Skip to main content

Advertisement

SpringerLink
Log in

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

  • Original Article
  • Published:
Annals of Hematology Aims and scope Submit manuscript

Abstract

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.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

References

  1. Batchelor T, Loeffler JS (2006) Primary CNS lymphoma. J Clin Oncol 24:1281–1288

    Article  CAS  PubMed  Google Scholar 

  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 374:1512–1520

    Article  CAS  PubMed  Google 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 60:134–140

    Article  CAS  PubMed  Google Scholar 

  4. Shah GD, Yahalom J, Correa D, Lai RK, Raizer J, Schiff D, LaRocca R, Grant B, DeAngelis LM, Abrey LE (2007) Combined immunochemotherapy with reduced radiotherapy for newly diagnosed primary CNS lymphoma. J Clin Oncol 25:4730–4735

    Article  CAS  PubMed  Google 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 24:3865–3870

    Article  CAS  PubMed  Google Scholar 

  6. Brastianos PK, Batchelor TT (2012) Primary central nervous system lymphoma: overview of current treatment strategies. Hematol Oncol Clin North Am 26:897–916

    Article  PubMed  Google 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 11:1036–1047

    Article  CAS  PubMed  Google 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 12:720–724

    Article  PubMed Central  PubMed  Google 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 21:266–272

    Article  PubMed  Google Scholar 

  10. Keegan TH, Glaser SL, Clarke CA, Gulley ML, Craig FE, Digiuseppe JA, Dorfman RF, Mann RB, Ambinder RF (2005) Epstein-Barr virus as a marker of survival after Hodgkin's lymphoma: a population-based study. J Clin Oncol 23:7604–7613

    Article  PubMed  Google 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 63:965–971

    CAS  PubMed  Google Scholar 

  12. Utsuki S, Oka H, Miyajima Y, Kijima C, Yasui Y, Fujii K (2011) Epstein-Barr virus (EBV)-associated primary central nervous system lymphoma: is incidence of EBV expression associated with median survival time? Brain Tumor Pathol 28:145–149

    Article  PubMed  Google 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 118:6018–6022

    Article  CAS  PubMed  Google 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 25:1797–1807

    Article  CAS  PubMed  Google 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 103:275–282

    Article  CAS  PubMed  Google 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 23:5034–5043

    Article  PubMed  Google Scholar 

  17. Kim SH, Cheong JW, Park KH, Kim TS, Yang WI (2007) Comparison of ataxia-telangiectasia mutated protein expression in diffuse large B cell lymphomas of primary central nervous system and non-central nervous system origin. Arch Pathol Lab Med 131:457–467

    CAS  PubMed  Google Scholar 

  18. Omuro A, Taillandier L, Chinot O, Sierra Del Rio M, Carnin C, Barrie M, Soussain C, Tanguy ML, Choquet S, Leblond V, Hoang-Xuan K (2011) Primary CNS lymphoma in patients younger than 60: can whole-brain radiotherapy be deferred? J Neurooncol 104:323–330

    Article  PubMed  Google Scholar 

  19. DeAngelis LM, Seiferheld W, Schold SC, Fisher B, Schultz CJ (2002) Combination chemotherapy and radiotherapy for primary central nervous system lymphoma: Radiation Therapy Oncology Group Study 93–10. J Clin Oncol 20:4643–4648

    Article  PubMed  Google Scholar 

  20. Ekenel M, Iwamoto FM, Ben-Porat LS, Panageas KS, Yahalom J, DeAngelis LM, Abrey LE (2008) Primary central nervous system lymphoma: the role of consolidation treatment after a complete response to high-dose methotrexate-based chemotherapy. Cancer 113:1025–1031

    Article  CAS  PubMed  Google Scholar 

  21. Beltran BE, Castillo J, Morales D, de Mendoza FH, Quinones P, Miranda RN, Gallo A, Lopez Ilasaca M, Butera JN, Sotomayor EM (2011) EBV-positive diffuse large B cell lymphoma of the elderly: a case series from Peru. Am J Hematol 86:663–667

    Article  PubMed  Google Scholar 

  22. Shimoyama Y, Oyama T, Asano N, Oshiro A, Suzuki R, Kagami Y, Morishima Y, Nakamura S (2006) Senile Epstein-Barr virus-associated B cell lymphoproliferative disorders: a mini review. J Clin Exp Hematop 46:1–4

    Article  PubMed  Google 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 12:460–464

    Article  CAS  PubMed  Google Scholar 

  24. Au WY, Pang A, Choy C, Chim CS, Kwong YL (2004) Quantification of circulating Epstein-Barr virus (EBV) DNA in the diagnosis and monitoring of natural killer cell and EBV-positive lymphomas in immunocompetent patients. Blood 104:243–249

    Article  CAS  PubMed  Google Scholar 

  25. Timms JM, Bell A, Flavell JR, Murray PG, Rickinson AB, Traverse-Glehen A, Berger F, Delecluse HJ (2003) Target cells of Epstein-Barr virus (EBV)-positive post-transplant lymphoproliferative disease: similarities to EBV-positive Hodgkin's lymphoma. Lancet 361:217–223

    Article  PubMed  Google 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 97:163–166

    Article  CAS  PubMed  Google Scholar 

  27. Clybouw C, McHichi B, Mouhamad S, Auffredou MT, Bourgeade MF, Sharma S, Leca G, Vazquez A (2005) EBV infection of human B lymphocytes leads to downregulation of Bim expression: relationship to resistance to apoptosis. J Immunol 175:2968–2973

    CAS  PubMed  Google Scholar 

  28. Snow AL, Lambert SL, Natkunam Y, Esquivel CO, Krams SM, Martinez OM (2006) EBV can protect latently infected B cell lymphomas from death receptor-induced apoptosis. J Immunol 177:3283–3293

    CAS  PubMed  Google Scholar 

  29. Saha A, Robertson ES (2011) Epstein-Barr virus-associated B cell lymphomas: pathogenesis and clinical outcomes. Clin Cancer Res 17:3056–3063

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

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.

Competing interests

The authors declare no conflicts of interest.

Author information

Authors and Affiliations

  1. Division of Hematology, Department of Internal Medicine, Severance Hospital, Yonsei University College of Medicine, 50 Yonsei-ro, Seodaemun-gu, Seoul, 120-752, South Korea

    Yu Ri Kim, Soo-Jeong Kim, Yundeok Kim, Doh Yu Hwang, Ji Eun Jang, Shin Young Hyun, June-Won Cheong, Yoo Hong Min & Jin Seok Kim

  2. Department of Pathology, Severance Hospital, Yonsei University College of Medicine, Seoul, South Korea

    Se Hoon Kim

  3. Department of Neurosurgery, Severance Hospital, Yonsei University College of Medicine, Seoul, South Korea

    Jong Hee Chang

  4. Department of Radiation Oncology, Severance Hospital, Yonsei University College of Medicine, Seoul, South Korea

    Chang-Ok Suh

Authors
  1. Yu Ri Kim
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Se Hoon Kim
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Jong Hee Chang
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Chang-Ok Suh
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Soo-Jeong Kim
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Yundeok Kim
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Doh Yu Hwang
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Ji Eun Jang
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Shin Young Hyun
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. June-Won Cheong
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Yoo Hong Min
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Jin Seok Kim
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Jin Seok Kim.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Kim, Y.R., Kim, S.H., Chang, J.H. et al. 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. Ann Hematol 93, 211–219 (2014). https://doi.org/10.1007/s00277-013-1853-7

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00277-013-1853-7

Keywords

Search

Navigation