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Researchers Link Immunosuppressive Mycophenolate Mofetil to Increased Risk of Central Nervous System Lymphoma

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Key Points

  • The analysis showed no post-transplant primary central nervous system cases diagnosed from 1986 to 1997, but the proportion of post-transplant primary central nervous system cases compared to other post-transplant lymphoproliferative diseases was fourfold higher from 2005 to 2014 compared to the proportion in 1995 to 2004, while the total number of post-transplant cases remained stable.
  • The researchers had prescription records on 16 patients who developed primary central nervous system lymphoproliferative disease; 15 had been taking mycophenolate mofetil in the year prior to, or at the time of, their lymphoproliferative disease diagnosis, whereas only 37 of 102 patients who had lymphoma outside the central nervous system had taken mycophenolate mofetil.
  • Among patients with post-transplant disease, primary central nervous system disease accounted for 66.7% of the cases among the six patients who took mycophenolate mofetil but not a calcineurin inhibitor, 23.9% of the cases among the 46 patients who took both an mycophenolate mofetil and a calcineurin inhibitor, and only 1.7% of the cases in the 60 people who took just a calcineurin inhibitor.

A study led by Johns Hopkins researchers has linked the immunosuppressive drug mycophenolate mofetil to an increased risk of central nervous system lymphoma in solid organ transplant patients. But the same study also found that another class of immunosuppressive drugs, calcineurin inhibitors, given alone or in combination with mycophenolate mofetil, appears to protect transplant patients against this rare form of lymphoma. These findings were published by Crane et al in Oncotarget.

Mycophenolate mofetil and calcineurin inhibitors are given to transplant patients to lower the body's natural immunity and to prevent the new organ from being rejected. “Mycophenolate mofetil remains one of the best current medications for immunosuppression that we have,” 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, “but a better understanding of its association with central nervous system lymphoproliferative disease will be crucial to further improving patients' transplant regimes based on all of the risks these patients face.”

Lymphomas and leukemias 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. In recent years, however, clinicians have begun to notice a rise in these primary central nervous system lymphoproliferative disorders in transplant patients. The new study is believed to be the first large enough to identify a link between mycophenolate mofetil treatment and these primary central nervous system tumors.

Study Details

As part of the new study, Dr. Crane and colleagues identified 177 cases of post-transplant lymphoproliferative disorder among patients seen between 1986 and 2014 at The Johns Hopkins Hospital. In that group, 29 people—mostly kidney transplant patients—were diagnosed with primary central nervous system disease.

Dr. Crane said her team's analysis showed no post-transplant primary central nervous system cases diagnosed between 1986 and 1997, but the diagnosis increased markedly in the next decades. The proportion of post-transplant primary central nervous system cases compared to other post-transplant lymphoproliferative diseases was fourfold higher between 2005 and 2014 compared to the proportion in 1995 to 2004, while the total number of post-transplant cases remained stable.

The researchers had prescription records for 16 patients who developed primary central nervous system lymphoproliferative disease. Fifteen of them had been taking mycophenolate mofetil in the year prior to, or at the time of, their lymphoproliferative disease diagnosis, whereas only 37 of 102 patients who had lymphoma outside the central nervous system had taken mycophenolate mofetil.

However, the scientists also said they found that patients who took calcineurin inhibitors either alone or in combination with mycophenolate mofetil seemed to be protected from developing primary central nervous system disease. Among patients with a post-transplant disease, primary central nervous system disease accounted for 66.7% of the cases among the six patients who took mycophenolate mofetil but not a calcineurin inhibitor, 23.9% of the cases among the 46 patients who took both an mycophenolate mofetil and a calcineurin inhibitor, and only 1.7% of the cases in the 60 people who took just a calcineurin inhibitor.

Mycophenolate mofetil was introduced for organ transplant patients in 1995. “Most solid organ transplant patients now receive mycophenolate mofetil as part of their initial regimen,” Dr. 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 mycophenolate mofetil.”

Calcineurin inhibitors such as cyclosporine and tacrolimus are also widely used in transplant patients, but they require careful monitoring to make sure that patients don't get a dose that would be toxic to the kidneys.

Nearly 30,000 people receive solid organ transplants each year in the United States. Some 1% to 2% develop lymphoproliferative disease of any kind, and 10% to 15% of that group develop the central nervous system type.

The monthly cost for mycophenolate mofetil ranges from approximately $67 to $90, depending on the dose. Calcineurin inhibitors tend to be more expensive, ranging from $126 to $578 per month, depending on the dose and type of drug. Calcineurin inhibitors 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 mycophenolate mofetil and calcineurin inhibitors may be protective against central nervous system lymphoproliferative disease in a way that had not previously been appreciated,” concluded Dr. Crane.

Dr. Duffield is the corresponding author for the Oncotarget article.

This study was supported in part by the National Institutes of Health's National Cancer Institute, the Health Resources and Services Administration, and the Mabel Smith Resident Research and Education Award from the Department of Pathology at the Johns Hopkins University School of Medicine.

The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.


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