• This record comes from PubMed

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

. 2019 May 10 ; 37 (14) : 1188-1199. [epub] 20190321

Language English Country United States Media print-electronic

Document type Clinical Trial, Phase III, Journal Article, Multicenter Study, Randomized Controlled Trial, Research Support, Non-U.S. Gov't

Persistent link   https://www.medvik.cz/link/pmid30897038

Grant support
P30 CA016672 NCI NIH HHS - United States

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.

Comment In

PubMed

See more in PubMed

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.

Casulo C, Burack WR, Friedberg JW. Transformed follicular non-Hodgkin lymphoma. Blood. 2015;125:40–47. PubMed

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. PubMed

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. PubMed PMC

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. PubMed

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. PubMed

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. PubMed

Izutsu K. Treatment of follicular lymphoma. J Clin Exp Hematop. 2014;54:31–37. PubMed

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. PubMed PMC

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] PubMed PMC

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. PubMed PMC

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. PubMed PMC

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. PubMed

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. PubMed

Lagrue K, Carisey A, Morgan DJ, et al. Lenalidomide augments actin remodeling and lowers NK-cell activation thresholds. Blood. 2015;126:50–60. PubMed PMC

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. PubMed

Smith SM. Dissecting follicular lymphoma: High versus low risk. Hematology (Am Soc Hematol Educ Program) 2013;2013:561–567. PubMed

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. PubMed

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. PubMed

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)

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)

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.

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. PubMed PMC

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. PubMed

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. PubMed

Morschhauser F, Fowler NH, Feugier P, et al. Rituximab plus lenalidomide in advanced untreated follicular lymphoma. N Engl J Med. 2018;379:934–947. PubMed PMC

Crawford J, Caserta C, Roila F. Hematopoietic growth factors: ESMO Clinical Practice Guidelines for the applications. Ann Oncol. 2010;21(suppl 5):v248–v251. PubMed

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. PubMed

Cheson BD, Pfistner B, Juweid ME, et al. Revised response criteria for malignant lymphoma. J Clin Oncol. 2007;25:579–586. PubMed

Cairo MS, Bishop M. Tumour lysis syndrome: New therapeutic strategies and classification. Br J Haematol. 2004;127:3–11. PubMed

Kaplan EL, Meier P. Non-parametric estimation from incomplete observations. J Am Stat Assoc. 1958;53:457–481.

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. PubMed

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. PubMed

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. PubMed

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. PubMed PMC

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. PubMed

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. PubMed

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. PubMed

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. PubMed PMC

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. PubMed PMC

See more in PubMed

ClinicalTrials.gov
NCT01938001

EudraCT
2013-001245-14

Find record

Citation metrics

Archiving options