Antiproliferative Effects of Lenalidomide in Combination with Chemotherapeutic Agents in Lymphoma Cell Lines

Introduction: Lenalidomide (Revlimid^®) is approved for the treatment of patients with myelodysplastic syndromes with a del(5q), and in combination with dexamethasone for previously treated multiple myeloma. It is currently being evaluated in lymphomas, as monotherapy or combination therapy. This study aims to identify beneficial combinations of lenalidomide with established or potential chemotherapeutic agents for lymphoma therapy.

Methods: Lenalidomide-sensitive lymphoma cell lines were selected for in vitro tumor cell proliferation studies. These included mantle cell lymphoma (MCL) lines Rec-1 and Jeko- 1, diffuse large-B-cell lymphoma (DLBCL) cell line Farage, the follicular lymphoma (FL) cell line DOHH2, and the chromosome 5-deleted Burkitt’s lymphoma cell line Namalwa CSN.70. Lenalidomide was tested with other therapeutic agents on cells incubated 72 hours and assayed for proliferation using ³H-thymidine incorporation. Twenty-one different therapeutic agents were tested in combination with lenalidomide, at concentrations ranging from 1 pM to 100 μM, depending upon the sensitivity of the cells to the particular agent.

Results: In MCL cells, lenalidomide was at least partially additive with mitoxantrone, rituximab, temsirolimus, bortezomib and azacytidine, and up to partially additive with doxorubicin. Results were similar in Rec-1 and Jeko-1 MCL cells. Lenalidomide was fully additive in the DLBCL cells with gemcitabine, melphalan, dexamethasone, carboplatin, and oxaliplatin, partially additive with cisplatin, mitoxantrone, vincristine, azacytidine, doxorubicin, carmustine, rituximab, etoposide and prednisolone, and non-additive with cytarabine. Synergy with lenalidomide was observed in the FL cells with rituximab, while partially additive with bendamustine and fludarabine, and non-additive with vincristine. In the Burkitt’s lymphoma cells, lenalidomide was synergistic with dexamethasone, rapamycin, and UCN-01. It was partially additive with prednisone and etoposide, and non-additive with other agents tested.

Conclusion: Among the tested lymphoma cell lines, lenalidomide combined synergistically with rituximab, dexamethasone, rapamycin, and UCN-01, and additively with mitoxantrone, temsirolimus, bortezomib, azacitidine, gemcitabine, melphalan, dexamethasone, carboplatin, and oxaliplatin. Thus, these results demonstrate a beneficial antineoplastic pharmacological interaction between lenalidomide and several therapeutic agents including monoclonal antibodies, corticosteroids, mTOR inhibitors, kinase inhibitors, proteasome inhibitors, DNA methyltransferase inhibitors, nucleoside analogs, alkylating agents, and topoisiomerase inhibitors in the treatment of lymphoma.