Pembrolizumab in Relapsed and Refractory Gray-Zone Lymphoma (GZL), Primary Central Nervous System Lymphoma (PCNSL), and Other Extranodal Diffuse Large B-cell Lymphomas

Background: * Gray-zone lymphomas (GZL) are rare, aggressive lymphomas that share clinical and biological features of diffuse large B-cell lymphoma (DLBCL) and Hodgkin lymphoma * Standard upfront therapy for GZL is dose-intensive chemotherapy, though disease is often resistant; consolidative radiation therapy reserved for patients who are relapsed or refractory, and patients who fail radiation therapy have a poor prognosis * Primary central nervous system lymphoma (PCNSL), primary testicular lymphoma (PTL), primary breast lymphoma (PBL), primary cutaneous DLBCL, leg-type, and intravascular B-cell lymphoma (IVBCL) are rare, aggressive extranodal subsets of DLBCL that usually have gene expression signatures of activated B-cell (ABC) DLBCL * ABC-DLBCL has cure rates below 40% after standard therapy, and is associated with late recurrences, often involving the central nervous system (CNS) where treatment options are limited by chemotherapy resistance and an inability of many agents to cross the blood-brain barrier * Molecular biology studies of GZL and extranodal DLBCL have identified potentially targetable genetic features involving the programmed death-1 (PD-1) signaling pathway * A high proportion of GZL, PCNSL, and PTL cases have copy number alterations or chromosomal rearrangements involving the PD-1 ligands, programmed death-ligand 1 (PD-L1) and programmed death-ligand 2 (PD-L2) * Pembrolizumab, a humanized immunoglobulin G4 (IgG4) monoclonal antibody that targets the PD-1 receptor, is a rational therapeutic target for patients with relapsed and refractory GZL, PCNSL, PTL, and other extranodal DLBCL Objectives: -To determine the best overall response rate of pembrolizumab in patients with relapsed and refractory GZL and extranodal DLBCL Eligibility: * Confirmed diagnosis of B-cell lymphoma, relapsed from or refractory to prior: * Cohort 1: B-cell lymphoma, unclassifiable, with features intermediate between diffuse large B-cell lymphoma and classical Hodgkin lymphoma (i.e., Gray-zone lymphoma or GZL) * Cohort 2: Extranodal diffuse large B-cell lymphoma involving one or more of the specified extranodal sites (i.e., extranodal DLBCL) * Adequate bone marrow and organ function defined * Age greater than or equal to 18 years Design: * Phase 2 study of patients with relapsed and refractory GZL and extranodal DLBCL * Patients will be treated with pembrolizumab 200 mg (flat dose) intravenous (IV) every 3 weeks provided they have clinical benefit and no unacceptable toxicity; patients who achieve a complete response (CR) will have the option stop after 1 year of therapy. * All responding patients (CR, partial response (PR), or stable disease (SD) with clinical benefit) who subsequently relapse or progress within 1 year after discontinuation of study drug are eligible for re-treatment. * At least 20 evaluable patients each with GZL and DLBCL will be evaluated on this protocol for the primary endpoint (overall accrual ceiling of 52 patients)