EBV-related lymphoproliferative disease complicating therapy with the anti-CD2 monoclonal antibody, siplizumab, in patients with T-cell malignancies

Abstract

Purpose: We report an increased incidence of EBV-induced B-cell lymphoproliferative disease (LPD) in patients treated with siplizumab, an anti-CD2 antibody. The development of EBV-LPD has been associated with the use of immunosuppressive agents used in solid organ, bone marrow, and stem cell transplantation and in certain congenital immunodeficiencies.

Experimental design: We conducted a single-institution phase I dose-escalation trial of siplizumab, a humanized monoclonal antibody to CD2, in 29 patients with T-cell malignancies.

Results: Although initial responses were encouraging, 4 (13.7%) patients developed EBV-LPD and the trial was stopped. Reductions in CD4(+) and CD8(+) cell count numbers in response to therapy were seen in all patients, but in those patients developing EBV-LPD a significantly greater reduction in natural killer (NK) cell number and CD2 expression on T cells was seen. These findings highlight the importance of NK-cell depletion and CD2 expression in addition to T-cell depletion in the etiology of EBV-LPD.

Conclusions: The emergence of EBV-LPD may be associated with the ability of siplizumab to deplete both T and NK cells without affecting B cells. Agents that deplete T- and NK-cell populations without affecting B cell number should be screened for this potentially serious adverse event.

Fig. 1.

Radiographic imaging of the 72-year-old patient with extranodal non-Hodgkin’s lymphoma of gastrointestinal tract. A, sagittal 18-fluorodeoxyglucose-positron emission tomography image at diagnosis of EBV lymphoma showing circumferential metabolic activity within the wall of the descending colon. B, sagittal 18-fluorodeoxyglucose-positron emission tomography imaging after completion of chemotherapy showing small residual focus of metabolic activity. Computed tomographic images showing left lower quadrant mass involving descending colon at diagnosis (C) and imaging post-therapy shows minor residual abnormality (D).

Fig. 2.

Computed tomography and 18-fluorodeoxyglucose-positron emission tomography images showing anterior mediastinal mass with 18-fluorodeoxyglucose metabolic activity at baseline (A and C) and after withdrawal of siplizumab therapy (B and D).

Fig. 3.

Histologic examination of colonic biopsy in 58-year-old Asian female showing involvement with ATLL (A) and EBV-associated B-cell lymphoma (B). A, paraffin-embedded sections of colonic mucosa containing ATLL. H&E staining at ×20 (i) and ×40 (ii) shows involvement by ATLL, which is CD25⁺ (iii) and CD30⁺ (iv). B, colonic mucosa with an area of extensive atypical lymphoid infiltrate visualized with H&E staining at ×5 (i) and ×20 (ii).These lymphocytes are CD20⁺ (iii) and the majority are EBV⁺ (iv). Images were taken using an Olympus Bx41microscope, objective UPlanFI 20×/0.50 ∞/0.17 and 40×/0.75 ∞/0.17, with an adaptor U-TV0.5×C using a digital camera Q-imaging Micropublisher 5.0RTV.The images were captured using “Q-Capture version 3.1”and imported into Adobe Photoshop 7.0.

Fig. 4.

Comparison of NK cell number changes between those who develop EBV-LPD and those who do not, showing a greater reduction in NK cell number in those who develop EBV-LPD (P = 0.04).

Fig. 5.

Comparison of trends in CD2 saturation between those who do and do not develop EBV-LPD (P = 0.03) with more sizable changes from baseline for the post-cycle 1and post-cycle 2 measurements for those who develop EBV-LPD.

Fig. 6.

Comparison of trends in CD2 saturation with different administration schedules of siplizumab with statistically significant differences between changes from baseline in weekly and biweekly schedules. Weekly showed more pronounced changes (P = 0.007).