Previous studies in HCT patients have been limited by small sample sizes, cross-sectional study designs, lack of a healthy comparison group, and limited inclusion of autologous HCT recipients. 2 , 7 - 15 These limitations likely have contributed to mixed evidence with respect to the extent and nature of cognitive compromise in HCT survivors. 16 In addition, the increasing use of reduced-intensity conditioning demands an understanding of the trajectory of cognitive functioning in this growing population. 17 We addressed these gaps by establishing a prospective cohort of adults who underwent autologous or allogeneic HCT for hematologic malignancies and a healthy comparison group. Our goal was to determine the longitudinal trajectory of cognitive functioning by using standardized neuropsychologic assessments from before HCT to 3 years after HCT and to identify host- and treatment-related factors associated with cognitive impairment and, thus, the identification of high-risk subpopulations for future targeted interventions.

Impaired cognition is an increasingly recognized consequence of myeloablative allogeneic hematopoietic cell transplantation (HCT) 1 , 2 and could affect societal reintegration and return to work or school. 3 , 4 Potentially neurotoxic agents, including cranial and total body irradiation, high-dose chemotherapy, intrathecal methotrexate, and corticosteroids, place cancer survivors at risk for cognitive impairment. 5 , 6 Decline in memory, learning, attention/concentration, and psychomotor and executive functioning have been reported after HCT, 1 with recovery for most domains by 5 years. 2 Nonetheless, deficits remain for 40% of survivors. 2

A summary score of cognitive functioning called the global deficit score 20 - 22 (Data Supplement) was calculated for all participants. A score of ≥ 0.5 (at least mild cognitive impairment) was used to identify the presence of global cognitive deficit. 20 We used a GEE to model the odds of global cognitive deficit at each time point, the post-HCT overall risk of impairment, and the post-HCT trends over time that compared autologous and myeloablative and reduced-intensity allogeneic HCT recipients with controls. Trend models included a group-time interaction to examine the direction and magnitude of the global deficit score slope after HCT. The proportion of HCT recipients who had not returned to work by 3 years and the odds of not returning to work in association with global cognitive deficit were estimated. Models with the global cognitive deficit outcome were adjusted for demographic and clinical variables where significant, and a P value significance threshold of 5% was used. All analyses were performed with SAS 9.4 statistical software (SAS Institute, Cary, NC).

We used piecewise GEE models (by using an indicator variable for modeling pre-HCT scores and overall post-HCT scores) to compare controls with autologous HCT recipients and with reduced-intensity and myeloablative allogeneic HCT recipients. We also compared reduced-intensity with myeloablative allogeneic HCT recipients. Next, within autologous and allogeneic cohorts, we compared pre-HCT scores with early (at 6 months) and late (at 3 years) post-HCT scores. Finally, we examined sociodemographic and clinical variables associated with cognitive impairment. Models with T scores were built by using backward selection of variables significant at P < .1, including demographic (age, sex, ethnicity, marital status, education, income) and clinical (fatigue, IQ, risk of relapse, disease status, primary diagnosis, preparative regimens) variables. By using Bonferroni’s method for multiple testing, a significance threshold of P ≤ .003 (.05/14 tests) was used to account for comparisons across groups.

Raw test scores were transformed to approach normality such that higher transformed scores indicated better performance. The Data Supplement lists the direction and transformation of each raw score. Practice effects 18 were estimated within controls and applied to HCT recipients with the assumption of comparable practice effects between HCT recipients and controls given similar demographic characteristics and testing time points (Data Supplement). Practice effects were measured by using generalized estimating equation (GEE) regression models 19 that adjusted for the number of previous tests, time interval between two consecutive tests, age, sex, marital status, and IQ and were estimated as the magnitude of difference between test scores at two consecutive time points. Adjusted scores corrected for practice effects were calculated as the difference between the transformed raw scores and the estimated cumulative practice effects for controls and HCT recipients. Corrected scores were transformed to standardized T scores (mean, 50; standard deviation, 10).

Self-reported demographic information was obtained at study enrollment and on return to work after HCT. Medical records were used to abstract information about primary diagnosis, stem-cell source (autologous, sibling, or unrelated donor), preparative regimen, risk of relapse at HCT (standard or high risk), and remission status. For allogeneic HCT recipients, information was collected about conditioning intensity (reduced intensity or myeloablative) and presence of chronic graft-versus-host disease (cGVHD) at each time point.

The study used a prospective, longitudinal design to assess cognitive functioning by using standardized neuropsychologic tests administered at five predetermined time points: pre-HCT (median of 16 days before HCT), 6 months (−45 to 95 days), 1 year (−1.4 to 4.1 months), 2 years (−3.3 to 4.9 months), and 3 years (−4.2 to 6.4 months) after HCT. Tests were administered to controls at commensurate time points. Fourteen standardized tests (Data Supplement) covered eight domains of cognitive functioning (executive function, verbal fluency, verbal speed, processing speed, working memory, auditory memory, visual memory, and fine motor dexterity). Cognitive reserve was assessed at enrollment by using an intelligence quotient (IQ) estimate. Fatigue was evaluated at each study time point. A description of all instruments is provided in the Data Supplement.

Patients scheduled to receive autologous or allogeneic HCT for hematologic malignancies at City of Hope between 2005 and 2011 were approached for study participation. Participants were at least 18 years of age and English literate and provided informed consent. Eligible controls without a chronic health condition (frequency matched for age at enrollment, sex, and annual household income) were recruited from family and friends of study participants or from the community. HCT recipients and controls were excluded if they had a preexisting neurologic or major psychiatric disorder; significant auditory, visual, or motor impairments; or neuropsychologic interventions within 6 months of study participation. The study was approved by the institutional review board at City of Hope. Informed consent was provided according to the Declaration of Helsinki.

Overall, 29.5% of HCT recipients who participated at the 3-year time point had not returned to work (autologous, 19.5%; reduced-intensity allogeneic, 31.2%; myeloablative allogeneic HCT, 46.3%). Multivariable analysis (Data Supplement) showed no association between global cognitive deficit and not returning to work by 3 years after HCT in autologous HCT recipients (OR, 0.4; 95% CI, 0.04 to 3.3). However, in allogeneic HCT recipients, global cognitive deficit was associated with a 9.9-fold increased odds of not returning to work (95% CI, 2.4 to 40.2).

Prevalence of global cognitive deficit was comparable with that of controls before HCT (22.3% v 17.2%; P = .4), but was significantly higher at 6 months (31.1% v 16.5%; P = .03), 2 years (34.6% v 16.4%; P = .02), and 3 years after HCT (36% v 8.7%; P = .002; Data Supplement). Adjusted risk of global cognitive deficit was significantly higher than that of controls (OR, 3.5; 95% CI, 1.5 to 7.9) and increased over time (OR, 1.3; 95% CI, 1.0 to 1.8; Fig 2B , Data Supplement). Older age (OR, 1.06; 95% CI, 1.02 to 1.1) and ethnicity other than NHW (OR, 5.6; 95% CI, 1.8 to 17.7) were associated with global cognitive deficit after HCT among myeloablative allogeneic HCT recipients (Data Supplement).

Prevalence of global cognitive deficit was comparable with controls before HCT and at 6 months and 1 and 2 years after HCT but was significantly higher at 3 years after HCT (35.4% v 8.7%; P = .001; Data Supplement). Although the adjusted risk for global cognitive deficit was not elevated at any of the post-HCT time points, the trend of impairment increased significantly over time (OR, 1.8; 95% CI, 1.3 to 2.5; Fig 2B ; Data Supplement). Older age (OR, 1.11; 95% CI, 1.05 to 1.17) and low cognitive reserve (OR, 7.1; 95% CI, 2.9 to 16.7) were associated with global cognitive deficit after HCT (Data Supplement).

No statistically significant differences were found in the prevalence of global cognitive deficit between autologous HCT recipients and controls before HCT (22.5% v 17.2%; P = .3) or 3 years after HCT (18.7% v 8.7%, P = .1; Data Supplement). Adjusted risk of global cognitive deficit was comparable with that of controls (odds ratio [OR], 1.35; 95% CI, 0.7 to 2.7; Fig 2B ; Data Supplement). Older age (OR, 1.05; 95% CI, 1.02 to 1.08), male sex (OR, 5.3; 95% CI, 2.4 to 11.1), lower income (< $50,000: OR, 7.1 [95% CI, 2.7 to 18.6]; $50,000 to $100,000: OR, 3.5 [95% CI, 1.5 to 8.0]), and lower cognitive reserve (OR, 10.0; 95% CI, 4.5 to 25.0) were associated with global cognitive deficit after HCT (Data Supplement).

Variables associated with significantly worse ( P ≤ .003) post-HCT cognitive scores were older age at time of test (all domains except verbal fluency and auditory memory), male sex (all domains except verbal speed, working memory, auditory memory, and fine motor dexterity), female sex (working memory), ethnicity other than NHW (working memory), lower education (executive function, verbal fluency, processing speed, and working memory), low income (executive function, verbal speed, processing speed, and working memory); and low cognitive reserve (all domains except visual memory and fine motor dexterity; Table 4 ).

Table 1 lists the demographic characteristics of HCT recipients and controls at enrollment. Age, sex, ethnicity, and income did not differ between HCT recipients and controls. HCT recipients had lower education (less than college graduate, 49.3% v 37.4%; P = .03) and lower cognitive reserve (IQ at or below the median for HCT recipients, 51.5% v 35.3%; P = .004). Median age at study enrollment for HCT recipients was 52.2 years (range, 18 to 74 years), 61.4% were male and 67.5% were non-Hispanic white (NHW), and 49.2% of allogeneic HCT recipients developed cGVHD.

A total of 477 HCT recipients (236 autologous, 128 reduced-intensity, and 113 myeloablative allogeneic) and 99 controls were enrolled in the study. Figure 1 shows participants at all time points. Sample size and power calculations are provided in the Data Supplement. The Data Supplement lists participants who completed testing at all time points and compares them with those who missed at least one time point. The most common reasons for attrition among HCT recipients were death (27.5%) and receipt of a second HCT (7.3%). Among eligible HCT recipients, 429 completed pre-HCT testing (89.9%), with 341 (81.6%) at 6 months, 308 (81.5%) at 1 year, 247 (80.7%) at 2 years, and 227 (81.4%) at 3 years.

DISCUSSION Section: Choose Top of page Abstract INTRODUCTION METHODS RESULTS DISCUSSION << REFERENCES

In this longitudinal assessment of cognitive functioning in adult HCT recipients, we found that post-HCT cognitive functioning in autologous and reduced-intensity allogeneic HCT recipients was comparable with that of healthy controls. However, myeloablative allogeneic HCT recipients had worse cognitive functioning after HCT in five of the eight domains examined. Compared with pre-HCT performance, autologous HCT recipients showed improvement in verbal fluency but a decline in visual memory and fine motor dexterity. Myeloablative allogeneic HCT recipients showed early decline in fine motor dexterity that persisted up to 3 years. Although no decline was observed at 6 months for reduced-intensity allogeneic HCT recipients, evidence showed a delayed decline in executive function, verbal fluency, and working memory at 3 years after HCT.

Previous studies that focused on autologous HCT showed improvement in cognitive functioning over time,23-26 whereas those that focused on allogeneic HCT recipients showed a decline after HCT with limited recovery over time.7,8,14 Most studies, however, focused primarily on myeloablative HCT recipients.8,11,27,28 In the current cohort, > 50% of the allogeneic HCT recipients received reduced-intensity conditioning, which allowed us to make the novel observation that the post-HCT cognitive trajectory for reduced-intensity allogeneic recipients resembles that of healthy controls, albeit with a delayed decline. On the other hand, global cognitive deficit was apparent at 6 months after HCT in myeloablative allogeneic HCT recipients, with no improvement at 3 years. The goal of reduced-intensity allogeneic HCT is to reduce early regimen-related toxicity17,29; this likely explains the low risk of cognitive impairment in the early post-transplantation period (6 months). The delayed cognitive decline in this group possibly is analogous to the risk of radiation-related adverse events, such as cataracts, where patients who receive single-dose total body irradiation have a shorter latency and a higher risk of cataracts; on the other hand, those who receive fractionated total body irradiation develop cataracts much later after exposure, and the risk is not as high.30

We identified older age, male sex, lower education and income, and lower cognitive reserve as predictors of post-HCT cognitive impairment across all HCT types. Similar to a previous study,8 we did not find an association between cognitive functioning and specific therapeutic exposures used in preparative regimens or with cGVHD. Older age, lower education, higher fatigue, and lower cognitive reserve have previously been described as predictors of cognitive decline after allogeneic HCT,8,10 and early recovery of cognitive functioning was reported among patients with greater cognitive reserve.31

In the current cohort, females had higher performance across all tests except for working memory tests that measure attention and arithmetic abilities. The lower cognitive performance in males in this study contrasts with a higher risk of cognitive impairment in female childhood cancer survivors32 and greater self-reported cognitive symptoms among adult female HCT survivors.33 In the general population, females have an advantage in verbal skills, processing speed, executive function, and the fine motor domain, whereas males outperform females in visuospatial, working memory, and mathematical abilities.34-36 Sex differences in cognitive functioning are likely influenced by the effects of estrogen (and testosterone through its conversion into estrogen) on the CNS.36-39 Although hypogonadism is observed frequently after HCT in both males and females, females are more likely to be supplemented with hormone replacement. Persistent untreated hypogonadism could possibly explain the lower performance observed in male HCT survivors; however, we were unable to evaluate this in the current study.

Findings from this large, prospectively followed cohort need to be placed in the context of the study’s limitations. The study was conducted at a single institution and could be limited by clinical practices unique to the institution. However, transplantation practices usually follow standard operating procedures mandated by cellular therapy–accrediting organizations; these regulatory processes minimize heterogeneity in clinical practice across transplantation centers. Neuropsychologic tests in the United States generally are normed and standardized in English-speaking individuals; validated instruments for use in non–English-speaking populations were not available when we conducted the study. Furthermore, these tests were originally developed to identify impairments associated with moderate to severe brain damage and, therefore, may not be sensitive in detecting mild dysfunction typically associated with cancer-related toxicities. Unavoidable attrition over the course of the study as a result of post-HCT illness or death could have introduced bias in the magnitude of cognitive impairment; however, among those alive and able to participate, the average participation rate was 83% across all time points. Although we found a 10-fold higher odds of not returning to work among allogeneic HCT recipients with global cognitive deficit at the 3-year time point, measures of anxiety, depression, financial toxicity, and quality of life were not collected longitudinally. Future directions of this research would involve comprehensive collection of functional and social outcomes data.

These limitations notwithstanding, this study had several strengths. We used a validated neuropsychological battery for objective assessment of cognitive functioning suitable for repeated administration in a longitudinal study that adjusted for practice effects. This adjustment is especially relevant for the evaluation of cognitive change across multiple time points and global performance scores over time.40,41 We used a novel approach to estimate practice effects while taking advantage of the data collected on healthy controls. We believe that our approach improved the accuracy of the estimation of practice effect in the study population by measuring practice effects in a population comparable to patients with respect to demographics and testing time points. Direct comparison with healthy controls also facilitated the contrast of cognitive changes in HCT recipients over time. The sufficiently large sample size allowed for valid comparisons by HCT type and conditioning intensity.1 Predetermined time points for assessment, including the pre-HCT assessment, provided a means to observe patterns and determinants of change in cognitive functioning during both the short-term and the long-term post-HCT period.

In conclusion, at 3 years after HCT, 18% of autologous HCT recipients and 35.7% of allogeneic HCT recipients demonstrated global cognitive deficits. Compared with healthy controls, myeloablative allogeneic HCT recipients were the most compromised, with evidence of cognitive impairment in multiple domains. Reduced-intensity allogeneic and autologous HCT recipients demonstrated cognitive functioning comparable to controls, with evidence for delayed cognitive impairment in reduced-intensity allogeneic HCT recipients. Allogeneic HCT recipients with global cognitive deficits were at a 10-fold increased risk of not returning to work, which suggests that cognitive impairment is a significant barrier to societal reintegration for this vulnerable population. Cognitive functioning needs to be monitored after HCT among patients identified to be at the highest risk to facilitate targeted cognitive interventions such as cognitive training.42-48