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Therapy-Related Late Effects of Hematologic Malignancies
The past several decades have seen a marked improvement in survival for patients with hematologic malignancies. The 5-year survival is as follows: leukemia, 66%; Hodgkin lymphoma (HL), 89%; non-Hodgkin lymphoma (NHL), 75%; and multiple myeloma (MM), 54%. As a consequence, the population of long-term cancer survivors continues to grow. As of January 1, 2019, there were 451,700 leukemia survivors living in the United States, 234,890 HL survivors, and 757,710 NHL survivors.
Attendant with this success is an increasing awareness of the occurrence of long-term morbidity and mortality associated with the very treatments responsible for the improvement in survival. The subject of long-term morbidity suffered by cancer survivors has been the topic of numerous reports. These reports demonstrate that survivors are at risk for developing adverse outcomes, including premature death, subsequent neoplasms, organ dysfunction (e.g., cardiac, pulmonary, gonadal), reduced growth, decreased fertility, impaired intellectual function, difficulties obtaining employment and insurance, and overall reduced quality of life.
Hematopoietic cell transplantation (HCT) is the treatment of choice for patients with hematologic malignancies experiencing disease recurrence after conventional regimens and for those with disease characteristics associated with poor prognosis if treated with conventional chemotherapy and radiation regimens. Complications observed after HCT often have a multifactorial origin encompassing issues related to prior cancer therapy, intensity of the preparative regimen, graft-versus-host disease (GVHD), and other posttransplantation complications.
This chapter summarizes select adverse outcomes among individuals treated for hematologic malignancies with conventional therapy alone or with HCT. Recommendations for providing ongoing follow-up care to this population are also reviewed.
Cardiovascular Disease
One of the more serious adverse events encountered in survivors of hematologic malignancies is late-occurring cardiovascular disease (CVD), which include arterial disease (coronary artery disease [CAD]: myocardial infarction, atherosclerotic heart disease, and angina pectoris; and cerebrovascular disease [stroke]) and cardiac disease (cardiomyopathy and congestive heart failure [CHF], valvular heart disease (VHD), conduction abnormalities, and constrictive pericarditis). These complications are more common than expected, and often occur at an earlier age than observed in the general population.
Mediastinal radiotherapy (RT) is associated with an increased risk of CAD, VHD, and CHF. Anthracycline chemotherapy increases the risks of VHD and CHF. Anthracyclines are directly toxic to the myocardium through a variety of mechanisms, including free radical-mediated oxidative damage and induction of cellular apoptosis. Joint effects of mediastinal RT, anthracyclines, and smoking appear to be additive. Outcome is poor, with less than 50% of patients surviving 5 years after a diagnosis of CHF.
Among adult-onset HL survivors, the risk of CVD increases with heart radiation dose and cumulative anthracycline dose. Throughout their lives, HL survivors treated as adolescents or adults are at high risk for CVD. For patients treated before 25 years of age, the cumulative incidence at 60 years or older is 20%, 31%, and 11% for CAD, VHD, and CHF as first events, respectively.
Cardiac Disease
The anthracycline class of drugs is a well-known cause of late-onset cardiomyopathy leading to CHF. There is a strong dose-dependent relation between anthracycline exposure and risk of CHF. Among childhood cancer survivors, the incidence of CHF is less than 5% with cumulative anthracycline exposure of less than 250 mg/m 2 , approaches 10% at doses between 250 mg/m 2 and 600 mg/m 2 , and exceeds 30% for doses higher than 600 mg/m 2 . However, cumulative anthracycline exposure as low as 101 to 150 mg/m 2 may be associated with a 3.9-fold increased risk for cardiomyopathy when compared with those unexposed to anthracyclines.
Among adult-onset cancer survivors, the 5-year cumulative risk of CHF is 10%. The incidence of CHF has been estimated to exceed 25% with a dosage of 550 mg/m 2 . Among survivors older than 65 years of age, the risk of late-onset CHF is 29% higher among those exposed to doxorubicin, compared with those not treated with doxorubicin, and an increase in the number of cycles of doxorubicin-containing chemotherapy is significantly associated with increasing risk of CHF.
Among blood or marrow transplant (BMT) recipients, the risk of CHF is highest after autologous BMT, approaching 10% at 15 years after BMT; (21976673) autologous BMT survivors are at a nearly fivefold higher risk of CHF when compared with age- and sex-matched individuals from the general population. The risk of late-occurring CHF is primarily due to pre-BMT exposure to anthracyclines. Doxorubicin dose ≥300 mg/m 2 and cardiac RT dose greater than 30 Gy are independent risk factors for left ventricular (LV) systolic dysfunction.
Young age at exposure is a significant modifier of anthracycline-related cardiotoxicity. Females treated in childhood are at greater risk of developing doxorubicin-induced ventricular dysfunction. The combined use of doxorubicin and chest radiation has been associated with a greater risk of late cardiac toxicity than either treatment given alone. The presence of one or more conventional cardiovascular risk factors (CVRFs; diabetes, dyslipidemia, and hypertension) has a significant effect on the incidence of heart disease among HL survivors and NHL survivors. The risk of post-BMT anthracycline-related cardiotoxicity also increases significantly among individuals with one or more conventional cardiac risk factors.
Arterial Disease
Chest radiation produces intimal thickening of the coronary arteries and microvascular damage that causes reduced myocardial perfusion. Patients who received mediastinal radiation for HL have an increased risk of CAD compared with the general population.
The risk of radiation-related CAD is generally higher among men and among younger patients. The risk of deaths related to myocardial infarction is 2.5-fold higher among HL patients when compared with an age- and sex-matched general population; the increased risk of myocardial infarction mortality persisted through to 25 years after first treatment. Risks are increased for patients treated with supra-diaphragmatic radiation, anthracyclines, or vincristine. Among those exposed to supra-diaphragmatic radiation and vincristine and followed for ≥20 years after first treatment, the risk is 15-fold that of the general population.
Using medically ascertained data, the cumulative burden metric was used to compare chronic cardiovascular health conditions among childhood HL survivors and general population controls. At 50 years of age, the cumulative incidence of survivors experiencing at least one grade 3 to 5 cardiovascular condition was 45.5%. The survivor cohort experienced, on average, 430 grade 1 to 5 and 101 grade 3 to 5 cardiovascular conditions per 100 survivors. At age 50, the grade 1 to 5 and 3 to 5 cumulative burdens in community-controls were appreciably lower at 227/100 and 17.0/100, respectively. Myocardial infarction and structural heart defects were the major contributors to the excess grade 3 to 5 cumulative burden among survivors. Higher cardiac radiation dose (≥35 Gy) was associated with higher grade 3 to 5 cardiovascular burden.
Arterial disease in the transplant setting is related to accelerated atherosclerosis, attributed to pre-BMT and conditioning-related RT, and is compounded by the presence of CVRFs in the early post-BMT period. The cumulative incidence of arterial events such as CAD or stroke among allogeneic BMT recipients is 10% at 15 years and the risk exceeds 20% at 20 years. In this population, the median age at first myocardial infarction is as low as 53 years (range: 35 to 66), which is earlier than would be expected for the general population (67 years) or that reported in survivors of autologous BMT (61 years). The risk of developing CVRFs is higher in allogeneic BMT recipients when compared with autologous BMT recipients, as well as age- and sex-matched general population. The 10-year cumulative incidence of hypertension, diabetes, and dyslipidemia in allogeneic BMT recipients is 38%, 18%, and 47%, respectively; the risk for multiple (>2) CVRFs approaches 40% (compared with 26% in autologous BMT survivors). Conditioning with total body irradiation (TBI) has been associated with an increased risk of dyslipidemia and diabetes in survivors of BMT. Abdominal RT possibly contributes to insulin resistance and/or metabolic syndrome, suggesting a role for radiation-induced pancreatic or hepatic injury. The increased risk of diabetes and dyslipidemia among BMT survivors with prior exposure to TBI could potentially be due to the combined effects of abdominal RT and post-BMT gonadal dysfunction.
Prevention of Cardiotoxicity
Given the known cardiovascular complications of cancer therapy, prevention of CVD is a focus of active investigation. There is strong evidence for dexrazoxane as a cardioprotectant. Dexrazoxane decreases oxygen free radicals through intracellular iron chelation. In two meta-analyses, dexrazoxane was associated with 60% to 80% fewer clinical and subclinical cardiac events during and after anthracycline-based therapy. Overall, toxicity and measures of tumor response were similar between patients exposed and unexposed to dexrazoxane. Currently, the Food and Drug Administration approves dexrazoxane for women with metastatic breast cancer who have received 300 mg/m 2 of doxorubicin and who need additional anthracycline-based therapy. The American Society of Clinical Oncology also recommends considering dexrazoxane for adults with any history of cancer who have already received 300 mg/m 2 of doxorubicin-based therapy.
Intermediate or surrogate endpoints (cardiac troponin T) in randomized clinical trials show that dexrazoxane reduces cardiotoxicity in children exposed to anthracyclines. Longer-term follow-up data demonstrate that various echocardiographic indices of LV structure and function are worse in those not receiving dexrazoxane. Girls benefit from dexrazoxane more than boys, particularly with respect to changes in the LV end-diastolic thickness-to-dimension ratio, a marker of pathologic LV remodeling. Further, there is no impact on late mortality among HL patients randomized to dexrazoxane. However, comprehensive longer-term follow-up is required to document that dexrazoxane does indeed have a cardioprotective effect while maintaining comparable event-free survival.
Liposome-encapsulated anthracyclines have been explored, using the premise that liposome-encapsulated anthracyclines escape the capillaries with wide endothelial gaps in the tumor, thus reaching high concentrations in the interstitial fluid of the tumor bed, but are less likely to escape the tight capillary junctions of the heart. Biopsy results have confirmed the relative safety in clinical use. Data on the potential cardioprotection associated with liposomal formulations of anthracyclines is limited. A phase I study of liposomal daunorubicin in 48 children reported no cardioprotection. A primary cardioprotection strategy (angiotensin-converting enzyme inhibitors and/or beta blockers as well as liposomal doxorubicin) in NHL patients with a high risk of anthracycline cardiotoxicity was found to result in fewer events (cardiovascular mortality and heart failure occurrence) when compared with historical controls.
Specific recommendations for monitoring have been developed for childhood cancer survivors ( http://www.survivorshipguidelines.org ) as well as for survivors of adult-onset cancer and BMT ( Table 101.1 ).
Table 101.1
Monitoring for Potential Late Effects
Modified from Children's Oncology Group: Long-term follow-up guidelines for survivors of childhood, adolescent, and young adult cancers , version 5.0, 2018, Children's Oncology Group. http://www.survivorshipguidelines.org
| Potential Late Effects | Therapeutic Exposure | Recommended Monitoring | Suggested Interventions |
|---|---|---|---|
| Adverse psychosocial effects (e.g., depression, anxiety, posttraumatic stress disorder, limitations in healthcare access, relationship problems, risky behaviors, psychosocial disability due to pain, sleep problems, fatigue) | Diagnosis and treatment for hematologic malignancy | Clinical interview: yearly | Psychologic or social work consultation if indicated |
| Dental abnormalities (abnormal tooth development, increased susceptibility to caries and gum disease) |
|
Dental examination: every 6 months | Professional dental cleaning every 6 months; use of fluoridated toothpaste; topical fluoride applications as indicated; Panorex radiograph before orthodontic or dental procedures for patients treated before completion of tooth development |
|
|
Neurologic examination if symptomatic | Physical therapy if indicated; advise patient to protect against precipitating factors (e.g., cold environment) |
| Neurocognitive deficits |
|
|
Referral for specialized educational services, curricular modifications, or vocational training programs if indicated |
| Clinical leukoencephalopathy |
|
|
Neurology consultation if clinically indicated |
| Cataracts |
|
|
Ophthalmology consultation if abnormalities detected |
| Xerophthalmia | Chronic GVHD related to HCT | History and eye examination yearly | Artificial tears, ophthalmology consultation if indicated |
| Xerostomia |
|
Dental evaluation: every 6 months |
|
| Hearing loss |
|
History and physical examination: yearly Audiogram: every 2–5 years for survivors who received platinum chemotherapy and/or cranial radiation dose ≥ 30 Gy | Audiology consultation if indicated |
|
Cranial, cervical, spinal, mantle, or mediastinal irradiation; TBI | Free T 4 , TSH, thyroid examination: yearly | Endocrine or surgical referral as indicated |
|
|
|
Cardiology consultation if indicated; additional cardiology evaluation of patients who are pregnant or planning to become pregnant if patient received ≥ 250 mg/m 2 of an anthracycline, radiation dose ≥ 35 Gy, or any dose of anthracycline combined with radiation ≥ 15 Gy |
|
Chest or thoracic irradiation (e.g., mantle, mediastinal) |
|
Cardiology consultation if indicated; additional cardiology evaluation in patients who are pregnant or planning to become pregnant if patient received ≥ 250 mg/m 2 anthracycline, anthracycline combined with radiation ≥15 Gy, or radiation dose ≥35 Gy |
| Pulmonary dysfunction (fibrosis, interstitial pneumonitis) |
|
Pulmonary function testing: baseline at entry into long-term follow-up and as clinically indicated for patients with progressive dysfunction | Pulmonary consultation for symptomatic patients; influenza and pneumococcal vaccine; counsel patients to avoid smoking and avoid SCUBA diving |
|
Central venous catheter | History and physical examination: yearly as clinically indicated | Surgical referral as indicated |
| Hepatic dysfunction | Mercaptopurine, thioguanine, methotrexate (systemic), abdominal radiation, HCT | ALT, AST, bilirubin: baseline on entry into long-term follow-up; repeat if clinically indicated | If abnormal results for baseline studies, obtain prothrombin time (to assess hepatic synthetic function) and viral hepatitis screening |
| Chronic viral hepatitis | Blood products |
|
Gastroenterology or hepatology consultation and annual AFP for patients with chronic hepatitis; hepatitis A and B immunizations in patients lacking immunity |
| HIV infection | Blood products | HIV-1 and HIV-2 antibodies: once if transfused before universal screening of blood supply (1985 in the United States) | Infectious disease consultation for patients with confirmed infection |
| Life-threatening infection |
|
Physical examination at time of febrile illness to evaluate degree of illness and for potential source of infection | Counsel patients regarding risk of life-threatening infections and indication for medical alert bracelet. Administer parenteral antibiotics and continue close medical observation in patients with temperature ≥ 38.3°C (101°F) or other signs of serious infection; immunize with pneumococcal, meningococcal, and HIB vaccines |
| Iron overload | HCT (and patients requiring multiple red blood cell transfusions) | Serum ferritin: at entry into long-term follow-up | If abnormal, consider chelation, or repeat as clinically indicated until within normal limits |
|
|
|
Surgical and gastroenterology consultations as clinically indicated |
| Renal insufficiency |
|
|
Nephrology consultation for proteinuria, hypertension, progressive renal insufficiency |
|
|
Voiding history: yearly | Urinalysis and urology consultation as clinically indicated for incontinence, dysfunctional voiding, macroscopic hematuria (culture negative) |
| Growth hormone deficiency |
|
|
Endocrine referral for patients failing to follow normal growth curve |
| Overweight/obesity | Cranial irradiation | BP, growth percentile, BMI: yearly | Endocrine referral as indicated |
| Dyslipidemia | TBI | Lipid profile every 2 years | |
| Hypogonadism/Infertility |
|
|
|
| Precocious puberty | Cranial irradiation |
|
Endocrine referral as indicated for accelerated puberty (<age 8 years in females, <age 9 years in males) |
| Adverse pregnancy outcomes (e.g., spontaneous abortion, premature delivery, low-birthweight infant) |
|
History: yearly and as clinically indicated | High-risk obstetric care |
| Osteopenia, osteoporosis |
|
Bone-density study (DXA scan): baseline at entry into long-term follow-up, repeat as clinically indicated | Calcium and vitamin D supplementation; weight-bearing exercise; treatment of exacerbating conditions (e.g., hypogonadism); consider pharmacologic intervention (e.g., bisphosphonates) |
| Avascular necrosis |
|
History: yearly; MRI if clinically indicated | Orthopedic consultation if indicated |
| Scoliosis/kyphosis | Irradiation of trunk (e.g., mantle, spine, abdomen, pelvis) |
|
Orthopedic referral |
| Joint contractures | Chronic GVHD related to HCT | Physical examination yearly | Orthopedic referral if indicated |
| Chronic infection | Chronic GVHD related to HCT | History: yearly | Prophylactic anti-infective agents; infectious disease consultation if indicated |
|
|
|
|
|
Cranial irradiation |
|
Neurosurgical consultation as indicated |
| Breast cancer |
|
|
Teach breast self-examination; instruct patient to perform monthly self-examination beginning at puberty and report changes immediately; surgical consultation if clinically indicated |
| Gastrointestinal malignancy | Abdominal, pelvic, spinal irradiation, TBI | Colonoscopy every 5 years beginning 5 years after radiation or at age 30, whichever occurs last; more frequently as clinically indicated; or multitarget stool DNA test every 3 years; other options may be considered based on informed decision-making between patient and provider | Surgical consultation if indicated |
| AML (preceding myelodysplastic phase associated with alkylating agents) |
|
|
Counsel patient to report fatigue, bruising, bleeding, bone pain |
AFP , α-Fetoprotein; ALT , alanine aminotransferase; AML , acute myeloid leukemia; AST , aspartate aminotransferase; BMI , body mass index; BP , blood pressure; BUN , blood urea nitrogen; CBC , complete blood cell count; CT , computed tomography; DXA , dual-energy X-ray absorptiometry; ECG , electrocardiogram; ECHO , echocardiogram; FSH , follicle-stimulating hormone; GFR , glomerular filtration rate; GVHD , graft-versus-host disease; HCT , hematopoietic cell transplantation; HCV , hepatitis C virus; hemoglobin A1c, glycosylated hemoglobin; HIB, Haemophilus influenzae type B; HIV , human immunodeficiency virus; LH , luteinizing hormone; MRI , magnetic resonance imaging; NHL , non-Hodgkin lymphoma; PCR , polymerase chain reaction; RNA , ribonucleic acid; T 4 , thyroxine; TBI , total body irradiation; TSH , thyroid-stimulating protein.
Pulmonary Effects
Pulmonary function compromise has been reported after conventional therapy in survivors of hematologic malignancies. Pulmonary function abnormalities include reductions in total lung capacity (TLC), forced vital capacity (FVC), forced expiratory volume in the first second of expiration (FEV 1 ), and gas transfer (diffusing capacity of lung for carbon monoxide [DLCO]), suggesting obstructive and restrictive defects. Risk factors include exposure to certain chemotherapeutic agents (particularly bleomycin), radiation to the chest, underlying lung disease, female sex, and a younger age at exposure to the pulmonary-toxic therapeutic agents. Patients present with chronic cough, emphysema, lung fibrosis, oxygen requirements, and recurrent pneumonia. The cumulative incidence of any pulmonary disease after 35 years of follow-up exceeds 20% in childhood cancer survivors. Childhood cancer survivors are 6.5-fold more likely to develop restrictive disease and 5.2-fold more likely to develop diffusion abnormalities when compared with healthy non-cancer controls. Higher radiation dose (>20 Gy) and younger age at exposure (<16 years) is associated with restrictive disease. Female sex and higher chest radiation dose are associated with diffusion abnormalities. Over a period of 5 years, diffusion capacity declines among females and those exposed to high doses of chest radiation.
Pulmonary complications, both infectious and noninfectious, are common after BMT. Multiple factors are thought to contribute to pulmonary complications in this population, including the type and duration of immunological defects produced by the underlying disease and treatment, the development of chronic GVHD, and the conditioning regimens employed. These complications are classified as early or late, depending on whether they occur before or after 100 days from transplantation. Early noninfectious pulmonary complications typically include pulmonary edema, upper airway complications, diffuse alveolar hemorrhage, and pleural effusion. Bronchiolitis obliterans occurs later after BMT. Idiopathic pneumonia syndrome, GVHD, and radiation-induced lung injury can occur in the early or late periods after BMT (reviewed in Khurshid and Anderson).
The following pulmonary function tests are noted to decline after BMT: FEV 1 /FVC, forced mid-expiratory flow, TLC, DLCO, residual volume (RV), functional residual capacity, and RV/TLC. Older age at allogeneic BMT is associated with lower FEV 1 /FVC and DLCO, and higher RV/TLC. Bronchiolitis obliterans syndrome is a progressive, insidious lung disease occurring after allogeneic BMT and results in progressive circumferential fibrosis and ultimate cicatrization of the small terminal airways, manifesting as new fixed airflow obstruction (reviewed in Williams et al.). Bronchiolitis obliterans has a strong correlation with chronic GVHD and has been reported in up to 6% of BMT recipients. Most patients present when the degree of airflow is severe, causing significant dyspnea on exertion and a persistent nonproductive cough. Lung biopsy findings demonstrating damage to the bronchiolar epithelium, obliteration of bronchiolar lumens, inflammation between the epithelium and the smooth muscle, and pulmonary fibrosis are characteristic. The National Institutes of Health definition of bronchiolitis obliterans requires the following: (1) absence of active infection, (2) decreased FEV 1 (<75% of predicted value), (3) evidence of airway obstruction with a ratio of FEV 1 to FVC of less than 0.7, (4) elevated RV of air (>120% of predicted normal), or (5) an expiratory chest computed tomographic (CT) scan or lung biopsy that reveals air trapping or bronchiectasis. Recommended therapy includes high-dose systemic steroids for a protracted course, with or without the addition of other immune suppressants. Leukotriene inhibitors have emerged as a potential therapy because of the elevated levels of leukotrienes implicated in bronchiolitis obliterans. Late-onset severe restrictive lung defect is also observed after allogeneic BMT, usually ∼3 months post-BMT. Major CT findings include pleuroparenchymal thickening with volume loss, and evidence for fibrosis, predominantly in upper lobes–a finding that is consistent with pleuroparenchymal fibroelastosis. Other findings include interstitial pneumonia. Pulmonary function tests reveal diffusion capacity abnormalities.
Specific recommendations for monitoring for pulmonary complications have been developed for childhood cancer survivors ( http://www.survivorshipguidelines.org ) and for survivors of BMT (see Table 101.1 ).
Endocrinologic Effects
Thyroid
Patients with hematologic malignancies treated with cranial, craniospinal, or mantle irradiation are at increased risk for thyroid complications. Among survivors of HL, and to a lesser extent leukemia, abnormalities of the thyroid gland, including hypothyroidism, hyperthyroidism, and thyroid neoplasms, have been reported to occur at rates significantly higher than those found in the general population. Hypothyroidism is the most common nonmalignant late effect involving the thyroid gland. Survivors of HL are at particularly increased risk; after exposure to radiation at doses of 30 to 45 Gy to the thyroid gland the cumulative incidence of hypothyroidism is 30% at 20 years, with the cumulative incidence increasing to 50% for radiation doses above 45 Gy. Hyperthyroidism is infrequently seen, but is also associated with a history of neck radiation. Thyroid nodules are common in patients treated with neck radiation for HL, but the majority of these do not undergo malignant transformation.
Monitoring for survivors at risk for thyroid complications is reviewed in Table 101.1 .
Obesity
An increased prevalence of obesity has been reported among survivors of childhood ALL. In an analysis from the Childhood Cancer Survivor Study, Oeffinger et al. compared the distribution of the body mass index (BMI) of 1765 adult survivors of childhood ALL with that of 2565 adult siblings of childhood cancer survivors. Survivors were significantly more likely to be overweight (BMI of 25 to <30) or obese (BMI ≥30). Risk factors for obesity were cranial irradiation, female sex, and age 0 to 4 years at diagnosis of leukemia. Females diagnosed under the age of 4 years who received a cranial radiation dose of more than 20 Gy were found to have a 3.8-fold increased risk for obesity. In a recent report of survivors of standard-risk childhood ALL treated without cranial radiation, there was no increased risk of overweight or obesity compared with general population health data. Obesity has the potential to adversely impact the overall health status in survivors and is associated with insulin resistance, diabetes mellitus, hypertension, and dyslipidemia. Yearly monitoring of BMI is recommended (see Table 101.1 ).
Gonadal Dysfunction
Treatment-related gonadal dysfunction has been well documented in male and female patients after therapy for hematologic malignancies and there is a reasonable body of research that provides a basis for counseling patients regarding the long-term gonadal effects of radiation and chemotherapy.
Radiation effects on the ovary are age and dose dependent. The ovaries are particularly sensitive to radiation, and it has been estimated that there is a 50% depletion in oocytes after exposure of the ovaries to 2 Gy, and premature menopause is associated with even low doses of ovarian radiation. The majority of females who receive ovarian radiation doses greater than 20 Gy develop acute ovarian failure; at lower radiation doses, post-pubertal adolescent and adult women are more susceptible to acute ovarian failure than are pre-pubertal girls. Spinal irradiation for the treatment of childhood leukemia appears to result in clinically significant ovarian damage in some survivors, and cranial irradiation in young girls is associated with an increased risk for premature puberty.
The effects of radiation on testicular function, including germ cell number and Leydig cell function, have been investigated. Reduced sperm production has been observed after testicular doses of 1 to 6 Gy and follows a dose-dependent pattern. Azoospermia has been reported among HL patients with calculated testicular irradiation exposures ranging from 1 to 3 Gy, which may be reversible. Testicular doses between 4 to 6 Gy have been associated with prolonged azoospermia and decreased testicular volume, whereas doses greater than 6 to 8 Gy are associated with irreversible injury. Spermatogenesis is impaired in 75% to 100% of male childhood HL survivors in whom radiation and chemotherapy were combined. Most pre-pubertal males treated with fractionated radiation doses less than 12 Gy to the testis will undergo normal pubertal maturation. Males treated for testicular leukemia with radiation doses greater than 20 Gy who pre- or peri-pubertal are at high risk of delayed sexual maturation as well as significant germ cell depletion. In males who have reached puberty and undergo testicular radiation, only about 50% develop Leydig cell failure at doses greater than 30 Gy.
Ovarian and testicular damage can also result from chemotherapeutic agents, with alkylating agents showing the strongest association. Effects of chemotherapy on gonadal function are typically sex-, age-, and dose-dependent. Ovarian dysfunction has been well documented in HL patients treated with alkylating agents, singly or in combination (e.g., MOPP regimen consisting of mechlorethamine, vincristine [Oncovin], procarbazine, and prednisolone, or a COPP regimen consisting of cyclophosphamide, vincristine [Oncovin], procarbazine, and prednisolone). MOPP and COPP regimens have been reported to result in azoospermia in more than 90% of exposed males, with a negative correlation seen between cumulative doses of alkylating agents and sperm concentration. Even with a reduction in the dose of cyclophosphamide in the hybrid COPP/adriamycin, bleomycin, and vinblastine (ABV) regimen for HL, the majority of young males are infertile, likely due to the procarbazine component in this regimen. In a study of 6224 male survivors of childhood cancer between 15 and 44 years of age, those with a diagnosis of hematologic malignancy were significantly less likely to sire a pregnancy compared with sibling controls; those with a diagnosis of HL were least likely to sire a pregnancy (RR of fertility: 0.34; 95% confidence interval [CI]: 0.28–0.41), followed by NHL (RR: 0.60; 95% CI: 0.48–0.74), and leukemia (RR: 0.70; 95% CI: 0.59–0.84); P < .001 for all comparisons.
Young boys and adolescent males with aplastic anemia who receive standard-dose cyclophosphamide alone (200 mg/kg) as the pretransplant conditioning regimen appear to retain normal Leydig cell function, as do males who receive busulfan and cyclophosphamide, with normal plasma concentrations of luteinizing hormone and testosterone, and normal progression through puberty. Semen analyses have been normal in approximately two-thirds of men after high-dose cyclophosphamide and several men have fathered normal children. Men treated with TBI-based regimens who have not received prior testicular irradiation generally retain normal Leydig cell function, regardless of their age at treatment. Germ cell dysfunction occurs in all men treated with TBI-based regimens and azoospermia is the rule; however, some younger males (age <25years at HCT) without chronic GVHD have showed some degree of spermatogenesis following standard-dose TBI.
The effect of alkylating agents alone on ovarian function in females is dependent upon dose and age at exposure. Females treated with busulfan and cyclophosphamide are at very high risk for ovarian failure and premature menopause, and procarbazine is also particularly gonadotoxic. The outcome of ovarian function after TBI appears to be determined by the age at exposure. Approximately 50% of prepubertal girls receiving fractionated TBI enter puberty spontaneously and premature ovarian failure is seen in all patients who are older than 10 years of age when treated with TBI. Pregnancies among survivors who received TBI are at an increased risk for spontaneous abortion, premature labor, and low-birthweight offspring.
Monitoring for gonadal dysfunction is reviewed in Table 101.1 .
Musculoskeletal Effects
Osteonecrosis is a painful and debilitating condition that develops when the blood supply to the bone is disrupted, usually in areas of terminal circulation. The condition is believed to be the result of vascular compromise with resultant death of bone and cell tissues or disruption of bone-repair mechanisms. Osteonecrosis has been reported after conventional therapy for hematologic malignancies, particularly after exposure to dexamethasone between the ages of 10 and 20 years. This complication usually develops during or shortly after completion of therapy but may progress over time.
Osteonecrosis is increasingly being reported among HCT recipients. Campbell et al. conducted a retrospective cohort study and described the cumulative incidence of osteonecrosis to be 2.9% among autologous HCT recipients, 5.4% among allogeneic HCT recipients, and 15% among unrelated donor HCT recipients. Among allogeneic HCT recipients, male sex, presence of chronic GVHD, and exposure to cyclosporine, tacrolimus, prednisone, and mycophenolate mofetil rendered patients at increased risk, in particular among patients with a history of exposure to three or more drugs. The mean latency period was 18 months. The hip joint was the most commonly involved joint (80%); however, the knee, wrist, and ankle joints were also affected. The cumulative incidence of surgery (mainly arthroplasty) approached 31% at 1 year from osteonecrosis diagnosis. Li et al. conducted a case-control study of children who underwent allogeneic HCT and found that children at highest risk included those who underwent transplant during the period of rapid pubertal growth and those who received myeloablative conditioning and immunosuppression for treatment of GVHD.
Osteopenia (bone density 1 to 2.5 standard deviations below mean) or osteoporosis (bone density >2.5 standard deviations below mean) is commonly seen in survivors of hematologic malignancies. Risk factors include therapy with corticosteroids, methotrexate (at higher doses), and cranial irradiation with resultant pituitary insufficiency or gonadal dysfunction. Survivors of HCT are also at increased risk for reduced bone mineral density; identified risk factors in these patients include treatment with corticosteroids for chronic GVHD, prior cranial irradiation (resulting in growth hormone deficiency), and gonadal failure. Lifestyle factors that increase the risk for osteopenia include lack of regular weight-bearing exercise, inadequate calcium and vitamin D intake, smoking, and excessive alcohol consumption.
Detection and diagnosis of musculoskeletal sequelae depend largely on anticipating these issues in vulnerable hosts, on taking a careful history, and on performing a thorough physical examination. Monitoring recommendations are reviewed in Table 101.1 .
Cognitive Impairment
Cognitive impairment affects over 10 million cancer survivors in the US. Cognitive impairment can range from subtle to severe and last for months or years after treatment. Many survivors of hematologic malignancies also experience memory loss, distractibility, and difficulty performing multiple tasks. These patients may also concurrently suffer from mood disturbances and symptoms including fatigue and pain; these may compromise their ability to function adequately. Decreased cognitive function is associated with poorer quality of life, inability to achieve work and educational goals, inability to drive or read, and decreased social connectedness (reviewed in Williams et al., 2016 ). There is evidence to suggest that impaired working memory and executive functioning is prevalent in older patients with hematologic malignancies and may have an impact on survival.
Many non-therapy-related factors can influence cognition in patients with a hematological malignancy. These include demographics (e.g., age and cognitive reserve) and comorbidities (physical comorbidities, as well as anxiety, depression, and fatigue). Cancer and its treatment may exacerbate normal aging and increase cognitive impairment in the cancer survivors. A National Health and Nutrition Examination Survey (NHANES) analysis showed that survivors aged 60 years and older scored worse on a test of processing speed, attention, working memory, and executive function domains compared to non-cancer survivors. Non-neurotoxic exposures, such as thoracic radiation, can adversely impact survivors’ cognitive function through chronic conditions. Management of chronic diseases may mitigate neurocognitive outcomes among aging survivors of childhood cancer. Cognitive impairment and its downstream effects become a major issue in survivors of hematological malignancies, given that many of these diagnoses are more common in older patients.
Cranial radiation has long been associated with cognitive impairment in childhood cancer survivors, although antimetabolite chemotherapy and corticosteroids have also been implicated as potential contributors. Additional risk factors include higher treatment intensity, younger age at treatment exposure, and female sex. Cognitive deficits usually become evident within 1 to 2 years following cranial radiation and are progressive in nature. The decline over time is typically reflective of the child’s failure to acquire new abilities or information at a rate similar to peers, rather than because of a progressive loss of skills and knowledge. The cognitive problems seen in childhood ALL survivors are generally characterized by reduced attention, processing speed, executive function and global intellectual function. Affected children with information-processing deficits exhibit academic difficulties and are prone to problems with receptive and expressive language, attention span, and visual and perceptual motor skills. The deficits observed after chemotherapy alone are restricted to attention, executive function, and complex fine-motor functioning; global intellectual function is relatively preserved. Cognitive function in long-term survivors of childhood cancer appears particularly vulnerable to the effects of fatigue and sleep disruption. The cognitive impairment observed in survivors of childhood ALL persists into adulthood; this impairment is associated with reduced educational attainment and unemployment, and challenges with independent living, and health care use.
A meta-analysis of existing evidence for the mechanisms underlying changes in the central nervous system (CNS) and cognitive function in ALL survivors after treatment compared with controls found that ALL survivors develop: (i) cognitive sequelae in intelligence, academics, attention, memory, processing speed, and executive function domains; (ii) decreased grey and white matter volume in cortical and several subcortical brain regions, with functional changes particularly in frontal regions and the hippocampus; (iii) cognitive impairments related to CNS changes; and (iv) reduction, but not resolution, of late cognitive sequelae in patients in whom prophylactic irradiation was replaced by systemic/intrathecal chemotherapy. Thus, ALL survivors treated with chemotherapy alone perform worse in processing speed, verbal selective reminding, and academics and display significant IQ deficits of 6 to 8 points compared with population norms but perform better than survivors treated with cranial RT on verbal selective reminding, processing speed, and memory span.
A spectrum of neuropathological syndromes related to leukoencephalopathy may occur in survivors of childhood hematologic malignancies, including radionecrosis, necrotizing leukoencephalopathy, mineralizing microangiopathy and dystrophic calcification, cerebellar sclerosis, and spinal cord dysfunction, manifesting clinically as ataxia, spasticity, dysarthria, hemiparesis, or seizures. Leukoencephalopathy has been primarily associated with methotrexate-induced injury of white matter. However, cranial irradiation may play an additive role through disruption of the blood-brain barrier, allowing greater exposure of the brain to systemic therapy. Acute leukoencephalopathy during chemotherapy treatment without cranial radiation for childhood ALL predicts higher risk for long-term neurobehavioral problems. Survivors of ALL may benefit from preventative cognitive and/or behavioral interventions, particularly those who develop acute leukoencephalopathy.
Long-term survivors of HL may also be at risk for cognitive impairment. HL survivors followed for an average of 10 to 15 years from diagnosis show impaired cognitive functioning, with reduced attention, memory, processing speed, and executive function. The cognitive impairment is associated with radiologic indices suggestive of reduced brain integrity and occurs in the presence of symptoms of cardiopulmonary dysfunction.
NHL is a heterogeneous group of diseases with diverse treatments including radiation, immunotherapy, and chemotherapy. Adult survivors of childhood NHL experience impaired neurocognitive function, which is associated with lower social attainment and poor health-related quality of life (HRQOL). Small studies of adult-onset B-cell NHL survivors find a higher prevalence of self-endorsed cognitive problems when compared with the general population. The domains affected include attention and executive function. The 18- to 59-year-olds endorse more problems than the 60- to 85-year-olds. Treatment of primary CNS lymphoma with cranial radiation and high-dose methotrexate has resulted in median overall survivals that exceed 5 years. Longitudinal studies in this population indicate that although there is some recovery over time, cognitive impairment does persist in the domains of attention, executive function, verbal fluency, memory, and psychomotor function 5 years or more after treatment.
BMT survivors are at risk for cognitive impairment. Among adults undergoing BMT, myeloablative allogeneic BMT recipients showed significant cognitive decline compared with healthy controls. Reduced-intensity allogeneic BMT recipients showed evidence of delayed decline. Cognitive functioning in autologous BMT recipients is generally spared. Older age, male sex, and lower education, income, and cognitive reserve are associated with post-BMT cognitive impairment. At 3 years post-BMT, global cognitive impairment is present in 19% of autologous and 36% of allogeneic BMT recipients. BMT recipients endorse more cognitive problems at all timepoints when compared with healthy controls. Fatigue is associated with greater endorsement of cognitive problems at 1 year after BMT. Overall, there is a modest correlation between self-endorsed cognitive problems and objective cognitive impairment. Higher self-endorsed cognitive problems are associated with higher odds of not returning to work at 3 years after BMT. These findings suggest that self-endorsed cognitive problems can identify vulnerable patient subpopulations in need of detailed cognitive assessment and possible cognitive remediation.
There is emerging interest in attempting to understand whether interpatient variability in cognitive outcomes can be explained by polymorphisms in candidate genes conferring susceptibility to cognitive decline. Among childhood cancer survivors, inferior cognitive or behavioral outcomes have been associated with polymorphisms in genes related to oxidative stress ( NOS3 , SLCO2A1 ) and/or neuroinflammation ( COMT ). Among BMT recipients, after adjusting for BMT type, age at BMT, sex, race/ethnicity, and cognitive reserve, SNPs in the blood-brain barrier, telomere homeostasis, and DNA repair genes are significantly associated with cognitive impairment. Inclusion of candidate genetic variants enhances the prediction of risk of post-BMT cognitive impairment beyond that offered by demographic/clinical characteristics and represents a step toward a personalized approach to managing patients at high risk for cognitive impairment after BMT.
Monitoring recommendations for cognitive dysfunction are reviewed in Table 101.1 .
Psychosocial Effects
Treatment for hematologic malignancies may result in adverse psychosocial effects, including mental health disorders, such as anxiety, depression, and posttraumatic stress; psychosocial disability due to pain, sleep problems, and fatigue; relationship problems; fear of recurrence; and limitations in healthcare access (see Table 101.1 ). Survivors of HL reported more impairments in physical (particularly fatigue), professional, and cognitive domains, as well as more financial limitations, when compared with age-matched healthy controls. In NHL survivors, treatment-related neurocognitive impairment (related to cranial radiation, intrathecal chemotherapy, and high-dose methotrexate and cytarabine), was found to be associated with lower educational attainment, occupational status, and unemployment. In those with diffuse large B-cell lymphoma, younger survivors (18 to 59 years of age) were found to have more financial and social functioning problems compared with the normative population; however, in older survivors the proportion experiencing these problems was comparable to that reported by the normative population. Survivors of primary CNS lymphoma treated with high-dose methotrexate and whole-brain radiation were more likely to report poorer self-perceived quality of life outcomes compared with survivors treated without radiation.
Monitoring for psychosocial adverse effects of cancer treatment in survivors of hematologic malignancies should include a yearly clinical interview, with referral for psychologic or social work consultation if problems are identified.
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