Abstract
We describe MR-CHOP therapy, a novel treatment regimen consisting of high-dose methotrexate and R-CHOP that provides systemic anti-tumor activity with penetration of the blood–brain barrier in patients with newly diagnosed primary central nervous system lymphoma. The MR-CHOP regimen was administered with 2 g/m2 of methotrexate and 375 mg/m2 of rituximab on day 1, 750 mg/m2 of cyclophosphamide on day 3, 50 mg/m2 of doxorubicin on day 3, 1.4 mg/m2 of vincristine on day 3 and 100 mg of prednisolone on days 1–5 in this pilot study of seven patients. Six cycles of MR-CHOP therapy were administered every 3 weeks, followed by high-dose chemotherapy with stem cell rescue in young patients, or an additional two cycles of 4 g/m2 methotrexate and rituximab in older patients. The overall response rate was 100%, with 85.7% complete remission (CR). One patient showed partial response, relapsed and subsequently died. Another relapsed following CR, and was rescued by further salvage therapy. The others survive without relapse at a median observation period of 24 months. Hematological toxicity included grade 4 leukocytopenia in 4/7 and neutropenia in 5/7, which were transient and tolerated well. Non-hematological toxicities were tolerated well. The efficacy of this novel regimen as remission induction therapy was found to be promising in this pilot study, although the number of patients was small and follow-up short.
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Kluin PM, Deckert M, Ferry JA. Primary diffuse large B-cell lymphoma of the CNS. In Swerdlow SH, Campo E, Harris NL, et al., editors. World Health Organization: pathology and genetics of tumors of haematopoietic and lymphoid tissues. 4th ed. Lyon: IARC Press; 2008. p. 240–1.
Hans CP, Weisenburger DD, Greiner TC, Gascoyne RD, Delabie J, Ott G, et al. Confirmation of the molecular classification of diffuse large B-cell lymphoma by immunohistochemistry using a tissue microarray. Blood. 2004;103:275–82.
Coiffier B, Lepage E, Briere J, Herbrecht R, Tilly H, Bouabdallah R, et al. CHOP chemotherapy plus rituximab compared with CHOP alone in elderly patients with diffuse large-B-cell lymphoma. N Engl J Med. 2002;346:235–42.
Pfreundshcuh M, Trumper L, Osterborg A, Perregell R, Trneny M, Imrie K, et al. CHOP-like chemotherapy plus rituximab versus CHOP-like chemotherapy alone in young patients with good-prognosis diffuse large-B-cell lymphoma: a randomised controlled trial by the MabThera International Trial (MInT) Group. Lancet Oncol. 2006;7:379–91.
Reni T, Ferreri AJ, Grancini MP, Villa E. Therapeutic management of primary central nervous system lymphoma in immunocompetent patients: results of a critical review of the literature. Ann Oncol. 1997;8:227–34.
Ferreri AJ, Reni M, Pasini F, Calderoni A, Tirelli U, Pivnik A, et al. A multicenter study of treatment of primary CNS lymphoma. Neurology. 2002;58:1513–20.
Batchelor T, Carson K, O’Neil A, et al. Treatment of primary CNS lymphoma with methotrexate and deferred radiotherapy: a report of NABTT 96-07. J Clin Oncol. 2003;21:1044–9.
Herrlinger U, Kuker W, Uhl M, Blaicher HP, Karnath HO, Kanz L, et al. Neuro-Oncology Working Group of the German Society. NOA-03 trial of high-dose methotrexate in primary central nervous system lymphoma: final report. Ann Neurol. 2005;57:834–47.
Ferreri AJ, Blay JY, Reni M, Pasini F, Spina M, Ambrosetti A, et al. Prognostic scoring system for primary CNS lymphomas: the international extranodal lymphoma study group experience. J Clin Oncol. 2003;21:266–72.
Oki Y, Ogura M, Kato H, Kikuchi A, Taji H, Kagami Y, et al. Phase II study of a salvage regimen using cyclophosphamide, high-dose cytarabine, dexamethasone, etoposide, and rituximab in patients with relapsed or refractory B-cell non-Hodgkin’s lymphoma. Cancer Sci. 2008;99:179–84. Epub 2007 Nov 7.
Han LN, Zhou J, Hirose T, Imai Y, Ishiguro T, Chou T. Feasibility and efficacy of high-dose melphalan, cyclophosphamide, etoposide, and dexamethasone (LEED) chemotherapy with or without rituximab followed by autologous stem cell transplantation for aggressive and relapsed non-Hodgkin’s lymphoma. Int J Hematol. 2006;84:174–81.
Nelson DF, Martz KL, Bonner H, Nelson JS, Newall J, Kerman HD, et al. Non-Hodgkin’s lymphoma of the brain: can high dose, large volume radiation therapy improve survival? Report on a prospective trial by the Radiation Therapy Oncology Group (RTOG) 8315. Int J Radiat Oncol Biol Phys. 1992;23:9–17.
Abrey LE, Yahalom J, DeAngelis LM. Treatment for primary CNS lymphoma: the next step. J Clin Oncol. 2000;18:3144–50.
Ferreri AJ, Reni M, Dell’Oro S, Ciceri F, Bernardi M, Camba L, et al. Combined treatment with high-dose methotrexate, vincristine and procarbazine, without intrathecal chemotherapy, followed by consolidation radiotherapy for primary central nervous system lymphoma in immunocompetent patients. Oncology. 2001;60:134–40.
DeAngelis LM, Seiferheld W, Schold SC, Fisher B, Schultz CJ. Combination chemotherapy and radiotherapy for primary central nervous system lymphoma: Radiation Therapy Oncology Group Study 93-10. J Clin Oncol. 2002;20:4643–8.
Pels H, Schmidt-Wolf IG, Glasmacher A, Schulz H, Engert A, Diehl V, et al. Primary central nervous system lymphoma: results of a pilot and phase II study of systemic and intraventricular chemotherapy with deferred radiotherapy. J Clin Oncol. 2003;21:4489–95.
Abrey LE, Moskowitz CH, Mason WP, Crump M, Stewart D, Forsyth P, et al. Intensive methotrexate and cytarabine followed by high-dose chemotherapy with autologous stem-cell rescue in patients with newly diagnosed primary CNS lymphoma: an intent to treat analysis. J Clin Oncol. 2003;21:4151–6.
Illerhaus G, Marks R, Ihorst G, Guttenberger R, Ostertag C, Derigs G, et al. High-dose chemotherapy with autologous stem-cell transplantation and hyperfractionated radiotherapy as first-line treatment of primary CNS lymphoma. J Clin Oncol. 2006;24:3865–70.
Cheng T, Forsyth P, Chaudhry A. High-dose thiotepa, busulfan, cyclophosphamide and ASCT without whole-brain radiotherapy for poor prognosis primary CNS lymphoma. Bone Marrow Transpl. 2003;31:679–85.
Illerhaus G, Müller F, Feuerhake F, Schäfer AO, Ostertag C, Finke J. High-dose chemotherapy and autologous stem-cell transplantation without consolidating radiotherapy as first-line treatment for primary lymphoma of the central nervous system. Haematologica. 2008;93:147–8.
Ferreri AJ, Reni M, Foppoli M, Martelli M, Pangalis GA, Frezzato M, et al. High-dose cytarabine plus high-dose methotrexate versus high-dose methotrexate alone in patients with primary CNS lymphoma: a randomised phase 2 trial. Lancet. 2009;374(9700):1512–20. Epub 2009 Sep 18.
Joerger M, Huitema AD, Krähenbühl S, Schellens JH, Cerny T, Reni M, et al. Methotrexate area under the curve is an important outcome predictor in patients with primary CNS lymphoma: a pharmacokinetic-pharmacodynamic analysis from the IELSG no.20 trial. Br J Cancer. 2010;102:673–7.
McCann KJ, Ashton-Key M, Smith KA, Stevenson FK, Ottensmeier CH. Primary central nervous system lymphoma: tumor-related clones exist in the blood and bone marrow with evidence for separate development. Blood. 2009;113:4677–80.
Takami A, Hayashi T, Kita D, Nishimura R, Asakura H, Nakao S. Treatment of primary central nervous system lymphoma with induction of complement-dependent cytotoxicity by intraventricular administration of autologous-serum-supplemented rituximab. Cancer Sci. 2006;97:80–3.
Rubenstein JL, Fridlyand J, Abrey L, Shen A, Karch J, Wang E, et al. Phase I study of intraventricular administration of rituximab in patients with recurrent CNS and intraocular lymphoma. J Clin Oncol. 2007;25:1350–6.
Enting RH, Demopoulos A, DeAngelis LM, Abley LE. Salvage therapy for primary CNS lymphoma with a combination of rituximab and temozolomide. Neurology. 2004;63:901–3.
Shah GD, Yahalom J, Correa DD, Lai RK, Raizer JJ, Schiff D, et al. Combined immunochemotherapy with reduced whole-brain radiotherapy for newly diagnosed primary CNS lymphoma. J Clin Oncol. 2007;25:4730–5.
Acknowledgments
We are grateful to the members of Hokuriku Hematological Tumor Research Group for their critical contributions. This work was supported by grants from Intractable Diseases, the Health and Labour Sciences Research Grants from the Ministry of Health, Labor and Welfare and the Japanese Ministry of Education, Culture, Sports, Science and Technology (22249041 to Umehara and 17591060 to Masaki), Uehara Memorial Foundation (to Umehara), The Vehicle Racing Commemorative Foundation, and the Kanazawa Medical University Research Foundation (C2009-4, C2010-1 to Umehara and S2004-16 and S2007-5 to Masaki).
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The authors declare no competing financial manuscript.
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Masaki, Y., Miki, M., Sun, Y. et al. High-dose methotrexate with R-CHOP therapy for the treatment of patients with primary central nervous system lymphoma. Int J Hematol 93, 720–726 (2011). https://doi.org/10.1007/s12185-011-0848-1
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DOI: https://doi.org/10.1007/s12185-011-0848-1