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Persistent Significant Neurocognitive Impairment in Adult Survivors of Childhood Acute Lymphoblastic Leukemia

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Key Points

  • Rates of mild to severe neurocognitive impairment ranged from 28.6% to 58.9%.
  • Patients treated with chemotherapy only demonstrated increased impairment in all domains.
  • Rates of severe impairment increased as a function of cranial radiotherapy dose.

In a study reported in the Journal of Clinical Oncology, Kevin R. Krill, PhD, and colleagues from St. Jude Children’s Research Hospital assessed neurocognitive function in adult survivors of childhood acute lymphoblastic leukemia (ALL). They found pervasive significant impairment across neurocognitive domains, with the frequency of severe impairment increasing in association with rising doses of cranial radiation therapy.

Study Details

In the study, survivors of childhood ALL treated at St. Jude Children’s Research Hospital who were still alive at ≥ 10 years after diagnosis and were aged ≥ 18 years were recruited for neurocognitive testing. Of 1,014 eligible survivors, 738 (72.8%) agreed to participate, and 567 (76.8%) of these have been evaluated thus far. There were no differences between the tested group and as yet untested group with regard to age, race, cranial radiotherapy dose, age at diagnosis, or decade of diagnosis.

Neurocognitive testing assessed the domains of intelligence, academic skills, attention, memory, processing speed, and executive function, and patients also completed a self-rating questionnaire to evaluate behavioral and cognitive problems. Scores were transformed into age-adjusted z scores (mean, 0; standard deviation, 1.0) using national norms, with z scores of > –1.5 to –1.0 indicating mild impairment, > –2.0 to –1.5 indicating moderate impairment, and ≤ –2.0 indicating severe impairment. Outcomes were analyzed in the total population and among patients who had received chemotherapy only (no cranial radiotherapy), cranial radiotherapy at 18 Gy, and cranial radiotherapy at 24 Gy.

Multivariate analyses assessed the impact of the cranial radiotherapy group (24 Gy, 18 Gy, no cranial radiotherapy), age at diagnosis (continuous) and its interaction with cranial radiotherapy, time since diagnosis (continuous) and its interaction with cranial radiotherapy, sex and its interaction with cranial radiotherapy, intravenous methotrexate (per 1 g of cumulative exposure), and intrathecal methotrexate (per 50 mL of cumulative exposure).

Patients had a mean age of 33 years, and the mean time since diagnosis was 26 years; 32.8% had been treated with 24 Gy cranial radiotherapy, 29.5% with 18 Gy, and 37.7% with chemotherapy only. Current age, time since diagnosis, and treatment exposures differed among groups due to changes in therapeutic approaches over time; there were no significant differences among groups in educational attainment or current employment.

Rates of Impairment in All Patients

Among all patients, rates of mild, moderate, or severe impairment ranged from 28.6% (18.3% moderate or severe) for self-reported behavior problems to 29.5% (18.3% moderate or severe) for self-reported cognitive problems, 34.9% (18.1% moderate or severe) in academics, 35.7% (22.1% moderate or severe) in intelligence, 41.3% (28.8% moderate or severe) in attention, 55.9% (29.9% moderate or severe) in memory, 56.3% (28.9% moderate or severe) in processing speed, and 58.9% (33.5% moderate or severe) in executive function. 

Severe Impairment and Radiotherapy Dose

Rates of severe impairment significantly increased with increasing cranial radiotherapy dose for intelligence (9.3% in chemotherapy-alone group, 12.0% in 18 Gy group, and 27.0% in 24 Gy group; P < .001), academics (6.1%, 9.2%, 15.4%; P = .002), attention (14.5%, 21.5%, 31.1%; P < .001), memory (13.1%, 18.7%, 30.6%; P < .001), processing speed (16.8%, 16.9%, 27.0%; P = .013), executive function (15.9%, 23.0%, 31.7%; P < .001), and self-reported behavior (5.7%, 12.7%, 16.7%; P < .001) but not for self-reported cognitive problems (7.6%, 9.6%, 11.8%; P = .15).

Increased Risk With Earlier Age at Diagnosis

In multivariate analysis, compared with the chemotherapy-only group, there was significantly greater risk of academic impairment in the 18 Gy group (odds ratio [OR] = 8.13, P = .01) and significantly greater risk of impairment in intelligence (relative risk [RR] = 6.63, P < .001), academics (OR = 8.56, P = .003), attention (RR = 2.15, P < .001), and memory (RR = 5.04, P < .001) in the 24 Gy group. In each case, risk was higher with earlier age at diagnosis. Female sex increased risk for impaired intelligence (RR = 1.61, P = .02) and academics (OR = 3.62, P < .001); female sex also increased risk for impaired processing speed (RR = 3.25, P < .001), but only after treatment with 24 Gy cranial radiotherapy.

Risk for some types of neurocognitive impairment increased with time from diagnosis. For example, compared with the chemotherapy-only group, patients treated with 24 Gy cranial radiotherapy had increased risk for impaired executive function with increasing years from diagnosis; the risk for impaired executive function 45 years after diagnosis was more than sixfold for patients receiving 24 Gy vs those receiving chemotherapy alone. Cranial radiotherapy dose did not have an impact on patient-reported outcomes, although risk for self-reported behavior problems increased by 5% with each year from diagnosis across all groups.

Outcome With Chemotherapy Alone

Increased rates of impairment were observed in all domains (all P=.006) in patients receiving chemotherapy only. Intravenous methotrexate increased the risk for slowed processing speed by 3% for each 1 g/m2 after controlling for cranial radiation. On multivariate analysis, dexamethasone exposure was significantly associated with increased risk for impairment in attention (RR = 2.12, 95% confidence interval [CI] = 1.11–4.03) and executive function (RR = 2.42, 95% CI = 1.20–4.91). Intrathecal hydrocortisone significantly increased risk for attention problems (RR = 1.24, 95% CI = 1.05–1.46). Risk for patient-reported outcomes was not increased by chemotherapy.

Education and Income Status

Adjusting for current age and sex, risk for not graduating from college was significantly associated with impairment in intellect (RR = 1.33), academics (RR = 1.28), executive function (RR = 1.21), and self-reported behavior problems (RR = 1.18). Increased risk for not maintaining full-time employment was significantly associated with impairment in intellect (RR = 1.42), academics (RR = 1.31), attention (RR = 1.29), processing speed (RR = 1.31), and self-reported cognitive problems (RR = 1.51). Female sex was significantly associated with increased risk for unemployment (RR = 1.33) and older current age was significantly associated with decreased risk for unemployment (RR = 0.98 per year of age). Overall, however, educational attainment and employment status in survivors were very similar to those in the general U.S. population after adjustment for sex and age.

The investigators concluded,This study demonstrates persistent and significant neurocognitive impairment in adult survivors of childhood ALL and warrants ongoing monitoring of brain health to facilitate successful adult development and to detect early onset of decline as survivors mature.”

The study was supported by a Cancer Center Support grant from the National Cancer Institute and by the American Lebanese Syrian Associated Charities.

The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.


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