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Late Effects of Hematopoietic Stem Cell Transplantation
Pediatric hematopoietic stem cell transplantation (HSCT) is considered standard-of-care treatment for a number of malignant and nonmalignant conditions. Treatment generally involves exposure to chemotherapy and occasionally radiation to encourage engraftment of donor stem cells and prevent donor and recipient rejection. The period of time immediately after transplant is associated with the risk for a number of serious acute complications, including profound immunosuppression and subsequent risk for infection, graft-versus-host disease (GVHD), and organ toxicities. Fortunately, significant progress has been made in supportive care strategies to reduce the risk of acute complications and treat them more effectively if they do arise. This has resulted in a growing number of pediatric patients who are now long-term survivors following HSCT. The estimated total number of HSCT survivors in 2009 was 108,900, and this is expected to increase 5 times by 2030 to 502,000. Of these survivors, approximately 14% (64,000) in 2030 will have received a transplant in childhood (<18 yr of age).
Exposure to chemotherapy, radiation, or both places patients at similar long-term risks as the pediatric cancer population; the high doses and types of chemotherapy and radiation often amplify the risk for issues such as ovarian failure/infertility and neurocognitive difficulties. Total body irradiation (TBI) has been shown to increase dramatically the risk for late complications after transplant. In addition, late effects may be additive if the patient received therapy before HSCT for their underlying malignancy. Moreover, the indication for transplant in pediatric patients is not always related to malignancy, but rather an underlying immunodeficiency, bone marrow failure syndrome, or metabolic disorder. These patients are potentially at risk for late effects related to this underlying disease alone and require different types of monitoring.
Essentially, every organ system can be impacted by the long-term effects of therapy, and each must be considered when undergoing late effects surveillance ( Table 165.1 ). As a result of growing evidence of the importance of lifelong care for HSCT survivors, multiple groups have published recent consensus guidelines to help in caring for this patient population. As the field of survivorship continues to expand, we recommend the following reference for real-time evidence-based recommendations from the Children's Oncology Group : http://survivorshipguidelines.org .
Table 165.1
Summary of Late Effects After Hematopoietic Stem Cell Transplantation (HSCT) in Childhood
From Chow EJ, Anderson L, Baker KS, et al: Late effects surveillance recommendations among survivors of childhood hematopoietic cell transplantation: a Children's Oncology Group report, Biol Blood Marrow Transplant 22:783–784, 2016.
| EXPOSURE | LATE EFFECT * |
|---|---|
| HSCT experience in general | Dental abnormalities Renal toxicity Hepatic toxicity Low BMD Avascular necrosis Increased risk of second cancers Adverse psychosocial/quality-of-life effects Mental health disorders, risk behaviors Psychosocial disability caused by pain or fatigue |
| TRANSPLANTATION CONDITIONING | |
| Alkylating agent | Cataract (busulfan) Pulmonary fibrosis (busulfan) Renal toxicity Urinary tract toxicity Gonadal dysfunction Therapy-related AML/MDS Bladder cancer |
| Epipodophyllotoxin ** DNA intersecting and cross-linking agents (i.e., platinum, heavy metal) |
Therapy-related AML/MDS Ototoxicity Renal toxicity Gonadal toxicity |
| TBI † | Neurocognitive deficits Leukoencephalopathy Cataract Dental abnormalities GH deficiency Hypothyroidism, thyroid nodule Pulmonary toxicity Breast tissue hypoplasia Cardiac toxicity Renal toxicity Gonadal dysfunction Uterine vascular insufficiency Diabetes Dyslipidemia Musculoskeletal growth problems Second cancers |
| PRETRANSPLANTATION EXPOSURES (Not Listed Above) | |
| Anthracycline/anthraquinone | Cardiac toxicity Therapy-related AML/MDS |
| Bleomycin | Pulmonary toxicity |
| Cytarabine | Neurocognitive deficits Leukoencephalopathy |
| Methotrexate | Neurocognitive deficits Leukoencephalopathy Renal toxicity Low BMD |
| Corticosteroid | Cataract Low BMD Avascular necrosis |
| Cranial radiation ‡ | Neurocognitive deficits Leukoencephalopathy Cerebrovascular disease Cataract Craniofacial abnormalities Dental abnormalities, xerostomia GH deficiency Hypothyroidism thyroid nodule Increased obesity Precocious puberty Brain tumor |
| Spinal radiation (in addition to cranial dose) | Cardiac toxicity Scoliosis/kyphosis, musculoskeletal problems |
| AFTER TRANSPLANTATION (Not Listed Above) | |
| Chronic GVHD | Xerophthalmia Xerostomia, dental abnormalities Pulmonary toxicity Gastrointestinal strictures Genitourinary strictures Skin and joint changes Immunodeficiency Second cancers, especially skin, oral, cervical, lymphoma |
| Tyrosine kinase inhibitor | Acute cardiac toxicity reported, but not known to cause late cardiotoxicity |
| OTHER EXPOSURES | |
| Blood transfusions | Hepatitis C, HIV |
AML/MDS, Acute myeloid leukemia/myelodysplastic syndrome; BMD, bone mineral density; GH, growth hormone; GVHD, graft-vs-host disease; HIV, human immunodeficiency virus.
* Focused on those late effects that can develop or persist even after cessation of therapy.
† At given total dose, risks greater for single-fraction vs fractionated total body irradiation (TBI); single-fraction myeloablative TBI (>500 cGy) now rarely used.
‡ Effects listed are those more likely to be associated with doses used in HSCT survivors (e.g., those given for leukemia treatment, <25 Gy); late effects are more likely if TBI also given.
Endocrine Effects
Children given HSCT before puberty may develop growth impairment , precluding achievement of the genetic target for adult height. The decrease in growth velocity is similar for boys and girls and is more frequently observed in patients given TBI as part of the preparative regimen. Chronic GVHD and its treatment with corticosteroids may also contribute to growth impairment.
Growth impairment of patients given TBI is mainly a result of direct damage of cartilage plates and to the effect of TBI on the hypothalamic-pituitary axis, which leads to an inappropriately low production of growth hormone (GH). GH deficiency is susceptible to at least partial correction through administration of hormonal replacement therapy. Annual growth evaluation should be performed in all children after HSCT. Children showing a decreased growth velocity should be further investigated through evaluation of bone age and secretion of GH in response to pharmacologic stimulus.
The use of TBI during the preparative regimen involves the thyroid gland in the irradiation field and may result in hypothyroidism . Younger children are at greater risk of developing hypothyroidism. Chemotherapy-only preparative regimens have far fewer adverse effects on normal thyroid function. The site of injury by irradiation is at the level of the thyroid gland rather than at the pituitary or hypothalamus. Therapy with thyroxine is very effective for overt hypothyroidism. The cumulative incidence of hypothyroidism increases over time, underscoring the importance of annual thyroid function studies.
Gonadal hormones are essential for normal pubertal growth, as well as for development of secondary sexual characteristics. A significant proportion of patients receiving TBI-containing preparative regimens as well as high doses of alkylating agents show delayed development of secondary sexual characteristics, resulting from primary ovarian or testicular failure. Laboratory evaluation of these patients reveals elevated follicle-stimulating hormone and luteinizing hormone levels with depressed estradiol and testosterone serum levels. These patients benefit from careful follow-up with evaluation of annual sexual maturity rating (Tanner) scores and endocrine function. Supplementation of gonadal hormones is useful for primary gonadal failure and is administered with GH to promote pubertal growth. Infertility during adulthood remains a common problem of these children, especially those undergoing traditional myeloablative conditioning for HSCT. The use of reduced-intensity regimens may result in sparing fertility in a large proportion of patients, although conditioning regimens vary and studies are limited.
Bone health of HSCT survivors can also be impacted by hormonal changes as well as lifestyle practices, such as inadequate exercise and/or dietary intake of vitamin D. Prior exposures, including corticosteroid use, can result in changes to bone density as well as predispose to the development of avascular necrosis. Dual-energy x-ray absorptiometry (DXA) scans are routinely incorporated into the care of those patients at risk for low bone mineral density.
Cardiovascular Effects
Survivors of childhood HSCT are at risk for the future development of cardiovascular complications. This population can be prone to developing metabolic syndrome (dyslipidemia, hypertension, diabetes mellitus, obesity), especially those with a history of TBI exposure and subsequent hormonal derangements. Prior exposures such as anthracycline chemotherapy and chest radiation further increase the risk for cardiomyopathy as well as atherosclerosis . As a result, routine anthropometric, imaging, and laboratory screening should be performed in survivors of childhood HSCT to assess and monitor their cardiovascular health.
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