Lenalidomide in Heavily Pretreated Refractory Diffuse Large B-cell Lymphoma: A Case Report

Katarzyna Krawczyk; Wojciech Jurczak; Krystyna Gałązka; Andrzej Gruchała; Aleksander B Skotnicki

Disclosures

J Med Case Reports. 2014;8(325) 

In This Article

Abstract and Introduction

Abstract

Introduction In diffuse large B-cell lymphoma, first-line treatment with rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone; salvage with cisplatin-based regimens for relapsing patients; and autologous stem cell therapy are standards of care. Treatment approaches are less clear for patients who are refractory or who are not candidates for autologous stem cell therapy. Options may include palliative regimens or clinical trial enrollment. One therapy under investigation in diffuse large B-cell lymphoma is lenalidomide, an immunomodulatory agent with antiangiogenic activity.

Case presentation We present the case of a 55-year-old Caucasian male patient diagnosed with diffuse large B-cell lymphoma who had an early relapse after treatment with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone. He then had a subsequent early relapse after cisplatin-based salvage consolidated with autologous stem cell therapy. The efficacy of gemcitabine-cisplatin-rituximab was limited to five months, followed by systemic and central nervous system progression. Fourth-line treatment with lenalidomide plus rituximab and involved-field radiotherapy followed by lenalidomide monotherapy greatly improved this patient's quality of life and performance status, allowing over two years of progression-free survival to date (excluding a brief relapse due to treatment interruption).

Conclusion A lenalidomide-based regimen was highly effective in this patient with diffuse large B-cell lymphoma.

Introduction

Although diffuse large B-cell lymphoma (DLBCL) is an aggressive lymphoma, immunochemotherapy with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) - widely regarded as the standard of care for first-line patients[1,2] - is effective in more than 50% of cases.[3] Treatment is not as defined for patients who are refractory or who relapse following standard first-line therapy. A number of agents are currently in development for treating relapsed or refractory DLBCL.

Lenalidomide (Revlimid®, Celgene Corporation, Summit, New Jersey, USA) is an immunomodulatory agent that is approved for patients with previously treated multiple myeloma and for patients with myelodysplastic syndrome who have the 5q cytogenetic abnormality. Lenalidomide has both direct tumoricidal and immunomodulatory effects. Direct effects include inhibition of vascular endothelial growth factor-mediated microvessel formation, indicating antiangiogenic and antimetastatic activities,[4,5] as well as inhibition of nuclear factor kappa B to bring about cell cycle arrest and tumor cell death.[6] Immunomodulatory effects of lenalidomide include inhibition of pro-inflammatory cytokines such as tumor necrosis factor α, increased anti-inflammatory cytokines such as interleukin-10, increased cytotoxicity of natural killer (NK) cells, and inhibition of regulatory T cells.[7–11] In addition, lenalidomide is a potent enhancer of NK cell-mediated and monocyte-mediated tumor cell antibody-dependent cellular cytotoxicity in non-Hodgkin's lymphoma cells treated with the anti-CD20 monoclonal antibody rituximab.[12]

Numerous studies of lenalidomide in DLBCL as monotherapy or in combination with other agents are ongoing in first-line patients and relapsed or refractory patients, as well as in the maintenance setting. In first-line patients with DLBCL, the combination of lenalidomide with rituximab plus CHOP (R2-CHOP) has yielded promising results in phase 1 and 2 studies.[13–18] In relapsed or refractory DLBCL, data from phase 2 studies of lenalidomide monotherapy and combination therapy with rituximab have been presented,[19–24] and overall or objective response rates range from 28% (DLBCL subset)[20] to 35%[21] in this setting. Based on presumptive cell of origin, there are two primary DLBCL subtypes with distinct pathophysiology: germinal center B-cell (GCB) and activated B-cell (ABC)/non-GCB lymphoma. These are associated with different prognoses. The ABC/non-GCB subtype has a significantly poorer prognosis than the GCB subtype, and this correlation is independent of the International Prognostic Index (IPI).[25,26] The benefit of lenalidomide may differ depending on the subtype of DLBCL.[14,27] In patients with relapsed or refractory DLBCL treated with salvage lenalidomide, a higher overall response rate (ORR) has been observed in patients with the non-GCB subtype compared with those with the GCB subtype (ORR 52.9% versus 8.7%; P=0.006).[27] The benefit of lenalidomide has also been reported in newly diagnosed patients with non-GCB subtype DLBCL treated with R2-CHOP. In this setting, several small (<70 patients), phase 2 studies have demonstrated that the addition of lenalidomide improves progression-free survival and overcomes the negative prognostic impact of the non-GCB subtype on patient outcome.[14,18] An ongoing phase 2 randomized trial (NCT01856192) is comparing progression-free survival in patients with GCB and non-GCB DLBCL treated with first-line lenalidomide combined with R-CHOP versus R-CHOP alone.[28]In vitro studies indicate that the differential effects of lenalidomide on non-GCB DLBCL cells are dependent on the expression of interferon regulatory factor 4 and cereblon, an E3 ubiquitin ligase complex co-receptor protein.[29]

Prognosis is poor for patients with multiply relapsed or refractory DLBCL, and current treatment guidelines suggest either autologous stem cell transplant (ASCT) or treatment within a clinical trial,[1,2] underscoring the dearth of therapeutic options for this population. In this report, we present the case of a patient with DLBCL who received lenalidomide plus rituximab after multiple relapses on other treatments.

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