Lenalidomide in non-Hodgkin lymphoma: biological perspectives and therapeutic opportunities

Kritharis, Athena; Coyle, Michael; Sharma, Jaydev; Evens, Andrew M.

doi:10.1182/blood-2014-11-567792

Cited by 52 publications

(31 citation statements)

References 59 publications

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“…26,27 Remarkably, given their anti-inflammatory activity, PDE4 inhibitors have been independently shown to actually protect against doxorubicin-induced cardiomyopathy in rats. 35 Although lenalidomide has also been suggested to inhibit lymphoma angiogenesis, 36 the proposed use of PDE4 inhibitors in this setting is grounded in a more robust mechanistic understanding of its effects on the tumor and endothelial cells, 9,[28][29][30][31] which may be leveraged for the development of successful antiangiogenesis initiatives.…”

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confidence: 99%

Phosphodiesterase 4 inhibitors have wide-ranging activity in B-cell malignancies

Cooney¹,

Aguiar

2016

Blood

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Phosphodiesterase 4 (PDE4) inhibition restores the suppressive effects of 3′,5′-cyclic adenosine monophosphate in lymphocytes. In this concise review, we detail how PDE4 inhibition downmodulates the B-cell receptor (BCR)-related kinases spleen tyrosine kinase and phosphatidylinositol 3-kinase and inhibits vascular endothelial growth factor A secretion by tumor cells, inducing cancer cell apoptosis and blocking angiogenesis in the microenvironment. We describe the successful clinical repurposing of PDE4 inhibitors in B-cell malignancies, and propose that given their anti-inflammatory/immunomodulatory activity, these agents will suppress BCR signals without the toxicity associated with other targeted biological doublets.

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confidence: 99%

Phosphodiesterase 4 inhibitors have wide-ranging activity in B-cell malignancies

Cooney¹,

Aguiar

2016

Blood

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“…Firstly, the maximum tolerated dose (MTD) and the dose-limiting toxicities (DLT) of lenalidomide plus R-CHOP in newly diagnosed DLBCL were determined in phase I trials [21][22][23]. In [14] translocation t (14;18), such as most FL [33]. Moreover, patients affected by DLBCL simultaneously bearing a translocation involving Bcl-2 and the proto-oncogene myc in DLBCL have a very dismal outcome why more intensive immunochemotherapy treatments are needed [34].…”

Section: Immunomodulatory Agentsmentioning

confidence: 99%

Changing treatment paradigms in lymphoma: new targets and new drugs

Mian

Chiappella²

2015

memo

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The knowledge about biological mechanisms contributing to lymphomagenesis represents the basis for targeted therapies in lymphoproliferative disorders. Herein, we provide a short overview about the novel drugs targeting B-cell non-Hodgkin lymphomas, with a focus on diffuse large B-cell lymphomas. Due to the plethora of new drugs, we present some of the most important new drug developments in lymphoma treatment, namely humanized monoclonal antibodies, monoclonal antibody conjugates, immunomodulatory agents, and tyrosine kinase inhibitors. The use of these agents alone or in combination with chemotherapy showed promising results with a good safety profile in a setting of relapsed/refractory lymphomas. Since many of them demonstrated to be highly active, several clinical trials evaluating their efficacy in first-line treatment are ongoing.

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“…Both bendamustine and lenalidomide have demonstrated single-agent activity across a broad range of haematological malignancies, particularly in the treatment of DLBCL (Weidmann et al, , 2011Wiernik et al, 2008;Wu et al, 2008;Cheson & Rummel, 2009;Rummel & Gregory, 2011;Witzig et al, 2011Witzig et al, , 2015Kritharis et al, 2015). Preclinical and clinical data suggest a synergistic effect for the combination of lenalidomide and rituximab as well as for bendamustine and rituximab (Chow et al, 2002;Zhang et al, 2009).…”

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confidence: 94%

Rituximab, bendamustine and lenalidomide in patients with aggressive B‐cell lymphoma not eligible for anthracycline‐based therapy or intensive salvage chemotherapy – SAKK 38/08

et al. 2016

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An increasing number of older patients are suffering from aggressive lymphoma. Effective and more tolerable treatment regimens are urgently needed for this growing patient population. Patients with aggressive lymphoma not eligible for anthracycline-based first-line therapy or intensive salvage regimens were treated with the rituximab-bendamustine-lenalidomide (R-BL) regimen (rituximab 375 mg/m(2) day 1, bendamustine 70 mg/m(2) d 1, 2, lenalidomide 10 mg d 1-21) for six cycles every 4 weeks. Forty-one patients with a median age of 75 (range 40-94) years were enrolled: 33 patients had substantial co-morbidities. 13 patients were not eligible for anthracycline-based first-line chemotherapy, 28 patients had relapsed/refractory disease. The primary endpoint, overall response, was achieved by 25 (61%) patients (95% confidence interval 45-76%). Grade ≥ 3 toxicity comprised haematological (59%), skin (15%), constitutional (15%) and neurological (12%) events. 9 patients died during trial treatment: 5 from lymphoma progression, 2 from toxicity, 2 with sudden death. After a median follow-up of 25·9 (interquartile range 20·4-31·6) months, 13 patients were still alive. Median overall survival was 14·5 months. In conclusion, R-BL can be considered a treatment option for elderly patients with treatment naïve or relapsed/refractory aggressive lymphoma not eligible for standard aggressive regimens.

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Lenalidomide in non-Hodgkin lymphoma: biological perspectives and therapeutic opportunities

Cited by 52 publications

References 59 publications

Phosphodiesterase 4 inhibitors have wide-ranging activity in B-cell malignancies

Phosphodiesterase 4 inhibitors have wide-ranging activity in B-cell malignancies

Changing treatment paradigms in lymphoma: new targets and new drugs

Rituximab, bendamustine and lenalidomide in patients with aggressive B‐cell lymphoma not eligible for anthracycline‐based therapy or intensive salvage chemotherapy – SAKK 38/08

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