Diffuse Large B-Cell Lymphoma with Leptomeningeal Disease: Role for High-Dose Intravenous Methotrexate

Introduction:
Leptomeningeal disease (LMD) is a condition whereby cancer cells metastasize to the arachnoid and pia mater, from where they gained access to the cerebrospinal fluid and caused various neurological complications. LMD is relatively rare in diffuse large B-cell lymphoma (DLBCL) or other types of non-Hodgkin lymphoma. As with LMD from solid tumors, the condition is considered incurable and treatment options are usually centered on improving neurological symptoms and prolonging survival. In recent years, high-dose intravenous methotrexate has been used as a means for prophylaxis in DLBCL with high risk of central nervous system (CNS) relapse, however, data is not conclusive on its efficacy.
Methods:
76-year-old male presented with progressively worsening generalized weakness. He was diagnosed with diffuse large B-cell lymphoma several months ago with subsequent development of leptomeningeal disease, for which he received systemic chemotherapy with R-EPOCH and R-CHOP, in addition to several sessions of intrathecal methotrexate. He was admitted to the hospital due to concern for spinal cord compression from lymphoma. Magnetic resonance imaging (MRI) of the spine showed no evidence of cord compression, and he was given supportive care for his symptoms. Given known history of LMD and high risk of relapse, decision was made to start high-dose intravenous methotrexate for CNS prophylaxis followed by leucovorin rescue. He developed profound renal failure and was started on intravenous fluids, while leucovorin rescue therapy was extended. His renal functions slowly improved and he was discharged to short-term nursing home for continued rehabilitation. However, he was brought back to the hospital within a week with worsening neurological symptoms including intermittent episodes of unilateral blindness, altered mentation, and fluctuating weakness. He also became critically ill with sepsis and febrile neutropenia. He passed away shortly after being transitioned to comfort measures only.
Results:
Systemic administration of HD-MTX is the most widely used alternative to intrathecal chemotherapy in patients with leptomeningeal metastases and achieves higher concentration of methotrexate in cerebrospinal fluid than does IT administration. Although recommended by some guidelines and increasingly utilized as a means of CNS prophylaxis in high-risk patients, the use of HD-MTX in DLBCL remains controversial, as evidence supporting this practice is limited to small retrospective studies and several recent studies had demonstrated no benefit. In the case of our patient, no obvious benefit was observed following the use of HD-MTX, as he developed signs of recurrent LMD within 2‚Äâweeks of therapy completion.
Discussion:
The role of high-dose intravenous methotrexate for CNS prophylaxis in patients with diffuse large B-cell lymphoma remains controversial and the approach is associated with significant toxicity. Further researches are needed to further evaluate its efficacy.