Advances in the Treatment of Secondary CNS Lymphoma
Authors: Norbert Schmitz, Huei Shan Wu
Journal: Journal of Clinical Oncology (2015)

Secondary involvement of the CNS by diffuse large B-cell lymphoma (DLBCL) occurs in less than 1% to more than 10% of patients with DLBCL depending on the presence or absence of five risk factors that compose the International Prognostic Index (age, elevated lactate dehydrogenase, poor performance status, advanced stage, and involvement of one extranodal site). Involvement of the kidneys and/or adrenal glands has been found to represent a site-specific additional risk factor for secondary CNS lymphoma (SCNSL). Other risk models have been proposed but not validated. It is also likely that molecular features of the tumor (eg, presence of MYC or BCL2 rearrangements, double-hit lymphomas) will add to or substitute for these clinical risk factors in the near future. SCNSL occurs early (frequently within weeks to months) after diagnosis of systemic disease; can affect the brain (or spinal cord and cranial nerves), the meninges, or both; and until recently, was almost always fatal. Because progression or relapse in the CNS occurs this early after diagnosis, most investigators believe that a significant number of patients prone to develop SCNSL harbor lymphoma cells in the brain parenchyma or the CSF at the time of diagnosis. Modern state-of-the-art techniques like magnetic resonance imaging or fluorescence-activated cell sorting analysis of CSF are much more sensitive in detecting SCNSL compared with clinical judgment, computed tomography scans, or microscopic interpretation of cytospin smears and probably would allow documentation of CNS involvement in an unknown but potentially significant number of patients scoring as CNS negative when traditional methodology is used. As a first step, however, consensus is needed regarding which patients are considered at high enough risk to warrant CNS-specific diagnostic approaches that will likely yield negative results in the majority of patients, will create discomfort, if not more serious adverse effects, in some patients, and will increase costs. The ability to identify patients with documented CNS disease could prompt immediate management with a CNS-specific treatment protocol, whereas patients who are CNS negative by magnetic resonance imaging and fluorescenceactivated cell sorting analysis (for instance) would receive immunochemotherapy like any other patient with DLBCL. Alternatively, the highest risk group might be candidates for CNS prophylaxis. With most retrospective analyses showing no benefit of intrathecal (IT) injections of cytotoxic drugs (methotrexate [MTX], cytarabine [Ara-C], prednisone, or combinations thereof), this prophylactic strategy can no longer be generally be recommended. If deemed necessary, more complex and more toxic approaches, such as administration of systemic high-dose MTX or combinations of cytotoxic drugs that cross the blood-brain barrier (BBB) as pioneered with the French doxorubicin, cyclophosphamide, vindesine, bleomycin, and prednisone regimen, should be considered. Treatment of SCNSL with IT injections, whole-brain radiotherapy, or systemic administration of cytotoxic drugs that do not cross the BBB has largely been ineffective. Only when repeated courses of high-dose MTX and Ara-C were introduced did patients begin to show measurable benefit and survive significantly longer; cure, however, remained the exception to the rule. Until today, virtually all other drugs known to cross the BBB (procarbazine, etoposide, ifosfamide, thiotepa, carmustine [BCNU], and others) have been used mostly in combination with MTX and/or Ara-C to further improve results. As with MTX and Ara-C, most other drugs seem to be most effective at high doses, necessitating transplantation of autologous hematopoietic stem cells. Consequently, the most recent and successful protocols to treat primary and secondary CNS lymphoma consist of complex treatment algorithms encompassing two or more courses of high-dose MTX and/or Ara-C administered together with other BBB-crossing agents, followed by high-dose therapy combining BBB-crossing agents like BCNU, thiotepa, busulfan, oretoposide,whichcanbedoseescalatediftransplantationofhematopoietic stem cells ensues. The first prospective phase II study demonstrating the potential of this strategy was reported by Korfel et al. Patients up to age 65 years received induction chemotherapy with high-dose MTX, ifosfamide, and dexamethasone followed by high-dose Ara-C, thiotepa, and dexamethasone. Responding patients were consolidated with highdose therapy consisting of BCNU, thiotepa, and etoposide and transplantation of autologous blood stem cells. With this approach, the 2-year treatment failure rate was 49% 19% and the 2-year overall survival rate was 63% 19%. Another study was reported by Doorduyn et al in 2012; this study, which is not fully published yet, is of particular interest because for the first time rituximab was given with the cytotoxic agents. Because many patients with lymphoma experiencing relapse in the CNS had received rituximab as part of conventional first-line therapy until shortly before relapse and intravenous rituximab does not result in significant therapeutic concentrations in the CNS when the BBB is intact, early protocols including high-dose therapy/ASCT did not use rituximab or any other lymphoma-directed antibody. After it was appreciated that rituximab monotherapy can induce short-lived remissions in patients with CNS disease and thus must be able to penetrate into the CNS of JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L VOLUME 33 NUMBER 33 NOVEMBER 2