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Current and Emerging Treatment Strategies for Primary Mediastinal B-Cell Lymphoma

  • Christin B. DeStefano
  • Kieron Dunleavy
  • Catherine LaiEmail author
Chapter

Abstract

Primary mediastinal B-cell lymphoma is rare, representing less than 5% of all non-Hodgkin lymphomas. Given its rarity, the only studies from which to derive optimal management are single arm, retrospective, or subgroup analyses of larger studies. Despite the paucity of high-level evidence, the historical standard frontline treatment is R-CHOP followed by consolidative mediastinal radiotherapy. Recent data suggest that increased intensity chemoimmunotherapy may obviate the need for mediastinal radiotherapy in the frontline setting and that combinations or sequences of novel immunotherapies, small molecule inhibitors, and monoclonal antibodies may improve outcomes in the relapsed or refractory setting which otherwise carries a dismal prognosis.

Keywords

Primary mediastinal B-cell lymphoma Chemotherapy Radiation therapy Checkpoint inhibitors CAR-T cells Monoclonal antibodies Small molecule inhibitors 

References

  1. 1.
    Jaffe ES, Harris NL, Stein H, et al. World Health Organization classification of tumors. Pathology and genetics of tumours of haematopoietic and lymphoid tissues. Lyon: IARC Press; 2001.Google Scholar
  2. 2.
    The Non-Hodgkin’s Lymphoma Classification Project. A clinical evaluation of the International Lymphoma Study Group classification of non-Hodgkin’s lymphoma. Blood. 1997;89:3909–18.CrossRefGoogle Scholar
  3. 3.
    Liu PP, Wang KF, Xia Y, et al. Racial patterns of patients with primary mediastinal large B-cell lymphoma. Medicine (Baltimore). 2016;95(27):e4054.CrossRefGoogle Scholar
  4. 4.
    Romaguera JE, Meilus S, Rodriguez J, et al. Endocrine characterization of primary mediastinal lymphoma. Leuk Lymphoma. 1996;23(5–6):613–5.PubMedCrossRefGoogle Scholar
  5. 5.
    Saarinen S, Kaasinen E, Karjalainen-Lindsberg ML, et al. Primary mediastinal large B-cell lymphoma segregating in a family: exome sequencing identifies MLL as a candidate predisposition gene. Blood. 2013;121(17):3428–30.PubMedCrossRefGoogle Scholar
  6. 6.
    Jacobson JO, Aisenberg AC, Lamarre L, et al. Mediastinal large cell lymphoma. An uncommon subset of adult lymphoma curable with combined modality therapy. Cancer. 1988;62:1893.PubMedCrossRefGoogle Scholar
  7. 7.
    Savage KJ, Al-Rajhi N, Voss N, et al. Favorable outcome of primary mediastinal large B-cell lymphoma in a single institution: the British Columbia experience. Ann Oncol. 2006;17:123.PubMedCrossRefGoogle Scholar
  8. 8.
    Swerdlow SH, Campo E, Harris NL, et al. World Health Organization classification of tumours of haematopoietic and lymphoid tissues. Lyon: IARC Press; 2008.Google Scholar
  9. 9.
    Dunleavy K, Wilson WH. Primary mediastinal B-cell lymphoma and mediastinal gray zone lymphoma: do they require a unique therapeutic approach? Blood. 2015;125(1):33–9.PubMedPubMedCentralCrossRefGoogle Scholar
  10. 10.
    Rosenwald A, Wright G, Leroy K, et al. Molecular diagnosis of primary mediastinal B cell lymphoma identifies a clinically favorable subgroup of diffuse large B cell lymphoma related to Hodgkin lymphoma. J Exp Med. 2003;198(6):851–62.PubMedPubMedCentralCrossRefGoogle Scholar
  11. 11.
    Savage KL, Monti S, Kutok JL, et al. The molecular signature of mediastinal large B-cell lymphoma differs from that of the other diffuse large B-cell lymphomas and shares features with classical Hodgkin lymphoma. Blood. 2003;102:3871–9.PubMedCrossRefGoogle Scholar
  12. 12.
    Gunawardana J, Chan FC, Telenius A, et al. Recurrent somatic mutations of PTPN1 in primary mediastinal B cell lymphoma and Hodgkin lymphoma. Nat Genet. 2014;46(4):329–35.PubMedCrossRefGoogle Scholar
  13. 13.
    Steidl C, Shah SP, Woolcock BW, et al. MHC class II transactivator CIITA is a recurrent gene fusion partner in lymphoid cancers. Nature. 2011;471(7338):377–81.PubMedPubMedCentralCrossRefGoogle Scholar
  14. 14.
    Rimsza LM, Roberts RA, Campo E, et al. Loss of major histocompatibility class II expression in non-immune-privileged site diffuse large B-cell lymphoma is highly coordinated and not due to chromosomal deletions. Blood. 2006;107:1101–7.PubMedPubMedCentralCrossRefGoogle Scholar
  15. 15.
    Twa DD, Chan FC, Ben-Neriah S, et al. Genomic rearrangements involving programmed death ligands are recurrent in primary mediastinal large B-cell lymphoma. Blood. 2014;123:2062–5.PubMedCrossRefGoogle Scholar
  16. 16.
    Cheson BD, Fisher RI, Barrington SF, et al. Recommendations for initial evaluation, staging, and response assessment of Hodgkin and non-Hodgkin lymphoma: the Lugano classification. J Clin Oncol. 2014;32(27):3059–67.PubMedPubMedCentralCrossRefGoogle Scholar
  17. 17.
    Surveillance, Epidemiology, and End Results (SEER) Program (www.seer.cancer.gov) SEER∗Stat Database: Overall Survival – SEER 18, Nov 2016 Sub (1973–2014) – Linked To County Attributes – Total U.S., 1969–2015 Counties, National Cancer Institute, DCCPS, Surveillance Research Program, released April 2017. Accessed 15 Nov 2017.
  18. 18.
    Lisenko K, Dingeldein G, Cremer M, et al. Addition of rituximab to CHOP-like chemotherapy in first line treatment of primary mediastinal B-cell lymphoma. BMC Cancer. 2017;17:359.PubMedPubMedCentralCrossRefGoogle Scholar
  19. 19.
    Lichtenstein AK, Levine A, Taylor CR, et al. Primary mediastinal lymphoma in adults. Am J Med. 1980;68(4):509–14.PubMedCrossRefGoogle Scholar
  20. 20.
    Lazzarino M, Orlandi E, Paulli M, et al. Primary mediastinal B-cell lymphoma with sclerosis: an aggressive tumor with distinctive clinical and pathologic features. J Clin Oncol. 1993;11(12):2306–13.PubMedCrossRefGoogle Scholar
  21. 21.
    Todeschini G, Secchi S, Morra E, et al. Primary mediastinal large B-cell lymphoma (PMlBCL): long-term results from a retrospective multicenter Italian experience in 138 patients treated with CHOP or MACOP-B/VACOP-B. Br J Cancer. 2004;90:372–6.PubMedPubMedCentralCrossRefGoogle Scholar
  22. 22.
    Zinzani PL, Martelli M, Bertini M, et al. Induction chemotherapy strategies for primary mediastinal large B-cell lymphoma with sclerosis: a retrospective multinational study on 426 previously untreated patients. Haematologica. 2002;87(12):1258–64.PubMedGoogle Scholar
  23. 23.
    Rieger M, Osterborg A, Pettengell R, et al. Primary mediastinal B-cell lymphoma treated with CHOP-like chemotherapy with or without rituximab: results of the Mabthera International Trial Group study. Ann Oncol. 2011;22:664–70.PubMedCrossRefGoogle Scholar
  24. 24.
    Zinzani PL, Stefoni V, Finolezzi E, et al. Rituximab combined with MACOP-B or VACOP-B and radiation therapy in primary mediastinal large B-cell lymphoma: a retrospective study. Clin Lymphoma Myeloma. 2009;9(5):381–5.PubMedCrossRefGoogle Scholar
  25. 25.
    Mazzarotto R, Boso C, Vianello F, et al. Primary mediastinal large B-cell lymphoma: results of intensive chemotherapy regimens (MACOP-B/VACOP-B) plus involved field radiotherapy on 53 patients. A single institution experience. Int J Radiat Oncol Biol Phys. 2007;68(3):823–9.PubMedCrossRefGoogle Scholar
  26. 26.
    Giri S, Bhatt VR, Pathak R, Bociek G, et al. Role of radiation therapy in primary mediastinal large B-cell lymphoma in rituximab era: a US population-based analysis. Am J Hematol. 2015;90(11):1052–4.PubMedCrossRefGoogle Scholar
  27. 27.
    Vassilakopoulos TP, Pangalis GA, Katsigiannis A, et al. Rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone with or without radiotherapy in primary mediastinal large B-cell lymphoma: the emerging standard of care. Oncologist. 2012;17:239–49.PubMedPubMedCentralCrossRefGoogle Scholar
  28. 28.
    Soumerai JD, Hellmann MD, Feng Y, et al. Treatment of primary mediastinal B-cell lymphoma with rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone is associated with a high rate of primary refractory disease. Leuk Lymphoma. 2014;55(3):538–43.PubMedCrossRefGoogle Scholar
  29. 29.
    Ahn HK, Kim SJ, Yun J, et al. Improved treatment outcome of primary mediastinal large B-cell lymphoma after introduction of rituximab in Korean patients. Int J Hematol. 2010;91(3):456–63.PubMedCrossRefGoogle Scholar
  30. 30.
    Schaapveld M, Aleman B, van Eggermond A, et al. Second cancer risk up to 40 years after treatment for Hodgkin’s lymphoma. N Engl J Med. 2015;373:2499–511.PubMedCrossRefGoogle Scholar
  31. 31.
    Van Nimwegen FA, Schaapveld M, Cutter DJ. Radiation dose-response relationship for risk of coronary heart disease in survivors of Hodgkin lymphoma. J Clin Oncol. 2016;34(3):235–43.PubMedCrossRefGoogle Scholar
  32. 32.
    Kamran SC, de Gonzalez AB, Ng A, et al. Therapeutic radiation and the potential risk of second malignancies. Cancer. 2016;122(12):1809–21.PubMedCrossRefGoogle Scholar
  33. 33.
    Martelli M, Ceriani L, Zucca E, et al. [18F]fluorodeoxyglucose positron emission tomography predicts survival after chemoimmunotherapy for primary mediastinal large B-cell lymphoma: results of the International Extranodal Lymphoma Study Group IELSG-26 Study. J Clin Oncol. 2014;32(17):1769–75.PubMedCrossRefGoogle Scholar
  34. 34.
    Dunleavy K, Pittaluga S, Maeda LS, et al. Dose-adjusted EPOCH-rituximab therapy in primary mediastinal B-cell lymphoma. N Engl J Med. 2013;368(15):1408–16.PubMedPubMedCentralCrossRefGoogle Scholar
  35. 35.
    Savage KJ, Yenson PR, Shenkier T, Klasa R, Villa D, Goktepe O et al. The outcome of primary mediastinal large B-cell lymphoma (PMBCL) in the R-CHOP treatment era. In: Proceedings from the 54th annual American Society of Hematology conference, Atlanta, GA. 2012.Google Scholar
  36. 36.
    Allen-Auerbach M, Weber WA. Measuring response with FDG-PET: methodological aspects. Oncologist. 2009;14:369–77.PubMedCrossRefGoogle Scholar
  37. 37.
    National Comprehensive Cancer Network. B-cell lymphomas (Version 1.2018). https://www.nccn.org/professionals/physician_gls/pdf/b-cell.pdf. Accessed 1 Feb 2018.
  38. 38.
    Melani C, Advani RH, Roschewski M, et al. End-of-treatment CT and serial FDG-PET imaging to assess residual disease in primary mediastinal B-cell lymphoma. In: Proceedings from the 59th American Society of Hematology annual meeting, Atlanta, GA. 2017. https://ash.confex.com/ash/2017/webprogram/Paper108834.html.
  39. 39.
    Kuruvilla J, Pintillie M, Tsang R, et al. Salvage chemotherapy and autologous stem cell transplantation are inferior for relapsed or refractory primary mediastinal large B-cell lymphoma compared with diffuse large B-cell lymphoma. Leuk Lymphoma. 2008;49(7):1329–36.PubMedCrossRefGoogle Scholar
  40. 40.
    Aoki T, Shimada K, Suzuki R, et al. High-dose chemotherapy followed by autologous stem cell transplantation for relapsed/refractory primary mediastinal large B-cell lymphoma. Blood Cancer J. 2015;e372:1–5.Google Scholar
  41. 41.
    Avivi I, Boumendil A, Finel H, et al. Autologous stem cell transplantation for primary mediastinal B-cell lymphoma: long-term outcome and role of post-transplant radiotherapy. A report of the European Society for Blood and Marrow Transplantation. Bone Marrow Transplant. 2018;53:1001–9.. Epub ahead of print.PubMedCrossRefGoogle Scholar
  42. 42.
    Crump M, Neelapu SS, Farooq U, et al. Outcomes in refractory diffuse large B-cell lymphoma: results from the international SCHOLAR-1 study. Blood. 2017;130(16):1800–8.PubMedPubMedCentralCrossRefGoogle Scholar
  43. 43.
    Khouri IF, Saliba RM, Xu-Monette ZY, et al. Outcomes following allogeneic stem cell transplantation (AlloSCT) in patients with primary mediastinal (PMBL), germinal center B (GCB) and non-GCB cell-like diffuse large B cell lymphomas (DLBCL). In: Proceedings from the 56th American Society of Hematology annual meeting, San Francisco, CA. 2014. http://www.bloodjournal.org/content/124/21/2563?sso-checked=true.
  44. 44.
    Giulino-Roth L, O’Donohue T, Chen Z, et al. Outcomes of adults and children with primary mediastinal B-cell lymphoma treated with dose-adjusted EPOCH-R. Br J Haematol. 2017;179(5):739–47.PubMedPubMedCentralCrossRefGoogle Scholar
  45. 45.
    Shah NN, Szabo A, Huntington SF, et al. R-CHOP versus dose-adjusted R-EPOCH in frontline management of primary mediastinal B-cell lymphoma: a multi-centre analysis. Br J Haematol. 2018;180(4):534–44.PubMedCrossRefGoogle Scholar
  46. 46.
    Gharwan H, Lai C, Grant C, Dunleavy K, Steinberg SM, Shovlin M, Fojo T, Wilson WH. Female fertility following dose-adjusted EPOCH-R chemotherapy in primary mediastinal B-cell lymphomas. Leuk Lymphoma. 2016;57(7):1616–24.PubMedCrossRefGoogle Scholar
  47. 47.
    Brudno JN, Kochenderfer JN. Chimeric antigen receptor T-cell therapies for lymphoma. Nat Rev Clin Oncol. 2018;15(1):31–46.PubMedCrossRefGoogle Scholar
  48. 48.
    Neelapu SS, Locke FL, Barlett NL, et al. Axicabtagene ciloleucel CAR T-cell therapy in refractory large B-cell lymphoma. N Engl J Med. 2017;377(26):2531–44.PubMedPubMedCentralCrossRefGoogle Scholar
  49. 49.
    Gravelle P, Burroni B, Pericart S, et al. Mechanisms of PD-1/PD-L1 expression and prognostic relevance in non-Hodgkin lymphoma: a summary of immunohistochemical studies. Oncotarget. 2017;4(27):44960–75.Google Scholar
  50. 50.
    Zinzani PL, Ribrag V, Moskowitz CH, et al. Safety and tolerability of pembrolizumab in patients with relapsed/refractory primary mediastinal large B-cell lymphoma. Blood. 2017;130(3):267–70.PubMedPubMedCentralCrossRefGoogle Scholar
  51. 51.
    Zinzani PL, Pellegrini C, Chiappella A, et al. Brentuximab vedotin in relapsed primary mediastinal large B-cell lymphoma: results from a phase 2 clinical trial. Blood. 2017;129(16):2328–30.PubMedCrossRefGoogle Scholar
  52. 52.
    Jacobsen ED, Sharman JP, Oki Y, et al. Brentuximab vedotin demonstrates objective responses in a phase 2 study of relapsed/refractory DLBCL with variable CD30 expression. Blood. 2015;125(9):1394–402.PubMedCrossRefGoogle Scholar
  53. 53.
    Higgins JP, Warnke RA. CD30 expression is common in mediastinal large B-cell lymphoma. Am J Clin Pathol. 1999;112(2):241–7.PubMedCrossRefGoogle Scholar
  54. 54.
    Hutchinson CB, Wang E. Primary mediastinal (thymic) large B-cell lymphoma: a short review with brief discussion of mediastinal gray zone lymphoma. Arch Pathol Lab Med. 2011;135(3):394–8.PubMedGoogle Scholar
  55. 55.
    Cherkassky L, Morello A, Villena-Vargas J, et al. Human CAR T cells with cell-intrinsic PD-1 checkpoint blockade resistant tumor-mediated inhibition. J Clin Invest. 2016;126(8):3130–44.PubMedPubMedCentralCrossRefGoogle Scholar
  56. 56.
    Hao Y, Chapuy B, Monti S, et al. Selective JAK2 inhibition specifically decreases Hodgkin lymphoma and mediastinal large B-cell lymphoma growth in vitro and in vivo. Clin Cancer Res. 2014;20(10):2674–83.PubMedPubMedCentralCrossRefGoogle Scholar
  57. 57.
    Philip T, Guglielmi C, Hagenbeek A, et al. Autologous bone marrow transplantation as compared with salvage chemotherapy in relapses of chemotherapy-sensitive non-Hodgkin’s lymphoma. N Engl J Med. 1995;333(23):1540–5.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Nature Switzerland AG 2020

Authors and Affiliations

  • Christin B. DeStefano
    • 1
  • Kieron Dunleavy
    • 2
  • Catherine Lai
    • 3
    Email author
  1. 1.Uniformed Services UniversityBethesdaUSA
  2. 2.George Washington University HospitalWashington, DCUSA
  3. 3.MedStar Georgetown University HospitalWashington, DCUSA

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