The immunosuppressive drug mycophenolate mofetil (CellCept, Roche Palo) may be linked to an increased risk for primary central nervous system (PCNS) lymphoma in patients who have undergone solid organ transplants, reports a new study.
However, in the same study, the authors found that calcineurin inhibitors, when used alone or in combination with mycophenolate mofetil, appear to be protective against CNS lymphoma. This class of drugs includes cyclosporine (multiple brands) and tacrolimus (multiple brands).
The authors identified 174 cases of posttransplant lymphoproliferative disease (PTLD) that occurred during a 28-year period at the Johns Hopkins Hospital in Baltimore, Maryland. Of these, 29 cases involved the central nervous system.
Although no cases of PCNS lymphoma were diagnosed at the facility between 1986 and 1997, they constituted 37% of PTLD cases that were diagnosed from 2011 to 2014. PCNS disease appeared to be more frequently associated with renal transplants (as opposed to other types of solid organ transplants), Epstein-Barr virus, large B-cell morphology, and the use of mycophenolate mofetil, as compared with PTLD that did not involve the CNS.
The article was published September 16 in Oncotarget.
“Our study is the first to describe the association of PCNS PTLD with mycophenolate mofetil and a protective role for calcineurin inhibitors,” said study author Genevieve Crane, MD, PhD, a fellow in hematopathology at the Johns Hopkins Hospital. “An increased risk of CNS PTLD had been seen with one of the new transplant regimens, including mycophenolate and belatacept, but it was not clear which aspect of the regimen this was associated with or how it could be addressed.”
“Given that the outcomes with these regimens appear otherwise quite favorable, our finding that calcineurin inhibitors are protective against this dreaded complication could be very powerful,” she told Medscape Medical News.
However, these findings will probably not have too much of an effect on the treatment regimen for transplant patients. The factors that go into the decision making regarding individual transplant regimens are complex; these include a risk for rejection, opportunistic infection, and damage to the transplanted organ by the medications themselves or from other types of toxicities that can vary between patients, explained Dr Crane.
“Given the relatively low incidence of PTLD, this will not be the dominant factor driving that decision making,” she said. “However, new regimens lacking calcineurin inhibitors are becoming increasingly common.”
Therefore, it is likely that the observed increase in the incidence of PCNS PTLD is likely due not only to immunosuppression with mycophenolate mofetil but also to a decline in the use of the protective calcineurin inhibitors.
“One intriguing possibility is that it may be possible to use lower levels of calcineurin inhibitors to protect against CNS disease, given how hydrophobic these drugs are and their distribution to the brain,” Dr Crane added. “In theory, this combination may avoid systemic — and particularly renal ― toxicities while still protecting the brain. We are hoping our findings stimulate further trials to investigate this.”
Higher Rates of CNS Disease
PTLD is a well-known complication of solid organ transplants, and both the type and level of immunosuppression are associated with the risk of developing lymphoproliferative disease. CNS involvement is relatively uncommon in PTLD, occurring in about 10% to 15% of cases, the authors note.
Dr Crane and colleagues conducted a retrospective review of all PTLDs diagnosed at Johns Hopkins Hospitals for the past 3 decades. They also analyzed publicly available data collected by the United Network for Organ Sharing (UNOS) and the Organ Procurement and Transplant Network (OPTN).
The proportion of PCNS PTLD cases that were diagnosed during the period 2005-2014 was 4.4-fold higher than in the period 1995-2004 (P < .0001).
As compared with patients who developed non-CNS PTLD, those with CNS involvement were more likely to have been taking mycophenolate mofetil (15/16) in the year prior to and/or at the time of diagnosis (37/102 non-CNS; odds ratio [OR], 41; 95% confidence interval [CI], 5.3 – 324; P < .001).
In contrast, in patients who were receiving regimens that included calcineurin inhibitors, the incidence of PCNS PTLD was significantly lower. PCNS disease accounted for 66.7% of the PTLD cases that developed in patients using mycophenolate mofetil but not calcineurin inhibitors, compared with only 1.7% of the PTLD diagnoses in patients receiving calcineurin inhibitors but not mycophenolate mofetil.
This extrapolated to a 118-fold higher risk for patients receiving mycophenolate mofetil without calcineurin inhibitors to develop PCNS compared with non-CNS PTLD than patients receiving calcineurin inhibitors alone (95% CI, 8.7-1597; P < .001).
Patients who received both drugs had an intermediate risk of developing PCNS disease, with an 18-fold increased risk compared with patients receiving calcineurin inhibitors alone (95% CI, 2.3 – 150; P < .01), suggesting that calcineurin inhibitors might confer a partial protective effect.
Second Analysis Adds Strength
The authors conducted a second analysis using the larger UNOS-OPTN STAR database that included 6966 PTLD cases, of which data on associated immunusuppression were available for 4569 cases. A multivariate analysis of these data confirmed their findings; both use of mycophenolate mofetil and lack of calcineurin inhibitors were independently associated with a risk of developing PCNS PTLD.
PCNS occurred in 11.4% of PTLD cases that developed in patients receiving mycophenolate mofetil but without calcineurin inhibitors. However, PCNS occurred in only 0.53% of PTLD cases that arose in patients receiving calcineurin inhibitors without mycophenolate mofetil.
Currently, there does not seem to be a way of identifying patients who may be at higher risk for PCNS lymphoproliferative disease. “Overall, we did not identify substantial differences in terms of patient demographics in terms of who developed primary CNS vs non-CNS disease,” said Dr Crane.
But she pointed out that PCNS disease was exceedingly rare in children and that patients with a renal transplant as opposed to a transplant involving a different solid organ were also at higher risk independently of the transplant regimen.
“A larger study would be required to identify further risk factors with the adult renal transplant population and would be extremely helpful for further tailoring treatment regimens to optimize patient outcomes,” Dr Crane added.
The study was supported in part by a grant from the National Institutes of Health and by the Health Resources and Services Administration and by funding from the Mabel Smith Resident Research and Education Award, Department of Pathology, the Johns Hopkins School of Medicine. The authors have disclosed no relevant financial relationships.
Oncotarget. Published online September 16, 2015.