Transplant Drug Linked to Increased Risk of Lymphoma

Immunosuppressive drug linked to central nervous system lymphoma in solid organ transplant patients.

The immunosuppressive drug mycophenolate mofetil (MMF) has been linked to an increased risk of central nervous system (CNS) lymphoma in solid organ transplant patients, according to a study from Johns Hopkins researchers.

The same study, however, also found that another class of immunosuppressive drugs called calcineurin inhibitors (CNIs), given singularly or in combination with MMF, appears to protect transplant patients against the rare form of lymphoma.

MMF and CNIs are administered to transplant patients to decrease the body’s natural immunity and to prevent new organs from being rejected.

“MMF remains one of the best current medications for immunosuppression that we have but a better understanding of its association with CNS lymphoproliferative disease will be crucial to further improving patients’ transplant regimes based on all of the risks these patients face,” said Amy Duffield, MD, PhD, assistant professor of pathology and oncology at the Johns Hopkins University School of Medicine and a member of the Johns Hopkins Kimmel Cancer Center.

Blood cancers like lymphomas and leukemia can be complications of solid organ transplants, but these cancers rarely start in the central nervous system, explained Genevieve Crane, MD, PhD, a fellow in hematopathology at The Johns Hopkins Hospital.

Physicians have recently begun to notice a rise in these primary central nervous system (PCNS) lymphoproliferative disorders in transplant patients, however. The new study is the first of its kind to be large enough to identify a link between MMF treatment and these PCNS tumors, Crane noted.

The researchers identified 177 cases of post-transplant lymphoproliferative disorder among patients seen between 1986 and 2014 at The Johns Hopkins Hospital. Of the 177 cases, 29 were diagnosed with PCNS disease.

The team did not notice any post-transplant PCNS cases diagnosed between 1986 and 1997, but the diagnosis increased significantly over the next decades with the proportion of post-transplant PCNS cases fourfold higher between 2005 and 2014.

The researchers had prescription records on 16 patients who developed PCNS lymphoproliferative disease.

Of those, 15 had been taking MMF in the year prior to, or at the time of, their lymphoproliferative disease diagnosis. However, only 37 of 102 patients who had lymphoma outside the central nervous system had taken MMF.

Scientists also found that patients who took CNIs either singularly or in combination with MMF appeared to be more protected from developing PCNS disease.

Of those who had a post-transplant disease, PCNS disease was found in 66.7% of the cases among 6 patients who took MMF but not a CNI, 23.9% of the cases among the 46 patients who took both an MMF, and a CNI; and just 1.7% of the cases in the 60 people who took only a CNI.

Researchers found these trends to be largely similar in a set of 6.966 patients with post-transplant lymphoproliferative disease.

The records of these patients were taken from an organ transplant database managed by the Organ Procurement and Transplantation Network and the United Network for Organ Sharing.

“Most solid organ transplant patients now receive MMF as part of their initial regimen,” Crane explained. “There is a standard daily dose, and it does not require monitoring of drug levels in the blood. This is one of the major advantages of MMF.”

CNIs are also widely used in transplant patients, but require monitoring to make sure that patients don’t get a toxic dose.

Of the 30,000 people receiving solid organ transplants each year in the United States, 1 to 2% develop lymphoproliferative disease and 10 to 15% of that group develop the CNS type, according to Crane.

Depending on the dosage, MMF cost can range between $67 and $90 per month. CNIs, however, are more expensive, costing between $126 and $578 per month. CNIs also require periodic blood tests to monitor levels of the drug.

“More research needs to be done to confirm our results, but our work suggests that, at least in some patients, the combination of MMF and CNIs may be protective against CNS lymphoproliferative disease in a way that had not previous been appreciated,” Crane concluded.