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Brentuximab Vedotin + Rituximab as Frontline Therapy for Pts w/ CD30+ and/or EBV+ Lymphomas

ABSTRACT: The purpose of this study is to evaluate how safe and effective the combination of two different drugs (brentuximab vedotin and rituximab) is in patients with certain types of lymphoma. This study is for patients who have a type of lymphoma that expresses a tumor marker called CD30 and/or a type that is associated with the Epstein-Barr virus (EBV-related lymphoma) and who have not yet received any treatment for their cancer, except for dose-reduction or discontinuation (stoppage) of medications used to prevent rejection of transplanted organs (for those patients who have undergone transplantation). This study is investigating the combination of brentuximab vedotin and rituximab as a first treatment for lymphoma patients

DISEASE(S): Adult Grade Iii Lymphomatoid Granulomatosis,Stage Iiib Mycosis Fungoides/sezary Syndrome,Stage Ib Mycosis Fungoides/sezary Syndrome,Lymphoma, Large-cell, Immunoblastic,Lymphoproliferative Disorders,Stage I Adult Diffuse Small Cleaved Cell Lymphoma,Stage Iva Mycosis Fungoides/sezary Syndrome,Stage Iv Adult Diffuse Mixed Cell Lymphoma,Progressive Hairy Cell Leukemia, Initial Treatment,Stage Iv Adult Immunoblastic Large Cell Lymphoma,Recurrent Grade 1 Follicular Lymphoma,Stage I Small Lymphocytic Lymphoma,Contiguous Stage Ii Adult Diffuse Small Cleaved Cell Lymphoma,Contiguous Stage Ii Marginal Zone Lymphoma,Leukemia, Hairy Cell,Stage Ivb Mycosis Fungoides/sezary Syndrome,Mycosis Fungoides,Stage Iv Adult Lymphoblastic Lymphoma,Stage Iii Adult Burkitt Lymphoma,Stage I Grade 1 Follicular Lymphoma,Stage Ii Cutaneous T-cell Non-hodgkin Lymphoma,Recurrent Adult Burkitt Lymphoma,Leukemia, T-cell,Lymphomatoid Granulomatosis,Lymphoma, T-cell, Peripheral,Lymphoma, B-cell, Marginal Zone,Stage Iiia Mycosis Fungoides/sezary Syndrome,Stage I Adult Immunoblastic Large Cell Lymphoma,Nodal Marginal Zone B-cell Lymphoma,Noncontiguous Stage Ii Grade 3 Follicular Lymphoma,Recurrent Small Lymphocytic Lymphoma,Lymphoma, T-cell, Cutaneous,Stage Iv Adult Burkitt Lymphoma,Contiguous Stage Ii Grade 3 Follicular Lymphoma,Stage I Adult Diffuse Large Cell Lymphoma,Stage Iii Adult T-cell Leukemia/lymphoma,Stage Iii Adult Diffuse Large Cell Lymphoma,Lymphoma, Follicular,Waldenstrom Macroglobulinemia,Recurrent Mantle Cell Lymphoma,Stage Iii Cutaneous T-cell Non-hodgkin Lymphoma,Contiguous Stage Ii Grade 1 Follicular Lymphoma,Leukemia,Hodgkin Disease,Recurrent Adult Hodgkin Lymphoma,Mycoses,Contiguous Stage Ii Adult Diffuse Large Cell Lymphoma,Recurrent Adult Lymphoblastic Lymphoma,Leukemia, Large Granular Lymphocytic,Stage Iib Mycosis Fungoides/sezary Syndrome,Contiguous Stage Ii Adult Diffuse Mixed Cell Lymphoma,Testicular Lymphoma,Stage I Grade 3 Follicular Lymphoma,Noncontiguous Stage Ii Mantle Cell Lymphoma,Contiguous Stage Ii Grade 2 Follicular Lymphoma,Lymphoma, T-cell,Noncontiguous Stage Ii Adult Diffuse Mixed Cell Lymphoma,Stage Iv Grade 3 Follicular Lymphoma,Untreated Hairy Cell Leukemia,Immunoblastic Lymphadenopathy,Noncontiguous Stage Ii Marginal Zone Lymphoma,Stage Ia Mycosis Fungoides/sezary Syndrome,Noncontiguous Stage Ii Small Lymphocytic Lymphoma,Recurrent Adult Diffuse Mixed Cell Lymphoma,Stage Ii Adult Hodgkin Lymphoma,Stage Iv Grade 2 Follicular Lymphoma,Contiguous Stage Ii Small Lymphocytic Lymphoma,Recurrent Adult T-cell Leukemia/lymphoma,Stage Iv Cutaneous T-cell Non-hodgkin Lymphoma,Contiguous Stage Ii Mantle Cell Lymphoma,Noncontiguous Stage Ii Adult Diffuse Large Cell Lymphoma,Stage I Grade 2 Follicular Lymphoma,Lymphoma, Non-hodgkin,Lymphoma, B-cell,Stage I Adult T-cell Leukemia/lymphoma,Extranodal Marginal Zone B-cell Lymphoma Of Mucosa-associated Lymphoid Tissue,Lymphoma, Large B-cell, Diffuse,Contiguous Stage Ii Adult Lymphoblastic Lymphoma,Stage Iv Adult T-cell Leukemia/lymphoma,Stage Iv Adult Diffuse Large Cell Lymphoma,Contiguous Stage Ii Adult Immunoblastic Large Cell Lymphoma,Noncontiguous Stage Ii Adult Immunoblastic Large Cell Lymphoma,Small Intestine Lymphoma,Refractory Hairy Cell Leukemia,Sezary Syndrome,T-cell Large Granular Lymphocyte Leukemia,Adult Nasal Type Extranodal Nk/t-cell Lymphoma,Splenic Marginal Zone Lymphoma,Stage I Marginal Zone Lymphoma,Lymphoma, Mantle-cell,Noncontiguous Stage Ii Adult Burkitt Lymphoma,Leukemia-lymphoma, Adult T-cell,Epstein-barr Virus Infections,Stage Iii Adult Diffuse Small Cleaved Cell Lymphoma,Recurrent Adult Immunoblastic Large Cell Lymphoma,Stage Iv Grade 1 Follicular Lymphoma,Stage Iv Mantle Cell Lymphoma,Stage I Adult Hodgkin Lymphoma,Stage I Adult Diffuse Mixed Cell Lymphoma,Contiguous Stage Ii Adult Burkitt Lymphoma,Lymphoma, Extranodal Nk-t-cell,Stage Ii Adult T-cell Leukemia/lymphoma,Plasmablastic Lymphoma,Stage I Cutaneous T-cell Non-hodgkin Lymphoma,Burkitt Lymphoma,Stage I Mantle Cell Lymphoma,Recurrent Adult Diffuse Small Cleaved Cell Lymphoma,Stage Iii Grade 1 Follicular Lymphoma,Stage Iii Adult Immunoblastic Large Cell Lymphoma,Post-transplant Lymphoproliferative Disorder,Stage Iii Marginal Zone Lymphoma,Stage Iii Adult Diffuse Mixed Cell Lymphoma,Recurrent Marginal Zone Lymphoma,Recurrent Adult Grade Iii Lymphomatoid Granulomatosis,Leukemia, Lymphocytic, Chronic, B-cell,Intraocular Lymphoma,Stage I Adult Lymphoblastic Lymphoma,Noncontiguous Stage Ii Adult Diffuse Small Cleaved Cell Lymphoma,Recurrent Grade 3 Follicular Lymphoma,Epstein-barr Virus Infection,Stage Iii Adult Hodgkin Lymphoma,Stage Iii Grade 2 Follicular Lymphoma,Waldenström Macroglobulinemia,Noncutaneous Extranodal Lymphoma,Angioimmunoblastic T-cell Lymphoma,Stage Iv Marginal Zone Lymphoma,Lymphoma, Large-cell, Anaplastic,Stage Iv Adult Hodgkin Lymphoma,Stage Iii Mantle Cell Lymphoma,Noncontiguous Stage Ii Grade 2 Follicular Lymphoma,Stage Iii Grade 3 Follicular Lymphoma,Hepatosplenic T-cell Lymphoma,Stage Iv Adult Diffuse Small Cleaved Cell Lymphoma,Precursor Cell Lymphoblastic Leukemia-lymphoma,Noncontiguous Stage Ii Grade 1 Follicular Lymphoma,Recurrent Cutaneous T-cell Non-hodgkin Lymphoma,Noncontiguous Stage Ii Adult Lymphoblastic Lymphoma,Stage Iv Small Lymphocytic Lymphoma,Lymphoma,Recurrent Mycosis Fungoides/sezary Syndrome,Anaplastic Large Cell Lymphoma,Stage Iii Small Lymphocytic Lymphoma,Recurrent Grade 2 Follicular Lymphoma,Peripheral T-cell Lymphoma,Stage Iii Adult Lymphoblastic Lymphoma,Stage Iia Mycosis Fungoides/sezary Syndrome,Cutaneous B-cell Non-hodgkin Lymphoma,Stage I Adult Burkitt Lymphoma

PROVIDER: 2141097 | ecrin-mdr-crc |

REPOSITORIES: ECRIN MDR

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Project description:Purpose: Despite recent advances in the treatment of patients with aggressive lymphomas, still a significant fraction of patients will succumb to their disease. Thus, novel therapeutic strategies are urgently needed. As the anti-CD20 antibody rituximab and the CD19-targeting antibody tafasitamab share distinct modes of actions, we investigated if dual-targeting of aggressive lymphoma B-cells by combining rituximab and tafasitamab might increase cytotoxic effects. Experimental Design: Antibody single and combination efficacy was determined investigating different modes of action including direct cytotoxicity, antibody-dependent cell-mediated cytotoxicity (ADCC) and antibody-dependent cellular phagocytosis (ADCP) in vitro and in vivo models of aggressive B-cell lymphoma comprising diffuse large B-cell lymphoma (DLBCL) and Burkitt lymphoma (BL). Results: Overall, three different sensitivity profiles to antibody monotherapy or combination treatment were observed in in vitro models: while 2/11 cell lines were primarily sensitive to tafasitamab and 2/11 were predominantly sensitive to rituximab treatment, the combination of tafasitamab and rituximab resulted in enhanced cell death in 7/11 cell lines in at least one mode of action. Treatment with either antibody or the combination resulted in decreased expression of the oncogenic transcription factor MYC and inhibition of AKT signaling which mirrored the cell line-specific sensitivities to direct cytotoxicity. At last, the combinatorial approach of the two antibodies resulted in a synergistic survival benefit in a PBMC-humanized Ramos NOD/SCID mouse model. Conclusions: This study demonstrates that the combination of tafasitamab and rituximab improves efficacy compared to antibody mono treatment in models of aggressive B-cell lymphoma in vitro and in vivo. Translational Relevance: The immunochemotherapy of rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) remains the standard of care for newly diagnosed DLBCL patients. However, 30-40% of patients are refractory or relapse after initial response to the immunochemotherapy, indicating a high-unmet medical need for these patients. Tafasitamab and rituximab target the B-cell surface proteins CD19 and CD20, respectively, and both antibodies feature overlapping modes of action , namely direct cytotoxicity, ADCC and ADCP. In this study, we show that the combination of tafasitamab and rituximab had additive and synergistic efficacy both in vitro and in vivo. Our findings shed new light on the underlying mechanism of the combination of both antibodies and lay the ground to translate the results into improved outcome for patients with aggressive lymphoma in future clinical trials.

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Brentuximab Vedotin + Rituximab as Frontline Therapy for Pts w/ CD30+ and/or EBV+ Lymphomas

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