ASH 2013- New Orleans, LA, USA

Full-intensity transplantation and short telomeres increase risk of cognitive impairment after allogeneic haematopoietic cell transplantation

Dr Smita Bhatia - City of Hope National Medical Center, Duarte, USA

There were some studies published before which had indicated that cognitive impairment did occur after transplantation but most of these studies were what were called cross-sectional studies so they were studies on patients who had been transplanted several years before, we did not know what their cognitive function was coming in to transplant and therefore we couldn’t ascribe the cognitive impairment of these patients to the transplantation process. So for that reason we wanted to conduct a prospective longitudinal study where we assessed them before transplantation and then followed them longitudinally at predefined time periods in order to assess what happened to their cognitive functions with the transplantation in the middle.

Which patients specifically have you looked at?

We have looked at adult patients who are undergoing transplantation so they have to be over 21 years of age. They’re English speaking patients and they were all transplanted at the City of Hope Cancer Centre in Los Angeles.

How did you go about the investigation?

We identified eligible patients and we consented them for participation in the study. They underwent a two-hour rigorous standardised cognitive function testing before transplantation and then at six months, one year and two years. There is a three year component which we’ll wait to see what the results are of that. We also obtained bloods from them prior to transplantation which, as I’ve mentioned in my press conference, is going to be used and was used for a variety of tests in order to understand if a certain subgroup was at a higher risk of developing cognitive impairment.

We also assessed healthy controls and these were individuals who didn’t have a history of cancer, no history of any significant comorbidities, and what we did was we tested them also in a similar fashion to the transplant recipients and what we found was that our transplant patients had a significantly lower level of cognitive function as compared to healthy controls. This was present before transplantation as well as after transplantation but more importantly what we found was that amongst our transplant patients those who had received full intensity transplants were at a higher risk of cognitive impairment as compared to those who had received a reduced intensity transplant. In fact, the patients who had received reduced intensity transplants recovered their cognitive function very nicely after transplantation and were no different from the healthy controls.

Does that mean it’s safe to explore potentially less toxic approaches?

You are absolutely correct, one of the primary reasons why reduced intensity transplants were developed was not only to reduce the immediate toxicity that patients do suffer from transplantation and especially in the patients who are at high risk for those toxicities but now increasingly reduced intensity transplant is being offered to patients who have very minimum risk of long-term toxicities. So this would be a very good way to say, yes, reduced intensity transplant is an option and should be explored and should be offered to patients as long as we can make sure that we have comparable relapse free survival in the two groups of patients.

Were there differences between men and women in terms of cognitive impairment?

What this study found was that men were at a higher risk of cognitive impairment as compared to women. This is actually contrary to findings in children where when we look at childhood cancer survivors it’s the girls who are at a higher risk of cognitive impairment as compared to boys. So this is a different finding. What we also found was that amongst women, if they had what’s called shorter telomere lengths prior to transplantation, they were at a higher risk of post-transplant cognitive impairment; men didn’t show any similar correlations with their telomere length.

The next steps are to figure out a) how does telomere length… What are the causes of telomere length being associated with cognitive impairment? Why is it restricted to females? What is maintaining the telomere length in these patients? Why are some more susceptible to having shorter telomere lengths as compared to those who have longer telomere lengths? So these are the things that we are now embarking upon.

What about differences between patients at baseline?

This was a heterogeneous group of patients; they were different by diagnosis, they were different by age, there was a mix of race and ethnicity, socio-economic status. But when we looked at the comparisons between, say, healthy controls and transplanted people, so those between full intensity and reduced intensity, we controlled for, in our statistical analysis, for all this heterogeneity.

How do you think we should approach treating patients based on your findings?

The most important point that comes out of this particular study is that the reduced intensity transplant recipients are spared. That’s a very important finding. The second important finding is, an equally important finding, is that the full intensity transplant recipients are indeed at a significantly increased risk and amongst them there’s a sub-population that is even more at a higher risk. These are the older patients, the patients from lower SEF status, those who have high levels of fatigue. What we need to do is a) increase awareness amongst our healthcare providers as well as amongst our patients so that we can catch this particular problem early and offer them interventions which will help them in improving their coping skill as well as their cognitive impairment.

What would your advice be for “real-world” doctors treating patients today?

In the real world situation when the patients come back for their visits after their immediate post-transplant period is over it’s very important to include questions regarding their attention, their memory, their executive functioning, processing speed, verbal speed, all of these can be incorporated into very simple questionnaires which have been developed or asking about their neurocognitive symptoms. Once those are identified to refer the patients to neuropsychologists who are then very skilled in being able to tell us exactly how to manage these symptoms in these patients.

What do you understand about the pathogenesis of what’s causing this impairment?

It’s not known right now but what we are doing is we’re trying to understand exactly what’s going on in the brain amongst patients who have cognitive impairment versus those who don’t, given the same kinds of treatment. So we’re doing what are called functional magnetic resonance imaging studies or FMRI studies and with the help of these studies we’re recruiting patients or enrolling patients into the study, those who have significant cognitive impairment, those who were spared cognitive impairment and healthy controls. What this will tell us is which areas of the brain are affected the most and that will shed light in terms of how they develop the cognitive impairment. In addition, we’re looking at the genetic predisposition to the cognitive impairment of these patients; so again looking at their DNA profiles amongst those who did and did not develop cognitive impairment.