Improved Neurocognitive Outcomes with Contemporary Treatments in Survivors of Early Adolescent and Young Adult Hematologic Malignancies from the Childhood Cancer Survivor Study
Authors: Wang Amy Yuan , Williams Annalynn M , Chen Yan , Yasui Yutaka , Stock Wendy , Leisenring Wendy , Armstrong Gregory , Oeffinger Kevin , Chow Eric J. , Krull Kevin R. , Henderson Tara O. 
Published: December 2023

Background:
Neurocognitive impairments in survivors of hematologic malignancies diagnosed specifically during adolescence and early young adulthood (eAYA survivors) are not well described, despite use of intensive neurotoxic therapies. We evaluated how recent shifts in therapeutic approaches have impacted neurocognitive outcomes in survivors diagnosed during eAYA compared to younger survivors and sibling controls.
Methods:
We identified 1213 eAYA (diagnosed at 15-21 years) and 4538 pediatric (diagnosed at &lt;15 years) survivors of acute lymphoblastic lymphoma (ALL; n= 301 v. 3274), acute myeloid leukemia (AML; n= 77 v. 424), and Hodgkin lymphoma (HL; n= 835 v. 840) as well as 1014 siblings from the Childhood Cancer Survivor Study (&gt;5 year survivors diagnosed 1970-1999) who completed the Neurocognitive Questionnaire ( Table 1). Impairment was defined as a score in worst 10% of the sibling cohort in task efficiency (TE), organization (Org), memory (Mem), and emotional regulation (ER) domains. Survivors were stratified into groups reflective of diagnosis, treatment era, and intensity: HL-chest RT ≥35Gy = HL with chest radiation ≥35Gy (High-risk disease, older regimens); HL-chest RT &lt;35Gy = HL with chest radiation &lt;35Gy (Intermediate risk disease, contemporary regimens); HL-salvage = HL with salvage therapy (High-risk disease, higher intensity regimens), ALL-CRT = ALL with use of cranial radiation (CRT) (Older regimens), ALL-no CRT = ALL without use of CRT (Contemporary regimens), ALL-salvage = ALL with salvage therapy (High-risk disease, higher intensity regimens), AML-chemo = AML with chemotherapy only (Lower risk disease), AML-SCT = AML with history of stem cell transplant (Higher risk disease). The prevalence of neurocognitive impairment compared to siblings was estimated using generalized-estimating-equation logistic regression accounting for potential within-family correlation. Health status and health behaviors were examined as risk factors for neurocognitive impairment. Adjusted odds ratios (OR) and corresponding 95% confidence intervals (CI) are reported.
Results:
Prevalence of any neurocognitive impairment in the eAYA, pediatric, and sibling groups was 30.8%, 37.7%, and 25.4%, respectively. Prevalence was similar for eAYAs and pediatric survivors of HL (31.0% v. 29.6%, p=0.54) and AML (36.4% v. 40.6%, p=0.49), while lower in eAYA ALL survivors (28.2% v. 38.7%, p&lt;0.01). Compared to siblings, eAYA HL survivors who received salvage therapy were more likely to have impaired Org (OR 2.5, 95% CI 1.2-5.1) and Mem (OR 2.7, 95% CI 1.3-5.8), while those who received high-dose chest RT experienced more Mem impairment (OR 2.0, 95% CI 1.2-3.4) ( Table 2). Compared to siblings, Mem was the most commonly affected domain in eAYA ALL survivors who received CRT (OR 4.0, 95% CI 2.0-7.9); this was not observed in the non-CRT or salvage groups. In a separate analysis of treatment exposures, anthracycline ≥120mg/m 2 uniquely increased prevalence of ER in eAYA ALL survivors (OR 4.7, 95% CI 1.7-12.9). Compared to siblings, survivors of eAYA AML who underwent SCT had higher odds of Mem impairment (OR 5.3, 95% CI 1.9-14.7). In a direct comparison with pediatric AML survivors, eAYA AML survivors were also more likely to have impaired Mem (OR 2.6, 95% CI 1.1-6.2) (data not shown). Being physically active (OR range 0.3-0.7), a never-smoker (OR range 0.5-0.6), and insured (OR range 0.4-0.5) were protective across all domains in eAYA-cancer survivors.
Conclusions:
Survivors of hematologic cancers diagnosed during eAYA are susceptible to neurocognitive impairment at rates similar to those diagnosed at younger ages for HL and AML but at reduced rates for survivors of ALL. Memory was the most affected domain in eAYA survivors. Contemporary regimens utilizing intermediate-dose (&lt;35Gy) chest RT for HL or omission of cranial RT for ALL attenuated the extent of risk. Future studies should focus on characterizing outcomes across the entire AYA age spectrum.