Lenalidomide plus rituximab can produce durable clinical responses in patients with relapsed or refractory, indolent non‐<scp>H</scp>odgkin lymphoma

Tuscano, Joseph M.; Dutia, Mrinal P.; Chee, Karen; Brunson, Ann; Reed-Pease, Christine; Abedi, Mehrdad; Welborn, Jeanna L; O’Donnell, Robert T.

doi:10.1111/bjh.12755

Cited by 71 publications

(48 citation statements)

References 33 publications

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“…Enhanced activity has been observed with R2 in MCL, 28,65 DLBCL, 66-68 FL, 69,70 and indolent NHL. 71,72 A recently published study of R2 shows evidence of overcoming rituximab-resistance in indolent NHL and MCL. 73 The feasibility of administering lenalidomide or R2 in combination with either dexamethasone or bortezomib in patients with MCL was also demonstrated.…”

Section: 59-61mentioning

confidence: 99%

Mechanisms of Action of Lenalidomide in B-Cell Non-Hodgkin Lymphoma

Gribben

Fowler

Morschhauser

2015

JCO

251

188

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Lenalidomide is an orally active immunomodulatory drug that has direct antineoplastic activity and indirect effects mediated through multiple types of immune cells found in the tumor microenvironment, including B, T, natural killer (NK), and dendritic cells. Recently, the E3 ubiquitin ligase cereblon was identified as a molecular target that may underlie the effects of lenalidomide on tumor cells, as well as on cells in the tumor microenvironment. Decreases in cereblon attenuate these effects and also confer resistance to lenalidomide. Tumoricidal effects of lenalidomide are associated with reduced interferon regulatory factor 4, a downstream target of cereblon. Lenalidomide stimulates proliferation and activation of NK cells, thereby enhancing NK cell–mediated cytotoxicity and antibody-dependent cellular cytotoxicity. These effects appear to be secondary to cytokine production from T cells. Lenalidomide has been shown to produce synergistic effects in experimental models when evaluated in combination with rituximab, dexamethasone, bortezomib, and B-cell receptor signaling inhibitors, consistent with mechanisms complementary to these agents. These experimental findings have translated to the clinic, where single-agent use displays durable responses in relapsed/refractory non-Hodgkin lymphoma, and combination with rituximab and other agents leads to improved responses at first line and in relapsed/refractory disease. The activity of lenalidomide is evident across multiple lymphoma subtypes, including indolent and aggressive forms. The interaction among cell types in the immune microenvironment is increasingly recognized as important to tumor cell recognition and destruction, as well as to protection of normal immune cells, as reflected by lenalidomide studies across multiple types of B-cell lymphomas.

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Section: 59-61mentioning

confidence: 99%

Mechanisms of Action of Lenalidomide in B-Cell Non-Hodgkin Lymphoma

Gribben

Fowler

Morschhauser

2015

JCO

251

188

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“…21 However, understanding the relationship between the neoplastic cells and the various cellular components of the microenvironment will be crucial for developing therapeutics aimed at the microenvironment in the battle against FL. At present, the proposed classes of new agents for manipulation of the microenvironment surrounding FL cells include immunomodulatory drugs, that is, lenalidomide, [22][23][24][25][26][27][28] as well as immune checkpoint blockers, such as those targeting the cytotoxic T-lymphocyte-associated protein 4 (CTLA4) 29 or the programed death 1 (PD1) 30 axes. Further investigations will be needed to improve the outcomes of FL patients who have been treated with the chimeric anti-CD20 monoclonal antibody during the rituximab era.…”

Section: Introductionmentioning

confidence: 99%

Follicular Lymphoma: The Role of the Tumor Microenvironment in Prognosis

Sugimoto

Watanabe

2016

JCEH

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The microenvironment of follicular lymphoma (FL) is composed of tumor-infiltrating CD8 + T cells, follicular regulatory T cells, lymphoma-associated macrophages and mast cells, follicular helper T cells, follicular dendritic cells, and follicular reticular cells, all of which have been reported to have relevance in the prognosis of FL patients. In addition, some of these cells play a role in the histologic transformation of FL. Macrophages contribute to a poor prognosis in FL patients treated in the prerituximab era, but are associated with good prognosis in those treated in the rituximab era. T-cell immunoglobulin and mucin domain protein (TIM) 3 are markers of T-cell exhaustion, and T cells co-expressing programed death 1 (PD1) in peripheral blood and lymph nodes secrete interleukin (IL)-12 in the serum. Serum CXCL9, IL-2 receptor, and IL-1 receptor agonist are associated with shorter survival of FL patients. Agents for manipulation of the microenvironment surrounding FL cells include the immunomodulatory drug lenalidomide, immune check-point inhibitors, and cyclophosphamide prior to rituximab. To battle FL and to improve the outcomes of FL patients, understanding the relationship between neoplastic cells and the various microenvironmental cellular components is crucial for developing therapeutics against the microenvironment.

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“…A phase ii study by Tuscano et al 27 of rituximablenalidomide in patients with relapsed and refractory indolent nhl demonstrated an orr of 77%, a median pfs of 12.4 months, and a median duration of response (dor) of 15.4 months after a median follow-up of 43 months. The most common grades 3 and 4 toxicities included lymphopenia (45%), neutropenia (55%), fatigue (23%), and hyponatremia (9%).…”

Section: Immunomodulatory Drugsmentioning

confidence: 99%

Emerging Therapies for the Treatment of Relapsed or Refractory Follicular Lymphoma

et al. 2016

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With no treatment standard having been established for relapsed and refractory follicular lymphoma, a number of therapeutic approaches are used in Canada. In patients who relapse early or who eventually become resistant to subsequent treatment, prognosis is poor, and new approaches are needed. A number of novel therapies are being examined in this setting, including monoclonal antibodies, immunoconjugates, immunomodulatory agents, and signal transduction inhibitors. With the body of evidence for those emerging therapies accumulating and the standard upfront treatment changing from rituximab and chop (cyclophosphamide-doxorubicin-vincristine-prednisone) or rituximab and cvp (cyclophosphamide-vincristine-prednisone) to bendamustine and rituximab, treatment decisions in the relapsed and refractory setting have become more complex. The choice of subsequent treatment must consider type of upfront treatment; duration of remission; and patient-related factors such as age, comorbidities, and treatment preferences. This paper summarizes the evidence for novel therapies and proposes recommendations for subsequent treatment options by remission duration after induction and maintenance.

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Lenalidomide plus rituximab can produce durable clinical responses in patients with relapsed or refractory, indolent non‐Hodgkin lymphoma

Cited by 71 publications

References 33 publications

Mechanisms of Action of Lenalidomide in B-Cell Non-Hodgkin Lymphoma

Mechanisms of Action of Lenalidomide in B-Cell Non-Hodgkin Lymphoma

Follicular Lymphoma: The Role of the Tumor Microenvironment in Prognosis

Emerging Therapies for the Treatment of Relapsed or Refractory Follicular Lymphoma

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