head osteonecrosis after bone marrow transplantation. Clin Orthop 1998;357:127–134 Fink JC, Leisenring WM, Sullivan KM et al. Avascular necrosis following bone marrow transplantation: a case-control study. Bone 1998;22:67–71 Schulte CM, Beelen DW. Avascular osteonecrosis after allogeneic hematopoietic stem-cell transplantation: diagnosis and gender matter. Transplantation 2004;78:1055–1063 Weilbaecher KN. Mechanisms of osteoporosis after hematopoietic cell transplantation. Biol Blood Marrow Transplant 2000;6(2A):165–174 Schimmer AD, Minden MD, Keating A. Osteoporosis after blood and marrow transplantation: clinical aspects. Biol Blood Marrow Transplant 2000;6(2A):175–181 Schulte CM, Beelen DW. Bone loss following hematopoietic stem cell transplantation: a long-term follow-up. Blood 2004;103:3635–3643 Stern JM, Sullivan KM, Ott SM et al. Bone density loss after allogeneic hematopoietic stem cell transplantation: a prospective study. Biol Blood Marrow Transplant 2001;7: 257–264 Sklar CA, Kim TH, Ramsay NK. Thyroid dysfunction among long-term survivors of bone marrow transplantation. Am J Med 1982;73:688–694 Boulad F, Bromley M, Black P et al. Thyroid dysfunction following bone marrow transplantation using hyperfractionated radiation. Bone Marrow Transplant 1995;15:71–76 Sanders JE. The impact of marrow transplant preparative regimens on subsequent growth and development. The Seattle Marrow Transplant Team. Semin Hematol 1991;28:244–249 Sanders JE, Pritchard S, Mahoney P et al. Growth and development following marrow transplantation for leukemia. Blood 1986;68:1129–1135 Sanders JE, Guthrie KA, Hoffmeister PA et al. Final adult height of patients who received hematopoietic cell transplantation in childhood. Blood 2005;105:1348–1354 Michel G, Socie G, Gebhard F et al. Late effects of allogeneic bone marrow transplantation for children with acute myeloblastic leukemia in first complete remission: the impact of

41. 42.

43. 44.

45. 46.

47. 48. 49. 50. 51.

52.

53.

54.

55.

56.

57.

58.

59.

60. 61. 62. 63.

64. 65. 66. 67.

68.

69.

70.

71. 72. 73.

conditioning regimen without total-body irradiation – a report from the Societe Francaise de Greffe de Moelle. J Clin Oncol 1997;15:2238–2246 Sarafoglou K, Boulad F, Gillio A, Sklar C. Gonadal function after bone marrow transplantation for acute leukemia during childhood. J Pediatr 1997;130:210–216 Rovo A, Tichelli A, Passweg JR et al. Spermatogenesis in long-term survivors after allogeneic hematopoietic stem cell transplantation is associated with age, time interval since transplantation, and apparently absence of chronic GvHD. Blood 2006;108:1100– 1105 Sanders JE, Buckner CD, Amos D et al. Ovarian function following marrow transplantation for aplastic anemia or leukemia 57. J Clin Oncol 1988;6:813–818 Carter A, Robison LL, Francisco L et al. Prevalence of conception and pregnancy outcomes after hematopoietic cell transplantation: report from the bone marrow transplant survivor study. Bone Marrow Transplant 2006;37:1023–1029 Salooja N, Szydlo RM, Socie G et al. Pregnancy outcomes after peripheral blood or bone marrow transplantation: a retrospective survey. Lancet 2001;358:271–276 Sanders JE, Hawley J, Levy W et al. Pregnancies following high-dose cyclophosphamide with or without high- dose busulfan or total-body irradiation and bone marrow transplantation. Blood 1996;87:3045–3052 Socie G. Secondary malignancies. Curr Opin Hematol 1996;3:466–470 Witherspoon RP, Deeg HJ, Storb R. Secondary malignancies after marrow transplantation for leukemia or aplastic anemia. Transplantation 1994;57:1413–1418 Witherspoon RP, Fisher LD, Schoch G et al. Secondary cancers after bone marrow transplantation for leukemia or aplastic anemia. N Engl J Med 1989;321:784–789 Deeg HJ, Witherspoon RP. Risk factors for the development of secondary malignancies after marrow transplantation. Hematol Oncol Clin North Am 1993;7:417–429 Stone RM, Neuberg D, Soiffer R et al. Myelodysplastic syndrome as a late complication following autologous bone marrow transplantation for non-Hodgkin’s lymphoma. J Clin Oncol 1994:2535–2542 Traweek ST, Slovak ML, Nademanee AP et al. Clonal karyotypic hematopoietic cell abnormalities occurring after autologous bone marrow transplantation for Hodgkin’s disease and non-Hodgkin’s lymphoma. Blood 1994;84:957–963 Miller JS, Arthur DC, Litz CE et al. Myelodysplastic syndrome after autologous bone marrow transplantation: an additional late complication of curative cancer therapy. Blood 1994;83:3780–3786 Krishnan A, Bhatia S, Slovak ML et al. Predictors of therapy-related leukemia and myelodysplasia following autologous transplantation for lymphoma: an assessment of risk factors. Blood 2000;95:1588–1593 Darrington DL, Vose JM, Anderson JR et al. Incidence and characterization of secondary myelodysplastic syndrome and acute myelogenous leukemia following high-dose chemoradiotherapy and autologous stem-cell transplantation for lymphoid malignancies. J Clin Oncol 1994:2527–2534 Andre M, Henry-Amar M, Blaise D et al. Treatment-related deaths and second cancer risk after autologous stem-cell transplantation for Hodgkin’s disease. Blood 1998;92: 1933–1940 Friedberg JW, Neuberg D, Stone RM et al. Outcome in patients with myelodysplastic syndrome after autologous bone marrow transplantation for non-Hodgkin’s lymphoma. J Clin Oncol 1999;10:3128–3135 Pedersen-Bjergaard J, Andersen MK, Christiansen DH, Nerlov C. Genetic pathways in therapy-related myelodysplasia and acute myeloid leukemia. Blood 2002;99:1909– 1912 Pedersen-Bjergaard J, Andersen MK, Christiansen DH. Therapy-related acute myeloid leukemia and myelodysplasia after high-dose chemotherapy and autologous stem cell transplantation. Blood 2000;95:3273–3279 Stone RM. Myelodysplastic syndrome after autologous transplantation for lymphoma: the price of progress. Blood 1994;83:3437–3440 Witherspoon RP, Deeg HJ. Allogeneic bone marrow transplantation for secondary leukemia or myelodysplasia. Haematologica 1999;84:1085–1087 Witherspoon RP, Deeg HJ, Storer B et al. Hematopoietic stem-cell transplantation for treatment-related leukemia or myelodysplasia. J Clin Oncol 2001;19:2134–2141 Yakoub-Agha I, de la Salmoniere P, Ribaud P et al. Allogeneic bone marrow transplantation for therapy-related myelodysplastic syndrome and acute myeloid leukemia: a long-term study of 70 patients – report of the French Society of Bone Marrow Transplantation. J Clin Oncol 2000;18:963–971 Curtis RE, Travis LB, Rowlings PA et al. Risk of lymphoproliferative disorders after bone marrow transplantation: a multi-institutional study. Blood 1999;94:2208–2216 Cohen JI. Epstein-Barr virus lymphoproliferative disease associated with acquired immunodeficiency. Medicine (Baltimore) 1991;70:137–160 Zutter MM, Durnam DM, Hackman RC et al. Secondary T-cell lymphoproliferation after marrow transplantation. Am J Clin Pathol 1990;94:714–721 Verschuur A, Brousse N, Raynal B et al. Donor B cell lymphoma of the brain after allogeneic bone marrow transplantation for acute myeloid leukemia. Bone Marrow Transplant 1994;14:467–470 Meignin V, Devergie A, Brice P et al. Hodgkin’s disease of donor origin after allogeneic bone marrow transplantation for myelogeneous chronic leukemia. Transplantation 1998;65:595–597 Rivet J, Moreau D, Daneshpouy M et al. T-cell lymphoma with eosinophilia of donor origin occurring 12 years after allogeneic bone marrow transplantation for myeloma. Transplantation 2001;72:965 Schouten HC, Hopman AH, Haesevoets AM, Arends JW. Large-cell anaplastic non-Hodgkin’s lymphoma originating in donor cells after allogenic bone marrow transplantation. Br J Haematol 1995;91:162–166 Rowlings PA, Curtis RE, Passweg JR et al. Increased incidence of Hodgkin’s disease after allogeneic bone marrow transplantation. J Clin Oncol 1999;17:3122–3127 Bhatia S, Louie AD, Bhatia R et al. Solid cancers after bone marrow transplantation. J Clin Oncol 2001;19:464–471 Bhatia S, Ramsay NK, Steinbuch M et al. Malignant neoplasms following bone marrow transplantation. Blood 1996;87:3633–3639

74.

75.

77. 78.

79.

80.

81. 82.

Socie G, Scieux C, Gluckman E et al. Squamous cell carcinomas after allogeneic bone marrow transplantation for aplastic anemia: further evidence of a multistep process. Transplantation 1998;66:667–670 Curtis RE, Metayer C, Rizzo JD et al. Impact of chronic GVHD therapy on the development of squamous-cell cancers after hematopoietic stem-cell transplantation: an international case-control study. Blood 2005;105:3802–3811 Favre-Schmuziger G, Hofer S, Passweg J et al. Treatment of solid tumors following allogeneic bone marrow transplantation. Bone Marrow Transplant 2000;25:895–898 Socie G, Henry-Amar M, Devergie A et al. Poor clinical outcome of patients developing malignant solid tumors after bone marrow transplantation for severe aplastic anemia. Leuk Lymphoma 1992;7:419–423

479

Chapter 46 Late effects

76.

Deeg HJ, Socie G, Schoch G et al. Malignancies after marrow transplantation for aplastic anemia and Fanconi anemia: a joint Seattle and Paris analysis of results in 700 patients. Blood 1996;87:386–392 Lowsky R, Lipton J, Fyles G et al. Secondary malignancies after bone marrow transplantation in adults. J Clin Oncol 1994;12:2187–2192 Socie G, Henry-Amar M, Cosset JM et al. Increased incidence of solid malignant tumors after bone marrow transplantation for severe aplastic anemia. Blood 1991;78:277–279 Socie G, Kolb HJ, Ljungman P. Malignant diseases after allogeneic bone marrow transplantation: the case for assessment of risk factors. Br J Haematol 1992;80:427–430 Socie G, Curtis RE, Deeg HJ et al. New malignant diseases after allogeneic marrow transplantation for childhood acute leukemia. J Clin Oncol 2000;18:348–357