Of the 1727 patients with PCNSL, most patients (69.3%) had diffuse large B-cell lymphoma (DLBCL), with the brain as the primary location (82.5%). There was a statistically significant difference in the prevalence of any autoimmune condition in the PCNSL compared with controls (21.1% vs 17.3%, respectively; adjusted OR (aOR), 1.24; 95% CI, 1.09-1.40; P =.0007). There were statistically significant associations found between PCNSL and multiple autoimmune conditions, including: SLE (aOR, 1.96; 95% CI, 1.31-2.92), PAN (aOR, 3.99; 95% CI, 1.62-9.81), AIH (aOR, 6.31; 95% CI, 1.50-26.57), MG (aOR, 3.40; 95% CI, 1.90-6.07), and uveitis (aOR, 3.86; 95% CI, 2.64-5.64).

The authors concluded that PCNSL is significantly associated with SLE, PAN, AIH, MG, and uveitis. The authors cited several limitations. Unfortunately, no data on medications was included in this study as the authors were concerned about limiting the patient population studied as Medicare Part D data was only available from 2007 onward. The study population was only based on Medicare patients, and the SEER database included significantly more patients who lived in urban or affluent areas.

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Outside of this study, multiple drugs that are typically administered for autoimmune conditions have been associated with developing PCSNL. These medications include azathioprine, prednisone, mycophenolate, methotrexate, and cyclophosphamide.6 Azathioprine is one of the most frequently mentioned medications in the literature, as it has been used to treat a multitude of autoimmune conditions. Both EBV-positive and -negative patients have been reported to develop PCNSL while taking azathioprine.7 The PCNSL risk is typically based on the duration of therapy and can potentially return back to the baseline risk of the general population after therapy discontinuation.7 It has been postulated that immunomodulatory medications such as azathioprine can cause a total decrease in both the qualitative and quantitative properties of CD4 and CD8 cells, which would predispose a patient to developing PCNSL.6,7

Another medication that has been reported in the literature to be associated with PCNSL is mycophenolate mofetil (MMF). MMF can be used for many purposes, such as after a liver or kidney transplant, in SLE, or to treat AIH.

It appears that the duration of therapy with MMF also plays a role in the risk of PCNSL.6 Similar to azathioprine, it also appears that discontinuation of MMF can help reduce the risk of PCNSL development. One study at a single center found that PCNSL was more commonly associated with patients who had a kidney transplant vs those who received other solid organs; and with those who had EBV, DLBCL, and MMF compared with those who had other posttransplant lymphoproliferative disorders (PTLDs) outside of the CNS.8 Interestingly, this study also found that the use of calcineurin inhibitors (CNIs) was protective against PCNSL, which was confirmed with a multivariate analysis of the United Network for Organ Sharing-Organ Procurement and Transplant Network (UNOS-OPTN) data.

As the pool of elderly patients who may be considered for solid organ transplant widens — such as the inclusion of those with chronic liver or kidney disease — the number of patients exposed to immunosuppressive medications will undoubtedly increase and may potentially provide another subgroup of patients to follow in the future. In addition, if life expectancy increases along with the precision of diagnostic studies for autoimmune conditions, more patients will be diagnosed with, and treated for, these conditions in the future.

Future studies will have to focus on whether or it is the medications for autoimmune conditions themselves that predispose elderly patients to PCNSL, the actual disease state itself that presents the risk, or a combination of these 2 factors. The role of EBV in patients older than 65 years will also have to be further characterized, as this could be a crucial prognostic tool when screening patients for the receipt of immunosuppressive medications.

References

  1. Grommes C et al. Primary CNS lymphoma. J Clin Oncol. 2017 Jul 20;35(21):2410-18.
  2. Shiels MS et al. Trends in primary central nervous system lymphoma incidence and survival in the U.S. Br J Haematol. 2016 Aug;174(3):417-24
  3. Mahale P et al. Autoimmune conditions and primary central nervous system lymphoma risk among older adults. Br J Haematol. 2019 Oct 17.  doi: 10.1111/bjh.16222. [Epub ahead of print]
  4. Shiels MS et al. The epidemic of non-Hodgkin lymphoma in the United States: disentangling the effect of HIV, 1992-2009. Cancer Epidemiol Biomarkers Prev. 2013 Jun;22(6):1069-78.
  5. Hochberg FH et al. Primary central nervous system lymphoma. J Neurosurg. 1988;68(6):835. 
  6. Kleinshcmidt-DeMasters BK et al. Epstein Barr virus-associated primary CNS lymphomas in elderly patients on immunosuppressive medications. J Neuropath Exp Neurol. 2008 Nov;67(11):1103-11.
  7. Glesner MK et al. Primary CNS lymphoma in a patient treated with azathioprine. BMJ Case Rep. 2014 Sep 1;2014.
  8. Crane GM et al. Primary CNS lymphoproliferative disease, mycophenolate and calcineurin inhibitor usage. Oncotarget. 2015 Oct 20;6(32):33849-66.