This Is a Title In Title Case: Safety and Efficacy of Intravenous 4.5g/m2 Methotrexate over 90 Minutes for Hematological Malignancy with Cerebral Involvement
Authors: Pan Ling , Chen Meng , Zhang Li , Jia Yongqian , Niu Ting 
Published: October 2019

Abstract

Background
Central nervous system (CNS) involvement is still a significant complication in hematological malignancy and makes an obvious obstacle on improving survival. Resolution of CNS involvement has been a therapeutic challenge and has not been clinically addressed even though application of transplantation. Although the presence of CNS involvement at diagnosis of hematological malignancy is uncommon, about >50% and 25% of patients will eventually develop CNS involvement in acute lymphocytic leukemia (ALL) and diffuse large B cell lymphoma (DLBCL) with high risk, respectively, significantly higher than that of 20% in adult acute myeloid leukemia (AML). Different from substantial efficacy achieved from childhood acute lymphocytic leukemia treated with radiation therapy, systemic chemotherapy, and/or intrathecal injection (IT), limited benefit was obtained for adult after CNS recurrence, due to toxicity and insufficient cranial concentrations. The published data showed that patients with B-cell malignancy with cerebral involvement can be treated with high-dose methotrexate (HD-MTX) by intravenous (IV) for 24 hour, but the efficacy is not satisfied. We have successfully employed 4.5g/m2methotrexate over 90 minutes for the treatment of two patients with cerebral involvement.

Method
Case 1 was a 40-year-old female with Philadelphia-positive (Ph+) ALL for 12 months and had been treated with three IVD induction chemotherapy regimen (which is commonly used in the hospital, as imatinib 400 mg, qd; vindesine 4 mg, on days 1, 8, 15 and 22; dexamethasone 10 mg/m2/d, days 1–4, days 8-11, days 15-18 and days 22-25) and achieved complete remission(CR), then she was treated with three courses of IVD regimen (imatinib 400 mg, qd; vindesine 4 mg, on days 1, 11; dexamethasone 10 mg/m2/d, days 1–5, days 11-15). But she refused to intrathecal injection as well as maintainance therapy. One year after the diagnosis of ALL, she developed headache then progressed to coma. Cerebral magnetic resonance imaging (MRI) showed encephaledema and meningeal infiltration and bone marrow examination showed ALL relapse. Case 2 was a 55-year-old female with DLBCL (non-germinal center) for 3 years and had been treated with 8 courses of R-CHOP. Three years after the last courses of chemotherapy, she developed weakness of right lower limb, cognitive impairment and disorientation. Cerebral MRI showed parenchymal brain enhancing lesions and peripheral edema. With the approval of local ethical committee, the two patients were subjected to the regimen of intravenous 4.5g/m2 methotrexate over 90 minutes, which was performed every 2 weeks.

Result
For case 1, headache was alleviated on the first day after HD-MTX, and coma attenuated subsequently. Cognition returned to normal on the third day after HD-MTX. Based on disease progress under the treatment with consistent administration of imatinib, the patient switched to dasatinib from imatinib. She successfully accepted 2 cycles of HD-MTX and obtained hematologic remission, with approximately half reduction of BCR-ABL fusion gene load. Meanwhile, cerebral MRI showed improvement of encephaledema. For case 2, Her cognitive impairment and disorientation improved on the first day after HD-MTX and eventually disappeared on the third day after HD-MTX. Weakness of right lower limb consistently existed. While hematological remission was maintained, cerebral MRI was performed respectively after 5 and 10 consecutive cycles of HD-MTX, and showed gradual improvement of parenchymal brain enhancing lesions and peripheral edema.
Both patients were well tolerant to HD-MTX without significant influence on complete blood cell counting, or severe side effects, such as mucositis, stomatitis and renal dysfunction.

Conclusion
Based on the two cases, for patients with hematological malignancy with cerebral involvement, HD-MTX can rapidly relieve physical manifestation and obviously prolong the expected survival to win time for transplantation or clinical trials. Meanwhile, it effectively improves life quality without myelosuppression and lethal toxicity. Therefore, HD-MTX administered as intravenous 4.5g/m2 over 90minutes demonstrates excellent efficacy and is well tolerated for patients with hematological malignancy with cerebral involvement.

Disclosures:
No relevant conflicts of interest to declare.