title: The emerging role of lenalidomide in the management of lymphoid malignancies.
abstract: Lenalidomide, a novel immunomodulatory drug (IMiD), is a promising therapeutic strategy for patients with relapsed/refractory chronic lymphocytic leukemia (CLL) and B-cell lymphomas. Biologically, the mechanisms responsible for lenalidomide activity are yet to be clearly defined. Based on preclinical models and early correlative studies conducted in parallel to clinical trials, lenalidomide has been found to enhance natural killer (NK)- and T-cell activity against tumor cells, alter the balance of pro- and anti-inflammatory cytokines in the tumor bed, inhibit angiogenesis, and, to a lesser degree, induce cell cycle arrest and apoptosis in cancer cells. Together, all of these biological effects appear to play a role in the activity observed in CLL or lymphoma patients treated with lenalidomide. Given the effect in NK- and T-cell function, lenalidomide is an alternative strategy to enhance the antitumor activity of monoclonal antibodies (mAbs). Clinical responses have been observed in patients with relapsed/refractory CLL, follicular lymphoma, small lymphocytic lymphoma, mantle cell lymphoma (MCL), and diffuse large B-cell lymphoma (DLBCL) treated with lenalidomide single agent. The favorable toxicity profile and route of administration made the use of lenalidomide an attractive therapy for certain types of patients (i.e. elderly, chemotherapy unfit, etc.). The erratic but serious incidence of tumor lysis syndrome and/or tumor flare reactions provides challenges in the incorporation of lenalidomide in the management of previously untreated CLL or CLL/lymphoma patients with bulky adenopathy. Correlative studies and/or retrospective analysis of lenalidomide-treated patients had identified several biomarkers associated with clinical endpoints in CLL (i.e. changes in tumor necrosis factor alpha [TNF-α] or vascular endothelial growth factor [VEGF] levels) or DLBCL (non-GCB phenotype) patients, but need to be validated. Early studies evaluating the efficacy and toxicity of lenalidomide in combination with rituximab in previously untreated indolent lymphoma are promising and warrant further study. In addition, the evaluation of lenalidomide in the maintenance setting or in combination with other target-specific agents (i.e. proteasome inhibitors) in aggressive lymphomas is being addressed in ongoing clinical trials. In summary, lenalidomide is emerging as a biologically active and novel agent in the treatment of B-cell neoplasms. Future translational and clinical studies will further define the role of lenalidomide in the management of de novo or relapsed/refractory CLL or B-cell lymphomas and identify the subset of patients most likely to gain clinical benefit.
authors.affiliation: Medical Oncology and Immunology, Roswell Park Cancer Institute (RPCI), Buffalo, NY, USA.
authors.forename: Francisco J
authors.initials: FJ
authors.lastname: Hernandez-Ilizaliturri
authors.forename: Sameer A
authors.initials: SA
authors.lastname: Batoo
keywords: B-cell lymphoma; chronic lymphocytic leukemia; immunomodulatory drug; lenalidomide
references.citation: Br J Haematol. 2008 Jan;140(1):36-45
references.pmid: 17995965
references.citation: Proc Natl Acad Sci U S A. 2007 Jul 3;104(27):11406-11
references.pmid: 17576924
references.citation: Blood. 2004 Mar 1;103(5):1787-90
references.pmid: 14512311
references.citation: Bioorg Med Chem Lett. 1999 Jun 7;9(11):1625-30
references.pmid: 10386948
references.citation: Blood. 2011 Nov 10;118(19):5119-25
references.pmid: 21937701
references.citation: Blood. 2009 Nov 19;114(21):4713-20
references.pmid: 19786615
references.citation: Eur J Haematol. 1991 Oct;47(4):277-81
references.pmid: 1954986
references.citation: Nat Rev Cancer. 2004 Apr;4(4):314-22
references.pmid: 15057291
references.citation: Leuk Lymphoma. 2010 Jan;51(1):85-8
references.pmid: 20055660
references.citation: J Clin Oncol. 2006 Dec 1;24(34):5343-9
references.pmid: 17088571
references.citation: Blood. 2004 Jan 1;103(1):275-82
references.pmid: 14504078
references.citation: J Clin Oncol. 2008 Oct 20;26(30):4952-7
references.pmid: 18606983
references.citation: J Exp Med. 1993 Jun 1;177(6):1675-80
references.pmid: 8496685
references.citation: Cell Immunol. 1995 May;162(2):248-55
references.pmid: 7743552
references.citation: Leukemia. 2001 Dec;15(12):1950-61
references.pmid: 11753617
references.citation: J Clin Oncol. 2009 Nov 10;27(32):5404-9
references.pmid: 19805688
references.citation: Am J Hematol. 2009 Sep;84(9):553-9
references.pmid: 19565649
references.citation: Clin Cancer Res. 2005 Aug 15;11(16):5984-92
references.pmid: 16115943
references.citation: Blood. 2008 Jun 1;111(11):5291-7
references.pmid: 18334676
references.citation: Cancer Res. 2009 Sep 15;69(18):7347-56
references.pmid: 19738071
references.citation: Blood. 1996 Jun 15;87(12):4990-7
references.pmid: 8652811
references.citation: Leukemia. 2008 Oct;22(10):1925-32
references.pmid: 18596740
references.citation: Ann Rheum Dis. 1999 Nov;58 Suppl 1:I107-13
references.pmid: 10577986
references.citation: Clin Cancer Res. 2008 Jul 15;14(14):4650-7
references.pmid: 18628480
references.citation: CA Cancer J Clin. 2010 Sep-Oct;60(5):277-300
references.pmid: 20610543
references.citation: J Immunol. 1999 Jul 1;163(1):380-6
references.pmid: 10384139
references.citation: Haematologica. 2008 Dec;93(12):1829-36
references.pmid: 18945747
references.citation: J Hematol Oncol. 2009 Aug 12;2:36
references.pmid: 19674465
references.citation: AAPS J. 2005 Mar 22;7(1):E14-9
references.pmid: 16146335
references.citation: Leuk Res. 2006 Jul;30(7):849-58
references.pmid: 16494942