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Late Effects of Treatment in Survivors of Childhood Acute Myeloid Leukemia

From the After Completion of Therapy Program and Departments of Hematology-Oncology, Behavioral Medicine, Biostatistics, Radiation Oncology, and Pharmaceutical Science, St. Jude Children’s Research Hospital; and the College of Medicine, University of Tennessee, Memphis, TN.

Address reprint requests to Wing Leung, MD, PhD, St. Jude Children’s Research Hospital, 332 N Lauderdale St, Memphis, TN 38105; email wing.leung{at}stjude.org

	ABSTRACT

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PURPOSE: To investigate the incidence of and risk factors for late sequelae of treatment in patients who survived for more than 10 years after the diagnosis of childhood acute myeloid leukemia (AML).

PATIENTS AND METHODS: Of 77 survivors (median follow-up duration, 16.7 years), 44 (group A) had received chemotherapy, 18 (group B) had received chemotherapy and cranial irradiation, and 15 (group C) had received chemotherapy, total-body irradiation, and allogeneic bone marrow transplantation. Late complications, tobacco use, and health insurance status were assessed.

RESULTS: Growth abnormalities were found in 51% of survivors, neurocognitive abnormalities in 30%, transfusion-acquired hepatitis in 28%, endocrine abnormalities in 16%, cataracts in 12%, and cardiac abnormalities in 8%. Younger age at the time of diagnosis or initiation of radiation therapy, higher dose of radiation, and treatment in groups B and C were risk factors for the development of academic difficulties and greater decrease in height Z score. In addition, treatment in group C was a risk factor for a greater decrease in weight Z score and the development of growth-hormone deficiency, hypothyroidism, hypogonadism, infertility, and cataracts. The estimated cumulative risk of a second malignancy at 20 years after diagnosis was 1.8% (95% confidence interval, 0.3% to 11.8%). Twenty-two patients (29%) were smokers, and 11 (14%) had no medical insurance at the time of last follow-up.

CONCLUSION: Late sequelae are common in long-term survivors of childhood AML. Our findings should be useful in defining areas for surveillance of and intervention for late sequelae and in assessing the risk of individual late effects on the basis of age and history of treatment.

	INTRODUCTION

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IN COMPARISON WITH childhood acute lymphoblastic leukemia (ALL), childhood acute myeloid leukemia (AML) is rarer and carries a poorer prognosis.¹ Although much is known about the incidences of and the risk factors for the late effects of treatment of childhood ALL, this aspect of treatment of childhood AML is largely unknown because there are few long-term survivors. When compared with the treatment of ALL, the treatment of AML is characterized by higher doses of anthracycline chemotherapy, shorter duration of treatment, less frequent use of CNS-directed radiation therapy (CRT), and more frequent use of allogeneic bone marrow transplantation (BMT).¹ Therefore, the spectrum and incidence of late sequelae may be different among survivors of childhood ALL and AML. Previous studies describing outcome and sequelae in small cohorts of patients after relatively brief follow-up periods do not allow accurate assessment of the incidence and risk of each of the many potential late effects.^2-4 As survivors increase in number, it is becoming possible, and increasingly important, to evaluate their late morbidity and social well-being. This information will have important bearing on the design of future therapeutic strategies and on defining the areas for surveillance and intervention of late complications. Furthermore, this information may permit assessment of the risk of individual late sequelae on the basis of history of treatment. With that goal, we evaluated the late treatment sequelae in 77 patients surviving 10 or more years after the diagnosis of childhood AML.

	PATIENTS AND METHODS

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Patient Characteristics
A review of the database of all patients treated for AML (n = 324) at the St. Jude Children’s Research Hospital (SJCRH) from January 1976 to July 1989 identified 77 patients who survived for at least 10 years since diagnosis. The institutional protocols used during this period have previously been described in detail: AML-76 (n = 21),⁵ AML-80 (n = 25),⁶ ANLL-83 (n = 17),⁷ and AML-87 (n = 14).⁸ All of these patients had de novo AML except for two in whom AML developed after treatment of ALL. Forty-four patients received intensive chemotherapy alone (group A), 18 received chemotherapy and CRT (group B), and 15 received chemotherapy, total-body irradiation (TBI), and allogeneic BMT (group C). The patients’ characteristics are listed in Table 1. One of the patients in group A received busulfan and cyclophosphamide but no irradiation before autologous BMT. CRT was administered as cranial irradiation (n = 16) or as craniospinal irradiation (n = 2) in group B. The dose of cranial irradiation was 18 Gy (n = 2), 20 Gy (n = 3), or 24 Gy (n = 12). One patient who had CNS disease at the time of diagnosis and at the time of relapse received a total radiation dose of 30 Gy to the cranium and 18 Gy to the spine. The dose of TBI given to patients in group C ranged from 12 Gy to 15 Gy. One patient in group C received 24 Gy of cranial irradiation for CNS disease at the time of diagnosis before receiving 12 Gy of TBI at the time of BMT. At the time of the initial radiation treatment, the median age of patients in groups B and C was 6 years (range, 0.7 to 17.5 years).

Patients who are at least 18 years old and who remain in remission for at least 10 years after diagnosis are discharged from the institution and observed thereafter by their community physicians. The status of these patients is monitored through the results of a two-page questionnaire mailed annually by the hospital’s tumor registry to the survivors that elicits information regarding current medical status, history of hospitalization, medications, schooling, employment status, fertility, pregnancy outcomes, tobacco use, and medical insurance status. Reports of serious sequelae are confirmed by contacting the local physicians and the survivors or their family members and by reviewing medical records and pathology reports from local hospitals. At the time of this report, 56 patients (73%) had been followed up within the last year, 69 patients (90%) within the last 2 years, and all within the last 3.5 years. The median length of follow-up since the diagnosis of AML was 16.7 years (range, 10.1 to 23.5 years).

Late Complications
Late complications were determined by review of the computer database and medical records and were categorized as follows: (1) cardiovascular, abnormalities detected by clinical cardiovascular examination, diagnostic imaging (echocardiograms or chest radiograph), or ECG; (2) endocrine, clinical evidence of endocrine dysfunction (eg, delayed pubertal development, abnormal menstrual patterns), abnormal results of thyroid function tests, or abnormalities of serum concentrations of insulin-like growth factor-I, insulin-like growth factor binding protein-3, growth hormone by provocative testing, gonadotropins, androgen, or estrogen, or the use of hormonal replacement therapy; (3) growth, height Z score ([survivor’s height - mean height of persons of the same sex and age]/SD of height for persons of the same sex and age)¹¹ that decreased by more than one SD at the last follow-up visit since diagnosis, weight Z score ([survivor’s weight - mean weight of persons of the same sex and age]/SD of weight for persons of the same sex and age) that decreased or increased by more than one SD at the last follow-up visit since diagnosis; (4) chronic graft-versus-host-disease (GVHD), diagnosed and classified according to the Seattle criteria¹²; (5) hepatitis, positive serology of hepatitis B or C; (6) musculoskeletal, clinical or radiographic abnormalities of teeth,¹³ bones, or soft tissue (eg, scoliosis, atrophy); (7) neurocognitive, clinical neurologic disorders (eg, seizure, hearing loss, speech delay), abnormal audiometric testing, abnormal neuropsychologic evaluation of global intellect and academic achievement (Wechsler Intelligence Scale and Wide Range Achievement Test)^14,15; (8) ophthalmologic, abnormalities detected by clinical ophthalmologic examination; (9) pulmonary, clinical symptoms suggesting pulmonary dysfunction (eg, exertional dyspnea), abnormalities of spirometry, lung volumes, or diffusing capacity by pulmonary function testing; and (10) renal, abnormal blood pressure, serum electrolyte levels, or creatinine values.

Statistical Analysis
The Wilcoxon rank sum test was used to compare the height or weight changes among treatment groups.¹⁶ The Fisher’s exact test was used to assess the differences in the distribution of late effects among treatment groups.¹⁷ Treatment effects were assessed by comparing group A with group B or group C. To evaluate the effects of other independent variables on the outcome, regression or logistic exact regression analysis was performed.¹⁸ No adjustment was made for multiple comparisons. Because of the small sample size in each subgroup of patients, multivariate analysis was not attempted.

	RESULTS

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Growth
The height Z score decreased more than one SD in 24 patients (31%; Table 2, Fig 1). Four of these 24 patients (all from group C) received growth-hormone replacement therapy for growth-hormone deficiency that had been confirmed by blood testing. One of these four patients also received therapy with gonadotropin-releasing hormone analog to maximize her growth potential, although she did not show signs of precocious puberty. Three of the four patients with growth-hormone deficiencies were also receiving thyroid hormone treatment for hypothyroidism, and two (one man and one woman) were receiving long-term sex hormone supplementation for hypogonadism.

View larger version (14K): [in this window] [in a new window]   Fig 1. Changes in height and weight Z scores at the time of last follow-up visit. Each letter (A, B, or C) represents one patient and the treatment group of the patient. For patients receiving growth-hormone replacement therapy, the height Z score immediately before growth-hormone treatment was used instead of the score at the time of last follow-up visit.

Risk Factors for Growth Problems
Among the three groups of patients, those in group B had a greater decline in height Z score (P = .0001), and patients in group C had the greatest decline in height Z score (P = .0008; Table 3). Although the weight Z scores in most patients in groups A and B increased during the same period of observation (Fig 1), those of the patients in group C dropped significantly (P = .0005; Table 3). Younger age at the time of diagnosis, younger age at the initiation of radiation therapy, higher dose of radiation, and higher height Z score at the time of diagnosis were all predictive factors for a greater decrease in height Z score (Table 4, Fig 2).

View larger version (16K): [in this window] [in a new window]   Fig 2. Magnitude of decline in height Z score can be predicted on the basis of height at the time of diagnosis. Changes in height Z scores at the time of last follow-up visit since diagnosis were plotted against height Z scores at the time of diagnosis. Regression line (——) is also shown (P = .002). For patients receiving growth-hormone replacement therapy, the height Z score immediately before growth-hormone treatment was used instead of the score at the time of last follow-up visit.

Our review of the annual questionnaires showed that 49 patients were either single or married and had not attempted to have a child. Twenty-eight patients married for more than one year had attempted to have a child. Of these 28, 19 had at least one full-term baby, and two each had one premature infant (32 and 34 weeks’ gestation). All 28 babies born to these 21 survivors are currently healthy with no birth defects or cancer. Of the seven patients (four men and three women) who failed to have a child, six had received TBI (group C) and one had received testicular irradiation to treat bilateral testicular relapse (group B). When compared with patients in group A, patients in group C had a higher incidence of hypogonadism and infertility (P < .0001; Table 3).

Neurocognitive Function
Our review of annual questionnaires and psychology reports showed that 66 patients did not have any academic problems in school. Eleven patients (14%) had academic difficulties identified by a positive response to the questions regarding the need for extra tutoring or need for special education classes. Psychologic evaluations in nine of these 11 patients did not reveal any specific pattern of learning disability but rather a general pattern of mild cognitive deficits with a tendency toward adjustment difficulties, on the basis of both parent report and self-report measures, suggesting problems with immaturity, shyness, and low self-esteem. Formal psychometric testing on seven of these nine patients showed that the measures of intelligence and academic achievement were approximately one SD below normal: the median for full-scale intelligence quotient was 84 (range, 68 to 111), for reading was 88 (range, 63 to 113), for spelling was 83 (range, 69 to 104), and for mathematics was 84 (range, 66 to 114).

Patients in groups B and C had a higher incidence of academic difficulties than did those in group A (Table 3). Younger age at the time of diagnosis, younger age at the initiation of radiation therapy, and higher dose of irradiation were all risk factors for academic problems (Table 4).

Four patients in group A and two patients in group B had seizure disorders that required them to undergo long-term anticonvulsant therapy. Two patients in group A and one patient each in group B and C were taking antidepressants for an affective mood disorder. Hearing deficits requiring amplification devices were identified in three patients in group A, two patients in group B, and one patient in group C.

Hepatitis B and C
This cohort of 77 patients had been diagnosed with AML before 1989; 74 of them were transfused a median of 24 (range, 2 to 101) times and exposed to a median of 55 (range, 3 to 481) donors. All blood products administered had been screened for hepatitis B virus (HBV). First- and second-generation screening for hepatitis C virus (HCV) was not available until 1990 and 1992, respectively. Among the 74 patients who had transfusions, 44 had been tested for HBV and 53 for HCV. Among the patients tested, two (5%) were seropositive for HBV and 15 (28%) were seropositive for HCV. The two patients with HBV infection were coinfected with HCV. Polymerase chain reaction testing of HCV in 13 of the 15 HCV-positive patients revealed chronic infection in 10 (77%) and absence of viral RNA in three (23%), consistent with spontaneous resolution of infection. Of the 10 patients with chronic HCV infection, six underwent biopsy at a median of 4.3 years (range, 0.3 to 23 years) after the diagnosis of AML. Histologic examination showed that three had stage I fibrosis, two had stage III fibrosis, and one had early cirrhosis. Two of these patients had been treated with interferon-alfa, and both treatments had failed.

Second Tumors and Late Relapse
Seven of the 77 patients had undergone surgery for benign solid tumors after treatment for AML, including four from group A with fibroadenoma of the breast (n = 2), uterine fibroid (n = 1) or ovarian cyst (n = 1); one from group B with CNS angioma; and two from group C with multiple osteochondroma. Two other patients from group C developed multiple asymptomatic osteochondroma and have not required surgical intervention thus far.

One patient in group C had undergone surgery for a mucoepidermoid carcinoma of the parotid gland 14 years after diagnosis. The estimated cumulative risk of a second malignancy in these 77 long-term survivors is 1.8% (95% confidence interval, 0.3% to 11.8%) at 20 years after the diagnosis of AML. One patient in group A had surgery and radiation for a granulocytic sarcoma in the ear canal 16 years after the diagnosis of M3 AML. He subsequently developed a hematologic relapse of promyelocytic leukemia and died of intractable congestive heart failure after induction therapy that had included all-trans-retinoic acid and anthracyclines.

Cardiac Dysfunction
The median cumulative dose of anthracycline administered to this cohort was 335 mg/m² (range, 100 to 515 mg/m²). Patients in groups A and B received higher cumulative doses of anthracycline (median, 383 and 385 mg/m², respectively) than did those in group C (median, 204 mg/m²) (P = .004). Many of these patients also received other potentially cardiotoxic agents, such as amsacrine (200 to 1,400 mg/m²), cyclophosphamide (2.3 to 6.4 g/m²), or TBI. Serial ECG and echocardiography after completion of therapy were all normal in 71 of the 77 survivors. Four patients (9%) in group A and one (7%) in group C developed cardiomyopathy, with shortening fractions less than 25%. All five patients are currently asymptomatic, with shortening fractions ranging from 22% to 25%. One patient in group A died of intractable congestive heart failure after induction therapy for a late relapse (described above).

Other Late Effects
Ophthalmologic examination detected cataracts in nine of the 77 patients; all nine patients were in treatment group C (Table 3). Radiation-induced dental abnormalities, including microdontia, excessive (> four) caries, enamel hypoplasia, and root stunting were detected by dental examination and panoramic radiographs in one (6%) of the 18 patients in group B and in six (40%) of the 15 patients in group C. Chronic GVHD that was limited to the skin was found in three patients (20%) in group C. Mild asymptomatic restrictive lung disease (total lung capacity, 75% to 78% of predicted) was found in three (20%) patients in group C. Except for one patient in group C who required long-term antihypertensive therapy because of radiation nephritis, all patients had normal blood pressure, serum electrolytes concentrations, and creatinine values.

Tobacco Use and Medical Insurance
Information about tobacco use and medical insurance status was obtained from the questionnaires. At the time of last follow-up, 22 (29%) of the 77 patients stated that they were currently smoking and had smoked more than 100 cigarettes in their lifetime. None of the patients used smokeless tobacco. Regarding medical insurance, 11 (14%) patients were uninsured at the time of their last follow-up.

	DISCUSSION

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This study systematically evaluated the late sequelae of the largest reported cohort of long-term survivors of childhood AML. The results of follow-up visits over a median period of more than 15 years after the time of diagnosis indicate that late sequelae of treatment are common and the spectrum of late effects is wide. Besides organ-specific treatment sequelae, as many as one in seven of our long-term survivors did not have medical insurance, and two in seven practiced unhealthy behavior, as manifested by active use of tobacco.

Growth abnormalities, as indicated by changes in height and weight Z scores, were one of the most common late effects in this cohort. Careful examination of changes in Z scores revealed interesting patterns: patients in groups A and B had, on average, a decrease in height Z score (greater in group B) but a gain in weight Z scores, whereas patients in group C had decreases in both kinds of Z scores (Table 3, Fig 1). These findings suggest that although CRT often results in short stature and obesity,¹⁹ TBI and BMT usually result in poor overall growth. The adverse growth outcomes after TBI and BMT were multifactorial, including endocrinopathies, chronic GVHD, and direct radiation effect on the musculoskeletal systems.

In agreement with the findings of other studies,^3,4 abnormal shortening fractions were found in 5% to 10% of the long-term survivors. Cardiac dysfunction was not more frequent in patients who received TBI and BMT than in other patients, possibly because the detrimental effect of TBI and BMT was compensated for by the lower cumulative dose of anthracyclines and other cardiotoxic chemotherapy that these children had received before BMT.³

Clinical studies have confirmed the survival advantage of using allogeneic BMT as consolidation therapy for children with AML.^6,20,21 However, our study, and many others, clearly demonstrate significant late sequelae after TBI and BMT.^3,22 In our study, many late complications were much more common, and some (eg, cataract or osteochondroma)^23,24 were observed only in group C patients. These late complications may not only decrease the quality of life but may also be life-threatening (eg, malignant degeneration of osteochondroma, other second cancers, or chronic GVHD).^25-27 Although many investigators currently attempt to reduce late effects by using busulfan-containing preparative regimens without TBI for matched sibling transplantation,³ TBI is still commonly used to overcome the histocompatibility barrier in alternate donor transplantation for the other 65% of patients who do not have a matched sibling donor.^28,29 Thus late complications related to TBI and BMT will still be commonly encountered in many long-term survivors in the near future.

Besides physical late effects, social well-being and health habits are other areas that deserve much attention in follow-up care. A diagnosis of childhood leukemia may limit access to medical insurance because of preexisting-condition clauses in policies, prohibitive premiums, or employment discrimination. Despite education about legislation protecting against insurance discrimination,³⁰ we found that as many as one in seven of our long-term survivors did not have medical insurance. This proportion is not lower than that reported in the 1991 childhood cancer survivor study and in the 1992 National Health Interview Survey.^31,32 Similarly, one might assume that our patients would avoid exposure to carcinogens after AML treatment. Nonetheless, two in seven of them were cigarette smokers, despite repeated counseling in our institution against its use.³³ This prevalence is not lower than that among people of similar age in the general population.³⁴ Although the reasons for the lack of insurance and for unhealthy behavior were not explored in detail in this study, these findings underscore the importance of further study and intervention, because the adverse consequences of being uninsured and engaging in unhealthy habits may be magnified among long-term survivors who are already vulnerable to health risks after cancer treatment.

Our study is not without limitations. First, although the annual questionnaire and many laboratory tests were routinely obtained for all patients, the other tests were performed only on the basis of clinical indications. Therefore, some cases of asymptomatic organ dysfunction may have been missed in our study. Second, late complications were not evaluated for the patients who died within 10 years after the diagnosis of AML. Third, although this is the largest population of long-term survivors of AML reported thus far, the number is still too small to allow multivariate analysis for the adjustment of risk factors. Analysis of some risk factors in this study may have been confounded by the presence of additional risk factors. Fourth, although 83% of our patients are currently 18 years or older and have completed growth and sexual development, the length of follow-up may be too short for the detection of some late sequelae, such as second cancer. Late effects in patients who were not treated with radiation may remain latent for an even longer period of time. Longer follow-up of this cohort and others will be necessary.

In summary, a wide spectrum of late sequelae, along with their incidences and risk factors, has been described in this study (Tables 2 through 4). All of these findings should provide valuable information for individual risk assessment and for determining guidelines of surveillance and intervention. Early identification and treatment of progressive abnormalities may improve the quality of life for many long-term survivors.

	ACKNOWLEDGMENTS

 
Supported in part by grant nos. CA-20180 and CA-21765 from the National Institutes of Health, Bethesda, MD; by a Center of Excellence Grant from the state of Tennessee; and by the American Lebanese Syrian Associated Charities, Memphis, TN.

We thank Xin Tong and Yingfu Li for statistical analysis; the staff of the Department of Behavioral Medicine at the St. Jude Children’s Hospital for psychologic evaluations; Dr Julia Cay Jones for scientific editing; Lisa Edwards, Sherri Patterson, and Margie Zacher for data management; the physicians and staff members who provided medical care; and the patients and families who completed the questionnaires and participated in this study.

	REFERENCES

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Submitted February 9, 2000; accepted May 3, 2000.

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