Methotrexate and Temozolomide Plus Intrathecal Liposomal Cytarabine for Primary or Secondary Central Nervous System Lymphoma
Authors: Falchi Lorenzo , Gunnellini Marco , Angeletti Ilaria , Franco Laura , Liberati Anna Marina 
Published: October 2019

Abstract
Abstract 4899
Treatment of central nervous system (CNS) lymphoma remains challenging, and balance between therapeutic effectiveness and toxicity is difficult to find. The addition of systemic chemotherapy to whole brain radiotherapy has significantly improved the outcome of these patients. However, this combined strategy is burdened with possible acute and/or delayed severe neurotoxicity, particularly in elderly patients. Chemotherapy-only approaches, with or without concomitant intrathecal (IT) therapy, for CNS lymphoma have been explored. Moreover, deferring radiotherapy to the time of first or subsequent relapse may reduce the risk of severe neurotoxicity, without altering outcome. Recently, high-dose methotrexate and temozolomide (HD-MTX-TMZ) without IT CNS prophylaxis have been studied in PCNSL elderly patients. This regimen appears effective, while substantially decreasing acute and/or delayed neurotoxicity. Conflicting data exist regarding the safety of combining IT liposomal cytarabine (LC) and systemic CNS-penetrating therapy. We report our preliminary experience with HD-MTX-TMZ plus IT LC used upfront or as salvage in 4 primary or secondary CNS lymphoma patients, only one of which under the age of 60 (56). Treatment consisted of induction: MTX 3g/ms d 1, 10, 20, TMZ 100 mg/ms d 1–5; and maintenance for ≥SD patients, and for up to 5 additional cycles: MTX 3g/ms d 1, TMZ 100 mg/ms d 1–5, every month. Fifty mg IT LC were given concomitantly for up to 6 doses planned. LC doses were separated by at least 14 days from one another and at least 7 days from HD-MTX. Pt n. 1 (56 year-old male) had a history of testicular diffuse large B cell lymphoma (DLBCL), stage IVA. He received chemo-radiotherapy with 4 concomitant IT LC injections as CNS prophylaxis. Complete response (CR) was achieved. Two months later, he presented with headache and dizziness. MRI and PET revealed metabolically active righ cerebellar lesion. Karnofsky performance status (KPS) was 50%. Rituximab plus TMZ and IT MTX were initiated but soon discontinued due to a G4 CMV-related pneumonia. After complete recovery, HD-MTX-TMZ was started with concomitant 4 IT LC injections, and precautionary stem cell harvest. No significant G3-4 toxicities were observed during treatment. At 9 months of follow-up post-treatment, the lesion is stable with no contrast enhancement at MRI and PET is negative, suggesting a CRu. Pt 2 (76 year-old male) was referred in May 2009 with a diagnosis of CNS peripheral T-cell lymphoma not otherwise specified with MRI- and PET-documented multiple brain localizations (i.e. hypophyseal infundibulum, cavernous sinus, cerebellum). KPS was 60%. He was treated with systemic steroids and TMZ 150 mg/ms d 1–5/28. In August 2009 disease progressed after two cycles, and HD-MTX-TMZ was started. IT LC was added as CNS prophylaxis with 4 drug injections. Toxicity consisted of G2 renal insufficiency and G3 steroid-induced diabetes mellitus, both resolved. Treatment resulted in marked shrinkage of all lesions, with no contrast enhancement and PET is negative, indicating CRu, which is stable at 5 months of follow-up. Pt 3 (68 year-old female) was diagnosed with PCNSL, DLBCL, with left cerebellar localization. KPS was 50%. HD-MTX-TMZ and concomitant IT LC injections were initiated as first-line therapy. Four maintenance cycles and 5 IT LC injections have been performed so far. Toxicities included G3 atrial fibrillation. Interim MRIs documented very good partial remission of the disease. Pt 4 (71 year-old female) was diagnosed with DLBCL stage IIIE (i.e. subcutaneous facial localization) in July 2009, and treated with R-COMP (liposomal doxorubicine in lieu of the free formulation) for 8 cycles. She obtained CR, but in July 2010 presented with aphasia and facial hemiparesis. Brain MRI showed multiple subcortical lesions in both hemispheres, biopsy-confirmed to be lymphoma. The first IT LC injection and HD-MTX dose were given without significant toxicity. All patients completed induction and 5 maintenance cycles. HD-MTX-TMZ and concomitant IT LC therapy appeared feasible and overall well tolerated. No acute neurologic complications were observed. Follow-up is too short to make comments on delayed neurotoxicity. Increasing the number of LC injections might be reasonable and at least 7 days should be interposed between systemic and IT therapy. HD-MTX-TMZ plus IT LC deserves further evaluation in a larger prospective setting.

Disclosures:
No relevant conflicts of interest to declare.