Pembrolizumab for T/NK-cell lymphomasNK-cell Lymphomas

Pembrolizumab is a potent and highly selective humanized monoclonal antibody (mAb) of the IgG4/kappa isotype against PD-1, designed to directly block its interaction with PD-L1 and PD-L2. KeytrudaTM (pembrolizumab) has recently been approved in the United Stated for the treatment of melanoma that is unresectable or metastatic, or has progressed following ipilumumab and, (if BRAF V600 mutation positive), a BRAF inhibitor. Mature T-cell and nature killer (NK)-cell lymphomas are lymphoid malignancies that are derived from T-cell and NK-cell lineages. They are less prevalent than B-cell lymphomas. Interestingly, there are distinct geographic differences in their distribution and prevalence. Nodal lymphomas including peripheral T-cell lymphoma, not otherwise specified (PTCL-NOS), angioimmunoblastic T-cell lymphoma (AITL), anaplastic large cell lymphoma (ALCL) and cutaneous T-cell lymphomas (CTCL) predominate in Western populations, accounting for about 10% of all lymphomas. In Asian countries, however, extranodal NK/T-cell lymphoma, nasal type, is much more prevalent, constituting 10% of all lymphomas; with AITL, ALCL and PTCL-NOS accounting for another 10%. Epstein Barr virus (EBV) infection is found in all cases of extranodal NK/T-cell lymphomas, the majority of AITL, and a significant proportion of PTCL-NOS, implying that it plays an important pathogenetic role. Conventional chemotherapeutic regimens designed for aggressive B-cell lymphomas are generally less effective when applied to mature T-cell or NK-cell lymphomas. The treatment outcome for relapsed or refractory disease is especially poor. In a recent retrospective analysis, the median overall survival (OS) and progression-free survival (PFS) in patients with disease relapse were found to be only 5.5 and 3.1 months respectively. The efficacy of newly approved agents such as pralatrexate and romidepsin for relapsed or refractory T-cell lymphomas is modest, with an average overall response rate (ORR) of around 20-30% only. Novel therapeutic approaches are therefore needed for this group of patients with dismal prognosis. PD-1 blockade using anti-PD1 monoclonal antibody has been shown to be highly effective for relapsed/refractory classical Hodgkin lymphoma. Furthermore, clinical response has also been seen in relapsed T-cell lymphomas after treatment with anti-PD-1 antibody in phase I studies. In addition, previous reports have shown that EBV infection may enhance the expression of PD-L1 in tumour cells, and that some EBV-associated lymphomas such as NK/T-cell lymphoma express high level of PD-L1, suggesting that EBV-associated mature T-cell and NK-cell lymphomas may be more susceptible to PD-1 blockade.