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EBV-Related Lymphoproliferative Disease Complicating Therapy with Siplizumab, a Novel Anti-CD2 Mediated T- and NK-Cell Depleting Agent, in Patients with T-Cell Malignancies.

Deirdre O’Mahony, John C. Morris, Maryalice Stetler-Stevenson, Helen Matthews, Stefania Pittaluga, Paul Albert, Karen Kaucic, Luz Hammershaimb, Thomas A. Waldmann and John E. Janik

Abstract

Epstein Barr virus (EBV) has the capacity to transform B lymphocytes and in the setting of immunosuppression increases the risk of developing EBV induced lymphoproliferative disease (EBV LPD). This is a heterogeneous condition ranging from a benign polyclonal B cell proliferation to frank non-Hodgkin’s lymphoma. EBV LPD is associated with immunosuppressive agents used in solid organ, bone marrow and stem cell transplantation, and in certain congenital immunodeficiencies. We conducted a single institution phase I dose escalation study of siplizumab, a humanized monoclonal antibody to CD2, in patients with T-cell malignancies. A total of 29 patients (pts) were enrolled, of which 4 (13.7%) developed EBV LPD. In the original trial design (n=23) pts received escalating drug doses over 2 or 3 consecutive days per treatment week every 2 weeks (cohorts 1–7). In an attempt to increase the rate of drug delivery the trial was amended, for pts (n=6) to receive a single dose on day 0 and 14, and then once weekly thereafter (cohorts 8–10). While initial responses were exciting (2 complete responses, 7 partial responses and 10 stable disease) the development of EBV LPD was a concern. One of 23 (4.3%) pts in the original design and 3 of 6 (50%) in the revised schema developed EBV LPD within 6 months of starting therapy. The 29 pts included adult T-cell leukemia/lymphoma (n=15), large granular lymphocyte leukemia (n=7), cutaneous T-cell lymphoma (n=4) and peripheral T-cell lymphoma (n=3). A median of 2 (range 0–6) prior therapies and a median of 4 (range 1–26) courses of siplizumab with doses ranging from 0.4mg/kg to 4.8mg/kg were administered either biweekly or weekly depending on the cohort. Of the 4 EBV LPD cases, one responded to withdrawal of siplizumab, one to rituximab, another to combination chemotherapy and rituximab, and the remaining patient succumbed to a combination of her underlying disease and EBV-LPD. Review of T-cell trends in response to therapy demonstrated a reduction in the geometric mean of CD4 (84.9%, p<0.001) and CD8 T-cell counts (91.5%, p<0.001) between baseline and a timepoint after administration of the second cycle. There was no statistically significant difference in the degree of reduction between the two trial designs or those pts who developed EBV LPD. However, a statistically significant greater reduction in CD2 expression was seen in pts treated on the weekly schema (p=0.007) rather than biweekly and in those who developed EBV LPD (p=0.05) rather than those who did not. There was also a statistically significant greater reduction in NK cell number (p=0.04) with 2 treatment cycles from baseline in patients developing EBV LPD. These findings highlight the importance not only of T-cell depletion in the aetiology of EBV LPD but also NK cell depletion and reduction in CD2 expression on lymphocytes. The emergence of B-cell malignancy may be associated with the ability of siplizumab to deplete both T and NK cell number, without B-cell depletion. This toxicity should be screened for in other agents that deplete T cells without affecting B cell number.