A combination of 5-azacytidine and nivolumab is a potentially effective rescue therapy in relapsed/refractory AITL

Abstract

Introduction: Angioimmunoblastic T-cell lymphoma (AITL) is a peripheral T-cell lymphoma characterized by a T follicular helper cell phenotype expressing PD-1 (programmed cell death-1). AITL exhibits a poor response to conventional chemotherapy, with a median 5-year overall survival of 44% and a progression-free survival of 32%. Relapse is common, resulting in a median overall survival of 6 months. Recurrent mutations are detected in genes regulating DNA methylation, including TET2, DNMT3A, and IDH2 variants, along with the prevalent RHOA G17V mutation. In this context, patients treated with the hypomethylating agent 5-azacytidine achieved overall response and complete response rates of 75% and 41%, respectively. We hypothesized that targeted therapies combining anti-PD-1 checkpoint blockers with hypomethylating agents could be efficient in AITL patients and less toxic than standard chemotherapy.

Methods: Here, we report the efficacy of a regimen combining 5-azacytidine and nivolumab in nine relapsed or refractory AITL patients.

Results: This regimen was well-tolerated, especially in elderly patients. The overall response rate was 78%, including four partial responses (44%) and three complete responses (33%). Allogeneic hematopoietic stem cell transplantation was performed in two patients who reached complete response.

Discussion: These preliminary favorable results may serve as a basis for further investigation in prospective studies.

Keywords: 5-azacytidine; RhoA; T follicular helper cell; TET2; angioimmunoblastic T cell lymphoma; nivolumab.

Figure 1

Time course of patients from first-line treatment to latest follow-up. The best response and duration of response during the different treatments are shown on the plots. CR, complete response, PR, partial response, PD, progressive disease. HSCT, hematopoietic stem cell transplantation.

Figure 2

Examples of PD-1 and PD-L1 expression in angioimmunoblastic T-cell lymphoma in some patients. x40 Hematoxylin-eosin staining showing typical histopathological features of angioimmunoblastic T-cell lymphoma. Immunostaining with PD-1 and PD-L1 highlighting tumoral T cells. Immunostaining is performed with anti-PD-1 (prediluted, clone NAT105; Roche) and anti-PDL-1 (1/100, Clone QR1; Diagomics) antibodies. The Leica Bond III automated platform (LEICA, Nanterre, France), is used, according to the protocols included in the instructions for antibodies use, applying Bond epitope retrieval solution 1 and 2, respectively for each antibody, 1 (10mn) and 2 (20mn). Tonsil tissue is included on each slide, as positive control.