PRIMARY OBJECTIVE:~I. Test the efficacy (overall response rate) of single-agent MK-3475 (pembrolizumab) in relapsed chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL) (Arm A) other low grade B-cell non-Hodgkin lymphoma (B-NHL), and CLL with Richter's transformation (Arm C).~SECONDARY OBJECTIVES:~I. Test the safety of single-agent MK-3475 in relapsed CLL/SLL (Arm A), other low grade B-NHL (Arm B), and CLL with Richter's transformation (Arm C).~II. Test the overall survival, progression free survival, treatment free survival, duration of response and time to next therapy of single-agent MK-3475 in relapsed CLL/SLL (Arm A), other low grade B-NHL (Arm B), and CLL with Richter's transformation (Arm C).~III. Test the complete response rate of single MK-3475 in relapsed CLL/SLL (Arm A), other low grade B-NHL (Arm B), and CLL with Richter's transformation (Arm C).~IV. Test the safety of MK-3475 in combination with the signal inhibitor (either idelalisib or ibrutinib) in relapsed CLL/SLL (Arm A) and CLL with Richter's transformation (Arm C).~V. Test the progression-free survival, treatment-free survival, duration of response and time to next therapy, as well as overall survival of MK-3475 in combination with the signal inhibitor (either idelalisib or ibrutinib) in relapsed CLL/SLL (Arm A) and CLL with Richter's transformation (Arm C).~VI. Test the overall and complete response rates of MK-3475 in combination with the signal inhibitor (either idelalisib or ibrutinib) in relapsed CLL/SLL (Arm A) and CLL with Richter's transformation (Arm C).~CORRELATIVE RESEARCH OBJECTIVES:~I. To assess the potential association between programmed cell death ligand 1 (PD-L1)/programmed cell death 1 (PD-1)/PD-L2 expression on tumor and T cells and/or PD-L1 soluble levels in plasma with clinical efficacy of PD-1 blockade.~II. To investigate the effects of MK-3475 on selected markers of immune modulation and immune profiles in peripheral blood and tumor samples.~III. Examine T-cell immune synapse function and expression/location of co-stimulatory and co-inhibitory molecules (including effector molecules) as potential biomarkers to response for anti-PD-1 immune checkpoint blockade immunotherapy.~OUTLINE:~ALL PATIENTS (ARMS A, B, and C): Patients receive pembrolizumab intravenously (IV) over 30 minutes on day 1. Treatment repeats every 21 days for up to 12 months in the absence of disease progression or unacceptable toxicity. Patients receiving benefit may continue to receive treatment for an additional 12 months at the discretion of the investigator. Patients with CLL or CLL with Richter's transformation experiencing stable disease without partial remission or progressive disease at 3 months of treatment with pembrolizumab proceed to the treatment continuation phase.~CONTINUATION PHASE (ARMS A and C): Patients receive pembrolizumab IV over 30 minutes on day 1. Patients also receive idelalisib orally (PO) twice daily (BID) on days 1-21 OR ibrutinib PO once daily (QD) on days 1-21. Treatment repeats every 21 days for up to 12 or 24 months in the absence of disease progression or unacceptable toxicity. Patients receiving benefit may continue to receive treatment for an additional 12 months at the discretion of the investigator.~After completion of study treatment, patients are followed up every 3 months for 1 year.
This phase II trial studies how well pembrolizumab alone or with idelalisib or ibrutinib works in treating patients with chronic lymphocytic leukemia or other low-grade B-cell non-Hodgkin lymphomas that have returned after a period of improvement (relapsed) or have not responded to treatment (refractory). Immunotherapy with monoclonal antibodies, such as pembrolizumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Idelalisib and ibrutinib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Giving pembrolizumab alone or with idelalisib or ibrutinib may be an effective treatment in patients with chronic lymphocytic leukemia or other low-grade B-cell non-Hodgkin lymphomas.