Providing Primary Care for Long-Term Survivors of Childhood Acute Lymphoblastic Leukemia

Hepatitis C

Because most ALL patients receive blood products during therapy, those treated before adequate blood donor screening for hepatitis C was initiated in the early 1990s are at risk for chronic liver disease.¹⁰² The prevalence of circulating hepatitis C virus (HCV) ribonucleic acid (RNA) in ALL patients treated in Italy before 1990 ranges from 23% to 49%.^103-105 The natural history of ALL survivors with hepatitis C is not well understood. In an Italian study, only 4% of the 56 HCV-RNA seropositive patients had persistently elevated alanine aminotransferase (ALT) over the course of follow-up (mean=17 years).¹⁰⁶ For a median of 14 years, 81 survivors of various childhood cancers who were HCV-RNA seropositive were followed, and none showed progression to liver failure.¹⁰⁷ In contrast, Paul and coworkers¹⁰⁸ reported that 12% of 75 leukemia survivors were anti-HCV positive, 6 of 9 had liver biopsies that showed at least moderate portal inflammation, and half had bridging fibrosis. The Centers for Disease Control and Prevention¹⁰² recommend universal screening with anti-HCV for all patients who received blood products before July 1992.

Second malignant neoplasms

Second malignant neoplasms (SMN) are rare in ALL survivors. Thirteen SMNs were diagnosed a median of 6.7 years from ALL diagnosis in a cohort study of 1597 ALL survivors and were associated with the use of radiation (8/13, CNS or head and neck) or chemotherapy (3/13, hematopoietic).¹⁰⁹ The cumulative incidence of brain tumors at 20 years in a cohort of 1612 patients was only 1.39%, and more than half of these tumors were either low-grade or benign.¹¹⁰ CNS tumors did not occur in patients treated with chemotherapy alone. Thyroid tumors (predominantly papillary carcinoma) can rarely occur after treatment with cranial or craniospinal irradiation.^111,112 Cases of basal cell carcinoma along the spinal axis have also been reported in patients treated with craniospinal irradiation.^113,114

Therapy-related acute myelogenous leukemia (t-AML) has been seen following treatment of several childhood cancers, such as ALL and Hodgkin’s and non– Hodgkin’s lymphoma. Cohort studies have shown that agents with leukemogenic potential include alklyating agents and epidophyllotoxin chemotherapy.^115-121 Most t-AMLs occur within 8 years of treatment, although cases occurring up to 13 years have been reported.¹¹⁵ Myelodysplasia (especially pancytopenia) generally precedes t-AML. The risk of t-AML following treatment for ALL has been small in 2 cohort studies.^109,122 However, because precancerous states (myelodysplastic changes or myelodysplastic syndrome) are usually antecedent to t-AML and early diagnosis may improve outcomes, most institutions recommend obtaining a complete blood count (CBC) with a platelet count and a white blood cell differential in the routine follow-up of ALL survivors who have been treated with an alkylating agent, such as cyclophosphamide, or an epidophyllotoxin, such as etoposide. How long and how frequently a CBC should be obtained in follow-up of an ALL survivor have not been established.

Fertility and reproduction

Most antimetabolite-based treatment protocols for ALL do not affect long-term fertility for men or women.^123,124 Craniospinal and abdominal irradiation have been associated with infertility in both sexes but are no longer used for ALL.^125-127 Cyclophosphamide (an alkylating agent commonly used in earlier protocols but currently limited to high-risk patients) is also associated with infertility in a dosedependent fashion in both sexes.^124,128,129 Resolution of germ-cell dysfunction may occur in men over time, but fertility remains poor for some. Women survivors treated with craniospinal or abdominal irradiation or with cyclophosphamide are at risk for ovarian failure and premature menopause and thus may be at increased risk for osteoporosis. If ovarian failure is suspected, measurement of follicle-stimulating hormone, luteinizing hormone, and serum estradiol and an evaluation by an endocrinologist should be considered.

ALL survivors should know that preliminary studies suggest that treatment is not associated with an increase in congenital malformations of their offspring. In a population-based prospective cohort study an increased rate of congenital defects was not found among 299 adult survivors.¹³⁰

Ocular abnormalities

Ocular abnormalities in patients treated with CRT are common but generally asymptomatic. Two studies have evaluated the effect of CRT and systemic corticosteroids on the eyes. In a study of 82 ALL survivors who were a mean of 32 months after completion of therapy, 52% of the patients had posterior subcapsular cataracts (PSC) that were generally not visually significant and were not related to age at treatment or gender.¹³¹ Eighty-three percent of the 18 patients who had received CRT and systemic corticosteroids were noted to have asymptomatic ocular abnormalities after a median surveillance of 4.1 years.¹³² Optical densities of the lens were seen in 13 of the 18 of the survivors. There have been no published studies evaluating long-term survivors who received systemic corticosteroids without CRT. Periodic vision and cataract screening is recommended for ALL survivors treated with CRT and should be considered for all survivors of ALL until the risk of prolonged corticosteroid use in childhood is better understood.