Biological Therapy Doublets: Pairing Rituximab with Interferon, Lenalidomide, and Other Biological Agents in Patients with Follicular Lymphoma Authors
Lymphomas (J Armitage and P McLaughlin, Section Editors)
First Online: 16 August 2012 DOI:
Cite this article as: Kimby, E. Curr Hematol Malig Rep (2012) 7: 221. doi:10.1007/s11899-012-0133-2 Abstract
Rituximab (R) is a monoclonal antibody with high therapeutic efficacy in low-grade CD20+ lymphoma. The combination of R with chemotherapy is the most common treatment option for patients with follicular lymphoma (FL). The efficacy of R has also been shown to be augmented, when used in combinations with biologicals such as interferon-alpha-2a (IFN), bortezomib, or lenalidomide. The best combination of these drugs are not well defined and a better understanding of pharmacokinetics and timing of drugs relative to the rituximab infusion is crucial. Other new targeted agents, such as inhibitors of BTK and PI3Kdelta, have also been promising in FL. Translational research questions should be added to clinical trial protocols to increase the knowledge on how the tumor microenvironment and the host immune system affect the response to the different drugs and combinations with the aim of a more individualized therapy.
Keywords Follicular lymphoma Biological therapy Rituximab Interferon Lenalidomide Bortezomib Tumor immunoenvironment References Papers of particular interests, published recently, have been highlighted as: • Of importance•• Of major importance
Horning SJ. Natural history of and therapy for the indolent non-Hodgkin’s lymphomas. Semin Oncol. 1993;20(5 Suppl 5):75–88.
Ardeshna KM, Smith P, Norton A, 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.
Marcus R, Imrie K, Belch A, et al. CVP chemotherapy plus rituximab compared with CVP as first-line treatment for advanced follicular lymphoma. Blood. 2005;105:1417–23.
Hiddemann W, Kneba M, Dreyling M, et al. Front-line therapy with rituximab added to the combination of cyclophosphamide, doxorubicin, vincristine and prednisone (CHOP) significantly improves the outcome of patients with advanced stage follicular lymphomas as compared to CHOP alone ─ results of a prospective randomised study of the German Low Grade Lymphoma Study Group (GLSG). Blood. 2005;106:3725–32.
•• Salles G, Seymour J-F, Offner F, 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;377:42–51. Salles et al 2011.
This large randomized trial shows a significant benefit of 2 years of rituximab maintenance after first-line treatment in patients with follicular lymphoma receiving a rituximab plus chemotherapy induction regimen
Rummel MJ, Niederle N, Maschmeyer G, et al. Bendamustin plus Riutximab is superior in respect of progression free survival and CR rate when compared to CHOP plus Rituximab as first-line treatment of patients with advanced follicular, indolent, and mantle cell lymphomas: final results of a randomized phase III study of the STIL. Abstracts of the 2009 Annual Meeting of the American Society of Hematology Dec 5, 2009 New Orleans, Louisiana. Abstract 405.
Rummel MJ, Niederle N, Maschmeyer G, et al. Bendamustin plus Riutximab (B-R) versus CHOP plus rituximab (CHOP-R) as first-line treatment in patients with indolent and mantle cell lymphomas (MCL): updated results from the StiL NHL1 study. Abstracts of the 2012 Annual Meeting of the American Society of Clinical Oncology; June 1–5, 2012; Chicago. Illinois. Abstract 3.
van Oers MH, Klasa R, Marcus RE, et al. Rituximab maintenance improves clinical outcome of relapsed/resistant follicular non-Hodgkin lymphoma in patients both with and without rituximab during induction: results of a prospective randomized phase 3 intergroup trial. Blood. 2006;108(10):3295–301.
van Oers MH, Van Glabbeke M, Giurgea L, et al. Rituximab maintenance treatment of relapsed/resistant follicular non-Hodgkin’s lymphoma: long-term outcome of the EORTC 20981 phase III randomized intergroup study. J Clin Oncol. 2010;28(17):2853–8.
A phase 3 open‐label randomized study to compare the efficacy and safety of Rituximab plus lenalidomide (CC‐5013) versus Rituximab plus chemotherapy followed by Rituximab in subjects with previously untreated follicular lymphoma. The “RELEVANCE” trial (Rituximab Lenalidomide Versus Any Chemotherapy). Sponsor: Celgene Corporation Collaborator: the lymphoma academic research organisation.
Dave SS, Wright G, Tan B, et al. Prediction of survival in follicular lymphoma based on molecular features of tumor-infiltrating immune cells. N Engl J Med. 2004;351(21):2159–69.
Wahlin BE, Sander B, Christensson B, Kimby E. CD8+ T-cell content in diagnostic lymph nodes measured by flow cytometry is a predictor of survival in follicular lymphoma. Clin Cancer Res. 2007;13:388–97.
Carreras J, Lopez-Guillermo A, Fox BC, et al. High numbers of tumor-infiltrating FOXP3-positive regulatory T cells are associated with improved overall survival in follicular lymphoma. Blood. 2006;108(9):2957–64.
Carreras J, Lopez-Guillermo A, Roncador G, et al. High numbers of tumor-infiltrating programmed cell death 1-positive regulatory lymphocytes are associated with improved overall survival in follicular lymphoma. J Clin Oncol. 2009;27(9):1470–6.
Wahlin BE, Aggarwal M, Montes-Moreno S, et al. A unifying microenvironment model in follicular lymphoma: outcome is predicted by programmed death-1–positive, regulatory, cytotoxic, and helper T cells and macrophages. Clin Cancer Res. 2010;16:637–50.
Farinha P, Masoudi H, Skinnider BF, et al. Analysis of multiple biomarkers shows that lymphoma-associated macrophage (LAM) content is an independent predictor of survival in follicular lymphoma (FL). Blood. 2005;106(6):2169–74. 15.
•• Hilchey SP, Hyrien O, Mosmann TR, et al. Rituximab immunotherapy results in the induction of a lymphoma idiotype-specific T-cell response in patients with follicular lymphoma: support for a “vaccinal effect” of rituximab. Blood. 2009;113(16):3809–12.
The response against the immunoglobulin expressed by the follicular lymphoma cells before and after rituximab monotherapy showed an increase in FL idiotype-specific T cells providing "proof of principle" for the ability of passive immunotherapy with rituximab to elicit an active FL-specific cellular response (vaccinal effect).
McLaughlin P, Grillo-Lopez AJ, Link BK, et al. Rituximab chimeric anti-CD20 monoclonal antibody therapy for relapsed indolent lymphoma: half of patients respond to a four-dose treatment program. J Clin Oncol. 1998;16:2825–33.
Piro LT, White CA, Grillo-López AJ, et al. Extended rituximab (anti CD20 monoclonal antibody) therapy for relapsed or refractory low-grade or follicular non-Hodgkin’s lymphoma. Ann Oncol. 1999;10:655–61.
Colombat P, Salles G, Brousse N, et al. Rituximab (anti-CD20 monoclonal antibody) as single first-line therapy for patients with follicular lymphoma with a low tumor burden: clinical and molecular evaluation. Blood. 2001;97:101–6.
Ghielmini M, Schmitz SF, Cogliatti SB, et al. Prolonged treatment with rituximab in patients with follicular lymphoma significantly increases event-free survival and response duration compared with the standard weekly x 4 schedule. Blood. 2004;103:4416–23.
•• Martinelli G, Schmitz SF, Utiger U, et al. Long-term follow-up of patients with follicular lymphoma receiving single-agent rituximab at two different schedules in trial SAKK 35/98. J Clin Oncol. 2010;28(29):4480–4. Of considerable interest.
In total 45 % of previously untreated patients responding to rituximab single induction (four weekly infusions) and receiving prolonged treatment (four additional doses of rituximab at 2-month intervals) were eventfree at 8 years.
Taskinen M, Karjalainen-Lindsberg ML, Nyman H, Eerola LM, Leppä S. A high tumor-associated macrophage content predicts favorable outcome in follicular lymphoma patients treated with rituximab and cyclophosphamide-doxorubicin-vincristine-prednisone. Clin Cancer Res. 2007;13(19):5784–921. 1.
Canioni D, Salles G, Mounier N, et al. High numbers of tumor-associated macrophages have an adverse prognostic value that can be circumvented by rituximab in patients with follicular lymphoma enrolled onto the GELA-GOELAMS FL-2000 trial. J Clin Oncol. 2008;26(3):440–6.
•• Wahlin BE, Sundström C, Holte H, et al. T cells in tumors and blood predict outcome in follicular lymphoma treated with rituximab. Clin Cancer Res. 2011;17:4136–44.
The therapeutic effects of rituximab were augmented by T cells in the microenvironment (lymphnodes) and in blood. Both CD4(+) and CD8(+) cells were favorable in patients treated with rituximab and with addition of IFN-α2a the negative impact of few CD8(+) cells was abrogated.
Brice P, Bastion Y, Lepage E, et al. Comparison in low-tumor-burden follicular lymphomas between an initial no-treatment policy, prednimustine, or interferon alfa: a randomized study from the Groupe d’Etude des Lymphomes Folliculaires. Groupe d’Etude des Lymphomes de l’Adulte. J Clin Oncol. 1997;15:1110–7.
Salles G, Mounier N, de Guibert S, et al. Rituximab combined with chemotherapy and interferon in follicular lymphoma patients: results of the GELA-GOELAMS FL2000 study. Blood. 2008;112:4824–31.
Rohatiner AZ, Gregory WM, Peterson B, et al. Meta-analysis to evaluate the role of interferon in follicular lymphoma. J Clin Oncol. 2005;23(10):2215–23.
Davis TA, Maloney DG, Grillo-Lopez AJ, et al. Combination immunotherapy of relapsed or refractory low-grade or follicular non-Hodgkin’s lymphoma with rituximab and interferon-alpha-2a. Clin Cancer Res. 2000;6:2644–52.
Sacchi S, Federico M, Vitolo U, et al. Clinical activity and safety of combination immunotherapy with IFN-alpha 2a and Rituximab in patients with relapsed low grade non-Hodgkin’s lymphoma. Haematologica. 2001;86:951–8.
Kimby E, Jurlander J, Geisler C, Nordic Lymphoma Group, et al. Long-term molecular remissions in patients with indolent lymphoma treated with rituximab as a single agent or in combination with interferon alpha-2a: a randomized phase II study from the Nordic Lymphoma Group. Leuk Lymphoma. 2008;49:102–12.
Kimby E, Östenstad B, de Nully Brown P, et al. Rituximab (R) in combination with interferon-α2a (IFN) shows better response than single R in patients with follicular or other CD20+ low-grade (indolent) lymphoma. A randomized phase III study from the Nordic Lymphoma Group. Ann Oncol. ICML Lugano 2011; abstract #.
Cartron G, Zhao-Yang L, Baudard M, et al. Granulocyte-macrophage colony-stimulating factor potentiates rituximab in patients with relapsed follicular lymphoma: results of a phase II study. J Clin Oncol. 2008;26(16):2725–31.
Rossi JD, et al. Blood. 2011; ASH abstract 98:607A.
Di Bella N, Taetle R, Kolibaba K, et al. Results of a phase 2 study of bortezomib in patients with relapsed or refractory indolent lymphoma. Blood. 2010;115:475–80.
O’Connor OA, Portlock C, Moskowitz C, et al. Time to treatment response in patients with follicular lymphoma treated with bortezomib is longer compared with other histologic subtypes. Clin Cancer Res. 2010;16:719–26.
Paoluzzi L, O’Connor OA. Mechanistic rationale and clinical evidence for the efficacy of proteasome inhibitors against indolent and mantle cell lymphomas. BioDrugs. 2006;20:13–23.
• Coiffier B, Osmanov EA, Hong X, et al. Bortezomib plus rituximab versus rituximab alone in patients with relapsed, rituximab-naive or rituximab-sensitive, follicular lymphoma: a randomised phase 3 trial. Lancet Oncol. 2011;12:773–84.
This is the largest randomized trial on relapsed refractory follicular lymphoma and with the main end-point, PFS, statistically significant, however, not clinically important as median PFS was extended only from 11.0 to 12.8 months.
de Vos S, Goy A, Dakhil SR, et al. Multicenter randomized phase II study of weekly or twice-weekly bortezomib plus rituximab in patients with relapsed or refractory follicular or marginal-zone B-cell lymphoma. J Clin Oncol. 2009;27:5023–30.
Agathocleous A, Rohatiner A, Rule S, et al. Weekly versus twice weekly bortezomib given in conjunction with rituximab, in patients with recurrent follicular lymphoma, mantle cell lymphoma and Waldenstrom macroglobulinaemia. Br J Haematol. 2010;151:346–53.
•• Ramsay AG, Clear AJ, Kelly G, et al. Follicular lymphoma cells induce T-cell immunologic synapse dysfunction that can be repaired with lenalidomide: implications for the tumor microenvironment and immunotherapy. Blood. 2009;114(21):4713–20.
A significant reduction in formation of the F-actin immune synapse was seen in tumor-infiltrating T cells from lymphoma patients compared with age-matched healthy donor cells. A repair of this defect was noted after treatment of both FL cells and T cells with the immunomodulatory drug lenalidomide.
Wu L, Adams M, Carter T, et al. Lenalidomide enhances natural killer cell and monocyte-mediated antibody-dependent cellular cytotoxicity of rituximab-treated CD20+ tumor cells. Clin Cancer Res. 2008;14(14):4650.
Witzig TE, Wiernik PH, Moore T, et al. Lenalidomide oral monotherapy produces durable responses in relapsed or refractory indolent non-Hodgkin’s Lymphoma. J Clin Oncol. 2009;27:5404–9.
Zinzani PL, Pellegrini C, Gandolfi L, et al. Combination of lenalidomide and rituximab in elderly patients with relapsed or refractory diffuse large B-cell lymphoma: a phase 2 trial. Clin Lymphoma Myeloma Leuk. 2011;11(6):462–6.
Nowakowski GS, LaPlant B, Habermann TM, et al. Lenalidomide can be safely combined with R-CHOP (R2CHOP) in the initial chemotherapy for aggressive B-cell lymphomas: phase I study. Leukemia. 2011;25(12):1877–81.
Wang M, Fayad L, Wagner-Bartak N, et al. Lenalidomide in combination with rituximab for patients with relapsed or refractory mantle-cell lymphoma: a phase 1/2 clinical trial. Lancet Oncol. 2012 Jun 1. E-pub.
Fowler N, Hagemeister F, McLaughlin P, et al. High response rates with lenalidomide plus rituximab for untreated indolent B cell non-Hodgkins Lymphoma. Ann Oncol ICML. 2011; Lugano abstract #137.
Leonard J, Jung S, Johnson JL, et al. CALGB 50401: a randomized trial of lenalidomide alone versus lenalidomide plus rituximab in patients with recurrent follicular lymphoma. Abstracts of the 2012 Annual Meeting of the American Society of Clinical Oncology; June 1–5, 2012; Chicago, Illinois. Abstract 8000.
Rituximab plus lenalidomide or rituximab monotherapy for untreated patients with follicular lymphoma in need of therapy. A randomized, open‐label, multicenter phase II trial. Swiss Group for Clinical Cancer Research (SAKK) in collaboration with the Nordic lymphoma group (NLG).
Kahl B, Byrd J, Flinn I, et al. Significant clinical activity of CAL-101, an isoform-selective inhibitor of phosphatidylinositol 3 kinase P110D, in patients with relapsed or refractory indolent and mantle cell lymphoma. Ann Oncol. 2011 Suppl 4 ICML; Lugano, abstract #350.
Sven de Vos, Marshall T. Schreeder, Ian W. Flinn, Steven E. Coutre, John P Leonard. A Phase 1 Study of the Selective Phosphatidylinositol 3-Kinase-Delta (PI3Kdelta Inhibitor, GS-1101 (CAL-101), in Combination with Rituximab and/or Bendamustine in Patients with Relapsed or Refractory Indolent Non-Hodgkin’s Lymphoma (iNHL). Abstracts of the 2011 Annual Meeting of the American Society of Hematology, San Diego, California #2699
Winer ES, Ingham RR, Castillo JJ. PCI-32765: a novel Bruton's tyrosine kinase inhibitor for the treatment of lymphoid malignancies. Expert Opin Investig Drugs. 2012;21(3):355–61.
© Springer Science+Business Media, LLC 2012