We are pleased to read the experience from the Royal Brisbane and Women's Hospital supporting the role of systemic methotrexate as prophylaxis against central nervous system (CNS) recurrence in high-risk patients with diffuse large B-cell lymphomas. The lack of substantial toxicity in their patients up to age 79 years further supports the tolerability of this agent in centers experienced in its use. Dr. O'Rourke and colleagues administered intrathecal methotrexate concurrently with rituximab-cyclophosphamide, hydroxydaunorubicin (doxorubicin or Adriamycin), vincristine (Oncovin), and prednisone combination (R-CHOP), followed by 2 infusions of systemic methotrexate with encouraging results similar to ours where intravenous methotrexate is interdigitated with R-CHOP without intrathecal therapy.1 Incorporation of both intrathecal and systemic prophylaxis has been validated as CNS protection compared with a regimen containing no CNS prophylaxis,2 but the relative contribution of the intrathecal versus systemic therapy remains unclear. Given the absence of clear benefit conferred by intrathecal prophylaxis alone,3, 4 we believe the systemic therapy is driving the reduction in CNS recurrences. Of note, CNS recurrence may occur before completion of R-CHOP therapy, so reserving prophylaxis until the end carries a theoretical risk of initiating therapy too late, but this did not occur in the Royal Brisbane and Women's experience.

We, too, administer high-dose systemic methotrexate on an outpatient basis, but we recommend this therapy be conducted only in experienced centers given the risk of treatment-related complications including renal failure, myelotoxicity, and mucositis. Our outpatient approach is to have patients hydrate and alkalinize orally at home the day prior to methotrexate administration. On day 15, patients are further alkalinized and hydrated intravenously in clinic, followed by the intravenous methotrexate. Patients return 24 hours later to check the methotrexate level and their renal function and to receive their initial dose of leucovorin rescue and additional intravenous hydration. Patients clearing the drug well without renal toxicity continue leucovorin rescue orally every 6 hours for 12-16 total doses and return on day 22 for their next cycle of R-CHOP. Patients with renal failure or delayed drug clearance are admitted for intensified leucovorin, hydration, and supportive care.


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  • 1
    Abramson JS, Hellmann M, Barnes JA, et al. Intravenous methotrexate as central nervous system prophylaxis is associated with a low risk of CNS recurrence in high-risk patients with diffuse large B-cell lymphoma. Cancer. 2010; 116: 4283-4290.
  • 2
    Tilly H, Lepage E, Coiffier B, et al.; Groupe d'Etude des Lymphomes de l'Adulte. Intensive conventional chemotherapy (ACVBP regimen) compared with standard CHOP for poor-prognosis aggressive non-Hodgkin lymphoma. Blood. 2003; 102: 4284-42899.
  • 3
    Bernstein SH, Unger JM, Leblanc M, Friedberg J, Miller TP, Fisher RI. Natural history of CNS relapse in patients with aggressive non-Hodgkin's lymphoma: a 20-year follow-up analysis of SWOG 8516—the Southwest Oncology Group. J Clin Oncol. 2009; 27: 114-119.
  • 4
    Boehme V, Schmitz N, Zeynalova S, Loeffler M, Pfreundschuh M. CNS events in elderly patients with aggressive lymphoma treated with modern chemotherapy (CHOP-14) with or without rituximab: An analysis of patients treated in the RICOVER-60 trial of the German high-grade non-Hodgkin lymphoma study group (DSHNHL). Blood. 2009; 113: 3896-3902.