Methotrexate for Primary central nervous system lymphoma

In neurooncology and onco-hematology, intraventricular injection of chemotherapeutic agents (most typically, methotrexate) is an inevitable part of many protocols for treating patients with malignant tumors of the CNS, neuroleukemia, CNS lymphomas and some other disorders.


High-dose MTX is associated with a high proportion of radiographic responses and a low proportion of grade III/IV toxicity in patients 70 or more years of age. High-dose MTX should be considered as a feasible treatment option in elderly patients with PCNSL 1).


MTX-monotherapy is tolerable in terms of adverse effects and still considered as a treatment option in patients with PCNSL. However, an additional therapeutic option should be prepared for non-CR responders to induction chemotherapy 2).


The addition of intraventricular MTX (rather than just intrathecal via LP) delivered through a Ommaya reservoir (6 doses of 12 mg twice a week, with IV leucovorin rescue) may result in even better survival 3)

In the event of an intrathecal MTX overdose (OD), interventions recommended 4) :

ODs of up to 85 mg can be well tolerated with little sequelae; immediate LP with drainage of CSF can remove a substantial portion of the drug (removing 15 ml of CSF can eliminate ≈ 20–30% of the MTX within 2 hrs of OD). This can be followed by ventriculolumbar perfusion over several hours using 240 ml of warmed isotonic preservative-free saline entering through the ventricular reservoir and exiting through a External lumbar cerebrospinal fluid drainage. For major OD of > 500 mg, add intrathecal administration of 2,000 U of carboxypeptidase G2 (an enzyme that inactivates MTX). In cases of MTX OD, systemic toxicity should be prevented by treating with IV dexamethasone and IV (not IT) leucovorin.


Therapeutic Outcomes and Toxicity of High-Dose Methotrexate-Based Chemotherapy for Elderly Patients with Primary Central Nervous System Lymphoma: A Report on Six Cases. 5).


A study provides Class III evidence that in immunocompetent patients with primary CNS lymphomas (PCNSLs), high-dose methotrexate (HD-MTX) plus rituximab compared with HD-MTX alone improves complete response (CR) and overall survival rates 6).

Case series

Yoon et al. presented the experiences with high-dose methotrexate (HD-MTX) monotherapy for immunocompetent patients with PCNSL at three institutions and investigate factors related to survival.

PCNSL patients, who were histologically confirmed with diffuse large B cells and treated with HD-MTX monotherapy from 2001 to 2016, were retrospectively reviewed. Patients underwent induction chemotherapy with 8 g/m2 of MTX every 10 days (maximum three cycles). Maintenance chemotherapy of 3.5 g/m2 of MTX (maximum six cycles) was selectively performed depending on the response to induction chemotherapy.

A total of 67 patients were included. Although seven patients discontinued induction chemotherapy because of MTX toxicity, 40 (59.7%) patients showed a complete response (CR) to induction chemotherapy. Twenty-six (38.8%) and three (4.5%) patients showed a CR and partial response, respectively, after maintenance chemotherapy. Forty-one patients with recurrence or progression following HD-MTX underwent second-line treatment. Progression-free survival rates were 43% and 24% at 1 and 2 years, respectively. The median overall survival was 40.3 months. In a multivariate analysis, a radiological CR to induction chemotherapy was a significant factor related to prolonged progression-free survival and overall survival (P < 0.05).

MTX-monotherapy is tolerable in terms of adverse effects and still considered as a treatment option in patients with PCNSL. However, an additional therapeutic option should be prepared for non-CR responders to induction chemotherapy 7).


A single-institution retrospective analysis was performed for 12 patients with newly diagnosed PCNSL treated with combined high-dose methotrexate (HD-MTX) and RTX. MTX was administered biweekly at 8 g/m2/dose until a complete response (CR) was achieved or for a maximum of eight doses. RTX was provided for a total of eight weekly doses at 375 mg/m2/dose. Following a median of 11 cycles of MTX, the radiographic overall response rate was 91% and the CR rate was 58%. A CR was achieved after a median 6 cycles of MTX. The median progression-free survival time was 22 months and the median overall survival time has not yet been attained. These results compare favorably to single-agent HD-MTX and suggest a role for immunochemotherapy in the treatment of PCNSL 8).


Zhu et al. studied the response and adverse effects of intravenous high-dose MTX in patients who were 70 or more years of age at the time of diagnosis. They identified 31 patients diagnosed with PCNSL at age > or =70 years (median, 74 years) who were treated with high-dose MTX (3.5-8 g/m(2)) as initial therapy from 1992 through 2006. The best response to MTX was determined by contrast-enhanced MRI. Toxicity was analyzed by chart review. These 31 patients received a total of 303 cycles of MTX (median, eight cycles per patient). Overall, 87.9% of the cycles required dose reduction because of impaired creatinine clearance. In 30 evaluable patients, the overall radiographic response rate was 96.7%, with 18 complete responses (60%) and 11 partial responses (36.7%). Progression-free survival and overall survivals were 7.1 months and 37 months, respectively. Grade I-IV toxicities were observed in 27 of 31 patients and included gastrointestinal disturbances in 58% (3.2% grade III), hematological complications in 80.6% (6.5% grade III), and renal toxicity in 29% (0% grade III/IV). High-dose MTX is associated with a high proportion of radiographic responses and a low proportion of grade III/IV toxicity in patients 70 or more years of age. High-dose MTX should be considered as a feasible treatment option in elderly patients with PCNSL 9).

References

1) , 9)

Zhu JJ, Gerstner ER, Engler DA, Mrugala MM, Nugent W, Nierenberg K, Hochberg FH, Betensky RA, Batchelor TT. High-dose methotrexate for elderly patients with primary CNS lymphoma. Neuro Oncol. 2009 Apr;11(2):211-5. doi: 10.1215/15228517-2008-067. Epub 2008 Aug 29. PMID: 18757775; PMCID: PMC2718993.
2) , 7)

Yoon WS, Park JS, Kim YI, Chung DS, Jeun SS, Hong YK, Yang SH. High-dose methotrexate monotherapy for newly diagnosed primary central nervous system lymphoma: 15-year multicenter experience. Asia Pac J Clin Oncol. 2020 Sep 25. doi: 10.1111/ajco.13427. Epub ahead of print. PMID: 32978898.
3)

DeAngelis LM, Yahalom J, Thaler HT, Kher U. Com- bined Modality Therapy for Primary CNS Lympho- mas.JClinOncol.1992;10:635–643
4)

O’Marcaigh AS, Johnson CM, Smithson WA, et al. Successful Treatment of Intrathecal Methotrexate Overdose by Using Ventriculolumbar Perfusion and Intrathecal Instillation of Carboxypeptidase G2. Mayo Clin Proc. 1996; 71:161–165
5)

Tempaku A, Takahashi Y, Kamada H. Therapeutic Outcomes and Toxicity of High-Dose Methotrexate-Based Chemotherapy for Elderly Patients with Primary Central Nervous System Lymphoma: A Report on Six Cases. Acta Haematol. 2019 May 21:1-2. doi: 10.1159/000499100. [Epub ahead of print] PubMed PMID: 31112947.
6)

Holdhoff M, Ambady P, Abdelaziz A, Sarai G, Bonekamp D, Blakeley J, Grossman SA, Ye X. High-dose methotrexate with or without Rituximab in newly diagnosed primary CNS lymphoma. Neurology. 2014 Jul 15;83(3):235-9. doi: 10.1212/WNL.0000000000000593. Epub 2014 Jun 13. PubMed PMID: 24928128; PubMed Central PMCID: PMC4117362.
8)

Ly KI, Crew LL, Graham CA, Mrugala MM. Primary central nervous system lymphoma treated with high-dose methotrexate and rituximab: A single-institution experience. Oncol Lett. 2016 May;11(5):3471-3476. doi: 10.3892/ol.2016.4393. Epub 2016 Mar 30. PMID: 27123138; PMCID: PMC4840907.

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