Skip to main content

Advertisement

Log in

Maintenance Therapies in Indolent Lymphomas: should Recent Data Change the Standard of Care?

  • Lymphoma (JW Sweetenham, Section Editor)
  • Published:
Current Treatment Options in Oncology Aims and scope Submit manuscript

Opinion statement

The overall benefit of maintenance therapy for patients with an indolent lymphoma continues to go unanswered. A myriad of variables contribute to the lack of clear clinical guidance. First, the disease course is slow and treatment may not be required for years, requiring a long follow-up to prospectively study. Second, due to the long lag time from study initiation to conclusion, many of the induction therapies used at the onset of the study may not be favored at present, providing a conclusion that cannot be reconciled with current clinical practice. For example, bendamustine and rituximab are typically the favored initial treatment agents in follicular lymphoma, which was not true when many maintenance trials were initiated. Third, several studies’ inclusion criteria allow for patient enrollment at both initial diagnosis as well as at disease recurrence. In some studies, patients who are asymptomatic are started on therapy, counter to the accepted watch and wait approach. This contributes to the difficulty of generalizing results. The question of the benefit of maintenance therapy has been studied enough, and there may not be a smoking gun in the foreseeable future. However, what does hold promise is focusing on the patients with minimum residual disease after conclusion of chemotherapy. This may be a population that could receive benefit from a prolonged treatment approach. In the meantime, maintenance therapy should not be used in all patients, and the rationale for use should be data-driven, as well as an assessment of a patient’s potential intolerability of cytotoxic chemotherapy.

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

Access this article

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

Instant access to the full article PDF.

Similar content being viewed by others

References and Recommended Reading

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. Ardeshna KM, Smith P, Norton A, Hancock BW, Hoskin PJ, MacLennan KA, et al. Long-term effect of a watch and wait policy versus immediate systemic treatment for asymptomatic advanced-stage non-Hodgkin lymphoma: a randomised controlled trial. Lancet. 2003;362(9383):516–22.

    Article  CAS  PubMed  Google Scholar 

  2. Hainsworth JD, Litchy S, Burris 3rd HA, Scullin Jr DC, Corso SW, Yardley DA, et al. Rituximab as first-line and maintenance therapy for patients with indolent non-hodgkin's lymphoma. J Clin Oncol Off J Am Soc Clin Oncol. 2002;20(20):4261–7.

    Article  CAS  Google Scholar 

  3. Hainsworth JD, Litchy S, Barton JH, Houston GA, Hermann RC, Bradof JE, et al. Single-agent rituximab as first-line and maintenance treatment for patients with chronic lymphocytic leukemia or small lymphocytic lymphoma: a phase II trial of the Minnie pearl cancer research network. J Clin Oncol Off J Am Soc Clin Oncol. 2003;21(9):1746–51.

    Article  CAS  Google Scholar 

  4. • Barta SK, Li H, Hochster HS, Hong F, Weller E, Gascoyne RD, et al. Randomized phase 3 study in low-grade lymphoma comparing maintenance anti-CD20 antibody with observation after induction therapy: a trial of the ECOG-ACRIN cancer research group (E1496). Cancer. 2016;122(19):2996–3004. This article reports the outcomes of patients over a decade after receiving maintenance therapy for FL. The robust data supports a significant increase in progression free survival in those receiving maintenance therapy, but an improvement in overal survival was not demonstrated

    Article  CAS  PubMed  Google Scholar 

  5. Flinn IW, van der Jagt R, Kahl BS, Wood P, Hawkins TE, Macdonald D, et al. Randomized trial of bendamustine-rituximab or R-CHOP/R-CVP in first-line treatment of indolent NHL or MCL: the BRIGHT study. Blood. 2014;123(19):2944–52.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Salles G, Seymour JF, Offner F, Lopez-Guillermo A, Belada D, Xerri L, et al. Rituximab maintenance for 2 years in patients with high tumour burden follicular lymphoma responding to rituximab plus chemotherapy (PRIMA): a phase 3, randomised controlled trial. Lancet. 2011;377(9759):42–51.

    Article  CAS  PubMed  Google Scholar 

  7. Sarkozy C, Trneny M, Xerri L, Wickham N, Feugier P, Leppa S, et al. Risk factors and outcomes for patients with follicular lymphoma who had histologic transformation after response to first-line Immunochemotherapy in the PRIMA trial. J Clin Oncol Off J Am Soc Clin Oncol. 2016;34(22):2575–82.

    Article  CAS  Google Scholar 

  8. Wagner-Johnston ND, Link BK, Byrtek M, Dawson KL, Hainsworth J, Flowers CR, et al. Outcomes of transformed follicular lymphoma in the modern era: a report from the national LymphoCare study (NLCS). Blood. 2015;126(7):851–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Taverna C, Martinelli G, Hitz F, Mingrone W, Pabst T, Cevreska L, et al. Rituximab maintenance for a maximum of 5 Years after single-agent rituximab induction in follicular lymphoma: results of the randomized controlled phase III trial SAKK 35/03. J Clin Oncol Off J Am Soc Clin Oncol. 2016;34(5):495–500.

    Article  CAS  Google Scholar 

  10. Horn H, Schmelter C, Leich E, Salaverria I, Katzenberger T, Ott MM, et al. Follicular lymphoma grade 3B is a distinct neoplasm according to cytogenetic and immunohistochemical profiles. Haematologica. 2011;96(9):1327–34.

    Article  PubMed  PubMed Central  Google Scholar 

  11. • Kahl BS, Hong F, Williams ME, Gascoyne RD, Wagner LI, Krauss JC, et al. Rituximab extended schedule or re-treatment trial for low-tumor burden follicular lymphoma: eastern cooperative oncology group protocol e4402. Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2014;32(28):3096–102. This study reported that maintenance rituximab in patients with FL was not superior to those who only received rituximab upon recurrence. While the outcome of interest was time to treatment failure, it was also noted that patients on the re-treatment arm did require chemotherapy sooner than those receiving maintenance therapy

    Article  CAS  Google Scholar 

  12. • Ardeshna KM, Qian W, Smith P, Braganca N, Lowry L, Patrick P, et al. Rituximab versus a watch-and-wait approach in patients with advanced-stage, asymptomatic, non-bulky follicular lymphoma: an open-label randomised phase 3 trial. The lancet oncology. 2014;15(4):424–35. This study identified that treatment with rituximab followed by maintenance therapy prolonged the progression free survival compared to those under the watch and wait strategy. The value of these findings does remain in question if overall survival is not improved when initiating therapy early

    Article  CAS  PubMed  Google Scholar 

  13. Ghielmini M, Schmitz SF, Cogliatti SB, Pichert G, Hummerjohann J, Waltzer U, et al. Prolonged treatment with rituximab in patients with follicular lymphoma significantly increases event-free survival and response duration compared with the standard weekly × 4 schedule. Blood. 2004;103(12):4416–23.

    Article  CAS  PubMed  Google Scholar 

  14. •• Martinelli G, Schmitz SF, Utiger U, Cerny T, Hess U, Bassi S, et al. Long-term follow-up of patients with follicular lymphoma receiving single-agent rituximab at two different schedules in trial SAKK 35/98. Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2010;28(29):4480–4. This article reports long-term outcomes using maintenance rituximab in follicular lymphoma. Overall survival benefit was noted in those receiving maintenance therapy in the relapsed/refractory setting. This is the largest single trial that has shown definitive evidence of benefit for maintenance therapy

    Article  CAS  Google Scholar 

  15. •• Marcus RE, Davies AJ, Ando K, Klapper W, Opat S, Owen C, et al. Obinutuzumab-based induction and maintenance prolongs Progression-Free Survival (PFS) in patients with previously untreated follicular lymphoma: primary results of the randomized phase 3 GALLIUM study. Blood. 2016. While rituximab has been used in most maintenance trials, this is the first time another agent was studied head-to-head. Given the improved progression-free survival, this may ultimately identify an overall survival benefit when using obinutuzumab for induction and maintenance therapy.

  16. Bourcier J, Gastinne T, Leux C, Moreau A, Bossard C, Mahe B, et al. Rituximab maintenance after autologous stem cell transplantation prolongs response duration in non-naive rituximab follicular lymphoma patients: a single institution experience. Ann Hematol. 2016;95(8):1287–93.

    Article  CAS  PubMed  Google Scholar 

  17. Vidal L, Gafter-Gvili A, Salles G, Dreyling MH, Ghielmini M, Hsu Schmitz SF, et al. Rituximab maintenance for the treatment of patients with follicular lymphoma: an updated systematic review and meta-analysis of randomized trials. J Natl Cancer Inst. 2011;103(23):1799–806.

    Article  CAS  PubMed  Google Scholar 

  18. Hallek M. Chronic lymphocytic leukemia: 2015 update on diagnosis, risk stratification, and treatment. Am J Hematol. 2015;90(5):446–60.

    Article  CAS  PubMed  Google Scholar 

  19. Del Poeta G, Del Principe MI, Buccisano F, Maurillo L, Capelli G, Luciano F, et al. Consolidation and maintenance immunotherapy with rituximab improve clinical outcome in patients with B-cell chronic lymphocytic leukemia. Cancer. 2008;112(1):119–28.

    Article  CAS  PubMed  Google Scholar 

  20. Foa R, Del Giudice I, Cuneo A, Del Poeta G, Ciolli S, Di Raimondo F, et al. Chlorambucil plus rituximab with or without maintenance rituximab as first-line treatment for elderly chronic lymphocytic leukemia patients. Am J Hematol. 2014;89(5):480–6.

    Article  CAS  PubMed  Google Scholar 

  21. Abrisqueta P, Villamor N, Terol MJ, González-Barca E, González M, Ferrà C, et al. Rituximab maintenance after first-line therapy with rituximab, fludarabine, cyclophosphamide, and mitoxantrone (R-FCM) for chronic lymphocytic leukemia. Blood. 2013;122(24):3951–9.

    Article  CAS  PubMed  Google Scholar 

  22. Greil R, Obrtlikova P, Smolej L, Kozak T, Steurer M, Andel J, et al. Rituximab maintenance versus observation alone in patients with chronic lymphocytic leukaemia who respond to first-line or second-line rituximab-containing chemoimmunotherapy: final results of the AGMT CLL-8a Mabtenance randomised trial. The Lancet Haematology. 2016;3(7):e317–29.

    Article  PubMed  Google Scholar 

  23. • van Oers MH, Kuliczkowski K, Smolej L, Petrini M, Offner F, Grosicki S, et al. Ofatumumab maintenance versus observation in relapsed chronic lymphocytic leukaemia (PROLONG): an open-label, multicentre, randomised phase 3 study. The lancet oncology. 2015;16(13):1370–9. This trial reported that in patients who received ofatumumab maintenance after a prior therapy for CLL/SLL, the progression free survival nearly doubled compared to those who did not receive maintenance therapy. It is possible that we may see an overall survival benefit with maintenance therapy in CLL/SLL after relapse, similar to follicular lymphoma

    Article  PubMed  Google Scholar 

  24. Chang JE, Havighurst T, Kim K, Eickhoff J, Traynor AM, Kirby-Slimp R, et al. Bendamustine + rituximab chemoimmunotherapy and maintenance lenalidomide in relapsed, refractory chronic lymphocytic leukaemia and small lymphocytic lymphoma: a Wisconsin oncology network study. Br J Haematol. 2016;173(2):283–91.

    Article  CAS  PubMed  Google Scholar 

  25. Mato AR, Foon KA, Feldman T, Schuster SJ, Svoboda J, Chow KF, et al. Reduced-dose fludarabine, cyclophosphamide, and rituximab (FCR-lite) plus lenalidomide, followed by lenalidomide consolidation/maintenance, in previously untreated chronic lymphocytic leukemia. Am J Hematol. 2015;90(6):487–92.

    Article  CAS  PubMed  Google Scholar 

  26. Byrd JC, Brown JR, O'Brien SM, Barrientos JC, Kay NE, Reddy NM, et al. Randomized comparison of ibrutinib versus ofatumumab in relapsed or refractory (R/R) chronic lymphocytic leukemia/small lymphocytic lymphoma: results from the phase III RESONATE trial. Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2014;32(5 s):LBA7008.

    Article  Google Scholar 

  27. • Williams ME, Hong F, Gascoyne RD, Wagner LI, Krauss JC, Habermann TM, et al. Rituximab extended schedule or retreatment trial for low tumour burden non-follicular indolent B-cell non-Hodgkin lymphomas: eastern cooperative oncology group protocol E4402. Br J Haematol. 2016;173(6):867–75. This study identified a long time to treatment failure in those who received maintenance rituximab. It is important to note that these findings are quite different than patients with follicular lymphoma on the same study

    Article  PubMed  Google Scholar 

  28. Ferrario A, Pulsoni A, Olivero B, Rossi G, Vitolo U, Tedeschi A, et al. Fludarabine, cyclophosphamide, and rituximab in patients with advanced, untreated, indolent B-cell nonfollicular lymphomas: phase 2 study of the Italian Lymphoma Foundation. Cancer. 2012;118(16):3954–61.

    Article  CAS  PubMed  Google Scholar 

  29. Karmali R, Kassar M, Venugopal P, Shammo JM, Fung HC, Bayer R, et al. Safety and efficacy of combination therapy with fludarabine, mitoxantrone, and rituximab followed by yttrium-90 ibritumomab tiuxetan and maintenance rituximab as front-line therapy for patients with follicular or marginal zone lymphoma. Clinical lymphoma, myeloma & leukemia. 2011;11(6):467–74.

    Article  CAS  Google Scholar 

  30. Hensel M, Villalobos M, Kornacker M, Krasniqi F, Ho AD. Pentostatin/cyclophosphamide with or without rituximab: an effective regimen for patients with Waldenström's macroglobulinemia/lymphoplasmacytic lymphoma. Clinical Lymphoma and Myeloma. 2005;6(2):131–5.

    Article  PubMed  Google Scholar 

  31. Treon SP, Hanzis C, Manning RJ, Ioakimidis L, Patterson CJ, Hunter ZR, et al. Maintenance rituximab is associated with improved clinical outcome in rituximab naive patients with Waldenstrom Macroglobulinaemia who respond to a rituximab-containing regimen. Br J Haematol. 2011;154(3):357–62.

    Article  CAS  PubMed  Google Scholar 

  32. Treon SP. How I treat Waldenström macroglobulinemia. Blood. 2015;126(6):721–32.

    Article  CAS  PubMed  Google Scholar 

  33. Treon SP, Tripsas CK, Meid K, Warren D, Varma G, Green R, et al. Ibrutinib in previously treated Waldenstrom's macroglobulinemia. N Engl J Med. 2015;372(15):1430–40.

    Article  CAS  PubMed  Google Scholar 

  34. Jacobs I, Petersel D, Shane LG, Ng CK, Kirchhoff C, Finch G, et al. Monoclonal antibody and fusion protein biosimilars across therapeutic areas: a systematic review of published evidence. BioDrugs : clinical immunotherapeutics, biopharmaceuticals and gene therapy. 2016;30(6):489–523.

    Article  CAS  Google Scholar 

  35. Wagner LI, Zhao F, Hong F, Williams ME, Gascoyne RD, Krauss JC, et al. Anxiety and health-related quality of life among patients with low-tumor burden non-Hodgkin lymphoma randomly assigned to two different rituximab dosing regimens: results from ECOG trial E4402 (RESORT). Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2015;33(7):740–8.

    Article  CAS  Google Scholar 

  36. Witzens-Harig M, Reiz M, Heiss C, Benner A, Hensel M, Neben K, et al. Quality of life during maintenance therapy with the anti-CD20 antibody rituximab in patients with B cell non-Hodgkin's lymphoma: results of a prospective randomized controlled trial. Ann Hematol. 2009;88(1):51–7.

    Article  PubMed  Google Scholar 

  37. Walker MS, Stepanski EJ, Reyes C, Satram-Hoang S, Houts AC, Schwartzberg LS. Symptom burden and quality of life in patients with follicular lymphoma undergoing maintenance treatment with rituximab compared with observation. Therapeutic advances in hematology. 2011;2(3):129–39.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Michael T. Tees M.D., M.PH.

Ethics declarations

Conflict of Interest

Michael T. Tees has received payment for development of educational presentations (including service on speakers’ bureaus) from Gilead and Celgene.

Ian W. Flinn has received research funding to his institution from Acerta, BeiGene, Celgene, Constellation, Curis, Forty Seven, Genentech, Gilead, ImmunoGen, Infinity, Janssen, Kite, Novartis, Portola, Seattle Genetics, Takeda, TG Therapeutics, and Trillium.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.

Additional information

This article is part of the Topical Collection on Lymphoma

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Tees, M.T., Flinn, I.W. Maintenance Therapies in Indolent Lymphomas: should Recent Data Change the Standard of Care?. Curr. Treat. Options in Oncol. 18, 16 (2017). https://doi.org/10.1007/s11864-017-0459-z

Download citation

  • Published:

  • DOI: https://doi.org/10.1007/s11864-017-0459-z

Keywords

Navigation