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BRIEF COMMUNICATIONS: Roelien H. Enting, Alexis Demopoulos, Lisa M. DeAngelis, and Lauren E. Abrey Salvage therapy for primary CNS lymphoma with a combination of rituximab and temozolomide Neurology 2004; 63: 901-903 [Abstract] [Full text] [PDF]

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Salvage therapy for primary CNS lymphoma with a combination of rituximab and temozolomide

Eric T. Wong   (23 November 2004)

Reply to Wong

Lauren Abrey   (23 November 2004)

Salvage therapy for primary CNS lymphoma with a combination of rituximab and temozolomide 23 November 2004
Eric T. Wong, Beth Israel Deaconess Medical Center Shapiro 867, 330 Brookline Avenue, Boston, MA 02215 Send Correspondence to journal: Re: Salvage therapy for primary CNS lymphoma with a combination of rituximab and temozolomide ewong{at}bidmc.harvard.edu Eric T. Wong	In the series of patients with relapsed primary CNS lymphomas treated with rituximab and temozolomide, Abrey et al [1] reported a 53% response rate, median overall survival of 14 months, and median progression-free survival of 7.7 months. However, there was a 20-30% grade 3 hematological toxicity. This high rate of hematological toxicity could be due to dose intensification of temozolomide, ranging from 100 mg/m2 to 200 mg/m2 on Days 1-7 and 15-21 per 28-day cycle. This is equivalent to a dose intensity of 1,400 mg/m2 to 2,800 mg/m2 per cycle, a 1.4- to 2.8-fold increase in dose intensity as compared to the standard regimen of 200 mg/m2 on Days 1-5 per cycle. In a phase I pharmacokinetic analysis, Tolcher et al [2] reported a maximum tolerated dose (MTD) of 150 mg/m2 for 7 days given every 2 weeks. However, when combined with rituximab, the MTD is probably lower than 150 mg/m2. Although formal phase I dose escalation data are unavailable for combination rituximab and temozolomide, our experience with rituximab 375 mg/m2 on Day 1 and temozolomide 150-200 mg/m2 on Days 1-5 in 28-day cycles suggests that the MTD is probably at 150 mg/m2 when combined with rituximab [3]. Therefore, in Abrey's dose intensified schedule, temozolomide would need to be reduced to less than 150 mg/m2. From an efficacy perspective, a temozolomide dose of 100 or 125 mg/m2 would have equivalent efficacy for suppressing O6-alkylguanine-DNA alkyltransferase activity [2], and probably still synergistic for CNS lymphoma when combined with rituximab. Another important issue is the lack of renal toxicity in rituximab and temozolomide. Although high-dose methotrexate has been the standard therapy for primary CNS lymphomas, about 10% of patients in our clinical experience could not tolerate it due to renal insufficiency, cardiomyopathy preventing aggressive fluid hydration, or prior renal transplant. Furthermore, elderly patients are susceptible to delayed neurotoxicity associated with high-dose methotrexate, even without prior cranial irradiation [5]. Rituximab and temozolomide, therefore, should be explored further in newly diagnosed patients. Lastly, the efficacy of rituximab and temozolomide for leptomeningeal lymphoma is overstated in this article. The rituximab concentration in CSF is 0.1% of that in the serum [4] and all of Abrey’s patients with positive CSF cytology received intra-Ommaya methotrexate. References 1. Enting RH, Demopoulos A, DeAngelis LM, Abrey LE. Salvage therapy for primary CNS lymphoma with a combination of rituximab and temozolomide. Neurology 2004;63:901-903. 2. Tolcher AW, Gerson SL, Denis L, et al. Marked inactivation of O6- alkylguanine-DNA alkyltransferase activity with protracted temozolomide schedules. Brit J Cancer 2003;88:1004-1011. 3. Wong ET, Tishler R, Barron L, Wu JK. Immunochemotherapy with rituximab and temozolomide for central nervous system lymphomas. Cancer 2004;101:139-145. 4. Rubenstein JL, Combs D, Rosenberg J, et al. Rituximab therapy for CNS lymphomas: targeting the leptomeningeal compartment. Blood 2003;101:466- 468. 5. Hoang-Xuan K, Taillandier L, Chinot O, et al. Chemotherapy alone as initial treatment of primary CNS lymphoma in patients older than 60 years: a multicenter phase II study (26952) of the European Organization for Research and Treatment of Cancer Brain Tumor Group. J Clin Oncol 2003;21:2726-2731.
Reply to Wong 23 November 2004
Lauren Abrey, Department of Neurology Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10021 Send Correspondence to journal: Re: Reply to Wong abreyl{at}MSKCC.ORG Lauren Abrey	We thank Dr. Wong for his interest in our paper. As this is a retrospective report of our clinical experience with the combination of rituximab and temozolomide it is difficult to comment on the optimal doses of this combination. Both the rituximab and the temozolomide were dosed higher than the standard recommended dose in an effort to optimize CNS penetration and efficacy. In spite of this increased exposure, the toxicity experienced by our patients was acceptable and actually lower than the toxicity reported using one week on/one week off temozolomide alone (50% grade 3 and 4 toxicity). [1,2] The tolerability of this regimen suggests that this may be a reasonable alternative for elderly patients or those with renal dysfunction that limits the use of high dose methotrexate. However, we think that it is critical to confirm our experience with prospective data before adopting this regimen for newly diagnosed patients. Ferreri et al have reported that single agent standard temozolomide has activity in recurrent PCNSL with a response rate of approximately 25%.3 The NABTT has an ongoing clinical trial investigating single agent rituximab in relapsed PCNSL. There is also an ongoing RTOG phase I/II study for newly-diagnosed PCNSL that incorporates both rituximab and temozolomide into a methotrexate-based regimen as well as a planned CALGB study. References 1. Enting RH, Demopoulos A, DeAngelis LM, Abrey LE. Salvage therapy for primary CNS lymphoma with a combination of rituximab and temozolomide. Neurology. 2004 Sep 14;63:901-3. 2. Wick W, Steinbach JP, Kuker WM, Dichgans J, Bamberg M, Weller M. One week on/one week off: a novel active regimen of temozolomide for recurrent glioblastoma. Neurology. 2004 Jun 8;62:2113-5. 3. Reni M, Mason W, Zaja F, et al. Salvage chemotherapy with temozolomide in primary CNS lymphomas: preliminary results of a phase II trial. Eur J Cancer. 2004 Jul;40:1682-8.