Targeting intratumoral B cells with rituximab in addition to CHOP in angioimmunoblastic T-cell lymphoma. A clinicobiological study of the GELA

Abstract

The online version of this article has a Supplementary Appendix. BackgroundIn angioimmunoblastic T-cell lymphoma, symptoms linked to B-lymphocyte activation are common, and variable numbers of CD20 + large B-blasts, often infected by Epstein-Barr virus, are found in tumor tissues. We postulated that the disruption of putative B-T interactions and/or depletion of the Epstein-Barr virus reservoir by an anti-CD20 monoclonal antibody (rituximab) could improve the clinical outcome produced by conventional chemotherapy. Design and MethodsTwenty-five newly diagnosed patients were treated, in a phase II study, with eight cycles of rituximab + chemotherapy (R-CHOP21). Tumor infiltration, B-blasts and Epstein-Barr virus status in tumor tissue and peripheral blood were fully characterized at diagnosis and were correlated with clinical outcome. ResultsA complete response rate of 44% (95% CI, 24% to 65%) was observed. With a median followup of 24 months, the 2-year progression-free survival rate was 42% (95% CI, 22% to 61%) and overall survival rate was 62% (95% CI, 40% to 78%). The presence of Epstein-Barr virus DNA in peripheral blood mononuclear cells (14/21 patients) correlated with Epstein-Barr virus score in lymph nodes (P<0.004) and the detection of circulating tumor cells (P=0.0019). Despite peripheral Epstein-Barr virus clearance after treatment, the viral load at diagnosis (>100 copy/mg DNA) was associated with shorter progression-free survival (P=0.06). ConclusionsWe report here the results of the first clinical trial targeting both the neoplastic T cells and the microenvironment-associated CD20 + B lymphocytes in angioimmunoblastic T-cell lymphoma, showing no clear benefit of adding rituximab to conventional chemotherapy. A strong relationship, not previously described, between circulating Epstein-Barr virus and circulating tumor cells is highlighted. (This trial was registered at www.clinicaltrials.gov as NCT00169156.)

A phase II clinical trial of fludarabine and cyclophosphamide followed by thalidomide for angioimmunoblastic T-cell lymphoma. An NCRI clinical trial. CRUK number C17050/A5320

“…The trial did not proceed to the 2 nd stage of recruitment as the CR rate was less than the pre-defined threshold of 40%. The CR rate was inferior to that reported with CHOP with or without rituximab [2,6] and remissions were short lived with a median PFS of 5.5 months.…”

“…The median age at presentation is 62-70 years and 80-90% of patients have advanced stage disease [2][3][4][5][6]. It typically follows an aggressive course with poor prognosis; although complete remission (CR) is achieved in 44-61% of patients, relapses are frequent and the median overall survival (OS) is approximately 3 years with 5-year survival of 32% [2,3,6]. Due to its low incidence, there have been few prospective clinical trials in AITL and most data informing treatment strategies are derived from retrospective and registry studies.…”

Molecular genetics of peripheral T-cell lymphomas

“…To test this hypothesis, the GELA group recently designed a clinical trial including rituximab in the treatment of AITL. Even though a preliminary analysis suggested a beneficial effect from the addition of rituximab, the final results did not confirm it [16]. Nonetheless, a functional role of B-cells in the pathogenesis of the disease could not be completely ruled out and further functional studies would be warranted.…”

“…In particular, as they are provided with diverse prognosis [4][5][6], different phenotypic and molecular profiles [6][7][8][9][10], and distinct genetic patterns [11][12][13][14][15], it is reasonable that in the near future ad hoc interventions will be adopted. In this regard, very recently Brentuximab Vedotin, a conjugated anti-CD30 monoclonal antibody (MoAb) was approved for the treatment of relapsed/refractory ALCL but not other PTCL subtypes, while clinical trials have been designed for specific subtypes [16], many of which are currently ongoing.…”

Recent Progress in the Understanding of Angioimmunoblastic T-cell Lymphoma

“…To target tumor-infiltrating B cells, newly diagnosed AITL was treated with a combination of rituximab plus CHOP (R-CHOP) in a clinical trial, although the benefit of rituximab was not demonstrated. 90 Some AITL patients responded to immunosuppressive agents, including cyclosporin A and corticosteroids 91 . These agents may contribute to the suppression of autoimmune-like manifestations, and to the regression of tumors.…”