Skip to main content
SpringerLink
Log in

Comparison of standardized prophylactic high-dose and intrathecal methotrexate for DLBCL with a high risk of CNS relapse

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

Abstract

The efficacy of high-dose methotrexate (HD-MTX) for central nervous system (CNS) relapse prophylaxis in patients with high-risk diffuse large B-cell lymphoma (DLBCL) is controversial. We compared the prophylactic effects of HD-MTX and intrathecal methotrexate (IT-MTX) on CNS relapse in high-risk DLBCL, in a multicenter retrospective study. A total of 132 patients with DLBCL at high risk of CNS relapse who received frontline chemotherapy and IT-MTX from 2003 to 2013 (n = 34) or HD-MTX from 2014 to 2020 (n = 98) were included. After a median follow-up of 52 months (range: 9–174), 11 patients had isolated CNS relapse: six (6.1%) in the HD-MTX group and five (14.7%) in the IT-MTX group. The median time until CNS relapse was 38 months (range: 11–122), and the cumulative incidence of CNS relapse at 3 years was 3.9% in the HD-MTX group and 6.1% in the IT-MTX group (P = 0.93). Similar results were obtained after adjusting for background factors using propensity score-matched analysis (4.5% HD-MTX vs. 7.6% IT-MTX, P = 0.84). The CNS relapse rate in HD-MTX-treated patients was equivalent to that in IT-MTX patients, demonstrating that HD-MTX was not superior to IT-MTX in preventing CNS relapse.

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

Similar content being viewed by others

Data availability

For original data, please contact the corresponding author (takuya_m@yokohama-cu.ac.jp).

Abbreviations

ABC:

Activated B-cell-like

Ccr:

Creatinine clearance

CNS:

Central nervous system relapse

DA-EPOCH-R:

Dose-adjusted etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, and rituximab combination therapy

DHL:

Double-hit lymphoma

DLBCL:

Diffuse large B-cell lymphoma

GCB:

Germinal center B-cell-like

HD-MTX:

High-dose methotrexate

IT-MTX:

Intrathecal methotrexate

IPI:

International Prognostic Index

OS:

Overall survival

PFS:

Progression-free survival

PS:

Performance status

R-CHOP:

Rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone combination therapy

SMD:

Standardized mean difference

References

  1. Schmitz N, Zeynalova S, Nickelsen M, Kansara R, Villa D, Sehn LH, et al. CNS international prognostic index: a risk model for CNS relapse in patients with diffuse large B-cell lymphoma treated with R-CHOP. J Clin Oncol. 2016;34:3150–6.

    Article  CAS  PubMed  Google Scholar 

  2. Roschewski M. Central nervous system prophylaxis in diffuse large B-cell lymphoma: a race to the bottom. Haematologica. 2021;106:332–4.

    Article  PubMed  PubMed Central  Google Scholar 

  3. Qualls D, Abramson JS. Advances in risk assessment and prophylaxis for central nervous system relapse in diffuse large B-cell lymphoma. Haematologica. 2019;104:25–34.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. El-Galaly TC, Cheah CY, Bendtsen MD, Nowakowski GS, Kansara R, Savage KJ, et al. Treatment strategies, outcomes and prognostic factors in 291 patients with secondary CNS involvement by diffuse large B-cell lymphoma. Eur J Cancer. 2018;93:57–68.

    Article  PubMed  PubMed Central  Google Scholar 

  5. Chin CK, Cheah CY. How I treat patients with aggressive lymphoma at high risk of CNS relapse. Blood. 2017;130:867–74.

    Article  CAS  PubMed  Google Scholar 

  6. Tomita N, Yokoyama M, Yamamoto W, Watanabe R, Shimazu Y, Masaki Y, et al. Central nervous system event in patients with diffuse large B-cell lymphoma in the rituximab era. Cancer Sci. 2012;103:245–51.

    Article  CAS  PubMed  Google Scholar 

  7. Vitolo U, Chiappella A, Ferreri AJ, Martelli M, Baldi I, Balzarotti M, et al. First-line treatment for primary testicular diffuse large B-cell lymphoma with rituximab-CHOP, CNS prophylaxis, and contralateral testis irradiation: final results of an international phase II trial. J Clin Oncol. 2011;29:2766–72.

    Article  CAS  PubMed  Google Scholar 

  8. Laskin JJ, Savage KJ, Voss N, Gascoyne RD, Connors JM. Primary paranasal sinus lymphoma: natural history and improved outcome with central nervous system chemoprophylaxis. Leuk Lymphoma. 2005;46:1721–7.

    Article  PubMed  Google Scholar 

  9. Miyazaki K, Yamaguchi M, Suzuki R, Kobayashi Y, Maeshima AM, Niitsu N, et al. CD5-positive diffuse large B-cell lymphoma: a retrospective study in 337 patients treated by chemotherapy with or without rituximab. Ann Oncol. 2011;22:1601–7.

    Article  CAS  PubMed  Google Scholar 

  10. Shimada K, Yamaguchi M, Atsuta Y, Matsue K, Sato K, Kusumoto S, et al. Rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone combined with high-dose methotrexate plus intrathecal chemotherapy for newly diagnosed intravascular large B-cell lymphoma (PRIMEUR-IVL): a multicentre, single-arm, phase 2 trial. Lancet Oncol. 2020;21:593–602.

    Article  CAS  PubMed  Google Scholar 

  11. Oki Y, Noorani M, Lin P, Davis RE, Neelapu SS, Ma L, et al. Double hit lymphoma: the MD Anderson cancer center clinical experience. Br J Haematol. 2014;166:891–901.

    Article  CAS  PubMed  Google Scholar 

  12. McKay P, Wilson MR, Chaganti S, Smith J, Fox CP, Cwynarski K, et al. The prevention of central nervous system relapse in diffuse large B-cell lymphoma: a British society for haematology good practice paper. Br J Haematol. 2020;190:708–14.

    Article  PubMed  Google Scholar 

  13. Arkenau HT, Chong G, Cunningham D, Watkins D, Agarwal R, Sirohi B, et al. The role of intrathecal chemotherapy prophylaxis in patients with diffuse large B-cell lymphoma. Ann Oncol. 2007;18:541–5.

    Article  PubMed  Google Scholar 

  14. Boehme V, Schmitz N, Zeynalova S, Loeffler M, Pfreundschuh M. CNS events in elderly patients with aggressive lymphoma treated with modern chemotherapy (CHOP-14) with or without rituximab: an analysis of patients treated in the RICOVER-60 trial of the German high-grade non-hodgkin lymphoma study group (DSHNHL). Blood. 2009;113:3896–902.

    Article  CAS  PubMed  Google Scholar 

  15. Tomita N, Takasaki H, Ishiyama Y, Kishimoto K, Ishibashi D, Koyama S, et al. Intrathecal methotrexate prophylaxis and central nervous system relapse in patients with diffuse large B-cell lymphoma following rituximab plus cyclophosphamide, doxorubicin, vincristine and prednisone. Leuk Lymphoma. 2015;56:725–9.

    Article  CAS  PubMed  Google Scholar 

  16. Eyre TA, Kirkwood AA, Wolf J, Hildyard C, Mercer C, Plaschkes H, et al. Stand-alone intrathecal central nervous system (CNS) prophylaxis provide unclear benefit in reducing CNS relapse risk in elderly DLBCL patients treated with R-CHOP and is associated increased infection-related toxicity. Br J Haematol. 2019;187:185–94.

    Article  CAS  PubMed  Google Scholar 

  17. Abramson JS, Hellmann M, Barnes JA, Hammerman P, Toomey C, Takvorian T, et al. Intravenous methotrexate as central nervous system (CNS) prophylaxis is associated with a low risk of CNS recurrence in high-risk patients with diffuse large B-cell lymphoma. Cancer. 2010;116:4283–90.

    Article  PubMed  Google Scholar 

  18. Ferreri AJ, Bruno-Ventre M, Donadoni G, Ponzoni M, Citterio G, Foppoli M, et al. Risk-tailored CNS prophylaxis in a mono-institutional series of 200 patients with diffuse large B-cell lymphoma treated in the rituximab era. Br J Haematol. 2015;168:654–62.

    Article  CAS  PubMed  Google Scholar 

  19. Ong SY, de Mel S, Grigoropoulos NF, Chen Y, Tan YC, Tan MSY, et al. High-dose methotrexate is effective for prevention of isolated CNS relapse in diffuse large B cell lymphoma. Blood Cancer J. 2021;11:143.

    Article  PubMed  PubMed Central  Google Scholar 

  20. Puckrin R, El Darsa H, Ghosh S, Peters A, Owen C, Stewart D. Ineffectiveness of high-dose methotrexate for prevention of CNS relapse in diffuse large B-cell lymphoma. Am J Hematol. 2021;96:764–71.

    Article  CAS  PubMed  Google Scholar 

  21. Jeong H, Cho H, Kim H, Chae H, Lee JB, Lee K, et al. Efficacy and safety of prophylactic high-dose MTX in high-risk DLBCL: a treatment intent-based analysis. Blood Adv. 2021;5:2142–52.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Bobillo S, Joffe E, Sermer D, Mondello P, Ghione P, Caron PC, et al. Prophylaxis with intrathecal or high-dose methotrexate in diffuse large B-cell lymphoma and high risk of CNS relapse. Blood Cancer J. 2021;11:113.

    Article  PubMed  PubMed Central  Google Scholar 

  23. Orellana-Noia VM, Reed DR, McCook AA, Sen JM, Barlow CM, Malecek MK, et al. Single-route CNS prophylaxis for aggressive non-Hodgkin lymphomas: real-world outcomes from 21 US academic institutions. Blood. 2022;139:413–23.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Miyazaki K, Asano N, Yamada T, Miyawaki K, Sakai R, Igarashi T, et al. DA-EPOCH-R combined with high-dose methotrexate in patients with newly diagnosed stage II-IV CD5-positive diffuse large B-cell lymphoma: a single-arm, open-label, phase II study. Haematologica. 2020;105:2308–15.

    Article  CAS  PubMed  Google Scholar 

  25. Kanda Y. Investigation of the freely available easy-to-use software “EZR” for medical statistics. Bone Marrow Transplant. 2013;48:452–8.

    Article  CAS  PubMed  Google Scholar 

  26. Eyre TA, Savage KJ, Cheah CY, El-Galaly TC, Lewis KL, McKay P, et al. CNS prophylaxis for diffuse large B-cell lymphoma. Lancet Oncol. 2022;23:e416–26.

    Article  CAS  PubMed  Google Scholar 

  27. Hegde U, Filie A, Little RF, Janik JE, Grant N, Steinberg SM, et al. High incidence of occult leptomeningeal disease detected by flow cytometry in newly diagnosed aggressive B-cell lymphomas at risk for central nervous system involvement: the role of flow cytometry versus cytology. Blood. 2005;105:496–502.

    Article  CAS  PubMed  Google Scholar 

  28. Alvarez R, Dupuis J, Plonquet A, Christov C, Copie-Bergman C, Hemery F, et al. Clinical relevance of flow cytometric immunophenotyping of the cerebrospinal fluid in patients with diffuse large B-cell lymphoma. Ann Oncol. 2012;23:1274–9.

    Article  CAS  PubMed  Google Scholar 

  29. Cheah CY, Wirth A, Seymour JF. Primary testicular lymphoma. Blood. 2014;123:486–93.

    Article  CAS  PubMed  Google Scholar 

  30. Dunleavy K, Fanale MA, Abramson JS, Noy A, Caimi PF, Pittaluga S, et al. Dose-adjusted EPOCH-R (etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, and rituximab) in untreated aggressive diffuse large B-cell lymphoma with MYC rearrangement: a prospective, multicentre, single-arm phase 2 study. Lancet Haematol. 2018;5:e609–17.

    Article  PubMed  PubMed Central  Google Scholar 

  31. Deng L, Xu-Monette ZY, Loghavi S, Manyam GC, Xia Y, Visco C, et al. Primary testicular diffuse large B-cell lymphoma displays distinct clinical and biological features for treatment failure in rituximab era: a report from the international PTL consortium. Leukemia. 2016;30:361–72.

    Article  CAS  PubMed  Google Scholar 

  32. Klanova M, Sehn LH, Bence-Bruckler I, Cavallo F, Jin J, Martelli M, et al. Integration of cell of origin into the clinical CNS international prognostic index improves CNS relapse prediction in DLBCL. Blood. 2019;133:919–26.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

We would like to thank all the members of the Yokohama Cooperative Study Group for Hematology for cooperating with this study.

Funding

This study received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.

Author information

Authors and Affiliations

  1. Department of Hematology, Yokohama City University Medical Center, 4-57, Urafune-Cho, Minami-Ku, Yokohama, Kanagawa, 232-0024, Japan

    Masahiro Akimoto, Takuya Miyazaki, Ayako Matsumura, Yuki Nakajima & Shin Fujisawa

  2. Department of Hematology and Medical Oncology, Kanagawa Cancer Center, Yokohama, Japan

    Hiroyuki Takahashi, Takaaki Takeda, Yuto Hibino, Mayumi Tokunaga & Rika Sakai

  3. Department of Biostatistics, Yokohama City University School of Medicine, Yokohama, Japan

    Yusuke Saigusa

  4. Department of Hematology and Clinical Immunology, Yokohama City University School of Medicine, Yokohama, Japan

    Takuma Ohashi, Haruka Teshigawara, Hiroshi Teranaka, Kenji Matsumoto & Hideaki Nakajima

  5. Department of Hematology, Fujisawa City Hospital, Fujisawa, Japan

    Taisei Suzuki & Katsumichi Fujimaki

  6. Department of Hematology/Oncology, Yamato Municipal Hospital, Yamato, Japan

    Chizuko Hashimoto

  7. Department of Hematology, Saiseikai Yokohama Nanbu Hospital, Yokohama, Japan

    Hiroyuki Fujita

Authors
  1. Masahiro Akimoto
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Takuya Miyazaki
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Hiroyuki Takahashi
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Yusuke Saigusa
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Takaaki Takeda
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Yuto Hibino
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Mayumi Tokunaga
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Takuma Ohashi
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Ayako Matsumura
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Haruka Teshigawara
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Taisei Suzuki
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Hiroshi Teranaka
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Yuki Nakajima
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Kenji Matsumoto
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. Chizuko Hashimoto
    View author publications

    You can also search for this author in PubMed Google Scholar

  16. Katsumichi Fujimaki
    View author publications

    You can also search for this author in PubMed Google Scholar

  17. Hiroyuki Fujita
    View author publications

    You can also search for this author in PubMed Google Scholar

  18. Rika Sakai
    View author publications

    You can also search for this author in PubMed Google Scholar

  19. Shin Fujisawa
    View author publications

    You can also search for this author in PubMed Google Scholar

  20. Hideaki Nakajima
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

MA: Data curation, statistical analysis and writing – original draft. TM: Statistical analysis and writing – original draft. HT: Data curation. TO: Data curation. HT: Data curation. HT: Data curation. KM: Data curation. CH: Data curation. KF: Data curation. HF: Data curation. YS: Statistical analysis. All authors reviewed, read, and approved the final version of the manuscript.

Corresponding author

Correspondence to Takuya Miyazaki.

Ethics declarations

Conflict of interest

Katsumichi Fujimaki has received honoraria from Pfizer. Shin Fujisawa has received research funding and honoraria from Pfizer. Hideaki Nakajima has received a scholarship donation from Pfizer. All the other authors have no conflict of interest to declare.

Ethical approval

Approval of the research protocol by an Institutional Reviewer Board: The Institutional Review Board of Yokohama City University Medical Center and affiliated institutions approved this study, and the study procedure complied with the principles of the Declaration of Helsinki.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary Information

Below is the link to the electronic supplementary material.

12185_2023_3700_MOESM1_ESM.docx

Figure S1. Central nervous system (CNS) prophylaxis protocol. Table S1. Prophylaxis-related toxicity Grade 3 or 4. Supplementary file1 (DOCX 33 KB)

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Akimoto, M., Miyazaki, T., Takahashi, H. et al. Comparison of standardized prophylactic high-dose and intrathecal methotrexate for DLBCL with a high risk of CNS relapse. Int J Hematol 119, 164–172 (2024). https://doi.org/10.1007/s12185-023-03700-0

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12185-023-03700-0

Keywords

Search

Navigation