Efficacy Of Lenalidomide In Combination Research Articles

R-GEM-Lenalidomide Versus R-GEM-P As Second-Line Treatment of Diffuse Large B-Cell Lymphoma: Results from the UK NCRI Phase II Randomized Legend Trial

R-GEM-Lenalidomide Versus R-GEM-P As Second-Line Treatment of Diffuse Large B-Cell Lymphoma: Results from the UK NCRI Phase II Randomized Legend Trial

Successful Treatment of MYC rearrangement Positive Large B Cell Lymphoma Patients with R-CHOP21 Plus Lenalidomide: Results of a Multicenter Phase II HOVON Trial

Successful Treatment of MYC rearrangement Positive Large B Cell Lymphoma Patients with R-CHOP21 Plus Lenalidomide: Results of a Multicenter Phase II HOVON Trial

Combination therapy with dendritic cells and lenalidomide is an effective approach to enhance antitumor immunity in a mouse colon cancer model.

In this study, we investigated efficacy of lenalidomide in combination with tumor antigen-loaded dendritic cells (DCs) in murine colon cancer model. MC-38 cell lines were injected subcutaneously to establish colon cancer-bearing mice. After tumor growth, lenalidomide (50 mg/kg/day) was injected intraperitoneally on 3 consecutive days in combination with tumor antigen-loaded DC vaccination on days 8, 12, 16, and 20. The tumor antigen-loaded DCs plus lenalidomide combination treatment exhibited a significant inhibition of tumor growth compared with the other groups. These effects were associated with a reduction in immune suppressor cells, such as myeloid-derived suppressor cells and regulatory T cells, with the induction of immune effector cells, such as natural killer cells, CD4+ T cells and CD8+ T cells in spleen, and with the activation of cytotoxic T lymphocytes and NK cells. This study suggests that a combination of tumor antigen-loaded DC vaccination and lenalidomide synergistically enhanced antitumor immune response in the murine colon cancer model, by inhibiting the generation of immune suppressive cells and recovery of effector cells, and demonstrated superior polarization of Th1/Th2 balance in favor of Th1 immune response. This combination approach with DCs and lenalidomide may provide a new therapeutic option to improve the treatment of colon cancer.

Lenalidomide in Combination with R-ESHAP (LR-ESHAP) in Patients with Relapsed or Refractory Diffuse Large B-Cell Lymphoma Who Are Candidates for Autologous Stem-Cell Transplantation: A Phase 2 Study from the Spanish Group Geltamo

Background: Diffuse large B-cell lymphoma (DLBCL) patients with relapsed or refractory disease after rituximab-containing first-line therapy have poor outcomes with current salvage regimens. Accordingly, prospective studies incorporating new agents are needed for these patients. We conducted a phase 1b/2 trial to analyze the safety and efficacy of lenalidomide in combination with R-ESHAP (LR-ESHAP) in patients with relapsed or refractory DLBCL. The phase 1b part of the trial has been completed and lenalidomide 10 mg/day was identified as the maximum tolerated dose (MTD) (Martín et al, Br J Haematol 2016; 173: 245-52). Here we present the preliminary results of the phase 2 (ClinicalTrials.gov Identifier: NCT02340936).Patients and methods: Eligible patients must be refractory to, or have relapsed following first-line treatment with rituximab in combination with an anthracycline-containing regimen and be eligible for autologous stem-cell transplantation (ASCT). Subjects received 3 cycles of lenalidomide 10 mg given on days 1 to 14 of every 21-day cycle, in combination with R-ESHAP salvage chemotherapy at standard doses (rituximab 375 mg/m2 day 1, etoposide 40 mg/m2 days 1-4, cisplatin 25 mg/m2 days 1-4, cytarabine 2000 mg/m2 day 5, and methylprednisolone 500 mg days 1-5). Responding patients received BEAM followed by ASCT. The primary endpoint was overall response rate (ORR) after 3 cycles of therapy. Secondary endpoints were complete remission (CR) rate, stem-cell mobilization activity, progression-free and overall survival, and toxicity.Results:Patient characteristics: 46 patients were included in the phase 2 analysis, of whom 12 were enrolled between January 2012 and March 2013, and had been given the MTD during phase 1; 34 were enrolled between January 2015 and November 2015. Median age was 58 (23-69) years, and 56.5% were male. Evaluable population per-protocol consisted of 44 patients because 2 patients were excluded during the first cycle due to withdrawal of consent and centralized diagnosis at relapse of lymphoblastic lymphoma, respectively. First-line treatment consisted of R-CHOP or similar in 38 patients, R-EPOCH in 3, VR-CAP in 1, and Burkitt lymphoma protocols in 2. Disease status at LR-ESHAP was: primary refractory disease in 67% of patients (partial response [PR] after first-line, n=13; and stable or progressive disease [<PR] after first-line, n=16), and relapsed disease in 33% (5 relapses occurred <1 year from diagnosis, and 10 late relapses). IPI was 0-1 in 38%, 2-3 in 48%, and 4-5 in 14%.Feasibility and efficacy: 40 out of 44 patients (91%) received the planned 3 cycles of treatment (2 without lenalidomide in the third cycle due to toxicity) and 2 patients two cycles (due to persistent hematological and renal toxicities, respectively). Two patients discontinued treatment during the first cycle due to grade 3 infections (fungal pulmonary infection and mastoiditis, respectively). ORR to LR-ESHAP in the per-protocol population (n=44) was 68% (41% CR). Patients with relapsed disease had significantly better ORR and CR rates (87% and 67%, respectively) than patients in PR (77% and 31%) or <PR (37% and 25%) (p=0.004 and 0.02, respectively). Evaluation of response according to cell of origin (COO) is ongoing. Thirty-nine out of 42 patients (93%) were successfully mobilized after one (n=32) or two (n=7) mobilization procedures, and 28 (64%) underwent ASCT according to protocol, 1 of them after bone-marrow harvest. Reasons for not performing the transplant were: early progression (n=13), trial discontinuation due to toxicity (n=2), mobilization failure (n=1), and diagnosis of colon adenocarcinoma (n=1).Toxicity: 42 serious adverse events (SAEs) have been reported during 128 cycles of treatment, including 14 episodes of febrile neutropenia (11%), 12 infections (9%), 2 renal disorders, 3 cardiac disorders, 3 thrombosis, and 8 other toxicities. All of them recovered except 1 case of colon adenocarcinoma in a patient with previous adenoma in the same location. There were no treatment-related deaths during LR-ESHAP cycles.Conclusions: LR-ESHAP is safe, feasible and associated with high response rates in rituximab-pretreated relapsed or refractory DLBCL patients. Longer follow-up is needed to perform survival analysis. Efficacy analysis according to COO is ongoing. DisclosuresMartín:Janssen: Honoraria; Celgene: Honoraria, Membership on an entity’s Board of Directors or advisory committees; Sevier: Honoraria, Membership on an entity’s Board of Directors or advisory committees; Gilead: Membership on an entity’s Board of Directors or advisory committees. González-Barca:Sanofi: Membership on an entity’s Board of Directors or advisory committees; Servier: Honoraria, Membership on an entity’s Board of Directors or advisory committees; Gilead: Honoraria; Janssen: Honoraria, Membership on an entity’s Board of Directors or advisory committees; Roche: Honoraria. Lopez-Guillermo:Roche: Consultancy, Research Funding; Celgene: Consultancy; Gilead: Consultancy; Janssen: Consultancy; Mundipharma: Consultancy.

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

This phase II study evaluated the safety and efficacy of lenalidomide in combination with rituximab in patients with relapsed/refractory, indolent non-Hodgkin lymphoma (NHL). Patients were treated with daily lenalidomide in 28-d cycles and weekly rituximab for 4 weeks. Lenalidomide was continued until progression or unacceptable toxicity. Twenty-two patients were assessed for FCGR3A polymorphisms. Thirty patients were enrolled; 27 were evaluable for response. The overall response rate (ORR) was 74% including 44% complete responses (CR); median progression-free survival (PFS) was 12·4 months. The 13 rituximab refractory patients had an ORR of 61·5% (four CR/unconfirmed CR). The ORR was 77% in the 22 follicular lymphoma patients (nine CR/unconfirmed CR). At a median follow-up time of 43 months, the median duration of response and time to next therapy were 15·4 and 37·4 months, respectively. Most common grade 3/4 adverse events were lymphopenia (45%), neutropenia (55%), fatigue (23%) and hyponatraemia (9%). The ORR and PFS in patients with low-affinity FCGR3A polymorphisms (F/F and F/V) suggest that lenalidomide may improve the activity of rituximab in these patients. These data suggest that combining lenalidomide with rituximab can produce durable responses with acceptable toxicity in patients with indolent NHL.

Immunotherapy in mantle cell lymphoma: Anti‐CD20‐based therapy and beyond

Mantle cell lymphoma (MCL), an aggressive non-Hodgkin's lymphoma characterized by t(11; 14)(q13; q32) chromosomal translocation and overexpression of cyclin D1, has the worst prognosis among all lymphomas. Recent advances in biology, genetics, and immunology have supported the development of immunotherapy in MCL. Rituximab monotherapy in MCL has limited activity. It is more effective when used in combination with chemotherapy such as R-CHOP, R-hyperCVAD/MTX-Ara-C, or R-FCM as front-line or salvage therapy for mantle cell lymphoma. Maintenance with Rituximab was shown to prolong response duration. Although most results have suggested that combining autologous stem cell transplantation with Rituximab may lead to durable remission, the sample size was not sufficient to declare survival benefit. Anti-CD20 radioimmunoconjugates (RICs) (90)Yttrium-ibritumomab tiuxetan and (131)Iodine-tositumomab have been used in mantle cell lymphoma even when patients are relatively resistant to Rituximab-based therapy. Allogeneic stem cell transplantation is a treatment modality in advanced or relapsed MCL, particularly using reduced-intensity conditioning. MCL may have high response rates and sustained remissions after donor lymphocyte infusion. Dendritic cells (DCs) fused with MCL cells for immunostimulation have preliminarily shown anti-lymphoma effects as well. Idiotype vaccination in MCL patients following Rituximab-containing chemotherapy induced tumor-specific T-cell immunity in the absence of B cells. Other immunotherapy, such as the combination of thalidomide with Rituximab, has shown substantial antitumor activity. A Phase I/II study is ongoing to determine the maximum tolerated dose (MTD) and the efficacy of lenalidomide in combination with Rituximab for relapsed/refractory MCL. This review summarizes the latest and exciting advances in MCL.