Lenalidomide treatment in relapsed/refractory B-cell lymphomas: A single center real-life experience

As an immunomodulatory drug, lenalidomide has been shown to have anti-lymphoma activity and is used in combination with several agents in the treatment of patients with relapsed/refractory disease. In this study, we aimed to evaluate the efficiency of lenalidomide in the treatment of B-cell NHL. This retrospective study included patients with relapsed/refractory B-cell NHL who received lenalidomide treatment between March 2018 and January 2021. Patients’ demographic data, dose, and duration of the lenalidomide treatment, combined agents, response rates, side effects, and survival rates were evaluated. Twelve patients who diagnosed with relapsed/refractory NHL were included in the study. Lenalidomide treatment was initiated in combination with rituximab for nine of these patients and with temozolomide for the remaining three of them. At the initiation of the lenalidomide treatment, patients’ median age was 72.5 (24-83) years. Number of females/males was 9/3. Nine of the patients were diagnosed with diffuse large b-cell lymphoma (DLBCL), 3 of whom had isolated central nervous system lymphoma (CNS) and 1 had Richter transformation of chronic lymphocytic leukemia. Two patients were diagnosed with mantle cell lymphoma (MCL) and 1 patient was diagnosed with marginal zone lymphoma. The median treatment duration was 4 (1-20) months. In the response assessment, 4 patients had complete response while progressed disease was observed in 5 patients. Three patients died before response assessment. In the median 33-month follow-up, progression-free survival and total survival were found as 4 (1-20) and 7 (1-22) months respectively. Due to its low toxicity profile and activity, lenalidomide could be a good option especially for elderly and fragile B-cell lymphoma patients. It is an agent to be considered particularly in lymphomas with CNS involvement with its good CNS penetration. Its synergistic effect may give better results when used in combination with several anti-lymphoma drugs.

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1. Shankland K R, Armitage J O and Hancock B W Non-Hodgkin lymphoma. Lancet 2012;380:848-57.
2. Arora M, Gowda S and Tuscano J A comprehensive review of lenalidomide in B-cell non-Hodgkin lymphoma. Ther Adv Hematol 2016;7:209-21.
3. Leonard J P, Trneny M, Izutsu K, et al. AUGMENT: A Phase III Study of Lenalidomide Plus Rituximab Versus Placebo Plus Rituximab in Relapsed or Refractory Indolent Lymphoma. J Clin Oncol. 2019;37:1188-99.
4. Shah H, Stephens D, Seymour J, et al. Incorporating Novel Targeted and Immunotherapeutic Agents in the Treatment of B-Cell Lymphomas. Am Soc Clin Oncol Educ Book. 2021;310-27.
5. Gandhi A K, Kang J, Havens C G, 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;164:811-21.
6. Kotla V, Goel S, Nischal S, et al. Mechanism of action of lenalidomide in hematological malignancies. J Hematol Oncol 2009;2:36.
7. Kotla V, Goel S, Nischal S, et al. Mechanism of action of lenalidomide in hematological malignancies. J Hematol Oncol. 2009;2:36.
8. Gupta D, Treon S P, Shima Y, et al. Adherence of multiple myeloma cells to bone marrow stromal cells upregulates vascular endothelial growth factor secretion: therapeutic applications. Leukemia 2001;15:1950-61.
9. Chang D H, Liu N, Klimek V, et al. Enhancement of ligand-dependent activation of human natural killer T cells by lenalidomide: therapeutic implications. Blood 2006;108:618-21.
10. Ramsay A G, Clear A J, 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;114:4713-20.
11. 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;14:4650-7.
12. Verhelle D, Corral L G, Wong K, et al. Lenalidomide and CC-4047 inhibit the proliferation of malignant B cells while expanding normal CD34+ progenitor cells. Cancer Res 2007;67:746-55.
13. Mitsiades N, Mitsiades C S, Poulaki V, et al. Apoptotic signaling induced by immunomodulatory thalidomide analogs in human multiple myeloma cells: therapeutic implications. Blood 2002;99:4525-30.
14. Cheson B D, Fisher R I, Barrington S F, et al. Recommendations for initial evaluation, staging, and response assessment of Hodgkin and non-Hodgkin lymphoma: the Lugano classification. J Clin Oncol 2014;32:3059-68.
15. Reddy N, Hernandez-Ilizaliturri F J, 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.
16. Hernandez-Ilizaliturri F J, 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;11:5984-92.
17. Chong E A, Ahmadi T, Aqui N A, et al. Combination of Lenalidomide and Rituximab Overcomes Rituximab Resistance in Patients with Indolent B-cell and Mantle Cell Lymphomas. 2015;21:1835-42.
18. Tuscano J M, Dutia M, Chee K, et al. Lenalidomide plus rituximab can produce durable clinical responses in patients with relapsed or refractory, indolent non-Hodgkin lymphoma. 2014;165:375-81.
19. Becnel M R, Nastoupil L J, Samaniego F, et al. Lenalidomide plus rituximab (R(2) ) in previously untreated marginal zone lymphoma: subgroup analysis and long-term follow-up of an open-label phase 2 trial. Br J Haematol 2019; 185: 874-82.
20. Wang M, Fowler N, Wagner-Bartak N, et al. Oral lenalidomide with rituximab in relapsed or refractory diffuse large cell, follicular and transformed lymphoma: a phase II clinical trial. Leukemia 2013;27:1902-9.
21. Zinzani P L, 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;11:462-6.
22. Lee Y P, Hong J Y, Yoon S E, et al. Real-World, Single-Center Data for Lenalidomide Plus Rituximab in Relapsed or Refractory Diffuse Large B-Cell Lymphoma and Transformed Follicular Lymphoma. Cancer Manag Res 2021;13:4241-50.
23. Ruan J, Martin P, Shah B, et al. Lenalidomide plus Rituximab as Initial Treatment for Mantle-Cell Lymphoma. 2015;373:1835-44.
24. 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. The Lancet Oncology 2012;13:716-23.
25. Kurzwelly D, Glas M, Roth P, et al. Primary CNS lymphoma in the elderly: temozolomide therapy and MGMT status. J Neurooncol 2010;97:389-92.
26. Anwer S, Collings F, Trace K, et al. Cerebrospinal fluid penetrance of lenalidomide in meningeal myeloma. Br J Haematol. 2013;162:281-2.
27. Ghesquieres H, Chevrier M, Laadhari M, et al. Lenalidomide in combination with intravenous rituximab (REVRI) in relapsed/refractory primary CNS lymphoma or primary intraocular lymphoma: a multicenter prospective 'proof of concept' phase II study of the French Oculo-Cerebral lymphoma (LOC) Network and the Lymphoma Study Association (LYSA)†. Ann Oncol 2019;30:621-8.
28. Houillier C, Choquet S, Touitou V, et al. Lenalidomide monotherapy as salvage treatment for recurrent primary CNS lymphoma. Neurology 2015; 84:325-6.
29. Cox M C, Mannino G, Lionetto L, et al. Lenalidomide for aggressive B-cell lymphoma involving the central nervous system? 2011;86:957-7.
30. Jerkeman M, Eskelund C W, Hutchings M, et al. Ibrutinib, lenalidomide, and rituximab in relapsed or refractory mantle cell lymphoma (PHILEMON): a multicentre, open-label, single-arm, phase 2 trial. The Lancet Haematology 2018;5:109-16.
31. Goy A, Ramchandren R, Ghosh N, et al. Ibrutinib plus lenalidomide and rituximab has promising activity in relapsed/refractory non–germinal center B-cell–like DLBCL. Blood 2019;134:1024-36.