Advertisement

Der Onkologe

, Volume 25, Issue 10, pp 880–891 | Cite as

Diffuses großzelliges B-Zell-Lymphom: Primär- und Rezidivtherapie

  • Gerhard HeldEmail author
  • Bertram Glaß
Leitthema
  • 78 Downloads

Zusammenfassung

Hintergrund

Das diffuse großzellige B‑Zell-Lymphom (DLBCL) subsumiert eine biologisch und prognostisch heterogene Gruppe an Erkrankungen.

Ziel

In diesem Artikel werden die gegenwärtigen therapeutischen Konzepte in der Primär- und Rezidivtherapie einschließlich ihrer Rationalen zusammengefasst.

Ergebnisse und Schlussfolgerung

Gegenwärtig ergeben sich aus biologischen Stratifikatoren keine differenzialtherapeutischen Konsequenzen. Die valideste Einschätzung der Prognose gewährleistet der International Prognostic Index (IPI). Die bei der Mehrzahl der Patienten kurative Primärtherapie beruht auf der systemischen Chemotherapie mit CHOP-basierten Protokollen, die Rituximab obligat einschließen. Der einheitlichen Behandlung mit R‑CHOP-21 steht das Konzept einer anhand des IPI stratifizierten risikoadaptierten Therapie gegenüber, welches auf Ergebnissen von in distinkten Risikogruppen durchgeführten randomisierten Studien basiert. Die Prognose im Rezidiv ist schlecht, welche v. a. durch die Zeit bis zu seinem Auftreten bestimmt ist. Die Salvagetherapie besteht überwiegend aus Protokollen, die ein Platinderivat beinhalten. Die geringe Rate von dauerhaften Remissionen macht bei eligiblen Patienten eine konsolidierende Hochdosistherapie, gefolgt von autologer Stammzelltransplantation (SZT) erforderlich. Bei frühem Rezidiv und Verfügbarkeit eines vollständig HLA-kompatiblen Spenders kann eine Hochdosistherapie und allogene SZT bei einem Teil der Patienten langfristige Remissionen erzielen. Eine wesentliche Innovation stellen autologe T‑Lymphozyten mit genetisch modifiziertem chimärem Antigenrezeptor (CAR-T-Zellen) dar, die nach mehrfachem Rezidiv z. T. eine anhaltende Krankheitskontrolle erreichen können.

Schlüsselwörter

Lymphom CHOP-basierte Protokolle Autologe Stammzelltransplantation Rezidiv Rezidivtherapie 

Diffuse large B cell lymphoma: first-line and salvage treatment

Abstract

Background

Diffuse large B cell lymphoma (DLBCL) represent a heterogeneous group of diseases with respect to biology and prognosis.

Objective

This article summarizes the current strategies and rationales in the treatment of DLBCL, in first-line as well as in salvage therapy.

Results and conclusion

Currently, no therapeutic consequences result from biological stratification factors. The best validated assessment of the prognosis is achieved by the clinical international prognostic index (IPI). In the majority of patients curative first-line treatment relies on systemic chemotherapy with CHOP-based protocols, which always include rituximab. Beyond the initial uniform treatment with R‑CHOP-21, a risk-adapted approach has evolved where, stratification is done by IPI risk groups. This concept emerged from randomized clinical trials, which have been performed in distinct prognostic risk groups. After relapse the prognosis, which is predominantly determined by the time period of occurrence (i.e. early vs. late relapse), is poor. Salvage treatment mostly consists of regimens containing platinum derivatives. The low rate of long-term remission necessitates a consolidating high-dose chemotherapy followed by autologous stem cell transplantation in eligible patients. Especially, in early relapse and availability of a fully HLA-matched donor, high-dose treatment and allogeneic stem cell transplantation can induce long-term remission in some patients. Recently, autologous T‑cells with genetically modified chimeric antigen receptors (CAR T‑cells) represents an important innovation and long-term disease control has partially been achieved after multiple recurrences.

Keywords

Lymphoma CHOP-based protocols Autologous stem cell transplantation Relapse Salvage therapy 

Notes

Einhaltung ethischer Richtlinien

Interessenkonflikt

G. Held weist auf folgende Beziehungen hin: Forschungsunterstützung durch Bristol-Myers Squibb, Acortech Biopharma, Roche, Amgen; Vortragstätigkeit für Bristol-Myers Squibb, Roche, Merck Sharp & Dohme; Beratertätigkeit für Bristol-Myers Squibb, Roche, Merck Sharp & Dohme. B. Glaß gibt an, dass kein Interessenkonflikt besteht.

Für diesen Beitrag wurden von den Autoren keine Studien an Menschen oder Tieren durchgeführt. Für die aufgeführten Studien gelten die jeweils dort angegebenen ethischen Richtlinien.

Literatur

  1. 1.
    Fisher RI, Gaynor ER, Dahlberg S et al (1993) Comparison of a standard regimen (CHOP) with three intensive chemotherapy regimens for advanced non-Hodgkin’s lymphoma. N Engl J Med 328:1002–1006CrossRefPubMedGoogle Scholar
  2. 2.
    Coiffier B, Lepage E, Brière J et al (2002) CHOP chemotherapy plus rituximab compared with CHOP alone in elderly patients with diffuse large-B-cell lymphoma. N Engl J Med 346:235–242CrossRefPubMedGoogle Scholar
  3. 3.
    Pfreundschuh M, Schubert J, Ziepert M et al (2008) Six versus eight cycles of bi-weekly CHOP-14 with or without rituximab in elderly patients with aggressive CD20+ B‑cell lymphomas: a randomised controlled trial (RICOVER-60). Lancet Oncol 9:105–116CrossRefPubMedGoogle Scholar
  4. 4.
    Pfreundschuh M, Trümper L, Österborg A et al (2006) 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 7:379–391CrossRefPubMedGoogle Scholar
  5. 5.
    Vitolo U, Trněný M, Belada D et al (2017) Obinutuzumab or rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone in previously untreated diffuse large B‑cell lymphoma. J Clin Oncol 35:3529–3537CrossRefPubMedGoogle Scholar
  6. 6.
    Younes A, Sehn LH, Johnson P et al (2019) Randomized phase III trial of ibrutinib and rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone in non–germinal center B‑cell diffuse large B‑cell lymphoma. J Clin Oncol 37:1285–1295CrossRefPubMedPubMedCentralGoogle Scholar
  7. 7.
    Bartlett NL, Wilson WH, Jung SH et al (2019) Dose-adjusted EPOCH‑R compared with R‑CHOP as frontline therapy for diffuse large B‑cell lymphoma: clinical outcomes of the phase III intergroup trial alliance/CALGB 50303. J Clin Oncol 37:1790–1799.  https://doi.org/10.1200/JCO.18.01994 CrossRefPubMedGoogle Scholar
  8. 8.
    Crump M, Neelapu SS, Farooq U et al (2017) Outcomes in refractory diffuse large B‑cell lymphoma: results from the international SCHOLAR‑1 study. Blood 130:1800–1808CrossRefPubMedPubMedCentralGoogle Scholar
  9. 9.
    Lenz G, Wright GW, Tolga Emre NC et al (2008) Molecular subtypes of diffuse large B‑cell lymphoma arise by distinct genetic pathways. Proc Natl Acad Sci 105:13520–13525CrossRefPubMedGoogle Scholar
  10. 10.
    Rosenwald A, Sehn LH, Maucort-Boulch D (2018) Prognostic significance of MYC single, double, triple hit and MYC-translocation partner status in diffuse large B‑cell lymphoma—a study by the Lunenburg Lymphoma Biomarker consortium (LLBC). Blood 132:344Google Scholar
  11. 11.
    Chapuy B, Stewart C, Dunford AJ et al (2018) Molecular subtypes of diffuse large B cell lymphoma are associated with distinct pathogenic mechanisms and outcomes. Nat Med 24:679–690CrossRefPubMedPubMedCentralGoogle Scholar
  12. 12.
    Schmitz R, Wright GW, Huang DW et al (2018) Genetics and pathogenesis of diffuse large B‑cell lymphoma. N Engl J Med 378:1396–1407CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    Lenz G, Wright G, Dave SS et al (2008) Stromal gene signatures in large-B-cell lymphomas. N Engl J Med 359:2313–2323CrossRefPubMedGoogle Scholar
  14. 14.
    Davies A, Cummin TE, Barrans S et al (2019) Gene-expression profiling of bortezomib added to standard chemoimmunotherapy for diffuse large B‑cell lymphoma (REMoDL-B): an open-label, randomised, phase 3 trial. Lancet Oncol 20:649–662CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    Cunningham D, Hawkes EA, Jack A et al (2013) Rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisolone in patients with newly diagnosed diffuse large B‑cell non-Hodgkin lymphoma: a phase 3 comparison of dose intensification with 14-day versus 21-day cycles. Lancet 381:1817–1826CrossRefPubMedGoogle Scholar
  16. 16.
    The International Non-Hodgkin’s Lymphoma Prognostic Factors Project (1993) A predictive model for aggressive non-Hodgkin’s lymphoma. N Engl J Med 329:987–994CrossRefGoogle Scholar
  17. 17.
    Ziepert M, Hasenclever D, Kuhnt E et al (2010) Standard international prognostic index remains a valid predictor of outcome for patients with aggressive CD20+ B‑cell lymphoma in the rituximab era. J Clin Oncol 28:2373–2380CrossRefPubMedGoogle Scholar
  18. 18.
    Poeschel V, Held G, Ziepert M et al (2018) Excellent outcome of young patients (18–60 years) with favourable-prognosis diffuse large B‑cell lymphoma (DLBCL) treated with 4 cycles CHOP plus 6 applications of Rituximab: results of the 592 patients of the flyer trial of the Dshnhl/GLA. Blood 132:781Google Scholar
  19. 19.
    Récher C, Coiffier B, Haioun C et al (2011) Intensified chemotherapy with ACVBP plus rituximab versus standard CHOP plus rituximab for the treatment of diffuse large B‑cell lymphoma (LNH03-2B): an open-label randomised phase 3 trial. Lancet 378:1858–1867CrossRefPubMedGoogle Scholar
  20. 20.
    Schmitz N, Nickelsen M, Ziepert M et al (2012) Conventional chemotherapy (CHOEP-14) with rituximab or high-dose chemotherapy (MegaCHOEP) with rituximab for young, high-risk patients with aggressive B‑cell lymphoma: an open-label, randomised, phase 3 trial (DSHNHL 2002-1). Lancet Oncol 13:1250–1259CrossRefPubMedGoogle Scholar
  21. 21.
    Cortelazzo S, Tarella C, Gianni AM et al (2016) Randomized trial comparing R‑CHOP versus high-dose sequential chemotherapy in high-risk patients with diffuse large B‑cell lymphomas. J Clin Oncol 34:4015–4022CrossRefPubMedGoogle Scholar
  22. 22.
    Chiappella A, Martelli M, Angelucci E et al (2017) Rituximab-dose-dense chemotherapy with or without high-dose chemotherapy plus autologous stem-cell transplantation in high-risk diffuse large B‑cell lymphoma (DLCL04): final results of a multicentre, open-label, randomised, controlled, phase 3 study. Lancet Oncol 18:1076–1088CrossRefPubMedGoogle Scholar
  23. 23.
    Delarue R, Tilly H, Mounier N et al (2013) Dose-dense rituximab-CHOP compared with standard rituximab-CHOP in elderly patients with diffuse large B‑cell lymphoma (the LNH03-6B study): a randomised phase 3 trial. Lancet Oncol 14:525–533CrossRefPubMedGoogle Scholar
  24. 24.
    Habermann TM, Weller EA, Morrison VA et al (2006) Rituximab-CHOP versus CHOP alone or with maintenance rituximab in older patients with diffuse large B‑cell lymphoma. J Clin Oncol 24:3121–3127CrossRefPubMedGoogle Scholar
  25. 25.
    Sehn LH, Congiu AG, Culligan DJ et al (2018) No added benefit of eight versus six cycles of CHOP when combined with rituximab in previously untreated diffuse large B‑cell lymphoma patients: results from the international phase III GOYA study. Blood 132:783Google Scholar
  26. 26.
    Peyrade F, Jardin F, Thieblemont C et al (2011) Attenuated immunochemotherapy regimen (R-miniCHOP) in elderly patients older than 80 years with diffuse large B‑cell lymphoma: a multicentre, single-arm, phase 2 trial. Lancet Oncol 12:460–468CrossRefPubMedGoogle Scholar
  27. 27.
    Morrison VA, Hamlin P, Soubeyran P et al (2015) Approach to therapy of diffuse large B‑cell lymphoma in the elderly: the International Society of Geriatric Oncology (SIOG) expert position commentary. Ann Oncol 26:1058–1068CrossRefPubMedGoogle Scholar
  28. 28.
    Dührsen U, Müller S, Hertenstein B et al (2018) Positron emission tomography–guided therapy of aggressive non-Hodgkin lymphomas (PETAL): a multicenter, randomized phase III trial. J Clin Oncol 36:2024–2034CrossRefPubMedGoogle Scholar
  29. 29.
    Pfreundschuh M, Kuhnt E, Trümper L et al (2011) CHOP-like chemotherapy with or without rituximab in young patients with good-prognosis diffuse large-B-cell lymphoma: 6‑year results of an open-label randomised study of the MabThera International Trial (MInT) Group. Lancet Oncol 12:1013–1022CrossRefPubMedGoogle Scholar
  30. 30.
    Van Den Neste E, Schmitz N, Mounier N et al (2016) Outcome of patients with relapsed diffuse large B‑cell lymphoma who fail second-line salvage regimens in the International CORAL study. Bone Marrow Transplant 51:51–57CrossRefGoogle Scholar
  31. 31.
    Guglielmi C, Gomez F, Philip T et al (1998) Time to relapse has prognostic value in patients with aggressive lymphoma enrolled onto the Parma trial. J Clin Oncol 16:3264–3269CrossRefPubMedGoogle Scholar
  32. 32.
    Gisselbrecht C, Glass B, Mounier N et al (2010) Salvage regimens with autologous transplantation for relapsed large B‑cell lymphoma in the rituximab era. J Clin Oncol 28:4184–4190CrossRefPubMedPubMedCentralGoogle Scholar
  33. 33.
    Baetz T, Chen BE, Couban S et al (2017) Effect of the addition of rituximab to salvage chemotherapy prior to autologous stem cell transplant in aggressive CD20+ lymphoma: a cohort comparison from the NCIC Clinical Trials Group Study LY.12. Leuk Lymphoma 58:64–69CrossRefPubMedGoogle Scholar
  34. 34.
    Sehn LH, Herrera AF, Matasar MJ et al (2018) Polatuzumab vedotin (Pola) plus bendamustine (B) with rituximab (R) or obinutuzumab (G) in relapsed/refractory (R/R) diffuse large B‑cell lymphoma (DLBCL): updated results of a phase (Ph) Ib/II study. Blood 132:1683Google Scholar
  35. 35.
    Verdière L, Mourcin F, Tarte K (2018) Microenvironment signaling driving lymphomagenesis. Curr Opin Hematol 25:335–345CrossRefPubMedGoogle Scholar
  36. 36.
    Advani R, Flinn I, Popplewell L et al (2018) CD47 blockade by Hu5F9-G4 and rituximab in non-Hodgkin’s lymphoma. N Engl J Med 379:1711–1721CrossRefPubMedGoogle Scholar
  37. 37.
    Philip T, Guglielmi C, Hagenbeek A et al (1995) Autologous bone marrow transplantation as compared with salvage chemotherapy in relapses of chemotherapy-sensitive non-Hodgkin’s lymphoma. N Engl J Med 333:1540–1545CrossRefPubMedGoogle Scholar
  38. 38.
    Crump M, Kuruvilla J, Couban S et al (2014) Randomized comparison of gemcitabine, dexamethasone, and cisplatin versus dexamethasone, cytarabine, and cisplatin chemotherapy before autologous stem-cell transplantation for relapsed and refractory aggressive lymphomas: NCIC-CTG LY.12. J Clin Oncol 32:3490–3496CrossRefPubMedGoogle Scholar
  39. 39.
    Robinson SP, Goldstone AH, Mackinnon S et al (2002) Chemoresistant or aggressive lymphoma predicts for a poor outcome following reduced-intensity allogeneic progenitor cell transplantation: an analysis from the Lymphoma Working Party of the European Group for Blood and Bone Marrow Transplantation. Blood 100:4310–4316CrossRefPubMedGoogle Scholar
  40. 40.
    Glass B, Hasenkamp J, Wulf G et al (2014) Rituximab after lymphoma-directed conditioning and allogeneic stem-cell transplantation for relapsed and refractory aggressive non-Hodgkin lymphoma (DSHNHL R3): an open-label, randomised, phase 2 trial. Lancet Oncol 15:757–766CrossRefPubMedGoogle Scholar
  41. 41.
    Neelapu SS, Locke FL, Bartlett NL et al (2017) Axicabtagene ciloleucel CAR T‑cell therapy in refractory large B‑cell lymphoma. N Engl J Med 377:2531–2544CrossRefPubMedPubMedCentralGoogle Scholar
  42. 42.
    Schuster SJ, Svoboda J, Chong EA et al (2017) Chimeric antigen receptor T cells in refractory B‑cell lymphomas. N Engl J Med 377:2545–2554CrossRefPubMedPubMedCentralGoogle Scholar
  43. 43.
    Cabanillas F, Hagemeister F, Bodey G, Freireich E (1982) IMVP-16: an effective regimen for patients with lymphoma who have relapsed after initial combination chemotherapy. Blood 60:693–697PubMedGoogle Scholar
  44. 44.
    Velasquez WS, McLaughlin P, Tucker S et al (1994) ESHAP—an effective chemotherapy regimen in refractory and relapsing lymphoma: a 4‑year follow-up study. J Clin Oncol 12:1169–1176CrossRefPubMedGoogle Scholar
  45. 45.
    Rodriguez-Monge EJ, Cabanillas F (1997) Long-term follow-up of platinum-based lymphoma salvage regimens: the MD Anderson Cancer Center Experience. Hematology/Oncology Clinics of North America 11:937–947CrossRefPubMedGoogle Scholar
  46. 46.
    Cabanillas F, Hagemeister FB, McLaughlin P et al (1987) Results of MIME salvage regimen for recurrent or refractory lymphoma. J Clin Oncol 5:407–412CrossRefPubMedGoogle Scholar
  47. 47.
    Enblad G, Hagberg H, Glimelius B (1996) Methyl-GAG, ifosfamide, methotrexate and etoposide (MIME) as salvage therapy for non-Hodgkin’s lymphomas: a Swedish national prospective study. Swedish Lymphoma Study Group. Acta Oncol 35:165–170CrossRefPubMedGoogle Scholar
  48. 48.
    Rodriguez MA, Cabanillas FC, Velasquez W et al (1995) Results of a salvage treatment program for relapsing lymphoma: MINE consolidated with ESHAP. J Clin Oncol 13:1734–1741CrossRefPubMedGoogle Scholar
  49. 49.
    Chao N, Rosenberg S, Horning S (1990) CEPP(B): an effective and well-tolerated regimen in poor-risk, aggressive non-Hodgkin’s lymphoma. Blood 76:1293–1298PubMedGoogle Scholar
  50. 50.
    Mounier N, El Gnaoui T, Tilly H et al (2013) Rituximab plus gemcitabine and oxaliplatin in patients with refractory/relapsed diffuse large B-cell lymphoma who are not candidates for high-dose therapy. A phase II Lymphoma Study Association trial. Haematologica 98:1726–1731CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Springer Medizin Verlag GmbH, ein Teil von Springer Nature 2019

Authors and Affiliations

  1. 1.Klinik für Innere Medizin I – Onkologie, Hämatologie, DiabetologieWestpfalz-Klinikum GmbHKaiserslauternDeutschland
  2. 2.Fachbereich Hämatologie und StammzelltransplantationHelios Klinikum Berlin-BuchBerlinDeutschland

Personalised recommendations