AUGMENT: A Phase III Study of Lenalidomide Plus Rituximab Versus Placebo Plus Rituximab in Relapsed or Refractory Indolent Lymphoma

John P Leonard, Marek Trneny, Koji Izutsu, Nathan H Fowler, Xiaonan Hong, Jun Zhu, Huilai Zhang, Fritz Offner, Adriana Scheliga, Grzegorz S Nowakowski, Antonio Pinto, Francesca Re, Laura Maria Fogliatto, Phillip Scheinberg, Ian W Flinn, Claudia Moreira, José Cabeçadas, David Liu, Stacey Kalambakas, Pierre Fustier, Chengqing Wu, John G Gribben, AUGMENT Trial Investigators, John P Leonard, Marek Trneny, Koji Izutsu, Nathan H Fowler, Xiaonan Hong, Jun Zhu, Huilai Zhang, Fritz Offner, Adriana Scheliga, Grzegorz S Nowakowski, Antonio Pinto, Francesca Re, Laura Maria Fogliatto, Phillip Scheinberg, Ian W Flinn, Claudia Moreira, José Cabeçadas, David Liu, Stacey Kalambakas, Pierre Fustier, Chengqing Wu, John G Gribben, AUGMENT Trial Investigators

Abstract

Purpose: Patients with indolent non-Hodgkin lymphoma typically respond well to first-line immunochemotherapy. At relapse, single-agent rituximab is commonly administered. Data suggest the immunomodulatory agent lenalidomide could increase the activity of rituximab.

Methods: A phase III, multicenter, randomized trial of lenalidomide plus rituximab versus placebo plus rituximab was conducted in patients with relapsed and/or refractory follicular or marginal zone lymphoma. Patients received lenalidomide or placebo for 12 cycles plus rituximab once per week for 4 weeks in cycle 1 and day 1 of cycles 2 through 5. The primary end point was progression-free survival per independent radiology review.

Results: A total of 358 patients were randomly assigned to lenalidomide plus rituximab (n = 178) or placebo plus rituximab (n = 180). Infections (63% v 49%), neutropenia (58% v 23%), and cutaneous reactions (32% v 12%) were more common with lenalidomide plus rituximab. Grade 3 or 4 neutropenia (50% v 13%) and leukopenia (7% v 2%) were higher with lenalidomide plus rituximab; no other grade 3 or 4 adverse event differed by 5% or more between groups. Progression-free survival was significantly improved for lenalidomide plus rituximab versus placebo plus rituximab, with a hazard ratio of 0.46 (95% CI, 0.34 to 0.62; P < .001) and median duration of 39.4 months (95% CI, 22.9 months to not reached) versus 14.1 months (95% CI, 11.4 to 16.7 months), respectively.

Conclusion: Lenalidomide improved efficacy of rituximab in patients with recurrent indolent lymphoma, with an acceptable safety profile.

Trial registration: ClinicalTrials.gov NCT01938001.

Figures

FIG 1.
FIG 1.
Lenalidomide plus rituximab and placebo plus rituximab group CONSORT diagram (flow of patients from enrollment to analysis). AE, adverse event; ITT, intention to treat.
FIG 2.
FIG 2.
Progression-free survival (PFS) and overall survival (OS) as assessed by independent review committee in the intention-to-treat population: (A) progression-free survival; (B) overall survival.
FIG 3.
FIG 3.
Forest plot: subgroup analyses of progression-free survival. GELF, Groupe d’Etude des Lymphomes Folliculaires; HR, hazard ratio.
FIG A1.
FIG A1.
Progression-free survival (PFS) as assessed by investigator in the intention-to-treat population.
FIG A2.
FIG A2.
Duration of response as assessed by independent review committee in the intention-to-treat population.
FIG A3.
FIG A3.
Event-free survival as assessed by independent review committee in the intention-to-treat population.
FIG A4.
FIG A4.
Time to next antilymphoma treatment in the intention-to-treat population.
FIG A5.
FIG A5.
Time to next antilymphoma chemotherapy in the intention-to-treat population.
FIG A6.
FIG A6.
Progression-free survival incorporating next antilymphoma treatment (PFS2) in the intention-to-treat population.
FIG A7.
FIG A7.
Overall survival (OS) in patients with follicular lymphoma in the intention-to-treat population.
FIG A8.
FIG A8.
Overall survival (OS) in patients with marginal zone lymphoma in the intention-to-treat population.

References

    1. Swerdlow SH CE, Harris NL, Jafie ES, et al. World Health Organization Classification of Tumors of Haematopoietic and Lymphoid Tissues. Lyon France: IARC Press; 2017.
    1. Casulo C, Burack WR, Friedberg JW. Transformed follicular non-Hodgkin lymphoma. Blood. 2015;125:40–47.
    1. Johnson PW, Rohatiner AZ, Whelan JS, et al. Patterns of survival in patients with recurrent follicular lymphoma: A 20-year study from a single center. J Clin Oncol. 1995;13:140–147.
    1. Kahl BS, Hong F, Williams ME, et al. Rituximab extended schedule or re-treatment trial for low-tumor burden follicular lymphoma: Eastern Cooperative Oncology Group protocol e4402. J Clin Oncol. 2014;32:3096–3102.
    1. A clinical evaluation of the International Lymphoma Study Group classification of non-Hodgkin’s lymphoma. The Non-Hodgkin’s Lymphoma Classification Project. Blood. 1997;89:3909–3918.
    1. Teras LR, DeSantis CE, Cerhan JR, et al. 2016 US lymphoid malignancy statistics by World Health Organization subtypes. CA Cancer J Clin. 2016;66:443–459.
    1. Dreyling M, Thieblemont C, Gallamini A, et al. ESMO Consensus conferences: Guidelines on malignant lymphoma. Part 2: Marginal zone lymphoma, mantle cell lymphoma, peripheral T-cell lymphoma. Ann Oncol. 2013;24:857–877.
    1. Izutsu K. Treatment of follicular lymphoma. J Clin Exp Hematop. 2014;54:31–37.
    1. Gandhi AK, Kang J, Havens CG, et al. Immunomodulatory agents lenalidomide and pomalidomide co-stimulate T cells by inducing degradation of T cell repressors Ikaros and Aiolos via modulation of the E3 ubiquitin ligase complex CRL4(CRBN.) Br J Haematol. 2014;164:811–821.
    1. Lopez-Girona A, Mendy D, Ito T, et al: Cereblon is a direct protein target for immunomodulatory and antiproliferative activities of lenalidomide and pomalidomide. Leukemia 26:2326-2335, 2012 [Erratum: Leukemia 26:2445, 2012]
    1. 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;114:4713–4720.
    1. Fowler NH, Davis RE, Rawal S, et al. Safety and activity of lenalidomide and rituximab in untreated indolent lymphoma: An open-label, phase 2 trial. Lancet Oncol. 2014;15:1311–1318.
    1. 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;14:4650–4657.
    1. Hernandez-Ilizaliturri FJ, Reddy N, Holkova B, et al. Immunomodulatory drug CC-5013 or CC-4047 and rituximab enhance antitumor activity in a severe combined immunodeficient mouse lymphoma model. Clin Cancer Res. 2005;11:5984–5992.
    1. Lagrue K, Carisey A, Morgan DJ, et al. Lenalidomide augments actin remodeling and lowers NK-cell activation thresholds. Blood. 2015;126:50–60.
    1. Reddy N, Hernandez-Ilizaliturri FJ, Deeb G, et al. Immunomodulatory drugs stimulate natural killer-cell function, alter cytokine production by dendritic cells, and inhibit angiogenesis enhancing the anti-tumour activity of rituximab in vivo. Br J Haematol. 2008;140:36–45.
    1. Smith SM. Dissecting follicular lymphoma: High versus low risk. Hematology (Am Soc Hematol Educ Program) 2013;2013:561–567.
    1. 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;12:773–784.
    1. Davis TA, Grillo-López AJ, White CA, et al. Rituximab anti-CD20 monoclonal antibody therapy in non-Hodgkin’s lymphoma: Safety and efficacy of re-treatment. J Clin Oncol. 2000;18:3135–3143.
    1. Link BK, Miller TP, Byrtek M, et al. Second-line therapy in follicular lymphoma in the United States: Report of NLCS observational study. J Clin Oncol. 2011;29(15_suppl; abstr 8049)
    1. Onukwugha E, Nagarajan M, Albarmawi H, et al. Treatment patterns among elderly follicular lymphoma patients diagnosed between 2000 and 2011: An analysis of linked SEER-Medicare data. J Clin Oncol. 2017;35(15_suppl; abstr 7563)
    1. Sortais C, Lok A, Gastinne T, et al. Progression of disease within 2 years (POD24) is a clinically significant endpoint to identify follicular lymphoma patients with high risk of death. Ann Oncol. 2018;29(suppl 8):359–371.
    1. Leonard JP, Jung SH, Johnson J, et al. Randomized trial of lenalidomide alone versus lenalidomide plus rituximab in patients with recurrent follicular lymphoma: CALGB 50401 (Alliance) J Clin Oncol. 2015;33:3635–3640.
    1. Chong EA, Ahmadi T, Aqui NA, et al. Combination of lenalidomide and rituximab overcomes rituximab resistance in patients with indolent B-cell and mantle cell lymphomas. Clin Cancer Res. 2015;21:1835–1842.
    1. Tuscano JM, Dutia M, Chee K, et al. Lenalidomide plus rituximab can produce durable clinical responses in patients with relapsed or refractory, indolent non-Hodgkin lymphoma. Br J Haematol. 2014;165:375–381.
    1. Morschhauser F, Fowler NH, Feugier P, et al. Rituximab plus lenalidomide in advanced untreated follicular lymphoma. N Engl J Med. 2018;379:934–947.
    1. Crawford J, Caserta C, Roila F. Hematopoietic growth factors: ESMO Clinical Practice Guidelines for the applications. Ann Oncol. 2010;21(suppl 5):v248–v251.
    1. Smith TJ, Bohlke K, Lyman GH, et al. Recommendations for the use of WBC growth factors: American Society of Clinical Oncology clinical practice guideline update. J Clin Oncol. 2015;33:3199–3212.
    1. Cheson BD, Pfistner B, Juweid ME, et al. Revised response criteria for malignant lymphoma. J Clin Oncol. 2007;25:579–586.
    1. Cairo MS, Bishop M. Tumour lysis syndrome: New therapeutic strategies and classification. Br J Haematol. 2004;127:3–11.
    1. Kaplan EL, Meier P. Non-parametric estimation from incomplete observations. J Am Stat Assoc. 1958;53:457–481.
    1. Ardeshna KM, Qian W, Smith 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. Lancet Oncol. 2014;15:424–435.
    1. 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;103:4416–4423.
    1. Hainsworth JD, Litchy S, Burris HA, III, et al. Rituximab as first-line and maintenance therapy for patients with indolent non-Hodgkin’s lymphoma. J Clin Oncol. 2002;20:4261–4267.
    1. Taverna C, Martinelli G, Hitz F, 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. 2016;34:495–500.
    1. McLaughlin P, Grillo-López 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;16:2825–2833.
    1. Sehn LH, Chua N, Mayer J, et al. Obinutuzumab plus bendamustine versus bendamustine monotherapy in patients with rituximab-refractory indolent non-Hodgkin lymphoma (GADOLIN): A randomised, controlled, open-label, multicentre, phase 3 trial. Lancet Oncol. 2016;17:1081–1093.
    1. Rummel M, Kaiser U, Balser C, et al. Bendamustine plus rituximab versus fludarabine plus rituximab for patients with relapsed indolent and mantle-cell lymphomas: A multicentre, randomised, open-label, non-inferiority phase 3 trial. Lancet Oncol. 2016;17:57–66.
    1. Gopal AK, Kahl BS, de Vos S, et al. PI3Kδ inhibition by idelalisib in patients with relapsed indolent lymphoma. N Engl J Med. 2014;370:1008–1018.
    1. Dreyling M, Morschhauser F, Bouabdallah K, et al. Phase II study of copanlisib, a PI3K inhibitor, in relapsed or refractory, indolent or aggressive lymphoma. Ann Oncol. 2017;28:2169–2178.

Source: PubMed

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