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Reduced-Intensity Conditioning Shown to Spare Cognitive Function

Carlson, Robert H.

doi: 10.1097/01.COT.0000444057.30762.d4

NEW ORLEANS—Stem cell transplant-related chemotherapy and radiation have long been associated with cognitive impairment after treatment. Now, a study from City of Hope has confirmed the risk of cognitive impairment after allogeneic hematopoietic cell transplantation in patients who underwent full-intensity conditioning, and also shown that the risk was not apparent in patients who underwent reduced intensity regimens.

In the prospective longitudinal study, reported here at the American Society of Hematology Annual Meeting (Abstract 913), the researchers also found that shortening of telomeres prior to transplant was associated with cognitive declines after transplant, but only in female patients.



The study was unique in that it included a healthy control group as well as patients who received full or reduced-intensity transplant, said the senior author, Smita Bhatia, MD, MPH, Professor and Chair of the Department of Population Sciences. First author was Alysia Bosworth, Clinical Research Coordinator.

“We found there is significant impairment in cognitive functioning in a variety of domains among transplant patients compared with healthy controls,” Bhatia said during a news conference at the meeting that highlighted noteworthy presentations on improving the availability and success of stem cell transplants. “We also found that it is primarily those who receive myeloablative transplants who are having these cognitive impairments.”

In the study of 242 transplant patients—median age of 49 for the transplant patients (age 19 to 71; and 51 for healthy controls—cognitive function was assessed pre-transplant (194 patients), and at six months (165), one year (155), and two years (125) post-transplant using standardized neuropsychological tests. Cognitive function was also assessed in 98 age- and gender-matched healthy controls at corresponding time points.

The tests assessed executive function, processing speed, verbal speed, verbal fluency, working memory, auditory memory, visual memory, and fine motor dexterity. IQ was assessed to estimate cognitive reserve.

The primary diagnoses for the transplant patients were acute leukemia in 69 percent and lymphoma in 14 percent. Reduced-intensity conditioning was used in 52 percent of transplant patients, and full-intensity conditioning in 48 percent. A total of 51 percent of all transplant patients developed chronic graft-versus-host disease, Bhatia reported.

She noted that in a previous study her team identified cognitive impairment after transplant as a major reason that patients do not return to work, but the researchers had not compared transplant patients with healthy controls until this study.

“Importantly, there were no significant differences in cognitive functioning between reduced-intensity transplant recipients and healthy controls,” she said.

The degree of decline stayed constant from immediately after transplant and at all time points, up to two years.

Significant contributors to cognitive impairment included older age, male gender, Hispanic ethnicity, less education, low income, low cognitive reserve, high risk of relapse, and high fatigue. After adjusting for these variables, cognitive function was found to be worse in patients who received full-intensity compared with reduced-intensity conditioning in executive functioning, processing speed, verbal speed, and visual memory.

The study also showed a significant association between short telomeres measured prior to transplant and post-transplant cognitive reduction, but only in female transplants, and only for executive function, processing speed, verbal speed, and working memory.

Bhatia explained that use of chemo-radiotherapy hastens telomeric attrition, and that glial cells are mitotic and susceptible to telomeric shortening. Telomeric shortening as measured in blood is also associated with the severity of Alzheimer's disease.

The researchers said the findings should make physicians aware of potential problems with cognition among their transplant patients.

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The moderator of the news conference, Jeffrey Miller, MD, Deputy Director of the Masonic Cancer Center and Clinical and Translational Sciences Institute at the University of Minnesota, commented on the study after Bhatia's presentation: “Reduced-intensity transplantation is allowing us to perform the procedure in older patients, and from this study, that seems to be a better way to go in terms of cognitive function.”



But, he pointed out that in the transplant field, decisions are highly tied together between the rate of relapse, which is higher with reduced-intensity, and cognitive impairment, which is improved at this intensity. “So what do we know about stratifying the risks and how to take these various conditions into account? If cognitive function is the most important thing at the end of the day, then maybe everybody should receive reduced-intensity transplantation. But then we're going to get higher rates for relapse and less tolerance in the elderly.”

Bhatia answered that the strategy that gives the best relapse-free survival should be the most important thing for a transplant specialist: “If that is equal between full-intensity and reduced-intensity transplantation, then we have the luxury of using the mode of therapy that is less toxic down the road,” she said.

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iPad Extra!

In a video on the iPad edition of this issue, Smita Bhatia, MD, MPH, also spoke to OT reporter Dan Keller, elaborating on the clinical implications of her research.



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