Date Published: June 27, 2012
Publisher: Hindawi Publishing Corporation
Author(s): Annalisa Chiappella, Umberto Vitolo.
Diffuse Large B-cell Lymphomas (DLBCL) are the most frequent Non-Hodgkin Lymphomas (NHL). The addition of Rituximab to the standard chemotherapy CHOP improved the outcome in this patients, but so far 40% of patients experienced relapse or progressive disease. Lenalidomide, an immunomodulatory agent, had direct tumoricidal and antiangiogenetic actions on tumor cells and was able to modulate tumor-cell microenvironment, with the restoration of impaired T-cell activity and the formation of immuno-synapsis. Based on these actions, lenalidomide represented an active drug on aggressive relapsed NHL. In this review, the most relevant clinical trials for the use of lenalidomide in DLBCL were reported. Monotherapy with lenalidomide showed an activity in term of overall response rate, with acceptable hematological and extrahematological toxicities in relapsed/refractory aggressive NHL. The role of lenalidomide as salvage therapy in both cell of origin patterns in DLBCL (germinal center B-cell/activated B-cell) was reported in preliminary data. Preliminary data regarding the role of lenalidomide in addition to chemoimmunotherapy (R-CHOP) in first line clinical trials were discussed; data of safety, feasibility and efficacy were promising.
Diffuse large B-cell lymphoma (DLBCL) represents roughly 40% of all non-Hodgkin lymphoma (NHL) (Figure 1), with a rate of incidence in continuous increase and median age at diagnosis of 55–60 years [1, 2].
Lenalidomide, CC-5013, is an immunomodulatory agent with multiple mechanisms of action and it is an active agent on aggressive NHL, blocking tumor growth and survival with direct tumoricidal and immunomodulatory actions. This drug has both antiproliferative and antiangiogenic activities. Lenalidomide’s activity is based on modulation of tumor-cell microenvironment and on stimulating the activity of effector cells, such as cytotoxic T and natural killer cells. Lenalidomide enhanced T-cell and NK-cell effector function to eliminate tumor B cells and it had a role in the restoration of impaired T-cell activity and formation of immunologic synapses  (see Figure 2).
On the basis of the invivo activity of IMiDs, Wiernik et al. conducted a phase II multicenter trial to evaluate safety and efficacy of lenalidomide monotherapy in relapsed/refractory aggressive lymphomas patients. Forty-nine patients were enrolled to receive oral lenalidomide 25 mg once daily on days 1 to 21, every 28 days, for 52 weeks, until disease progression or intolerance. Median age was 65 years, 53% of patients had DLBCL, and all of them received at least four prior therapeutic regimens; 92% of patients had received prior rituximab and 29% of them had been previously transplanted. The overall response rate (ORR) was 35% for all histology and 19% for DLBCL. The estimated median duration of response was 6.2 months (range: 0 to 12.8 months) and median PFS was 4 months (range: 0 to 14.5 months). Regarding safety, the most common grade 4 adverse events were neutropenia (8.2%) and thrombocytopenia (8.2%); the most common grade 3 adverse events were neutropenia (24.5%), leukopenia (14.3%), thrombocytopenia (12.2%), and thrombocytopenia in 8.2%, resolved with dose reduction. The results showed that lenalidomide monotherapy is active in relapsed or refractory aggressive NHL, with manageable side effects . The same schedule of lenalidomide was tested by Witzig in the NHL-003 international phase II trial for relapsed or refractory aggressive B-cell non-Hodgkin’s lymphoma. Two hundred and seventeen patients were enrolled and 108 had DLBCL. In all histologic subgroups, ORR was 35% with CR 13%, partial remission (PR) 22%, and stable disease 21%; ORR for DLBCL was 28%. Moreover, ORR was 37% for patients who underwent prior stem cell transplantation and 33% for rituximab refractory ones. Median PFS for all 217 patients was 3.7 months; for 77 responders, the median response duration lasted 10.6 months. Despite the fact that patients were heavily pretreated, lenalidomide was well tolerated. The administered median daily dose of lenalidomide was 25 mg (range 7.1–25 mg) and 117 patients (53.9%) required at least one dose reduction or interruption due to neutropenia in 56% and thrombocytopenia in 31%. Grade 3 or 4 adverse events included neutropenia in 41%, with only 2% of febrile neutropenia, thrombocytopenia in 19%, and anemia in 9.2%. Discontinuation from study treatment occurred in 49 patients (23%). Extrahematological toxicities included tumor flares in 7 patients, 4 (1.8%) with grade 1 or 2 and 3 with grade 3, gastrointestinal events in 61.3%, rash in 18% and fatigue in 28%. Granulocyte colony stimulating factors (GCSF) were administered to 54 patients (25%) during the study .
The promising results of lenalidomide in relapsed/refractory DLBCL setting, encouraged the development of trial with this drug in first line treatment.
The introduction of IMiDs in the treatment of DLBCL represented an improvement in the outcome of this patients. Lenalidomide represents a manageable drug, with good results in relapsed or refractory DLBCL patients heavily pretreated. The role of lenalidomide in association to standard chemoimmunotherapy RCHOP in first line is under investigation, with promising results in term of feasibility, toxicity and with promising results in term of response. The activity of lenalidomide in histological subtypes at poor outcome, like in activated B-cell DLBCL, may be demonstrated in prospective trials.