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Systemic High-Dose Methotrexate Plus Ifosfamide Is Highly Effective For Systemic high-dose methotrexate plus ifosfamide is highly effective for central nervous system (CNS) involvement of lymphoma Lars Fischer, Agnieszka Korfel, Philipp Kiewe, Martin Neumann, Kristoph Jahnke, Eckhard Thiel To cite this version: Lars Fischer, Agnieszka Korfel, Philipp Kiewe, Martin Neumann, Kristoph Jahnke, et al.. Sys- temic high-dose methotrexate plus ifosfamide is highly effective for central nervous system (CNS) involvement of lymphoma. Annals of Hematology, Springer Verlag, 2008, 88 (2), pp.133-139. 10.1007/s00277-008-0575-8. hal-00477969 HAL Id: hal-00477969 https://hal.archives-ouvertes.fr/hal-00477969 Submitted on 30 Apr 2010 HAL is a multi-disciplinary open access L’archive ouverte pluridisciplinaire HAL, est archive for the deposit and dissemination of sci- destinée au dépôt et à la diffusion de documents entific research documents, whether they are pub- scientifiques de niveau recherche, publiés ou non, lished or not. The documents may come from émanant des établissements d’enseignement et de teaching and research institutions in France or recherche français ou étrangers, des laboratoires abroad, or from public or private research centers. publics ou privés. Ann Hematol (2009) 88:133–139 DOI 10.1007/s00277-008-0575-8 ORIGINAL ARTICLE Systemic high-dose methotrexate plus ifosfamide is highly effective for central nervous system (CNS) involvement of lymphoma Lars Fischer & Agnieszka Korfel & Philipp Kiewe & Martin Neumann & Kristoph Jahnke & Eckhard Thiel Received: 25 January 2008 /Accepted: 21 July 2008 / Published online: 5 August 2008 # Springer-Verlag 2008 Abstract Patients with malignant central nervous system Keywords Neoplastic meningitis . CNS lymphoma . (CNS) involvement of lymphoma have a poor prognosis Ifosfamide . Methotrexate with intrathecal chemotherapy and radiation. In this paper, we report the results we obtained in such patients by intravenous chemotherapy with high-dose methotrexate and ifosfamide (HDMTX/IFO). The study involved a review of Introduction all patients who received HDMTX/IFO for CNS involve- ment of malignant lymphoma at our hospital. Therapy Central nervous system (CNS) involvement is a serious consisted of 4 g/m2 of MTX (4 h infusion on day 1) and complication of hematologic malignancies. Standard thera- 1.5–2 g/m2/day of IFO (3 h infusion on days 3–5). The py has not been established for these patients. Patients with study included 20 patients with a median age of 65 years leptomeningeal involvement usually receive intrathecal (IT) (range, 30–83) and CNS relapse of a malignant lymphoma. chemotherapy consisting of methotrexate (MTX) or cytar- Seventeen patients had been pretreated with up to two abine, which is sometimes combined with radiotherapy for chemotherapy regimens. The objective response rate was nodular tumor masses [1–4]. Patients presenting with 90% with 12 complete or unconfirmed complete (CR and parenchymal brain involvement are usually submitted to CRu) and six partial remissions. All patients had at least whole-brain irradiation (WBI). With this therapy, patients stabilization of their neurological symptoms. Myelosup- with malignant CNS involvement generally have a poor pression was the most common toxicity. The median prognosis with a median survival of usually less than follow-up time was 14.9 months. The median time to 6 months. Systemic disease is a frequent cause of death in neurological progression was 8.9 months. Twelve patients these patients [5–8]. received subsequent therapy, including high-dose chemo- In the management of CNS malignancies, systemic therapy with autologous stem cell transplantation in five therapy offers several potential advantages over local cases. The median overall survival was not reached. treatment modalities like IT chemotherapy or radiation, Systemic chemotherapy with HDMTX/IFO is a feasible the most important one being simultaneous treatment of and promising treatment modality for CNS relapse of a thesystemicdisease[5, 8, 9]. Furthermore, systemic malignant lymphoma. application achieves a more uniform distribution of the drug throughout the neuroaxis and obviates ventricular reservoir insertion or multiple lumbar punctures (LP) for drug instillation with all the potential acute and late L. Fischer (*) : A. Korfel : P. Kiewe : M. Neumann : K. Jahnke : complications. Finally, a much wider array of chemother- E. Thiel apeutic agents can be administered by intravenous (IV) Department of Hematology, Oncology & Transfusion Medicine, than by IT application. On the other hand, considerable Charité Universitätsmedizin Berlin, Campus Benjamin Franklin, systemic toxicity is associated with IV chemotherapy, Hindenburgdamm 30, 12200 Berlin, Germany whereas IT therapy poses potential infectious and neuro- e-mail: [email protected] toxic risks. 134 Ann Hematol (2009) 88:133–139 Both systemic ifosfamide and high-dose MTX (doses of abnormalities on brain imaging or patients fulfilling the 1.0 g/m2 or more) reach cytostatic levels in the cerebrospinal criteria for complete remission (CR) but still receiving fluid (CSF) and are effective for treating various malignan- corticosteroids. In three patients treated before 2005, IPCG cies [10–12]. This monocenter study retrospectively ana- guidelines were used for a retrospective evaluation of lyzed the activity and toxicity of combination chemotherapy parenchymal brain lesions. These patients had CR accord- with high-dose methotrexate and ifosfamide (HDMTX/IFO) ing to both Cheson criteria [14] used initially and IPCG for CNS manifestations of non-Hodgkin’slymphoma. criteria used for the present analysis. In leptomeningeal disease, CR was defined as a negative CSF cytomorphology in two consecutive LP and disap- Materials and methods pearance of meningeal enhancement on gadolinium MRI, if present at first presentation. Progressive disease (PD) was Patients defined as an increase of CSF tumor cells, while stable disease (SD) was considered to be any other condition. The study included all patients treated with HDMTX/IFO Response and SD were only documented if neurological for CNS lymphoma (including the retina) at our institution symptoms had improved or remained stable; patients were from July 2002 to August 2007. CNS disease was otherwise assessed as having PD [2, 4]. Response of diagnosed radiologically [brain lesions and/or meningeal measurable systemic disease was documented according enhancement on cranial and spinal magnetic resonance to Cheson’s criteria [14]. imaging (MRI) or computed tomography (CT)] or by CSF Neurological response was classified as complete re- cytomorphology or immunocytology. Intraocular malignan- sponse, improvement, stable disease, or worsening. Neuro- cy was diagnosed by slit-lamp examination and aqueous logical complete response was defined as complete cytology or chorioretinal biopsy. All patients underwent a resolution of all neurological symptoms and signs attribut- staging procedure for systemic tumor manifestations with able to the malignant disease, improvement as regression of bone marrow biopsy and contrast-enhanced CT of the symptoms with residual deficits, worsening as neurological thorax and abdomen. deterioration, and stable disease as no improvement in the Exclusion criteria were creatinine clearance <50 ml/min, absence of new symptoms. liver disease with elevation of bilirubin >2 mg/dl, previous Response evaluation of all CNS tumor sites using the WBI, and active systemic infection. All patients gave initial method (MRI, CT, CSF cytomorphology/immunocy- written informed consent before starting treatment. tology, and ophthalmologic examination) was performed at least after every second chemotherapy cycle and every Treatment 3 months after therapy. A full clinical and neurological assessment, including toxicity evaluation, was performed Patients received an IV infusion of MTX 4 g/m2 over 4 h on before each chemotherapy course. day 1 and IFO 1.5 or 2 g/m2/day over 3 h on days 3 to 5. Adverse events were graded according to the Common The MTX dose was adjusted for creatinine clearance (CC) Terminology Criteria (CTC) of the National Cancer <100 ml/min as follows: CC/100×4g/m2. Supportive Institute, version 3.0, and the highest observed grade was therapy included antiemetics, intravenous hydration, urine recorded for each patient. alkalization, mesna, and a leucovorin rescue beginning 24 h after the start of MTX infusion. Systemic corticosteroids Statistical analysis were applied only for symptom control at the beginning of therapy. Treatment was continued for a maximum of eight A descriptive analysis of qualitative and quantitative cycles and stopped in cases where further therapy was variables was done. Frequencies, median values, and ranges prevented by radiologic or CSF progression, clinical were specified when applicable. Estimates of the overall deterioration, or toxicity. survival (OAS) and time to neurological progression (TTP) were calculated for all patients using the Kaplan–Meier Response and toxicity method. The OAS was calculated from the start of therapy to the last follow-up or to death from any cause. The time to In patients treated after August 2005, response of paren- neurological progression was measured from the start of chymal lesions was evaluated according to the then therapy until neurological deterioration, death from CNS published criteria of the International Primary CNS Lym- disease, or the last follow-up. Responding or stable patients phoma Collaborative Group (IPCG) [13]. Those included who continued with other
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