Early response to high-dose methotrexate, vincristine, and procarbazine chemotherapy-adapted strategy for primary CNS lymphoma: no consolidation therapy for patients achieving early complete response
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Optimal treatment strategies for primary central nervous system lymphoma (PCNSL) have not been established. In this study, we investigated the treatment outcomes and prognostic factors of high-dose methotrexate, vincristine, and procarbazine (MVP) chemotherapy followed by an interim response-adapted intensification strategy in immunocompetent patients with PCNSL. We evaluated the evidence of infection with Epstein-Barr virus (EBV) in both brain tumor tissue and whole blood. Forty patients were retrospectively reviewed. Ten (25 %) patients who achieved complete response (CR) in the interim analysis did not receive any additional consolidation treatment after completion of planned high-dose MVP chemotherapy. Additional radiotherapy (n = 9) or autologous stem cell transplantation (ASCT) (n = 7) was performed in patients who did not achieve CR in the interim analysis. The median age was 55 years. The overall CR rate was 62.5 % (n = 25), and the objective response rate was 75.0 %. Two-year overall survival (OS) was 59.8 %, and 2-year progression-free survival was 47.1 %. Grade 3 or 4 neutropenia and thrombocytopenia occurred in 47.5 and 32.5 % of patients, respectively. Treatment-related mortality was 15.0 % (n = 6), and four patients developed delayed neurotoxicity. There was no evidence of EBV-encoded RNA expression in brain tumor tissue. Ten (29.4 %) of 34 patients showed detectable EBV-DNA in whole blood. Poor performance status and EBV-DNA positivity in whole blood were significantly associated with inferior OS (p = 0.032, p = 0.023, respectively). We suggest that high-dose MVP chemotherapy followed by an early response-adapted intensification strategy may be effective and minimize the number of patients who receive radiotherapy or ASCT in the early course of treatment.
KeywordsPrimary central nervous system lymphoma High-dose methotrexate Consolidation Complete response Epstein-Barr virus
This study was supported by a 2010 faculty research grant at Yonsei University College of Medicine (6-2010-0065). This study was presented in the form of poster presentation at the 54th annual meeting of the American Society of Hematology, Atlanta, GA, December 8–12, 2012.
The authors declare no conflicts of interest.
- 2.Ferreri AJ, Reni M, Foppoli M, Martelli M, Pangalis GA, Frezzato M, Cabras MG, Fabbri A, Corazzelli G, Ilariucci F, Rossi G, Soffietti R, Stelitano C, Vallisa D, Zaja F, Zoppegno L, Aondio GM, Avvisati G, Balzarotti M, Brandes A, Fajardo J, Gomez H, Guarini A, Pinotti G, Rigacci L, Uhlmann C, Picozzi P, Vezzulli P, Ponzoni M, Zucca E, Caligaris Cappio F, Cavalli F (2009) High-dose cytarabine plus high-dose methotrexate versus high-dose methotrexate alone in patients with primary CNS lymphoma: a randomized phase 2 trial. Lancet 374:1512–1520PubMedCrossRefGoogle Scholar
- 3.Ferreri AJ, Reni M, Dell'Oro S, Ciceri F, Bernardi M, Camba L, Ponzoni M, Terreni MR, Tomirotti M, Spina M, Villa E (2001) 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 60:134–140PubMedCrossRefGoogle Scholar
- 5.Illerhaus G, Marks R, Ihorst G, Guttenberger R, Ostertag C, Derigs G, Frickhofen N, Feuerhake F, Volk B, Finke J (2006) High-dose chemotherapy with autologous stem cell transplantation and hyperfractionated radiotherapy as first-line treatment of primary CNS lymphoma. J Clin Oncol 24:3865–3870PubMedCrossRefGoogle Scholar
- 7.Thiel E, Korfel A, Martus P, Kanz L, Griesinger F, Rauch M, Roth A, Hertenstein B, von Toll T, Hundsberger T, Mergenthaler HG, Leithauser M, Birnbaum T, Fischer L, Jahnke K, Herrlinger U, Plasswilm L, Nagele T, Pietsch T, Bamberg M, Weller M (2010) High-dose methotrexate with or without whole brain radiotherapy for primary CNS lymphoma (G-PCNSL-SG-1): a phase 3, randomized, non-inferiority trial. Lancet Oncol 11:1036–1047PubMedCrossRefGoogle Scholar
- 8.Pels H, Juergens A, Schirgens I, Glasmacher A, Schulz H, Engert A, Schackert G, Reichmann H, Kroschinsky F, Vogt-Schaden M, Egerer G, Bode U, Deckert M, Fimmers R, Urbach H, Schmidt-Wolf IG, Schlegel U (2010) Early complete response during chemotherapy predicts favorable outcome in patients with primary CNS lymphoma. Neuro-Oncol 12:720–724PubMedCentralPubMedCrossRefGoogle Scholar
- 9.Ferreri AJ, Blay JY, Reni M, Pasini F, Spina M, Ambrosetti A, Calderoni A, Rossi A, Vavassori V, Conconi A, Devizzi L, Berger F, Ponzoni M, Borisch B, Tinguely M, Cerati M, Milani M, Orvieto E, Sanchez J, Chevreau C, Dell'Oro S, Zucca E, Cavalli F (2003) Prognostic scoring system for primary CNS lymphomas: the International Extranodal Lymphoma Study Group experience. J Clin Oncol 21:266–272PubMedCrossRefGoogle Scholar
- 11.Roychowdhury S, Peng R, Baiocchi RA, Bhatt D, Vourganti S, Grecula J, Gupta N, Eisenbeis CF, Nuovo GJ, Yang W, Schmalbrock P, Ferketich A, Moeschberger M, Porcu P, Barth RF, Caligiuri MA (2003) Experimental treatment of Epstein-Barr virus-associated primary central nervous system lymphoma. Cancer Res 63:965–971PubMedGoogle Scholar
- 13.Suzuki R, Yamaguchi M, Izutsu K, Yamamoto G, Takada K, Harabuchi Y, Isobe Y, Gomyo H, Koike T, Okamoto M, Hyo R, Suzumiya J, Nakamura S, Kawa K, Oshimi K (2011) Prospective measurement of Epstein-Barr virus-DNA in plasma and peripheral blood mononuclear cells of extranodal NK/T cell lymphoma, nasal type. Blood 118:6018–6022PubMedCrossRefGoogle Scholar
- 14.Deckert M, Engert A, Bruck W, Ferreri AJ, Finke J, Illerhaus G, Klapper W, Korfel A, Kuppers R, Maarouf M, Montesinos-Rongen M, Paulus W, Schlegel U, Lassmann H, Wiestler OD, Siebert R, DeAngelis LM (2011) Modern concepts in the biology, diagnosis, differential diagnosis, and treatment of primary central nervous system lymphoma. Leukemia 25:1797–1807PubMedCrossRefGoogle Scholar
- 15.Hans CP, Weisenburger DD, Greiner TC, Gascoyne RD, Delabie J, Ott G, Muller-Hermelink HK, Campo E, Braziel RM, Jaffe ES, Pan Z, Farinha P, Smith LM, Falini B, Banham AH, Rosenwald A, Staudt LM, Connors JM, Armitage JO, Chan WC (2004) Confirmation of the molecular classification of diffuse large B cell lymphoma by immunohistochemistry using a tissue microarray. Blood 103:275–282PubMedCrossRefGoogle Scholar
- 16.Abrey LE, Batchelor TT, Ferreri AJ, Gospodarowicz M, Pulczynski EJ, Zucca E, Smith JR, Korfel A, Soussain C, DeAngelis LM, Neuwelt EA, O'Neill BP, Thiel E, Shenkier T, Graus F, van den Bent M, Seymour JF, Poortmans P, Armitage JO, Cavalli F (2005) Report of an international workshop to standardize baseline evaluation and response criteria for primary CNS lymphoma. J Clin Oncol 23:5034–5043PubMedCrossRefGoogle Scholar
- 23.Gandhi MK, Lambley E, Burrows J, Dua U, Elliott S, Shaw PJ, Prince HM, Wolf M, Clarke K, Underhill C, Mills T, Mollee P, Gill D, Marlton P, Seymour JF, Khanna R (2006) Plasma Epstein-Barr virus (EBV) DNA is a biomarker for EBV-positive Hodgkin's lymphoma. Clin Cancer Res 12:460–464PubMedCrossRefGoogle Scholar
- 26.Yoshino T, Nakamura S, Matsuno Y, Ochiai A, Yokoi T, Kitadai Y, Suzumiya J, Tobinai K, Kobayashi Y, Oda I, Mera K, Ohtsu A, Ishikura S (2006) Epstein-Barr virus involvement is a predictive factor for the resistance to chemoradiotherapy of gastric diffuse large B cell lymphoma. Cancer Sci 97:163–166PubMedCrossRefGoogle Scholar