ALL and chemotherapy-only CNS therapy

Systemic methotrexate in high doses with or without radiation therapy can lead to an infrequent but well-described leukoencephalopathy, which has been linked to neurocognitive impairment.[53]

When neurocognitive outcomes after radiation therapy and chemotherapy-only regimens are directly compared, the evidence suggests a better outcome for those treated with chemotherapy alone, although some studies show no significant difference.[60,61]

In a longitudinal analysis of 210 childhood ALL survivors, the development of acute leukoencephalopathy during chemotherapy-only CNS therapy predicted higher risks of developing long-term neurobehavioral problems (e.g., deficits in organization and task initiation [components of executive function]) and reduced white matter integrity in frontal brain regions.[62]

Compared with cranial irradiation, chemotherapy-only CNS-directed treatment produces neurocognitive deficits involving processes of attention, speed of information processing, memory, verbal comprehension, visual-spatial skills, visual-motor functioning, and executive functioning. Global intellectual function is typically preserved.[56,60,63-65]

Few longitudinal studies evaluating long-term neurocognitive outcome report adequate data for a decline in global IQ after treatment with chemotherapy alone.[63]

The academic achievement of ALL survivors in the long term seems to be generally average for reading and spelling, with deficits mainly affecting arithmetic performance.[60,66]

Risk factors for poor neurocognitive outcome after chemotherapy-only CNS-directed treatment are younger age and female sex.[65,67]

Reduced cognitive status has been observed in association with reduced integrity in neuroanatomical regions essential in memory formation (e.g., reduced hippocampal volume with increased activation and thinner parietal cortices).[62]

The long-term impact of these prevalent neurocognitive and neuroimaging abnormalities on functional status in aging adults treated for childhood ALL, particularly those treated with contemporary approaches using chemotherapy alone, remains an active area of research.

Research in childhood ALL survivors treated with chemotherapy alone suggests that genetic predisposition may modulate risk of developing neurocognitive late effects. It also provides insights into potential mechanisms underlying neurocognitive deficits.[68,69]

CCSS investigators identified sex-specific associations between treatment and chronic health conditions with neurocognitive impairment among 1,207 survivors of ALL (mean age, 30.6 years) who were treated with chemotherapy only.[7]

CCSS investigators identified sex-specific associations between treatment and chronic health conditions with neurocognitive impairment among 1,207 survivors of ALL (mean age, 30.6 years) who were treated with chemotherapy only.[7]

Both male and female survivors reported increased prevalence of impaired task efficiency (attention and processing speed; adjusted odds ratio [OR], 1.89 for males; OR, 1.50 for females) and impaired memory (OR, 1.89 for males; OR, 1.96 for females) compared with 2,273 same-sex siblings.

CCSS investigators identified sex-specific associations between treatment and chronic health conditions with neurocognitive impairment among 1,207 survivors of ALL (mean age, 30.6 years) who were treated with chemotherapy only.[7]

Among male survivors, impaired task efficiency was associated with grades 2 to 4 neurological conditions (OR, 4.33) and pulmonary conditions (OR, 4.99). Impaired memory was associated with increased cumulative dose of intrathecal methotrexate (OR, 1.68) and exposure to dexamethasone (OR, 2.44).

CCSS investigators identified sex-specific associations between treatment and chronic health conditions with neurocognitive impairment among 1,207 survivors of ALL (mean age, 30.6 years) who were treated with chemotherapy only.[7]

In female survivors, grades 2 to 4 endocrine conditions were associated with higher risk of impaired task efficiency (OR, 2.19) and memory (OR, 2.26).

The CCSS examined parent-reported cognitive, behavior, and learning problems from 1,560 adolescent survivors of childhood ALL who were treated with chemotherapy alone between 1970 and 1999.[70]

The CCSS examined parent-reported cognitive, behavior, and learning problems from 1,560 adolescent survivors of childhood ALL who were treated with chemotherapy alone between 1970 and 1999.[70]

Survivors treated with cranial irradiation had significantly higher frequency of problems in anxiety-depression, inattention-hyperactivity, and social withdrawal than did patients who were not treated with cranial irradiation.

The CCSS examined parent-reported cognitive, behavior, and learning problems from 1,560 adolescent survivors of childhood ALL who were treated with chemotherapy alone between 1970 and 1999.[70]

Compared with siblings, survivors treated with chemotherapy only were more likely to demonstrate headstrong behavior (19% of survivors vs. 14% of siblings, P = .010), inattention-hyperactivity (19% vs. 14%, P < .0001), social withdrawal (18% vs. 12%, P = .002), and had higher rates of learning problems (28% vs. 14%, P < .0001).

The CCSS examined parent-reported cognitive, behavior, and learning problems from 1,560 adolescent survivors of childhood ALL who were treated with chemotherapy alone between 1970 and 1999.[70]

In multivariable models among survivors, increased cumulative dose of intravenous methotrexate (i.e., >4.3 g/m2) conferred increased risk of inattention-hyperactivity (RR, 1.53).

The CCSS examined parent-reported cognitive, behavior, and learning problems from 1,560 adolescent survivors of childhood ALL who were treated with chemotherapy alone between 1970 and 1999.[70]

Adolescent survivors with cognitive or behavior problems and those with learning problems were less likely to graduate from college as young adults than adolescent survivors without cognitive or behavior problems.

The CCSS examined parent-reported cognitive, behavior, and learning problems from 1,560 adolescent survivors of childhood ALL who were treated with chemotherapy alone between 1970 and 1999.[70]

Inattention and hyperactivity problems were associated with the highest risk of special education placement during adolescence. Participation in special education during adolescence did not improve adult educational attainment.

The SJCRH TOTAL XVI (NCT00549848) trial evaluated whether a higher dose of pegaspargase and early intensification of triple intrathecal therapy (ITT; methotrexate, hydrocortisone, and cytarabine) would improve systemic and CNS control in children with newly diagnosed ALL. Intensified ITT was defined as more than 21 cumulative doses for patients with low-risk ALL (70 of 194) and more than 27 doses for those with standard- and high-risk ALL (81 of 206). Neurocognitive testing was completed at the end of therapy.[71]

The SJCRH TOTAL XVI (NCT00549848) trial evaluated whether a higher dose of pegaspargase and early intensification of triple intrathecal therapy (ITT; methotrexate, hydrocortisone, and cytarabine) would improve systemic and CNS control in children with newly diagnosed ALL. Intensified ITT was defined as more than 21 cumulative doses for patients with low-risk ALL (70 of 194) and more than 27 doses for those with standard- and high-risk ALL (81 of 206). Neurocognitive testing was completed at the end of therapy.[71]

The overall group had below age-based norms on measures of global intelligence (P < .0001), attention (P = .0051), working memory (P = .0001), processing speed (P = .0002), fine motor speed (P = .0001), and math skills (P = .0087). Caregiver ratings of patient functioning showed elevated risks of problems in attention (P = .0173), executive function (P = .0001), and adaptive skills (P = .0001).

The SJCRH TOTAL XVI (NCT00549848) trial evaluated whether a higher dose of pegaspargase and early intensification of triple intrathecal therapy (ITT; methotrexate, hydrocortisone, and cytarabine) would improve systemic and CNS control in children with newly diagnosed ALL. Intensified ITT was defined as more than 21 cumulative doses for patients with low-risk ALL (70 of 194) and more than 27 doses for those with standard- and high-risk ALL (81 of 206). Neurocognitive testing was completed at the end of therapy.[71]

In the low-risk group, there were no significant differences between patients treated with and without intensified ITT.

The SJCRH TOTAL XVI (NCT00549848) trial evaluated whether a higher dose of pegaspargase and early intensification of triple intrathecal therapy (ITT; methotrexate, hydrocortisone, and cytarabine) would improve systemic and CNS control in children with newly diagnosed ALL. Intensified ITT was defined as more than 21 cumulative doses for patients with low-risk ALL (70 of 194) and more than 27 doses for those with standard- and high-risk ALL (81 of 206). Neurocognitive testing was completed at the end of therapy.[71]

Patients with standard- and high-risk ALL who were treated with intensified ITT had poorer working memory (P = .0328) and fine motor speed (P = .0403), and elevated ratings of inattention (P = .0189) and executive dysfunction (P = .0245). Females in this risk group treated with intensified ITT had lower working memory scores.

In the SJCRH Total XV (NCT00137111) trial, which omitted prophylactic cranial irradiation, comprehensive cognitive testing of 243 participants at week 120 revealed the following:[72]

In the SJCRH Total XV (NCT00137111) trial, which omitted prophylactic cranial irradiation, comprehensive cognitive testing of 243 participants at week 120 revealed the following:[72]

A higher risk of below-average performance on a measure of sustained attention but not on measures of intellectual functioning, academic skills, or memory.

In the SJCRH Total XV (NCT00137111) trial, which omitted prophylactic cranial irradiation, comprehensive cognitive testing of 243 participants at week 120 revealed the following:[72]

The risk of cognitive deficits correlated with treatment intensity but not with age at diagnosis or sex.

In the SJCRH Total XV (NCT00137111) trial, which omitted prophylactic cranial irradiation, comprehensive cognitive testing of 243 participants at week 120 revealed the following:[72]

Prolonged follow-up (average, 7.7 years from diagnosis) of this cohort demonstrated that intelligence was within normal limits compared with population expectations, but measures of executive function, processing speed, and memory were less than population means.

In the SJCRH Total XV (NCT00137111) trial, which omitted prophylactic cranial irradiation, comprehensive cognitive testing of 243 participants at week 120 revealed the following:[72]

Higher plasma methotrexate was associated with executive dysfunction, thicker cerebral cortex, and higher activity in frontal brain regions on functional MRI.

In a large prospective study of neurocognitive outcomes in children with newly diagnosed ALL, 555 children were randomly assigned to receive CNS-directed therapy according to risk group.[73]

In a large prospective study of neurocognitive outcomes in children with newly diagnosed ALL, 555 children were randomly assigned to receive CNS-directed therapy according to risk group.[73]

The low-risk group was randomly assigned to receive either intrathecal methotrexate or high-dose methotrexate.

In a large prospective study of neurocognitive outcomes in children with newly diagnosed ALL, 555 children were randomly assigned to receive CNS-directed therapy according to risk group.[73]

The high-risk group was randomly assigned to receive either high-dose methotrexate or 24 Gy of cranial radiation therapy.

In a large prospective study of neurocognitive outcomes in children with newly diagnosed ALL, 555 children were randomly assigned to receive CNS-directed therapy according to risk group.[73]

A significant reduction in IQ scores (4–7 points) was observed in all patient groups when compared with controls, regardless of the CNS treatment delivered.

In a large prospective study of neurocognitive outcomes in children with newly diagnosed ALL, 555 children were randomly assigned to receive CNS-directed therapy according to risk group.[73]

Children younger than 5 years at diagnosis were more likely to have IQs below 80 at 3 years posttherapy than were children older than 5 years at diagnosis, irrespective of treatment allocation, suggesting that younger children are more vulnerable to treatment-related neurological toxic effects.

Persistent cognitive deficits and progressive intellectual decline have been observed in cohorts of adults treated for ALL during childhood and associated with reduced educational attainment and unemployment.[5,55,59] The results of a study of more than 500 adult survivors of childhood ALL (average, 26 years postdiagnosis) showed the following:[55]

Persistent cognitive deficits and progressive intellectual decline have been observed in cohorts of adults treated for ALL during childhood and associated with reduced educational attainment and unemployment.[5,55,59] The results of a study of more than 500 adult survivors of childhood ALL (average, 26 years postdiagnosis) showed the following:[55]

Survivors demonstrated increased rates of impairment across all neurocognitive domains (ranging from 28.6%–58.9% for each domain).

Persistent cognitive deficits and progressive intellectual decline have been observed in cohorts of adults treated for ALL during childhood and associated with reduced educational attainment and unemployment.[5,55,59] The results of a study of more than 500 adult survivors of childhood ALL (average, 26 years postdiagnosis) showed the following:[55]

Rate of severe impairment increased as a function of cranial radiation dose and was common among survivors treated with lower doses of cranial irradiation and chemotherapy only.

Persistent cognitive deficits and progressive intellectual decline have been observed in cohorts of adults treated for ALL during childhood and associated with reduced educational attainment and unemployment.[5,55,59] The results of a study of more than 500 adult survivors of childhood ALL (average, 26 years postdiagnosis) showed the following:[55]

Impairment in executive function skills increased with time since diagnosis in a cranial radiation dose-dependent manner; impairment in intellect, academics, and memory progressively increased with younger age at treatment in a cranial radiation dose-dependent manner; and neurocognitive impairment was related to functional outcomes as adults, including reduced likelihood of college graduation and full-time employment.